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US20160222455A1 - Methods for diagnosing ischemia - Google Patents

Methods for diagnosing ischemia Download PDF

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US20160222455A1
US20160222455A1 US15/092,599 US201615092599A US2016222455A1 US 20160222455 A1 US20160222455 A1 US 20160222455A1 US 201615092599 A US201615092599 A US 201615092599A US 2016222455 A1 US2016222455 A1 US 2016222455A1
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ischemia
genes
expression
stroke
protein
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Huichun Xu
Frank Sharp
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University of California
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University of California
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Priority to US16/454,755 priority patent/US11421276B2/en
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    • C12Q1/00Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
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    • C12Q2600/112Disease subtyping, staging or classification
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    • C12Q2600/00Oligonucleotides characterized by their use
    • C12Q2600/136Screening for pharmacological compounds
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    • C12Q2600/00Oligonucleotides characterized by their use
    • C12Q2600/158Expression markers
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Definitions

  • Ischemic events such as stroke are the third leading cause of death in America.
  • Different subtypes of stroke have their own specific management strategy and a precise diagnosis is critical for the timely treatment of various stroke patients.
  • the gold standard for the diagnosis of acute ischemic stroke versus hemorrhagic stroke relies on imaging technology.
  • the etiology of ischemic stroke largely depends on the clinician's judgment from indirect clinical information.
  • the main etiologies of acute ischemic stroke include atherothrombotic stroke and cardioembolic stroke. Atheroembolic stroke dictates surgery or aspirin and platelet inhibitor(s); and cardioembolic strokes require treatment with anticoagulant medications such as, e.g., coumadin.
  • patients have magnetic resonance imaging or carotid dopplers to determine if they have atherosclerosis in the carotid and cardiac echocardiograms to determine if they have clot in the heart.
  • the cardiac echocardiogram is very specific, but very insensitive. Even with the best of information, determining the actual cause of stroke is impassible: that is, there is no current direct test for cause. Moreover, somewhere between 30% and 50% of all subjects with transient ischemic attacks and stroke have an unknown cause of stroke.
  • the present invention provides methods for diagnosing ischemia (e.g., embolic and thrombotic stroke and transient ischemic attacks) by detecting expression levels of genes differentially expressed in ischemia.
  • ischemia e.g., embolic and thrombotic stroke and transient ischemic attacks
  • One embodiment of the invention provides methods for diagnosing an ischemia or a predisposition for developing an ischemia.
  • the methods comprise: determining a level of expression of a plurality of ischemia-associated genes in a biological sample from a mammalian subject, wherein a difference (i.e. increase or decrease) of said level compared to a normal control level of the genes indicates that said subject suffers from or is at risk of developing ischemia, wherein said plurality of ischemia-associated genes is selected from the genes set forth in Table 1, 2, 3, 4, 5, 6, or 7.
  • the level of expression of a plurality, i.e., two or more genes, selected from Table 1 is determined, i.e., two or more of LEPROT, PCGF3, PPP3R1, PVRL2, INSR, BIRC1 (also called, NAIP///LOC728519), TSHZ3, DF (also called, CFD), FBN2, IER3, NUMB, LAK (also called, ALPK1), CD8B1, RRAS2, C21orf7, DAB2, JAM3, ITGA2B, PPBP, SYNJ2, SLC25A37, ZNF185 and C7orf41.
  • the expression level of 5 or more, 10 or more, 15 or more, 20 or more, or 23 of the genes listed in Table 1 is determined.
  • the difference i.e., increase or decrease
  • the difference is at least about 1.3 fold, 1.4 fold, or 1.5 fold higher or lower, respectively, than a normal control level.
  • the expression level of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 genes selected from LEPROT, PCGF3, PPP3R1, PVRL2, INSR, BIRC1, TSHZ3, DF, FBN2, IER3, NUMB, LAK, CD8B1 and RRAS2, identified in Tables 1, 9 and 10, is determined.
  • the expression level of 2, 3, 4, 5, 6, 7, 8, 9 or 10 genes selected from C21orf7, DAB2, JAM3, ITGA2B, PPBP, SYNJ2, SLC25A37, ZNF185, C7orf41 and LAK, identified in Tables 1, 8 and 10, is determined.
  • at least about a 1.3 fold decrease in expression of the following genes: C21orf7, DAB2, JAM3, ITGA2B, PPBP, SYNJ2, SLC25A37, ZNF185, C7orf41 and LAK when compared to the normal control level indicates that the subject has experienced or is at risk for an atherothrombotic stroke or atheroembolic stroke.
  • the ischemia is selected from embolic stroke, thrombotic stroke, and transient ischemic attack.
  • the sample is blood.
  • the level of expression is determined by detecting hybridization of an ischemia-associated gene probe to a gene transcript of said biological sample.
  • the hybridization step is carried out on a nucleic acid array.
  • Another embodiment of the invention provides an ischemia reference expression profile, comprising a pattern of gene expression of a plurality of the genes set forth in Table 1, 2, 3, 4, 5, 6, or 7.
  • the ischemia reference expression profile comprises a pattern of gene expression of a plurality of the genes set forth in Table 1.
  • At least about a 1.3 fold decrease in expression of the following genes: C21orf7, DAB2, JAM3, ITGA2B, PPBP, SYNJ2, SLC25A37, ZNF185, C7orf41, and LAK when compared to the normal control level is a reference expression profile for atherothrombotic stroke or atheroembolic stroke.
  • Yet another embodiment of the invention provides methods of screening for a compound for treating or preventing ischemia.
  • the methods comprise: a) contacting a candidate compound with a cell expressing one or more genes set forth in Table 1, 2, 3, 4, 5, 6, or 7; and b) selecting a compound that modulates the expression level of one or more genes set forth in Table 1, 2, 3, 4, 5, 6, or 7.
  • a compound that decreases the expression of at least one gene selected from the group consisting of: LEPROT, PCGF3, PPP3R1, PVRL2, INSR, BIRC1, TSHZ3, DF, FBN2, IER3, NUMB, and LAK when compared to the normal control level, or increases the expression of at least one gene selected from the group consisting of: CD8B1 and RRAS2 relative to a control level is identified as a compound useful for treating or preventing ischemia, including, e.g., cardioembolic stroke.
  • a compound that increases the expression of at least one gene selected from the group consisting of: C21orf7, DAB2, JAM3, ITGA2B, PPBP, SYNJ2, SLC25A37, ZNF185, C7orf41, and LAK is identified as a compound useful for treating or preventing ischemia, including, e.g., atherothrombotic stroke or atheroembolic stroke.
  • a further embodiment of the invention provides an array comprising a plurality of polynucleotides which specifically bind (i.e., specifically hybridize) to a plurality of nucleic acid sequences set forth in Table 1, 2, 3, 4, 5, 6 or 7.
  • the invention provides an array comprising a plurality of polynucleotides which specifically bind (i.e., specifically hybridize) to a plurality of nucleic acid sequences set forth in Table 1.
  • Another embodiment of the invention provides a reaction mixture comprising a plurality of polynucleotides which specifically hybridize (e.g., primers) to a plurality of nucleic acid sequences set forth in Table 1, 2, 3, 4, 5, 6 or 7.
  • the invention provides a reaction mixture comprising a plurality of polynucleotides which specifically hybridize (e.g., primers) to a plurality of nucleic acid sequences set forth in Table 1.
  • the reaction mixture is a PCR mixture, for example, a multiplex PCR mixture.
  • Table 1 sets forth a list of 23 genes differentially expressed in ischemia (e.g., cardioembolic stroke, artherothrombotic stroke, and transient ischemic attacks).
  • ischemia e.g., cardioembolic stroke, artherothrombotic stroke, and transient ischemic attacks.
  • Table 2 sets forth a list of 77 genes differentially expressed in ischemia (e.g., cardioembolic stroke, artherothrombotic stroke, and transient ischemic attacks).
  • ischemia e.g., cardioembolic stroke, artherothrombotic stroke, and transient ischemic attacks.
  • Table 3 sets forth a list of 95 genes differentially expressed in ischemia (e.g., cardioembolic stroke, artherothrombotic stroke, and transient ischemic attacks).
  • Table 4 sets forth a list of 133 genes differentially expressed in ischemia (e.g., cardioembolic stroke, artherothrombotic stroke, and transient ischemic attacks).
  • ischemia e.g., cardioembolic stroke, artherothrombotic stroke, and transient ischemic attacks.
  • Table 5 sets forth a list of 259 genes differentially expressed in ischemia (e.g., cardioembolic stroke, artherothrombotic stroke, and transient ischemic attacks).
  • ischemia e.g., cardioembolic stroke, artherothrombotic stroke, and transient ischemic attacks.
  • Table 6 sets forth a list of 466 genes differentially expressed in ischemia (e.g., cardioembolic stroke, artherothrombotic stroke, and transient ischemic attacks).
  • ischemia e.g., cardioembolic stroke, artherothrombotic stroke, and transient ischemic attacks.
  • Table 7 sets forth a list of 706 genes differentially expressed in ischemia (e.g., cardioembolic stroke, artherothrombotic stroke, and transient ischemic attacks).
  • ischemia e.g., cardioembolic stroke, artherothrombotic stroke, and transient ischemic attacks.
  • Table 8 sets forth relative expression levels of selected genes described in Example 1 as differentially expressed in atherothrombotic stroke relative to normal control subjects.
  • Table 9 sets forth relative expression levels of selected genes described in Example 1 as differentially expressed in cardioembolic stroke subjects relative to normal control subjects.
  • Table 10 sets forth the relative expression levels of genes listed in Table 1 in cardioembolic stroke subjects relative to normal control subjects; atheroembolic stroke subjects relative to normal control, and cardioembolic stroke subjects relative to atheroembolic stroke subjects.
  • FIG. 1 illustrates an expression heatmap of genes differentially regulated between cardioembolic and atherosclerotic stroke patients with at least a 1.5 fold change.
  • FIG. 2 illustrates etiology prediction of stroke samples with unknown etiology according to the expression pattern of 23 genes using PAM.
  • FIG. 3 illustrates a function comparison of cardioembolic stroke-specific genes versus atherosclerotic stroke-specific genes. Obvious duplication of function classes is omitted for clarity purposes.
  • FIG. 4 a illustrates expression activities of atherosclerotic stroke-specific genes across subtypes of healthy blood cells.
  • FIG. 4 b illustrates expression activities of cardioembolic stroke-specific genes across subtypes of healthy blood cells.
  • FIG. 5 illustrates etiology prediction of stroke samples from unknown etiologies by cluster analysis.
  • FIG. 6 illustrates a 10-fold cross validation result for known cardioembolic stroke samples with 23 genes in PAM.
  • FIG. 7 illustrates a 10-fold cross validation result for known atherosclerotic stroke samples with 23 genes in PAM.
  • the present invention provides methods for the diagnosis of ischemia (e.g., stroke and transient ischemic attacks (“TIA”)).
  • ischemia e.g., stroke and transient ischemic attacks (“TIA”).
  • the invention is based on identification of differential gene expression patterns in subjects with an ischemia (e.g., stroke and TIA). Detection of the expression patterns of a plurality of the genes set forth in Table 1, 2, 3, 4, 5, 6, or 7 leads to a definitive diagnosis of the type of ischemia that a subject has developed or is at risk for developing. Therefore, this invention provides the first direct method for determining the causes of ischemia (stroke and TIA).
  • the gene expression patterns described herein can conveniently be used to diagnose, monitor and prognose ischemia (e.g., stroke and TIA).
  • the gene expression patterns can be detected to definitively classify the type of ischemic event that a subject has developed or has a predisposition for developing.
  • the gene expression patterns can also be used as ischemic reference profiles.
  • the gene expression patterns can be used to identify compounds for treating or preventing ischemia.
  • Ischemia or “ischemic event” as used herein refers to diseases and disorders characterized by inadequate blood supply (i.e., circulation) to a local area due to blockage of the blood vessels to the area. Ischemia includes for example, strokes and transient ischemic attacks.
  • Strokes include, e.g., ischemic stroke (including, but not limited to, cardioembolic strokes, atheroembolic or atherothrombotic strokes, i.e., strokes caused by atherosclerosis in the carotid, aorta, heart, and brain, small vessel strokes (i.e., lacunar strokes), strokes caused by diseases of the vessel wall, i.e., vasculitis, strokes caused by infection, strokes caused by hematological disorders, strokes caused by migraines, and strokes caused by medications such as hormone therapy), hemorrhagic ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage.
  • ischemic stroke including, but not limited to, cardioembolic strokes, atheroembolic or atherothrombotic strokes, i.e., strokes caused by atherosclerosis in the carotid, aorta, heart, and brain
  • Ischemia reference expression profile refers to the pattern of expression of a set of genes (e.g., a plurality of the genes set forth in Tables 1, 2, 3, 4, 5, 6 or 7) differentially expressed (i.e., overexpressed or underexpressed) in ischemia relative to a normal control.
  • a gene from Tables 1, 2, 3, 4, 5, 6 or 7 that is expressed at a level that is at least about 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9 or 10 fold higher than the level in a normal control is a gene overexpressed in ischemia and a gene from Tables 1, 2, 3, 4, 5, 6 or 7 that is expressed at a level that is at least about 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9 or 10 fold lower than the level in a normal control is a gene underexpressed in ischemia.
  • genes that are expressed at a level that is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% higher than the level in a normal control is a gene overexpressed in ischemia and a gene that is expressed at a level that is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% lower than the level in a normal control is a gene underexpressed in ischemia.
  • a “plurality” refers to two or more, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or more (e.g., genes).
  • a plurality refers to 50, 96, 100, 150, 192, 200, 250, 384 or 500 genes.
  • “plurality” refers to all genes listed in one or more tables, e.g., all genes listed in Table 1, Table 2, Table 3, Table 4, Table 5, Table 6 and/or Table 7.
  • sample or “biological sample” includes sections of tissues such as biopsy and autopsy samples, and frozen sections taken for histologic purposes. Such samples include blood, sputum, tissue, lysed cells, brain biopsy, cultured cells, e.g., primary cultures, explants, and transformed cells, stool, urine, etc.
  • a biological sample is typically obtained from a eukaryotic organism, most preferably a mammal such as a primate, e.g., chimpanzee or human; cow; dog; cat; a rodent, e.g., guinea pig, rat, mouse; rabbit; or a bird; reptile; or fish.
  • Array refers to a solid support comprising attached nucleic acid or peptide probes. Arrays typically comprise a plurality of different nucleic acid or peptide probes that are coupled to a surface of a substrate in different, known locations. These arrays, also described as “microarrays” or colloquially “chips” have been generally described in the art, for example, U.S. Pat. Nos. 5,143,854, 5,445,934, 5,744,305, 5,677,195, 6,040,193, 5,424,186 and Fodor et al., Science , 251:767-777 (1991).
  • arrays may generally be produced using mechanical synthesis methods or light directed synthesis methods which incorporate a combination of photolithographic methods and solid phase synthesis methods. Techniques for the synthesis of these arrays using mechanical synthesis methods are described in, e.g., U.S. Pat. No. 5,384,261.
  • Arrays may comprise a planar surface or may be nucleic acids or peptides on beads, gels, polymeric surfaces, fibers such as fiber optics, glass or any other appropriate substrate as described in, e.g., U.S. Pat. Nos. 5,770,358, 5,789,162, 5,708,153, 6,040,193 and 5,800,992.
  • Arrays may be packaged in such a manner as to allow for diagnostics or other manipulation of an all inclusive device, as described in, e.g., U.S. Pat. Nos. 5,856,174 and 5,922,591.
  • gene means the segment of DNA involved in producing a polypeptide chain; it includes regions preceding and following the coding region (leader and trailer) as well as intervening sequences (introns) between individual coding segments (exons).
  • nucleic acid and “polynucleotide” are used interchangeably herein to refer to deoxyribonucleotides or ribonucleotides and polymers thereof in either single- or double-stranded form.
  • the term encompasses nucleic acids containing known nucleotide analogs or modified backbone residues or linkages, which are synthetic, naturally occurring, and non-naturally occurring, which have similar binding properties as the reference nucleic acid, and which are metabolized in a manner similar to the reference nucleotides.
  • Examples of such analogs include, without limitation, phosphorothioates, phosphoramidates, methyl phosphonates, chiral-methyl phosphonates, 2-O-methyl ribonucleotides, peptide-nucleic acids (PNAs).
  • nucleic acid sequence also encompasses conservatively modified variants thereof (e.g., degenerate codon substitutions) and complementary sequences, as well as the sequence explicitly indicated.
  • degenerate codon substitutions may be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and/or deoxyinosine residues (Batzer et al., Nucleic Acid Res. 19:5081 (1991); Ohtsuka et al., J. Biol. Chem. 260:2605-2608 (1985); Rossolini et al., Mol. Cell. Probes 8:91-98 (1994)).
  • nucleic acid is used interchangeably with gene, cDNA, mRNA, oligonucleotide, and polynucleotide.
  • stringent hybridization conditions refers to conditions under which a probe will hybridize to its target subsequence, typically in a complex mixture of nucleic acid, but to no other sequences. Stringent hybridization conditions are sequence-dependent and will be different in different circumstances. Longer sequences hybridize specifically at higher temperatures. An extensive guide to the hybridization of nucleic acids is found in Tijssen, Techniques in Biochemistry and Molecular Biology - Hybridization with Nucleic Probes , “Overview of principles of hybridization and the strategy of nucleic acid assays” (1993). Generally, stringent hybridization conditions are selected to be about 5-10° C. lower than the thermal melting point for the specific sequence at a defined ionic strength Ph.
  • the T m is the temperature (under defined ionic strength, Ph, and nucleic concentration) at which 50% of the probes complementary to the target hybridize to the target sequence at equilibrium (as the target sequences are present in excess, at T m , 50% of the probes are occupied at equilibrium).
  • Stringent hybridization conditions will be those in which the salt concentration is less than about 1.0 M sodium ion, typically about 0.01 to 1.0 M sodium ion concentration (or other salts) at Ph 7.0 to 8.3 and the temperature is at least about 30° C. for short probes (e.g., 10 to 50 nucleotides) and at least about 60° C. for long probes (e.g., greater than 50 nucleotides).
  • Stringent hybridization conditions may also be achieved with the addition of destabilizing agents such as formamide.
  • destabilizing agents such as formamide.
  • a positive signal is at least two times background, optionally 10 times background hybridization.
  • Exemplary stringent hybridization conditions can be as following: 50% formamide, 5 ⁇ SSC, and 1% SDS, incubating at 42° C., or, 5 ⁇ SSC, 1% SDS, incubating at 65° C., with wash in 0.2 ⁇ SSC, and 0.1% SDS at 65° C.
  • Nucleic acids that do not hybridize to each other under stringent hybridization conditions are still substantially identical if the polypeptides which they encode are substantially identical. This occurs, for example, when a copy of a nucleic acid is created using the maximum codon degeneracy permitted by the genetic code. In such cases, the nucleic acids typically hybridize under moderately stringent hybridization conditions.
  • Exemplary “moderately stringent hybridization conditions” include a hybridization in a buffer of 40% formamide, 1 M NaCl, 1% SDS at 37° C., and a wash in 1 ⁇ SSC at 45° C. A positive hybridization is at least twice background. Those of ordinary skill will readily recognize that alternative hybridization and wash conditions can be utilized to provide conditions of similar stringency.
  • isolated refers to material that is substantially or essentially free from components that normally accompany it as found in its native state. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. A protein that is the predominant species present in a preparation is substantially purified.
  • purified denotes that a nucleic acid or protein gives rise to essentially one band in an electrophoretic gel. Particularly, it means that the nucleic acid or protein is at least 85% pure, more preferably at least 95% pure, and most preferably at least 99% pure.
  • heterologous when used with reference to portions of a nucleic acid indicates that the nucleic acid comprises two or more subsequences that are not found in the same relationship to each other in nature.
  • the nucleic acid is typically recombinantly produced, having two or more sequences from unrelated genes arranged to make a new functional nucleic acid, e.g., a promoter from one source and a coding region from another source.
  • a heterologous protein indicates that the protein comprises two or more subsequences that are not found in the same relationship to each other in nature (e.g., a fusion protein).
  • an “expression vector” is a nucleic acid construct, generated recombinantly or synthetically, with a series of specified nucleic acid elements that permit transcription of a particular nucleic acid in a host cell.
  • the expression vector can be part of a plasmid, virus, or nucleic acid fragment.
  • the expression vector includes a nucleic acid to be transcribed operably linked to a promoter.
  • polypeptide “peptide” and “protein” are used interchangeably herein to refer to a polymer of amino acid residues.
  • the terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymer.
  • amino acid refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids.
  • Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, ⁇ -carboxyglutamate, and O-phosphoserine.
  • amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an a carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid.
  • amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid.
  • Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes.
  • “Conservatively modified variants” applies to both amino acid and nucleic acid sequences. With respect to particular nucleic acid sequences, conservatively modified variants refers to those nucleic acids which encode identical or essentially identical amino acid sequences, or where the nucleic acid does not encode an amino acid sequence, to essentially identical sequences. Because of the degeneracy of the genetic code, a large number of functionally identical nucleic acids encode any given protein. For instance, the codons GCA, GCC, GCG and GCU all encode the amino acid alanine. Thus, at every position where an alanine is specified by a codon, the codon can be altered to any of the corresponding codons described without altering the encoded polypeptide.
  • nucleic acid variations are “silent variations,” which are one species of conservatively modified variations. Every nucleic acid sequence herein which encodes a polypeptide also describes every possible silent variation of the nucleic acid.
  • each codon in a nucleic acid except AUG, which is ordinarily the only codon for methionine, and TGG, which is ordinarily the only codon for tryptophan
  • TGG which is ordinarily the only codon for tryptophan
  • amino acid sequences one of skill will recognize that individual substitutions, deletions or additions to a nucleic acid, peptide, polypeptide, or protein sequence which alters, adds or deletes a single amino acid or a small percentage of amino acids in the encoded sequence is a “conservatively modified variant” where the alteration results in the substitution of an amino acid with a chemically similar amino acid. Conservative substitution tables providing functionally similar amino acids are well known in the art. Such conservatively modified variants are in addition to and do not exclude polymorphic variants, interspecies homologs, and alleles of the invention.
  • nucleic acids or polypeptide sequences refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same (i.e., 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, or 95% identity over a specified region of an ischemia-associated gene (e.g., a gene set forth in Table 1, 2, 3, 4, 5, 6, or 7), when compared and aligned for maximum correspondence over a comparison window, or designated region as measured using one of the following sequence comparison algorithms or by manual alignment and visual inspection.
  • an ischemia-associated gene e.g., a gene set forth in Table 1, 2, 3, 4, 5, 6, or 7
  • sequences are then said to be “substantially identical.” This definition also refers to the compliment of a test sequence. Preferably, the identity exists over a region that is at least about 25 amino acids or nucleotides in length, or more preferably over a region that is 50-100 amino acids or nucleotides in length.
  • sequence comparison typically one sequence acts as a reference sequence, to which test sequences are compared.
  • test and reference sequences are entered into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. Default program parameters can be used, or alternative parameters can be designated.
  • sequence comparison algorithm then calculates the percent sequence identities for the test sequences relative to the reference sequence, based on the program parameters.
  • sequence comparison of nucleic acids and proteins to ischemia-associated nucleic acids and proteins the BLAST and BLAST 2.0 algorithms and the default parameters discussed below are used.
  • a “comparison window”, as used herein, includes reference to a segment of any one of the number of contiguous positions selected from the group consisting of from 20 to 600, usually about 50 to about 200, more usually about 100 to about 150 in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned.
  • Methods of alignment of sequences for comparison are well-known in the art. Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith & Waterman, Adv. Appl. Math. 2:482 (1981), by the homology alignment algorithm of Needleman & Wunsch, J. Mol. Biol.
  • BLAST and BLAST 2.0 are used, with the parameters described herein, to determine percent sequence identity for the nucleic acids and proteins of the invention.
  • Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (http://www.ncbi.nlm.nih.gov/).
  • This algorithm involves first identifying high scoring sequence pairs (HSPs) by identifying short words of length W in the query sequence, which either match or satisfy some positive-valued threshold score T when aligned with a word of the same length in a database sequence.
  • T is referred to as the neighborhood word score threshold (Altschul et al., supra).
  • a scoring matrix is used to calculate the cumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached.
  • the BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment.
  • the BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, e.g., Karlin & Altschul, Proc. Nat'l. Acad. Sci. USA 90:5873-5787 (1993)).
  • One measure of similarity provided by the BLAST algorithm is the smallest sum probability (P(N)), which provides an indication of the probability by which a match between two nucleotide or amino acid sequences would occur by chance.
  • P(N) the smallest sum probability
  • a nucleic acid is considered similar to a reference sequence if the smallest sum probability in a comparison of the test nucleic acid to the reference nucleic acid is less than about 0.2, more preferably less than about 0.01, and most preferably less than about 0.001.
  • nucleic acid sequences or polypeptides are substantially identical is that the polypeptide encoded by the first nucleic acid is immunologically cross reactive with the antibodies raised against the polypeptide encoded by the second nucleic acid, as described below.
  • a polypeptide is typically substantially identical to a second polypeptide, for example, where the two peptides differ only by conservative substitutions.
  • Another indication that two nucleic acid sequences are substantially identical is that the two molecules or their complements hybridize to each other under stringent conditions, as described below.
  • Yet another indication that two nucleic acid sequences are substantially identical is that the same primers can be used to amplify the sequence.
  • the phrase “selectively (or specifically) hybridizes to” refers to the binding, duplexing, or hybridizing of a molecule only to a particular nucleotide sequence under stringent hybridization conditions when that sequence is present in a complex mixture (e.g., total cellular or library DNA or RNA).
  • host cell is meant a cell that contains an expression vector and supports the replication or expression of the expression vector.
  • Host cells may be, for example, prokaryotic cells such as E. coli or eukaryotic cells such as yeast cells or mammalian cells such as CHO cells.
  • Inhibitors “Inhibitors,” “activators,” and “modulators” of expression or of activity are used to refer to inhibitory, activating, or modulating molecules, respectively, identified using in vitro and in vivo assays for expression or activity, e.g., ligands, agonists, antagonists, and their homologs and mimetics.
  • modulator includes inhibitors and activators.
  • Inhibitors are agents that, e.g., inhibit expression of a polypeptide or polynucleotide of the invention or bind to, partially or totally block stimulation or enzymatic activity, decrease, prevent, delay activation, inactivate, desensitize, or down regulate the activity of a polypeptide or polynucleotide of the invention, e.g., antagonists.
  • Activators are agents that, e.g., induce or activate the expression of a polypeptide or polynucleotide of the invention or bind to, stimulate, increase, open, activate, facilitate, enhance activation or enzymatic activity, sensitize or up regulate the activity of a polypeptide or polynucleotide of the invention, e.g., agonists.
  • Modulators include naturally occurring and synthetic ligands, antagonists, agonists, small chemical molecules and the like.
  • Assays to identify inhibitors and activators include, e.g., applying putative modulator compounds to cells, in the presence or absence of a polypeptide or polynucleotide of the invention and then determining the functional effects on a polypeptide or polynucleotide of the invention activity.
  • Samples or assays comprising a polypeptide or polynucleotide of the invention that are treated with a potential activator, inhibitor, or modulator are compared to control samples without the inhibitor, activator, or modulator to examine the extent of effect. Control samples (untreated with modulators) are assigned a relative activity value of 100%.
  • Inhibition is achieved when the activity value of a polypeptide or polynucleotide of the invention relative to the control is about 80%, optionally 50% or 25-1%.
  • Activation is achieved when the activity value of a polypeptide or polynucleotide of the invention relative to the control is 110%, optionally 150%, optionally 200-500%, or 1000-3000% higher.
  • test compound or “drug candidate” or “modulator” or grammatical equivalents as used herein describes any molecule, either naturally occurring or synthetic, e.g., protein, oligopeptide (e.g., from about 5 to about 25 amino acids in length, preferably from about 10 to 20 or 12 to 18 amino acids in length, preferably 12, 15, or 18 amino acids in length), small organic molecule, polysaccharide, lipid, fatty acid, polynucleotide, RNAi, oligonucleotide, etc.
  • the test compound can be in the form of a library of test compounds, such as a combinatorial or randomized library that provides a sufficient range of diversity.
  • Test compounds are optionally linked to a fusion partner, e.g., targeting compounds, rescue compounds, dimerization compounds, stabilizing compounds, addressable compounds, and other functional moieties.
  • a fusion partner e.g., targeting compounds, rescue compounds, dimerization compounds, stabilizing compounds, addressable compounds, and other functional moieties.
  • new chemical entities with useful properties are generated by identifying a test compound (called a “lead compound”) with some desirable property or activity, e.g., inhibiting activity, creating variants of the lead compound, and evaluating the property and activity of those variant compounds.
  • HTS high throughput screening
  • a “small organic molecule” refers to an organic molecule, either naturally occurring or synthetic, that has a molecular weight of more than about 50 Daltons and less than about 2500 Daltons, preferably less than about 2000 Daltons, preferably between about 100 to about 1000 Daltons, more preferably between about 200 to about 500 Daltons.
  • the invention provides methods for diagnosing ischemia (e.g., stroke or transient ischemic attacks) or a predisposition for developing ischemia by detecting the expression of a plurality of ischemia-associated genes in a sample (e.g., a blood sample) from a subject.
  • a sample e.g., a blood sample
  • expression of a plurality of the genes set forth in Table 1, 2, 3, 4, 5, 6, or 7 is detected.
  • expression of a plurality of the genes set forth in Table 1 is detected.
  • At least about a 1.3 fold decrease in expression of the following genes: C21orf7, DAB2, JAM3, ITGA2B, PPBP, SYNJ2, SLC25A37, ZNF185, C7orf41, and LAK when compared to the normal control level indicates that the subject has experienced or is at risk for an atherothrombotic stroke or atheroembolic stroke.
  • Gene expression may be measured using any method known in the art.
  • One of skill in the art will appreciate that the means of measuring gene expression is not a critical aspect of the invention.
  • a variety of methods of specific DNA and RNA measurement using nucleic acid hybridization techniques are known to those of skill in the art (see, Sambrook, supra and Ausubel, supra) and may be used to detect the expression of the genes set forth in Table 1, 2, 3, 4, 5, 6, or 7.
  • Some methods involve an electrophoretic separation (e.g., Southern blot for detecting DNA, and Northern blot for detecting RNA), but measurement of DNA and RNA can also be carried out in the absence of electrophoretic separation (e.g., by dot blot).
  • Southern blot of genomic DNA e.g., from a human
  • RFLP restriction fragment length polymorphism
  • nucleic acid hybridization format is not critical.
  • a variety of nucleic acid hybridization formats are known to those skilled in the art.
  • common formats include sandwich assays and competition or displacement assays.
  • Hybridization techniques are generally described in Hames and Higgins Nucleic Acid Hybridization, A Practical Approach , IRL Press (1985); Gall and Pardue, Proc. Natl. Acad. Sci. U.S.A., 63:378-383 (1969); and John et al. Nature, 223:582-587 (1969).
  • Detection of a hybridization complex may require the binding of a signal-generating complex to a duplex of target and probe polynucleotides or nucleic acids. Typically, such binding occurs through ligand and anti-ligand interactions as between a ligand-conjugated probe and an anti-ligand conjugated with a signal.
  • the binding of the signal generation complex is also readily amenable to accelerations by exposure to ultrasonic energy.
  • the label may also allow indirect detection of the hybridization complex.
  • the label is a hapten or antigen
  • the sample can be detected by using antibodies.
  • a signal is generated by attaching fluorescent or enzyme molecules to the antibodies or in some cases, by attachment to a radioactive label (see, e.g., Tijssen, “ Practice and Theory of Enzyme Immunoassays,” Laboratory Techniques in Biochemistry and Molecular Biology , Burdon and van Knippenberg Eds., Elsevier (1985), pp. 9-20).
  • the probes are typically labeled either directly, as with isotopes, chromophores, lumiphores, chromogens, or indirectly, such as with biotin, to which a streptavidin complex may later bind.
  • the detectable labels used in the assays of the present invention can be primary labels (where the label comprises an element that is detected directly or that produces a directly detectable element) or secondary labels (where the detected label binds to a primary label, e.g., as is common in immunological labeling).
  • labeled signal nucleic acids are used to detect hybridization.
  • Complementary nucleic acids or signal nucleic acids may be labeled by any one of several methods typically used to detect the presence of hybridized polynucleotides. The most common method of detection is the use of autoradiography with 3 H, 125 I, 35 S, 14 C. or 32 P-labeled probes or the like.
  • labels include, e.g., ligands that bind to labeled antibodies, fluorophores, chemiluminescent agents, enzymes, and antibodies which can serve as specific binding pair members for a labeled ligand.
  • ligands that bind to labeled antibodies, fluorophores, chemiluminescent agents, enzymes, and antibodies which can serve as specific binding pair members for a labeled ligand.
  • An introduction to labels, labeling procedures and detection of labels is found in Polak and Van Noorden Introduction to Immunocytochemistry, 2nd ed., Springer Verlag, NY (1997); and in Haugland Handbook of Fluorescent Probes and Research Chemicals , a combined handbook and catalogue Published by Molecular Probes, Inc. (1996).
  • a detector which monitors a particular probe or probe combination is used to detect the detection reagent label.
  • Typical detectors include spectrophotometers, phototubes and photodiodes, microscopes, scintillation counters, cameras, film and the like, as well as combinations thereof. Examples of suitable detectors are widely available from a variety of commercial sources known to persons of skill in the art. Commonly, an optical image of a substrate comprising bound labeling moieties is digitized for subsequent computer analysis.
  • the amount of RNA is measured by quantifying the amount of label fixed to the solid support by binding of the detection reagent.
  • the presence of a modulator during incubation will increase or decrease the amount of label fixed to the solid support relative to a control incubation which does not comprise the modulator, or as compared to a baseline established for a particular reaction type.
  • Means of detecting and quantifying labels are well known to those of skill in the art.
  • the target nucleic acid or the probe is immobilized on a solid support.
  • Solid supports suitable for use in the assays of the invention are known to those of skill in the art. As used herein, a solid support is a matrix of material in a substantially fixed arrangement.
  • microarrays are used to detect the pattern of gene expression.
  • Microarrays provide one method for the simultaneous measurement of the expression levels of large numbers of genes.
  • Each array consists of a reproducible pattern of a plurality of nucleic acids (e.g., a plurality of nucleic acids that hybridize to a plurality of the genes set forth in Table 1, 2, 3, 4, 5, 6, or 7) attached to a solid support.
  • the array contains a plurality of nucleic acids that hybridize to a plurality of the genes listed in Table 1.
  • Labeled RNA or DNA is hybridized to complementary probes on the array and then detected by laser scanning. Hybridization intensities for each probe on the array are determined and converted to a quantitative read-out of relative gene expression levels in ischemia (e.g., stroke or transient ischemic attacks).
  • a sample is obtained from a subject, total mRNA is isolated from the sample and is converted to labeled cRNA and then hybridized to an array. Relative transcript levels are calculated by reference to appropriate controls present on the array and in the sample. See Mahadevappa and Warrington, Nat. Biotechnol. 17, 1134-1136 (1999).
  • VLSIPSTM very large scale immobilized polymer arrays
  • Affymetrix, Inc. can be used to detect changes in expression levels of a plurality of genes involved in the same regulatory pathways simultaneously. See, Tijssen, supra, Fodor et al. (1991) Science, 251: 767-777; Sheldon et al. (1993) Clinical Chemistry 39(4): 718-719, and Kozal et al. (1996) Nature Medicine 2(7): 753-759.
  • Detection can be accomplished, for example, by using a labeled detection moiety that binds specifically to duplex nucleic acids (e.g., an antibody that is specific for RNA-DNA duplexes).
  • a labeled detection moiety that binds specifically to duplex nucleic acids
  • a labeled detection moiety that binds specifically to duplex nucleic acids
  • One preferred example uses an antibody that recognizes DNA-RNA heteroduplexes in which the antibody is linked to an enzyme (typically by recombinant or covalent chemical bonding). The antibody is detected when the enzyme reacts with its substrate, producing a detectable product.
  • the nucleic acids used in this invention can be either positive or negative probes. Positive probes bind to their targets and the presence of duplex formation is evidence of the presence of the target. Negative probes fail to bind to the suspect target and the absence of duplex formation is evidence of the presence of the target.
  • the use of a wild type specific nucleic acid probe or PCR primers may serve as a negative probe in an assay sample where only the nucleotide sequence of interest is present.
  • the sensitivity of the hybridization assays may be enhanced through use of a nucleic acid amplification system that multiplies the target nucleic acid being detected.
  • a nucleic acid amplification system that multiplies the target nucleic acid being detected.
  • PCR polymerase chain reaction
  • LCR ligase chain reaction
  • Other methods recently described in the art are the nucleic acid sequence based amplification (NASBA, Cangene, Mississauga, Ontario) and Q Beta Replicase systems. These systems can be used to directly identify mutants where the PCR or LCR primers are designed to be extended or ligated only when a selected sequence is present.
  • the selected sequences can be generally amplified using, for example, nonspecific PCR primers and the amplified target region later probed for a specific sequence indicative of a mutation.
  • An alternative means for determining the level of expression of the nucleic acids of the present invention is in situ hybridization.
  • In situ hybridization assays are well known and are generally described in Angerer et al., Methods Enzymol. 152:649-660 (1987).
  • cells preferentially human cells from the cerebellum or the hippocampus, are fixed to a solid support, typically a glass slide. If DNA is to be probed, the cells are denatured with heat or alkali. The cells are then contacted with a hybridization solution at a moderate temperature to permit annealing of specific probes that are labeled.
  • the probes are preferably labeled with radioisotopes or fluorescent reporters.
  • microarrays are used to detect the pattern of gene expression.
  • Microarrays provide one method for the simultaneous measurement of the expression levels of large numbers of genes.
  • Each array consists of a reproducible pattern of a plurality of nucleic acids (e.g., a plurality of nucleic acids that hybridize to a plurality of the genes set forth in Table 1, 2, 3, 4, 5, 6 or 7) attached to a solid support.
  • the array contains a plurality of nucleic acids that hybridize to a plurality of the genes listed in Table 1.
  • Labeled RNA or DNA is hybridized to complementary probes on the array and then detected by laser scanning. Hybridization intensities for each probe on the array are determined and converted to a quantitative read-out of relative gene expression levels in ischemia (e.g., stroke or transient ischemic attacks)
  • a sample is obtained from a subject, total mRNA is isolated from the sample and is converted to labeled cRNA and then hybridized to an array. Relative transcript levels are calculated by reference to appropriate controls present on the array and in the sample. See Mahadevappa and Warrington, Nat. Biotechnol. 17, 1134-1136 (1999).
  • quantitative RT-PCR is used to detect the expression of a plurality of the genes set forth in Tables 1, 2, 3, 4, 5, 6 or 7.
  • quantitative RT-PCR is used to detect a plurality of the genes listed in Table 1.
  • a general overview of the applicable technology can be found, for example, in A - Z of Quantitative PCR , Bustin, ed., 2004, International University Line; Quantitative PCR Protocols , Kochanowski and Reischl, eds., 1999, Humana Press; Clinical Applications of PCR , Lo, ed., 2006, Humana Press; PCR Protocols: A Guide to Methods and Applications (Innis et al. eds.
  • the invention provides a reaction mixture comprising a plurality of polynucleotides which specifically hybridize (e.g., primers) to a plurality of nucleic acid sequences of the genes set forth in Table 1, 2, 3, 4, 5, 6 or 7.
  • the invention provides a reaction mixture comprising a plurality of polynucleotides which specifically hybridize (e.g., primers) to a plurality of nucleic acid sequences of the genes set forth in Table 1.
  • the reaction mixture is a PCR mixture, for example, a multiplex PCR mixture.
  • This invention relies on routine techniques in the field of recombinant genetics.
  • the nomenclature and the laboratory procedures in recombinant DNA technology described below are those well known and commonly employed in the art. Standard techniques are used for cloning, DNA and RNA isolation, amplification and purification. Generally enzymatic reactions involving DNA ligase, DNA polymerase, restriction endonucleases and the like are performed according to the manufacturer's specifications. Basic texts disclosing the general methods of use in this invention include Sambrook et al., Molecular Cloning, A Laboratory Manual (3rd ed. 2001); Kriegler, Gene Transfer and Expression: A Laboratory Manual (1990); and Current Protocols in Molecular Biology (Ausubel et al., eds., 1994-2008, Wiley Interscience)).
  • nucleic acids sizes are given in either kilobases (kb) or base pairs (bp). These are estimates derived from agarose or acrylamide gel electrophoresis, from sequenced nucleic acids, or from published DNA sequences.
  • kb kilobases
  • bp base pairs
  • proteins sizes are given in kilodaltons (kDa) or amino acid residue numbers. Proteins sizes are estimated from gel electrophoresis, from sequenced proteins, from derived amino acid sequences, or from published protein sequences.
  • Oligonucleotides that are not commercially available can be chemically synthesized according to the solid phase phosphoramidite triester method first described by Beaucage & Caruthers, Tetrahedron Letts. 22:1859-1862 (1981), using an automated synthesizer, as described in Van Devanter et. al., Nucleic Acids Res. 12:6159-6168 (1984). Purification of oligonucleotides is by either native acrylamide gel electrophoresis or by anion-exchange HPLC as described in Pearson & Reanier, J. Chrom. 255:137-149 (1983).
  • the invention also provides ischemia reference profiles.
  • the reference profiles comprise information correlating the expression levels of a plurality of ischemia-associated genes (i.e., a plurality of the genes set forth in Table 1, 2, 3, 4, 5, 6, or 7) to particular types of ischemia.
  • the ischemia reference profile correlates the expression levels of a plurality of the genes listed in Table 1 to particular types of ischemia.
  • the profiles can conveniently be used to diagnose, monitor and prognose ischemia.
  • One embodiment of the invention provides an ischemia reference profile for subjects who have experienced or are at risk for experiencing cardioembolic stroke. Accordingly, the ischemia reference profile correlates the expression levels of a plurality of the genes selected from LEPROT, PCGF3, PPP3R1, PVRL2, INSR, BIRC1, TSHZ3, DF, FBN2, IER3, NUMB, LAK, CD8B1 and RRAS2.
  • One embodiment of the invention provides an ischemia reference profile for subjects who have experienced or are at risk for experiencing atherothrombotic stroke. Accordingly, the ischemia reference profile correlates the expression levels of a plurality of the genes selected from C21orf7, DAB2, JAM3, ITGA2B, PPBP, SYNJ2, SLC25A37, ZNF185, C7orf41, and LAK.
  • An expression profile exhibiting at least about a 1.3 fold decrease in expression of the following genes: C21orf7, DAB2, JAM3, ITGA2B, PPBP, SYNJ2, SLC25A37, ZNF185, C7orf41, and LAK when compared to the normal control level is a reference profile for a subject who has experienced or is at risk for an atherothrombotic stroke.
  • the reference profiles can be entered into a database, e.g., a relational database comprising data fitted into predefined categories.
  • a database e.g., a relational database comprising data fitted into predefined categories.
  • Each table, or relation contains one or more data categories in columns.
  • Each row contains a unique instance of data for the categories defined by the columns.
  • a typical database for the invention would include a table that describes a sample with columns for age, gender, reproductive status, expression profile and so forth. Another table would describe a disease: symptoms, level, sample identification, expression profile and so forth.
  • the invention matches the experimental sample to a database of reference samples.
  • the database is assembled with a plurality of different samples to be used as reference samples. An individual reference sample in one embodiment will be obtained from a patient during a visit to a medical professional.
  • Information about the physiological, disease and/or pharmacological status of the sample will also be obtained through any method available. This may include, but is not limited to, expression profile analysis, clinical analysis, medical history and/or patient interview. For example, the patient could be interviewed to determine age, sex, ethnic origin, symptoms or past diagnosis of disease, and the identity of any therapies the patient is currently undergoing. A plurality of these reference samples will be taken. A single individual may contribute a single reference sample or more than one sample over time.
  • confidence levels in predictions based on comparison to a database increase as the number of reference samples in the database increases.
  • the database is organized into groups of reference samples. Each reference sample contains information about physiological, pharmacological and/or disease status.
  • the database is a relational database with data organized in three data tables, one where the samples are grouped primarily by physiological status, one where the samples are grouped primarily by disease status and one where the samples are grouped primarily by pharmacological status. Within each table the samples can be further grouped according to the two remaining categories. For example the physiological status table could be further categorized according to disease and pharmacological status.
  • the present invention may be embodied as a method, data processing system or program products. Accordingly, the present invention may take the form of data analysis systems, methods, analysis software, etc.
  • Software written according to the present invention is to be stored in some form of computer readable medium, such as memory, hard-drive, DVD ROM or CD ROM, or transmitted over a network, and executed by a processor.
  • the present invention also provides a computer system for analyzing physiological states, levels of disease states and/or therapeutic efficacy.
  • the computer system comprises a processor, and memory coupled to said processor which encodes one or more programs.
  • the programs encoded in memory cause the processor to perform the steps of the above methods wherein the expression profiles and information about physiological, pharmacological and disease states are received by the computer system as input.
  • Computer systems may be used to execute the software of an embodiment of the invention (see, e.g., U.S. Pat. No. 5,733,729).
  • the invention also provides methods of identifying compounds for treating or preventing ischemia.
  • Compounds for treating or preventing ischemia can be readily identified according to methods well known to those of skill in the art.
  • a number of different screening protocols can be utilized to identify agents that modulate the level of activity or expression of ischemia-associated genes (i.e., agents that decrease the activity or expression of genes overexpressed in ischemia and increase the activity or expression of genes underexpressed in ischemia).
  • Preliminary screens can be conducted by screening for agents that modulate expression of ischemia-associated genes.
  • the screening methods of the invention can be performed as in vitro or cell-based assays.
  • Cell based assays can be performed in any cells which express one or more ischemia-associated genes.
  • ischemia-associated genes can be expressed in cells that do not contain endogenous ischemia-associated genes.
  • Cell-based assays may involve whole cells or cell fractions to screen for agent binding or modulation of ischemia-associated genes Suitable cell-based assays are described in, e.g., DePaola et al., Annals of Biomedical Engineering 29: 1-9 (2001).
  • In vivo assays can also be used to identify agents that can be used to treat or prevent ischemia.
  • the basic format of such methods involves administering a lead compound identified during an initial screen to an animal that serves as a model for ischemia and then determining if in fact the ischemia is ameliorated.
  • the animal models utilized in validation studies generally are mammals of any kind. Specific examples of suitable animals include, but are not limited to, primates (e.g., chimpanzees, monkeys, and the like) and rodents (e.g., mice, rats, guinea pigs, rabbits, and the like).
  • the agents tested as potential modulators of ischemia-associated gene expression can be any small chemical compound, or a biological entity, such as a polypeptide, sugar, nucleic acid or lipid.
  • any chemical compound can be used as a potential modulator in the assays of the invention, although most often compounds that can be dissolved in aqueous or organic (especially DMSO-based) solutions are used.
  • the assays are designed to screen large chemical libraries by automating the assay steps and providing compounds from any convenient source to assays, which are typically run in parallel (e.g., in microtiter formats on microtiter plates in robotic assays).
  • high throughput screening methods involve providing a combinatorial chemical or peptide library containing a large number of potential therapeutic compounds (potential modulator or ligand compounds). Such “combinatorial chemical libraries” or “ligand libraries” are then screened in one or more assays, as described herein, to identify those library members (particular chemical species or subclasses) that display a desired characteristic activity. The compounds thus identified can serve as conventional “lead compounds” or can themselves be used as potential or actual therapeutics.
  • a combinatorial chemical library is a collection of diverse chemical compounds generated by either chemical synthesis or biological synthesis, by combining a number of chemical “building blocks” such as reagents.
  • a linear combinatorial chemical library such as a polypeptide library is formed by combining a set of chemical building blocks (amino acids) in every possible way for a given compound length (i.e., the number of amino acids in a polypeptide compound). Millions of chemical compounds can be synthesized through such combinatorial mixing of chemical building blocks.
  • combinatorial chemical libraries include, but are not limited to, peptide libraries (see, e.g., U.S. Pat. No. 5,010,175, Furka, Int. J. Pept. Prot. Res. 37:487-493 (1991) and Houghton et al., Nature 354:84-88 (1991)).
  • chemistries for generating chemical diversity libraries can also be used. Such chemistries include, but are not limited to: peptoids (e.g., PCT Publication No.
  • nucleic acid libraries see Ausubel, Berger and Sambrook, all supra
  • peptide nucleic acid libraries see, e.g., U.S. Pat. No. 5,539,083
  • antibody libraries see, e.g., Vaughn et al., Nature Biotechnology, 14(3):309-314 (1996) and PCT/US96/10287)
  • carbohydrate libraries see, e.g., Liang et al., Science, 274:1520-1522 (1996) and U.S. Pat. No.
  • kits for diagnosing ischemia or a predisposition for developing ischemia are provided.
  • the invention provides kits that include one or more reaction vessels that have aliquots of some or all of the reaction components of the invention in them. Aliquots can be in liquid or dried form.
  • Reaction vessels can include sample processing cartridges or other vessels that allow for the containment, processing and/or amplification of samples in the same vessel.
  • the kits may comprise a plurality of nucleic acid probes that hybridize to a plurality the genes set forth in Table 1, 2, 3, 4, 5, 6, or 7.
  • the kits comprise a plurality of nucleic acid probes that hybridize to a plurality of the genes set forth in Table 1.
  • the probes may be immobilized on an array as described herein.
  • the kit can comprise appropriate buffers, salts and other reagents to facilitate amplification and/or detection reactions (e.g., primers) for determining the expression levels of a plurality of the genes set forth in Table 1, 2, 3, 4, 5, 6, or 7.
  • the kit comprises appropriate buffers, salts and other reagents to facilitate amplification and/or detection reactions (e.g., primers) for determining the expression levels of a plurality of the genes set forth in Table 1.
  • the kits can also include written instructions for the use of the kit.
  • standard-dose r-tPA Activase
  • Activase a combination of eptifibatide and low-dose r-tPA
  • the etiology of the strokes was assessed using the TOAST criteria (Adams et al. Stroke (1993) 24:35-41) and classified as: Atherosclerotic stroke, Cardioembolic stroke and Stroke with undetermined etiology. Patients with small artery lacunar stroke were generally excluded from the CLEAR trial because of the study design, and none of the patients reported here had lacunar stroke.
  • PMNs Neurotrophils, basophils and eosinophils
  • PBMC-lymphocytes mononuclear cells
  • macrophage/monocytes platelets and red blood cell precursors.
  • RNA samples were labeled, hybridized and scanned according to standard Affymetrix Protocols (Affymetrix Expression Analysis Technical Manual). 10 ⁇ g total RNA was labeled using the One-Cycle Target Labeling protocol. Affymetrix Human U133 Plus 2 arrays that contain more that 54,000 probe sets were used for each RNA sample. The RNA samples are also subject to RT-PCR.
  • Probe-level data was saved in Affymetrix.cel files and summarized with Robust Multi-array Average (RMA) software (on the worldwide web at bioconductor.org/).
  • RMA Robust Multi-array Average
  • Statistical analyses including a one-way analysis of variance (ANOVA) for cardioembolic stroke, atherosclerotic stroke, Stroke of undetermined etiology and controls) were performed using Genespring software (Silicon Genetics, Redwood City, Calif.).
  • the Benjamini-Hochberg false discovery rate (FDR) was used to control for multiple comparisons with a 5% FDR ( ⁇ 0.05) being considered significant. Different fold change filters were applied to minimize type-two error.
  • the one-way ANOVA (FDR ⁇ 0.05, Student-Newman-Keuls post hoc test, equal variance) yielded 660 genes that were differentially regulated for cardioembolic vs. atherosclerotic stroke.
  • the Student t-test (p ⁇ 0.001) yielded 135 genes that were differentially regulated for cardioembolic stroke vs atherosclerotic stroke. Of these 135 genes identified using the t-test, 95 of these were also identified using the one-way ANOVA. Using a 1.5 fold change filter, a total of 77 genes were significantly regulated between cardioembolic stroke and atherosclerotic stroke (significant using ANOVA or T-test; fold change>1.5).
  • PAM Microarrays
  • the 23 genes can be classified into 3 subgroups, using a 1.3 fold change in expression as a significant change.
  • LEPROT, PCGF3, PPP3R1, PVRL2, INSR, BIRC1, TSHZ3, DF, FBN2, IER3, NUMB, and LAK exhibit at least a 1.3 fold increase in expression in subjects with cardioembolic stroke versus control subjects and RRAS2 and CD8B1 exhibit at least a 1.3 fold decrease in expression in subjects with cardioembolic stroke versus control subjects.
  • C21orf7, DAB2, JAM3, ITGA2B, PPBP, SYNJ2, SLC25A37, ZNF185, C7orf41, and LAK exhibit at least 1.3 fold decrease in expression in subjects with atherothrombotic stroke versus control subjects.
  • the gene expression profiles disclosed herein can be used to determine the cause of the stroke or TIA in those patients who have an unknown etiology.
  • PAM and the minimum set of 23 genes were used to predict the etiology of the subjects whose cause of stroke could not be determined based upon clinical TOAST criteria.
  • PAM classified all 12 of the unknown samples as being cardioembolic stroke with probabilities over 90% (92.9-99.9%, FIG. 2 ).
  • the differentially regulated genes between cardioembolic stroke and atherosclerotic stroke were then classified by cluster analysis. Two subgroups of genes were identified: one is mainly regulated in cardioembolic stroke relative to healthy control (281 genes at 1.2 fold filter or 148 genes at 1.3 fold filter), the other is mainly regulated in atherosclerotic stroke relative to healthy control (84 genes at 1.2 fold filter or 63 genes at 1.3 fold filter).
  • the functions of the two etiology-specific gene lists were then explored in the Nextbio System (Cupertino, Calif., USA), a web-based data search and analysis engine. The genes were ranked according to fold change and then queried against GO, KEGG pathways and REACTOME databases in Nextbio with p value 0.05 cut off.
  • cardioembolism-specific expression profiles were most similar to those from patients with sepsis and septic shock (105 genes and 109 genes in common at day 1, respectively)(GEO Series GSE4607). (Wong et al., Physiol Genomics (2007) 30(2):146-55).
  • the genes regulated in cardioembolic versus atherosclerotic stroke might or might not be expressed in restricted cell types in blood.
  • RNA is isolated from the blood sample and the RNA labeled and applied to a microarray or similar platform to examine all expressed genes in blood (including, e.g., the genes set forth in Tables 1, 2, 3, 4, 5, or 6). From the microarray the expression of every gene in blood can then be calculated. Suitable software such as Prediction Analysis of Microarrays (PAM) is then used to calculate the probability that the changes of gene expression in the patient are due to a stroke. A probability of 85% of more that the changes represent a stroke is used to confirm the diagnosis of stroke.
  • PAM Prediction Analysis of Microarrays
  • the next step is to then determine the cause of the stroke. This is important because strokes from atherosclerosis may require surgery or vascular stenting; and strokes from cardioembolism require anti-coagulation with suitable mediacations including, e.g., Coumadin, Warfarin, and the like; and strokes from lacunar disease/hypertension require treatment with aspirin and other anti-platelet agents combined with drugs for the hypertension. From the same microarray used to make the diagnosis of a stroke, the expression of the genes listed in Table 1 is assessed in the patient's blood sample. The expression of these genes is compared to a control or reference sample, or to a combination of genes on the array that serve as control genes.
  • the genes that increase in stroke due to atherosclerosis are decreased in stroke due to cardioembolism; and the genes that increase in stroke due to cardioembolism decrease in stroke due to atherosclerosis; and some genes only change either in stroke due to cardioembolism or only change in stroke due to atherosclerosis.
  • the profile of expression of all 23 genes is again entered into PAM, and PAM calculates the probability that the stroke in a given patient is either cardioembolic, atherosclerotic or due to some other cause. If the probability is 85% or greater for a given cause of stroke, then the cause of stroke will be reported. If the probability is 50% for any cause of stroke then the gene expression profile will not have been able to determine the cause of stroke.
  • NM_001999 Hs.519294 FBN2 fibrillin 2 (congenital contractural arachnodactyly) AI520949 Hs.110675 PVRL2 poliovirus receptor-related 2 (herpesvirus entry mediator B) AW051321 Hs.464137 CDNA FLJ30303 fis, clone BRACE2003269 BE896490 Hs.595327 SNAP29 synaptosomal-associated protein, 29 kDa AA181060 Hs.349283 Clone IMAGE: 5288883, mRNA BE867789 Hs.110675 PVRL2 poliovirus receptor-related 2 (herpesvirus entry mediator B) NM_007150 Hs.16622 ZNF185 zinc5t finger protein 185 (LIM domain) NM_001928 Hs.155597 DF D component of complement (adipsin) NM_001343 Hs.481980 DAB2 disabled homolog 2, mitogen-responsive phosphoprotein ( D
  • NM_000107 Hs.643521 DDB2 damage-specific DNA binding protein 2 48 kDa NM_005317 Hs.465511 GZMM granzyme M (lymphocyte met-ase 1) BC040914 Hs.322462 Clone IMAGE: 5745627, mRNA AK001164 Hs.599785 CDNA FLJ10302 fis, clone NT2RM2000042 NM_005608 Hs.155975 PTPRCAP protein tyrosine phosphatase, receptor type, C-associated protein NM_013330 Hs.642710 NA4E7 non-metastatic cells 7, protein expressed in (nucleoside-diphosphate kinase) AB020630 Hs.45719 PPP1R16B protein phosphatase 1, regulatory (inhibitor) subunit 16B AB020630 Hs.45719 PPP1R16B protein phosphatase 1, regulatory (inhibitor)
  • BIR1_HUMAN Baculoviral IAP repeat-containing protein 1 AW270105 Hs.643902 RNF3 ring finger protein 3 BG913589 Hs.59214 LOC144871 DnaJ (Hsp40) homolog, subfamily C, member 3 W73230 Hs.200100 Ells1 zd56c09.s1
  • B4GALT5 UDP-Gal betaGlcNAc beta 1,4-galactosyltransferase, polypeptide 5 NM_005502 Hs.429294 ABCA1 ATP-binding cassette, sub-family A (ABC1), member 1 NM_000361 Hs.2030 THBD thrombomodulin AK024569 Hs.195403 DOCKS dedicator of cytokinesis 5 AB051833 Hs.123239 ACRBP acrosin binding protein NM_004126 Hs.83381 GNG11 guanine nucleotide binding protein (G protein), gamma 11 Y07846 Hs.322852 GAS2L1 growth arrest-specific 2 like 1 BE327727 Hs.443301 Transcribed sequences M36532 Hs.155097 CA2 carbonic anhydrase II NM_017526 Hs.23581 OBRGRP leptin
  • BIR1_HUMAN Baculoviral IAP repeat-containing protein 1 AW270105 Hs.643902 RNF3 ring finger protein 3 BG913589 Hs.59214 LOC144871 DnaJ (Hsp40) homolog, subfamily C, member 3 W73230 Hs.200100 Ells1 zd56c09.s1
  • B4GALT5 UDP-Gal betaGlcNAc beta 1,4-galactosyltransferase, polypeptide 5 NM_005502 Hs.429294 ABCA1 ATP-binding cassette, sub-family A (ABC1), member 1 NM_000361 Hs.2030 THBD thrombomodulin AK024569 Hs.195403 DOCK5 dedicator of cytokinesis 5 AB051833 Hs.123239 ACRBP acrosin binding protein NM_004126 Hs.83381 GNG11 guanine nucleotide binding protein (G protein), gamma 11 Y07846 Hs.322852 GAS2L1 growth arrest-specific 2 like 1 BE327727 Hs.443301 Transcribed sequences M36532 Hs.155097 CA2 carbonic anhydrase II NM_017526 Hs.23581 OBRGRP leptin
  • AI022066 Hs.480763 Transcribed sequences AI953847 Hs.148741
  • PTGS2 prostaglandin-endoperoxide synthase 2 prostaglandin G/H synthase and cyclooxygenase
  • cDNA DKFZp667O0416 from clone DKFZp667O0416
  • AI831952 Hs.567518 NDE1 nudE nuclear distribution gene E homolog 1 ( A.
  • AF188298 Hs.481980 DAB2 disabled homolog 2, mitogen-responsive phosphoprotein ( Drosophila ) NM_005906 Hs.446125 MAK male germ cell-associated kinase BC002716 Hs.496572 FLJ22679 hypothetical protein FLJ22679 AK023512 Hs.463439 SPAG9 sperm associated antigen 9 AA010315 Hs.60371 Transcribed sequences AF051151 Hs.135853 TLR5 toll-like receptor 5 BU929456 OSTF1 AGENCOURT_10424238 NIH_MGC_79 Homo sapiens cDNA clone IMAGE: 6663343 5′, mRNA sequence.
  • NP_002607 Hs.535898 PDGFA platelet-derived growth factor alpha polypeptide AK024748 Hs.297343 CAMKK2 calcium/calmodulin-dependent protein kinase kinase 2, beta U76248 Hs.477959 SIAH2 seven in absentia homolog 2 ( Drosophila ) AI819198 Hs.208229 GPR54 G protein-coupled receptor 54 AI452469 Hs.605187 Transcribed sequence with weak similarity to protein ref: NP_009032.1 ( H.
  • AK024382 unnamed protein product; Homo sapiens cDNA FLJ14320 fis, clone PLACE3000455. AA702409 Hs.592017 Transcribed sequences AI074467 Hs.593643 Transcribed sequences AI368358 Hs.496969 NPL N-acetylneuraminate pyruvate lyase (dihydrodipicolinate synthase) H28667 Hs.444451 ZAK sterile alpha motif and leucine zipper containing kinase AZK AL544951 Hs.280604 PPP3R1 AL544951 Homo sapiens PLACENTA COT 25-NORMALIZED Homo sapiens cDNA clone CS0DI012YC11 5-PRIME, mRNA sequence.
  • BIR1_HUMAN Baculoviral IAP repeat-containing protein 1 AW270105 Hs.643902 RNF3 ring finger protein 3 BG913589 Hs.59214 LOC144871 DnaJ (Hsp40) homolog, subfamily C, member 3 W73230 Hs.200100 Ells1 zd56c09.s1
  • B4GALT5 UDP-Gal betaGlcNAc beta 1,4-galactosyltransferase, polypeptide 5 NM_005502 Hs.429294 ABCA1 ATP-binding cassette, sub-family A (ABC1), member 1 NM_000361 Hs.2030 THBD thrombomodulin AK024569 Hs.195403 DOCK5 dedicator of cytokinesis 5 AB051833 Hs.123239 ACRBP acrosin binding protein NM_004126 Hs.83381 GNG11 guanine nucleotide binding protein (G protein), gamma 11 Y07846 Hs.322852 GAS2L1 growth arrest-specific 2 like 1 BE327727 Hs.443301 Transcribed sequences M36532 Hs.155097 CA2 carbonic anhydrase II NM_017526 Hs.23581 OBRGRP leptin
  • AI022066 Hs.480763 Transcribed sequences AI953847 Hs.148741
  • PTGS2 prostaglandin-endoperoxide synthase 2 prostaglandin G/H synthase and cyclooxygenase
  • cDNA DKFZp667O0416 from clone DKFZp667O0416
  • AI831952 Hs.567518 NDE1 nudE nuclear distribution gene E homolog 1 ( A.
  • AF188298 Hs.481980 DAB2 disabled homolog 2, mitogen-responsive phosphoprotein ( Drosophila ) NM_005906 Hs.446125 MAK male germ cell-associated kinase BC002716 Hs.496572 FLJ22679 hypothetical protein FLJ22679 AK023512 Hs.463439 SPAG9 sperm associated antigen 9 AA010315 Hs.60371 Transcribed sequences AF051151 Hs.135853 TLR5 toll-like receptor 5 BU929456 OSTF1 AGENCOURT_10424238 NIH_MGC_79 Homo sapiens cDNA clone IMAGE: 6663343 5′, mRNA sequence.
  • NP_002607 Hs.535898 PDGFA platelet-derived growth factor alpha polypeptide AK024748 Hs.297343 CAMKK2 calcium/calmodulin-dependent protein kinase kinase 2, beta U76248 Hs.477959 SIAH2 seven in absentia homolog 2 ( Drosophila ) AI819198 Hs.208229 GPR54 G protein-coupled receptor 54 AI452469 Hs.605187 Transcribed sequence with weak similarity to protein ref: NP_009032.1 ( H.
  • AK024382 unnamed protein product; Homo sapiens cDNA FLJ14320 fis, clone PLACE3000455. AA702409 Hs.592017 Transcribed sequences AI074467 Hs.593643 Transcribed sequences AI368358 Hs.496969 NPL N-acetylneuraminate pyruvate lyase (dihydrodipicolinate synthase) H28667 Hs.444451 ZAK sterile alpha motif and leucine zipper containing kinase AZK AL544951 Hs.280604 PPP3R1 AL544951 Homo sapiens PLACENTA COT 25-NORMALIZED Homo sapiens cDNA clone CSODI012VC11 5-PRIME, mRNA sequence.
  • AK025898 Hs.525232 LRP10 low density lipoprotein receptor-related protein 10 AB062477 Homo sapiens OK/SW-c1.41 mRNA, complete cds. AW467357 Hs.371720 SYK spleen tyrosine kinase AI808120 Hs.479766 RRM1 TPA regulated locus BE966748 ERO1L 601661247R1 NIH_MGC_72 Homo sapiens cDNA clone IMAGE: 3916235 3′, mRNA sequence.
  • AK024677 Hs.632602 ASAHL N-acylsphingosine amidohydrolase (acid ceramidase)-like AL038191 Hs.474536 DKFZp566P1724_s1 566 (synonym: hfkd2) Homo sapiens cDNA clone DKFZp566P1724 3′, mRNA sequence. BG432887 Hs.442789 Transcribed sequence with weak similarity to protein ref: NP_005210.1 ( H.
  • AI807658 Hs.192326 Transcribed sequences BE693389 Transcribed sequences N32832 Hs.159430 FAD104 FAD104 AF015452 Hs.390736 CFLAR CASP8 and FADD-like apoptosis regulator AL049273 Hs.429434 MRNA; cDNA DKFZp564H023 (from clone DKFZp564H023) BC039388 Hs.237886 Clone IMAGE: 5298774, mRNA AA382004 Hs.122514 MSCP EST95296 Activated T-cells II Homo sapiens cDNA 5′ end, mRNA sequence.
  • AV699911 Hs.310421 Transcribed sequence with weak similarity to protein sp: P23961 ( H. sapiens ) ALUC_HUMAN !!! ALU CLASS C WARNING ENTRY !!! NM_002350 Hs.491767 LYN v-yes-1 Yamaguchi sarcoma viral related oncogene homolog AI698731 Hs.202238 Transcribed sequences AA215519 zr97a07.r1 NCI_CGAP_GCB1 Homo sapiens cDNA clone IMAGE: 683604 5′, mRNA sequence.
  • AF288573 Hs.2007 TNFSF6 tumor necrosis factor (ligand) superfamily member 6 NM_031213 Hs.465542 C19orf27 hypothetical protein MGC5244 AF044954 Hs.513266 NDUFB10 NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 10, 22 kDa BE671663 Hs.592102 EVER2 epidermodysplasia verruciformis 2 NM_007237 Hs.632549 SP140 SP140 nuclear body protein AI003777 Hs.632176 1-Sep septin 1 AI421559 Hs.106185 RALGDS ral guanine nucleotide dissociation stimulator NM_020886 Hs.503891 USP28 ubiquitin specific protease 28 AI042377 Hs.470457 Transcribed sequences AA742584 Hs.125914 C8orf5 chromosome 8 open reading frame 5 BG231773 Hs
  • NM_003175 Hs.458346 XCL1 chemokine (C motif) ligand 2 U96394 Hs.449601 IGL1 Clone P2-147 anti-oxidized LDL immunoglobulin light chain Fab mRNA, partial cds M27331 Hs.534032 TRGV9 T cell receptor gamma locus U23772 Hs.546295 XCL1 chemokine (C motif) ligand 1 NM_004931 Hs.405667 CD8B1 CD8 antigen, beta polypeptide 1 (p37) NM_006275 Hs.6891 SFRS6 splicing factor, arginine/serine-rich 6 BC020552 Hs.379186 PDCD6 programmed cell death 6 NM_001548 Hs.20315 IFIT1 interferon-induced protein with tetratricopeptide repeats 1 BC005248 Hs.461178 EIF1AY eukaryotic translation initiation factor 1
  • AK024382 “unnamed protein product; Homo sapiens cDNA FLJ14320 fis, clone PLACE3000455.” AA702409 Hs.592017 Transcribed sequences AI074467 Hs.593643 Transcribed sequences AI368358 Hs.496969 N-acetylneuraminate pyruvate lyase (dihydrodipicolinate synthase) H28667 Hs.444451 sterile alpha motif and leucine zipper containing kinase AZK AL544951 Hs.280604 “AL544951 Homo sapiens PLACENTA COT 25-NORMALIZED Homo sapiens cDNA clone CS0DI012YC11 5-PRIME, mRNA sequence.” AL050388 Hs.487046 “superoxide dismutase 2, mitochondrial” AI829674 Hs.584845 Transcribed sequences NM_018324
  • RNA polymerase II, 2 AI650285 Hs.287299 Transcribed sequence with weak similarity to protein ref:NP_060312.1 ( H. sapiens ) hypothetical protein FLJ20489 [ Homo sapiens ] AU147506 Hs.7886 pellino homolog 1 ( Drosophila ) BF435852 Hs.464137 “acyl-Coenzyme A oxidase 1, palmitoyl” W03103 Hs.106015 “za04b05.r1 Soares melanocyte 2NbHM Homo sapiens cDNA clone IMAGE:291537 5′, mRNA sequence.” AI458949 Hs.520414 interferon gamma receptor 1 AB030034 Hs.444451 sterile alpha motif and leucine zipper containing kinase AZK BC011877 Hs.195403 “Hypothetical protein LOC286061 (LOC286061), mRNA” AL13
  • cytokine receptor- like factor 2 cytokine receptor CRL2 precusor [ Homo sapiens ] AB029030 Hs.21554 KIAA1107 protein AI935717 Hs.471637 hypothetical protein MGC42174 AL050042 Hs.538604 Homo sapiens mRNA; cDNA DKFZp566L0824 (from clone DKFZp566L0824).
  • NM_014450 Hs.88012 SHP2-interacting transmembrane adaptor protein BF345244 Hs.378501 hypothetical protein LOC283989 AI057637 Hs.234898 acetyl-Coenzyme A carboxylase beta BC002918 Hs.213088 carbohydrate (chondroitin 4) sulfotransferase 12 X79782 Hs.449601 H.
  • Atheroembolic/ Cardioembolic/ Cardioembolic/ Common Name control control Atheroembolic LAK 1.42 ⁇ 1.375 1.952 PVRL2 1.357 ⁇ 1.15 1.561 PVRL2 1.432 ⁇ 1.145 1.64 PCGF3 1.323 ⁇ 1.129 1.495 PPP3R1 1.34 ⁇ 1.122 1.503 LEPROT 1.314 ⁇ 1.114 1.464 INSR 1.369 ⁇ 1.096 1.501 PVRL2 1.859 ⁇ 1.09 2.028 NUMB 1.821 ⁇ 1.041 1.896 FBN2 1.622 ⁇ 1.011 1.64 BIRC1 1.426 1.007 1.417 TSHZ3 1.457 1.013 1.439 DF 1.595 1.034 1.542 IER3 1.701 1.197 1.421 RRAS2 ⁇ 1.449 1.198 ⁇ 1.736 CD8B1 ⁇ 1.259 1.213 ⁇ 1.526 CD8B1 ⁇ 1.447 1.234 ⁇ 1.785

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Abstract

This invention provides methods and compositions for diagnosing ischemia, ischemia reference expression profiles, and methods for identifying compounds for treating or preventing ischemia.

Description

    CROSS-REFERENCES TO RELATED APPLICATIONS
  • This application is a divisional of U.S. application Ser. No. 12/598,107, filed on Mar. 25, 2010, which is the U.S. national stage entry under 35 U.S.C. §371 of Intl. Appl. No. PCT/US2008/062064, filed on Apr. 30, 2008, which claims the benefit of U.S. Provisional Application No. 60/915,366, filed on May 1, 2007, which are hereby incorporated herein by reference in their entireties for all purposes.
  • STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT
  • This invention was made with Government support under Grant No. NS043252, NS028167, NS042774, NS044283 and NS056302, awarded by the National Institutes of Health and National Institute of Neurological Disorders and Stroke (NINDS). The government has certain rights in this invention.
  • BACKGROUND OF THE INVENTION
  • Ischemic events such as stroke are the third leading cause of death in America. Different subtypes of stroke have their own specific management strategy and a precise diagnosis is critical for the timely treatment of various stroke patients. Currently the gold standard for the diagnosis of acute ischemic stroke versus hemorrhagic stroke relies on imaging technology. However, so far there is no such gold standard for determining the etiology of ischemic stroke. Currently the etiology of ischemic stroke largely depends on the clinician's judgment from indirect clinical information. The main etiologies of acute ischemic stroke include atherothrombotic stroke and cardioembolic stroke. Atheroembolic stroke dictates surgery or aspirin and platelet inhibitor(s); and cardioembolic strokes require treatment with anticoagulant medications such as, e.g., coumadin.
  • To determine the cause of stroke, patients have magnetic resonance imaging or carotid dopplers to determine if they have atherosclerosis in the carotid and cardiac echocardiograms to determine if they have clot in the heart. The cardiac echocardiogram is very specific, but very insensitive. Even with the best of information, determining the actual cause of stroke is impassible: that is, there is no current direct test for cause. Moreover, somewhere between 30% and 50% of all subjects with transient ischemic attacks and stroke have an unknown cause of stroke.
  • Thus, there is a need in the art for methods for accurately diagnosing ischemic events (including e.g., stroke and transient ischemic attacks). The present invention meets these and other needs.
  • BRIEF SUMMARY OF THE INVENTION
  • The present invention provides methods for diagnosing ischemia (e.g., embolic and thrombotic stroke and transient ischemic attacks) by detecting expression levels of genes differentially expressed in ischemia.
  • One embodiment of the invention provides methods for diagnosing an ischemia or a predisposition for developing an ischemia. The methods comprise: determining a level of expression of a plurality of ischemia-associated genes in a biological sample from a mammalian subject, wherein a difference (i.e. increase or decrease) of said level compared to a normal control level of the genes indicates that said subject suffers from or is at risk of developing ischemia, wherein said plurality of ischemia-associated genes is selected from the genes set forth in Table 1, 2, 3, 4, 5, 6, or 7. For example, in some embodiments, the level of expression of a plurality, i.e., two or more genes, selected from Table 1 is determined, i.e., two or more of LEPROT, PCGF3, PPP3R1, PVRL2, INSR, BIRC1 (also called, NAIP///LOC728519), TSHZ3, DF (also called, CFD), FBN2, IER3, NUMB, LAK (also called, ALPK1), CD8B1, RRAS2, C21orf7, DAB2, JAM3, ITGA2B, PPBP, SYNJ2, SLC25A37, ZNF185 and C7orf41. In some embodiments, the expression level of 5 or more, 10 or more, 15 or more, 20 or more, or 23 of the genes listed in Table 1 is determined.
  • In some embodiments, the difference (i.e., increase or decrease) is at least about 1.3 fold, 1.4 fold, or 1.5 fold higher or lower, respectively, than a normal control level.
  • In some embodiments, the expression level of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 genes selected from LEPROT, PCGF3, PPP3R1, PVRL2, INSR, BIRC1, TSHZ3, DF, FBN2, IER3, NUMB, LAK, CD8B1 and RRAS2, identified in Tables 1, 9 and 10, is determined. In some embodiments, at least about a 1.3 fold increase in expression of the following genes: LEPROT, PCGF3, PPP3R1, PVRL2, INSR, BIRC1, TSHZ3, DF, FBN2, IER3, NUMB, and LAK when compared to the normal control level, and at least about a 1.3 fold decrease in expression of the following genes: CD8B1 and RRAS2 when compared to the normal control level indicates that the subject has experienced or is at risk for a cardioembolic stroke.
  • In some embodiments, the expression level of 2, 3, 4, 5, 6, 7, 8, 9 or 10 genes selected from C21orf7, DAB2, JAM3, ITGA2B, PPBP, SYNJ2, SLC25A37, ZNF185, C7orf41 and LAK, identified in Tables 1, 8 and 10, is determined. In some embodiments, at least about a 1.3 fold decrease in expression of the following genes: C21orf7, DAB2, JAM3, ITGA2B, PPBP, SYNJ2, SLC25A37, ZNF185, C7orf41 and LAK when compared to the normal control level indicates that the subject has experienced or is at risk for an atherothrombotic stroke or atheroembolic stroke. In some embodiments, the ischemia is selected from embolic stroke, thrombotic stroke, and transient ischemic attack. In some embodiments, the sample is blood. In some embodiments, the level of expression is determined by detecting hybridization of an ischemia-associated gene probe to a gene transcript of said biological sample. In some embodiments, the hybridization step is carried out on a nucleic acid array.
  • Another embodiment of the invention provides an ischemia reference expression profile, comprising a pattern of gene expression of a plurality of the genes set forth in Table 1, 2, 3, 4, 5, 6, or 7. In some embodiments, the ischemia reference expression profile, comprises a pattern of gene expression of a plurality of the genes set forth in Table 1. In some embodiments, at least about a 1.3 fold increase in expression of the following genes: LEPROT, PCGF3, PPP3R1, PVRL2, INSR, BIRC1, TSHZ3, DF, FBN2, IER3, NUMB, and LAK when compared to the normal control level, and at least about a 1.3 fold decrease in expression of the following genes: CD8B1 and RRAS2 when compared to the normal control level is a reference expression profile for cardioembolic stroke. In some embodiments, at least about a 1.3 fold decrease in expression of the following genes: C21orf7, DAB2, JAM3, ITGA2B, PPBP, SYNJ2, SLC25A37, ZNF185, C7orf41, and LAK when compared to the normal control level is a reference expression profile for atherothrombotic stroke or atheroembolic stroke.
  • Yet another embodiment of the invention provides methods of screening for a compound for treating or preventing ischemia. The methods comprise: a) contacting a candidate compound with a cell expressing one or more genes set forth in Table 1, 2, 3, 4, 5, 6, or 7; and b) selecting a compound that modulates the expression level of one or more genes set forth in Table 1, 2, 3, 4, 5, 6, or 7. In some embodiments a compound that decreases the expression of at least one gene selected from the group consisting of: LEPROT, PCGF3, PPP3R1, PVRL2, INSR, BIRC1, TSHZ3, DF, FBN2, IER3, NUMB, and LAK when compared to the normal control level, or increases the expression of at least one gene selected from the group consisting of: CD8B1 and RRAS2 relative to a control level is identified as a compound useful for treating or preventing ischemia, including, e.g., cardioembolic stroke. In some embodiments, a compound that increases the expression of at least one gene selected from the group consisting of: C21orf7, DAB2, JAM3, ITGA2B, PPBP, SYNJ2, SLC25A37, ZNF185, C7orf41, and LAK is identified as a compound useful for treating or preventing ischemia, including, e.g., atherothrombotic stroke or atheroembolic stroke.
  • A further embodiment of the invention provides an array comprising a plurality of polynucleotides which specifically bind (i.e., specifically hybridize) to a plurality of nucleic acid sequences set forth in Table 1, 2, 3, 4, 5, 6 or 7. In some embodiments, the invention provides an array comprising a plurality of polynucleotides which specifically bind (i.e., specifically hybridize) to a plurality of nucleic acid sequences set forth in Table 1.
  • Another embodiment of the invention provides a reaction mixture comprising a plurality of polynucleotides which specifically hybridize (e.g., primers) to a plurality of nucleic acid sequences set forth in Table 1, 2, 3, 4, 5, 6 or 7. In some embodiments, the invention provides a reaction mixture comprising a plurality of polynucleotides which specifically hybridize (e.g., primers) to a plurality of nucleic acid sequences set forth in Table 1. In some embodiments, the reaction mixture is a PCR mixture, for example, a multiplex PCR mixture.
  • These and other embodiments of the invention are further described by the detailed description that follows.
  • BRIEF DESCRIPTION OF THE TABLES
  • Table 1 sets forth a list of 23 genes differentially expressed in ischemia (e.g., cardioembolic stroke, artherothrombotic stroke, and transient ischemic attacks).
  • Table 2 sets forth a list of 77 genes differentially expressed in ischemia (e.g., cardioembolic stroke, artherothrombotic stroke, and transient ischemic attacks).
  • Table 3 sets forth a list of 95 genes differentially expressed in ischemia (e.g., cardioembolic stroke, artherothrombotic stroke, and transient ischemic attacks).
  • Table 4 sets forth a list of 133 genes differentially expressed in ischemia (e.g., cardioembolic stroke, artherothrombotic stroke, and transient ischemic attacks).
  • Table 5 sets forth a list of 259 genes differentially expressed in ischemia (e.g., cardioembolic stroke, artherothrombotic stroke, and transient ischemic attacks).
  • Table 6 sets forth a list of 466 genes differentially expressed in ischemia (e.g., cardioembolic stroke, artherothrombotic stroke, and transient ischemic attacks).
  • Table 7 sets forth a list of 706 genes differentially expressed in ischemia (e.g., cardioembolic stroke, artherothrombotic stroke, and transient ischemic attacks).
  • Table 8 sets forth relative expression levels of selected genes described in Example 1 as differentially expressed in atherothrombotic stroke relative to normal control subjects.
  • Table 9 sets forth relative expression levels of selected genes described in Example 1 as differentially expressed in cardioembolic stroke subjects relative to normal control subjects.
  • Table 10 sets forth the relative expression levels of genes listed in Table 1 in cardioembolic stroke subjects relative to normal control subjects; atheroembolic stroke subjects relative to normal control, and cardioembolic stroke subjects relative to atheroembolic stroke subjects.
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1 illustrates an expression heatmap of genes differentially regulated between cardioembolic and atherosclerotic stroke patients with at least a 1.5 fold change.
  • FIG. 2 illustrates etiology prediction of stroke samples with unknown etiology according to the expression pattern of 23 genes using PAM.
  • FIG. 3 illustrates a function comparison of cardioembolic stroke-specific genes versus atherosclerotic stroke-specific genes. Obvious duplication of function classes is omitted for clarity purposes.
  • FIG. 4a illustrates expression activities of atherosclerotic stroke-specific genes across subtypes of healthy blood cells.
  • FIG. 4b illustrates expression activities of cardioembolic stroke-specific genes across subtypes of healthy blood cells.
  • FIG. 5 illustrates etiology prediction of stroke samples from unknown etiologies by cluster analysis.
  • FIG. 6 illustrates a 10-fold cross validation result for known cardioembolic stroke samples with 23 genes in PAM.
  • FIG. 7 illustrates a 10-fold cross validation result for known atherosclerotic stroke samples with 23 genes in PAM.
  • DETAILED DESCRIPTION OF THE INVENTION I. Introduction
  • The present invention provides methods for the diagnosis of ischemia (e.g., stroke and transient ischemic attacks (“TIA”)).
  • The invention is based on identification of differential gene expression patterns in subjects with an ischemia (e.g., stroke and TIA). Detection of the expression patterns of a plurality of the genes set forth in Table 1, 2, 3, 4, 5, 6, or 7 leads to a definitive diagnosis of the type of ischemia that a subject has developed or is at risk for developing. Therefore, this invention provides the first direct method for determining the causes of ischemia (stroke and TIA).
  • The gene expression patterns described herein can conveniently be used to diagnose, monitor and prognose ischemia (e.g., stroke and TIA). For example, the gene expression patterns can be detected to definitively classify the type of ischemic event that a subject has developed or has a predisposition for developing. In some embodiments, the gene expression patterns can also be used as ischemic reference profiles. In other embodiments, the gene expression patterns can be used to identify compounds for treating or preventing ischemia.
  • II. Definitions
  • Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry and nucleic acid chemistry and hybridization described below are those well known and commonly employed in the art. Standard techniques are used for nucleic acid and peptide synthesis. Generally, enzymatic reactions and purification steps are performed according to the manufacturer's specifications. The techniques and procedures are generally performed according to conventional methods in the art and various general references (see generally, Sambrook et al. MOLECULAR CLONING: A LABORATORY MANUAL, 3rd ed. (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. and Ausubel, et al., CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, 1990-2008, Wiley Interscience), which are provided throughout this document. The nomenclature used herein and the laboratory procedures in analytical chemistry, and organic synthetic described below are those well known and commonly employed in the art. Standard techniques, or modifications thereof, are used for chemical syntheses and chemical analyses.
  • “Ischemia” or “ischemic event” as used herein refers to diseases and disorders characterized by inadequate blood supply (i.e., circulation) to a local area due to blockage of the blood vessels to the area. Ischemia includes for example, strokes and transient ischemic attacks. Strokes include, e.g., ischemic stroke (including, but not limited to, cardioembolic strokes, atheroembolic or atherothrombotic strokes, i.e., strokes caused by atherosclerosis in the carotid, aorta, heart, and brain, small vessel strokes (i.e., lacunar strokes), strokes caused by diseases of the vessel wall, i.e., vasculitis, strokes caused by infection, strokes caused by hematological disorders, strokes caused by migraines, and strokes caused by medications such as hormone therapy), hemorrhagic ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage.
  • “Ischemia reference expression profile” refers to the pattern of expression of a set of genes (e.g., a plurality of the genes set forth in Tables 1, 2, 3, 4, 5, 6 or 7) differentially expressed (i.e., overexpressed or underexpressed) in ischemia relative to a normal control. A gene from Tables 1, 2, 3, 4, 5, 6 or 7 that is expressed at a level that is at least about 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9 or 10 fold higher than the level in a normal control is a gene overexpressed in ischemia and a gene from Tables 1, 2, 3, 4, 5, 6 or 7 that is expressed at a level that is at least about 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9 or 10 fold lower than the level in a normal control is a gene underexpressed in ischemia. Alternately, genes that are expressed at a level that is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% higher than the level in a normal control is a gene overexpressed in ischemia and a gene that is expressed at a level that is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% lower than the level in a normal control is a gene underexpressed in ischemia.
  • A “plurality” refers to two or more, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or more (e.g., genes). In some embodiments, a plurality refers to 50, 96, 100, 150, 192, 200, 250, 384 or 500 genes. In some embodiments, “plurality” refers to all genes listed in one or more tables, e.g., all genes listed in Table 1, Table 2, Table 3, Table 4, Table 5, Table 6 and/or Table 7.
  • “Sample” or “biological sample” includes sections of tissues such as biopsy and autopsy samples, and frozen sections taken for histologic purposes. Such samples include blood, sputum, tissue, lysed cells, brain biopsy, cultured cells, e.g., primary cultures, explants, and transformed cells, stool, urine, etc. A biological sample is typically obtained from a eukaryotic organism, most preferably a mammal such as a primate, e.g., chimpanzee or human; cow; dog; cat; a rodent, e.g., guinea pig, rat, mouse; rabbit; or a bird; reptile; or fish.
  • “Array” as used herein refers to a solid support comprising attached nucleic acid or peptide probes. Arrays typically comprise a plurality of different nucleic acid or peptide probes that are coupled to a surface of a substrate in different, known locations. These arrays, also described as “microarrays” or colloquially “chips” have been generally described in the art, for example, U.S. Pat. Nos. 5,143,854, 5,445,934, 5,744,305, 5,677,195, 6,040,193, 5,424,186 and Fodor et al., Science, 251:767-777 (1991). These arrays may generally be produced using mechanical synthesis methods or light directed synthesis methods which incorporate a combination of photolithographic methods and solid phase synthesis methods. Techniques for the synthesis of these arrays using mechanical synthesis methods are described in, e.g., U.S. Pat. No. 5,384,261. Arrays may comprise a planar surface or may be nucleic acids or peptides on beads, gels, polymeric surfaces, fibers such as fiber optics, glass or any other appropriate substrate as described in, e.g., U.S. Pat. Nos. 5,770,358, 5,789,162, 5,708,153, 6,040,193 and 5,800,992. Arrays may be packaged in such a manner as to allow for diagnostics or other manipulation of an all inclusive device, as described in, e.g., U.S. Pat. Nos. 5,856,174 and 5,922,591.
  • The term “gene” means the segment of DNA involved in producing a polypeptide chain; it includes regions preceding and following the coding region (leader and trailer) as well as intervening sequences (introns) between individual coding segments (exons).
  • The terms “nucleic acid” and “polynucleotide” are used interchangeably herein to refer to deoxyribonucleotides or ribonucleotides and polymers thereof in either single- or double-stranded form. The term encompasses nucleic acids containing known nucleotide analogs or modified backbone residues or linkages, which are synthetic, naturally occurring, and non-naturally occurring, which have similar binding properties as the reference nucleic acid, and which are metabolized in a manner similar to the reference nucleotides. Examples of such analogs include, without limitation, phosphorothioates, phosphoramidates, methyl phosphonates, chiral-methyl phosphonates, 2-O-methyl ribonucleotides, peptide-nucleic acids (PNAs).
  • Unless otherwise indicated, a particular nucleic acid sequence also encompasses conservatively modified variants thereof (e.g., degenerate codon substitutions) and complementary sequences, as well as the sequence explicitly indicated. Specifically, degenerate codon substitutions may be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and/or deoxyinosine residues (Batzer et al., Nucleic Acid Res. 19:5081 (1991); Ohtsuka et al., J. Biol. Chem. 260:2605-2608 (1985); Rossolini et al., Mol. Cell. Probes 8:91-98 (1994)). The term nucleic acid is used interchangeably with gene, cDNA, mRNA, oligonucleotide, and polynucleotide.
  • The phrase “stringent hybridization conditions” refers to conditions under which a probe will hybridize to its target subsequence, typically in a complex mixture of nucleic acid, but to no other sequences. Stringent hybridization conditions are sequence-dependent and will be different in different circumstances. Longer sequences hybridize specifically at higher temperatures. An extensive guide to the hybridization of nucleic acids is found in Tijssen, Techniques in Biochemistry and Molecular Biology-Hybridization with Nucleic Probes, “Overview of principles of hybridization and the strategy of nucleic acid assays” (1993). Generally, stringent hybridization conditions are selected to be about 5-10° C. lower than the thermal melting point for the specific sequence at a defined ionic strength Ph. The Tm is the temperature (under defined ionic strength, Ph, and nucleic concentration) at which 50% of the probes complementary to the target hybridize to the target sequence at equilibrium (as the target sequences are present in excess, at Tm, 50% of the probes are occupied at equilibrium). Stringent hybridization conditions will be those in which the salt concentration is less than about 1.0 M sodium ion, typically about 0.01 to 1.0 M sodium ion concentration (or other salts) at Ph 7.0 to 8.3 and the temperature is at least about 30° C. for short probes (e.g., 10 to 50 nucleotides) and at least about 60° C. for long probes (e.g., greater than 50 nucleotides). Stringent hybridization conditions may also be achieved with the addition of destabilizing agents such as formamide. For selective or specific hybridization, a positive signal is at least two times background, optionally 10 times background hybridization. Exemplary stringent hybridization conditions can be as following: 50% formamide, 5×SSC, and 1% SDS, incubating at 42° C., or, 5×SSC, 1% SDS, incubating at 65° C., with wash in 0.2×SSC, and 0.1% SDS at 65° C.
  • Nucleic acids that do not hybridize to each other under stringent hybridization conditions are still substantially identical if the polypeptides which they encode are substantially identical. This occurs, for example, when a copy of a nucleic acid is created using the maximum codon degeneracy permitted by the genetic code. In such cases, the nucleic acids typically hybridize under moderately stringent hybridization conditions. Exemplary “moderately stringent hybridization conditions” include a hybridization in a buffer of 40% formamide, 1 M NaCl, 1% SDS at 37° C., and a wash in 1×SSC at 45° C. A positive hybridization is at least twice background. Those of ordinary skill will readily recognize that alternative hybridization and wash conditions can be utilized to provide conditions of similar stringency.
  • The terms “isolated,” “purified,” or “biologically pure” refer to material that is substantially or essentially free from components that normally accompany it as found in its native state. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. A protein that is the predominant species present in a preparation is substantially purified. The term “purified” denotes that a nucleic acid or protein gives rise to essentially one band in an electrophoretic gel. Particularly, it means that the nucleic acid or protein is at least 85% pure, more preferably at least 95% pure, and most preferably at least 99% pure.
  • The term “heterologous” when used with reference to portions of a nucleic acid indicates that the nucleic acid comprises two or more subsequences that are not found in the same relationship to each other in nature. For instance, the nucleic acid is typically recombinantly produced, having two or more sequences from unrelated genes arranged to make a new functional nucleic acid, e.g., a promoter from one source and a coding region from another source. Similarly, a heterologous protein indicates that the protein comprises two or more subsequences that are not found in the same relationship to each other in nature (e.g., a fusion protein).
  • An “expression vector” is a nucleic acid construct, generated recombinantly or synthetically, with a series of specified nucleic acid elements that permit transcription of a particular nucleic acid in a host cell. The expression vector can be part of a plasmid, virus, or nucleic acid fragment. Typically, the expression vector includes a nucleic acid to be transcribed operably linked to a promoter.
  • The terms “polypeptide,” “peptide” and “protein” are used interchangeably herein to refer to a polymer of amino acid residues. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymer.
  • The term “amino acid” refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, α-carboxyglutamate, and O-phosphoserine. “Amino acid analogs” refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an a carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. “Amino acid mimetics” refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid.
  • Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes.
  • “Conservatively modified variants” applies to both amino acid and nucleic acid sequences. With respect to particular nucleic acid sequences, conservatively modified variants refers to those nucleic acids which encode identical or essentially identical amino acid sequences, or where the nucleic acid does not encode an amino acid sequence, to essentially identical sequences. Because of the degeneracy of the genetic code, a large number of functionally identical nucleic acids encode any given protein. For instance, the codons GCA, GCC, GCG and GCU all encode the amino acid alanine. Thus, at every position where an alanine is specified by a codon, the codon can be altered to any of the corresponding codons described without altering the encoded polypeptide. Such nucleic acid variations are “silent variations,” which are one species of conservatively modified variations. Every nucleic acid sequence herein which encodes a polypeptide also describes every possible silent variation of the nucleic acid. One of skill will recognize that each codon in a nucleic acid (except AUG, which is ordinarily the only codon for methionine, and TGG, which is ordinarily the only codon for tryptophan) can be modified to yield a functionally identical molecule. Accordingly, each silent variation of a nucleic acid which encodes a polypeptide is implicit in each described sequence.
  • As to amino acid sequences, one of skill will recognize that individual substitutions, deletions or additions to a nucleic acid, peptide, polypeptide, or protein sequence which alters, adds or deletes a single amino acid or a small percentage of amino acids in the encoded sequence is a “conservatively modified variant” where the alteration results in the substitution of an amino acid with a chemically similar amino acid. Conservative substitution tables providing functionally similar amino acids are well known in the art. Such conservatively modified variants are in addition to and do not exclude polymorphic variants, interspecies homologs, and alleles of the invention.
  • The following eight groups each contain amino acids that are conservative substitutions for one another:
      • 1) Alanine (A), Glycine (G);
      • 2) Aspartic acid (D), Glutamic acid (E);
      • 3) Asparagine (N), Glutamine (Q);
      • 4) Arginine I, Lysine (K);
      • 5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V);
      • 6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W);
      • 7) Serine (S), Threonine (T); and
      • 8) Cysteine (C), Methionine (M)
      • (see, e.g., Creighton, Proteins (1984)).
  • The terms “identical” or percent “identity,” in the context of two or more nucleic acids or polypeptide sequences, refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same (i.e., 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, or 95% identity over a specified region of an ischemia-associated gene (e.g., a gene set forth in Table 1, 2, 3, 4, 5, 6, or 7), when compared and aligned for maximum correspondence over a comparison window, or designated region as measured using one of the following sequence comparison algorithms or by manual alignment and visual inspection. Such sequences are then said to be “substantially identical.” This definition also refers to the compliment of a test sequence. Preferably, the identity exists over a region that is at least about 25 amino acids or nucleotides in length, or more preferably over a region that is 50-100 amino acids or nucleotides in length.
  • For sequence comparison, typically one sequence acts as a reference sequence, to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are entered into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. Default program parameters can be used, or alternative parameters can be designated. The sequence comparison algorithm then calculates the percent sequence identities for the test sequences relative to the reference sequence, based on the program parameters. For sequence comparison of nucleic acids and proteins to ischemia-associated nucleic acids and proteins, the BLAST and BLAST 2.0 algorithms and the default parameters discussed below are used.
  • A “comparison window”, as used herein, includes reference to a segment of any one of the number of contiguous positions selected from the group consisting of from 20 to 600, usually about 50 to about 200, more usually about 100 to about 150 in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned. Methods of alignment of sequences for comparison are well-known in the art. Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith & Waterman, Adv. Appl. Math. 2:482 (1981), by the homology alignment algorithm of Needleman & Wunsch, J. Mol. Biol. 48:443 (1970), by the search for similarity method of Pearson & Lipman, Proc. Nat'l. Acad. Sci. USA 85:2444 (1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by manual alignment and visual inspection (see, e.g., Current Protocols in Molecular Biology (Ausubel et al., eds. 1995 supplement)).
  • A preferred example of algorithm that is suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al., Nuc. Acids Res. 25:3389-3402 (1977) and Altschul et al., J. Mol. Biol. 215:403-410 (1990), respectively. BLAST and BLAST 2.0 are used, with the parameters described herein, to determine percent sequence identity for the nucleic acids and proteins of the invention. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (http://www.ncbi.nlm.nih.gov/). This algorithm involves first identifying high scoring sequence pairs (HSPs) by identifying short words of length W in the query sequence, which either match or satisfy some positive-valued threshold score T when aligned with a word of the same length in a database sequence. T is referred to as the neighborhood word score threshold (Altschul et al., supra). These initial neighborhood word hits act as seeds for initiating searches to find longer HSPs containing them. The word hits are extended in both directions along each sequence for as far as the cumulative alignment score can be increased. Cumulative scores are calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always >0) and N (penalty score for mismatching residues; always <0). For amino acid sequences, a scoring matrix is used to calculate the cumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) uses as defaults a word length (W) of 11, an expectation (E) of 10, M=5, N=−4 and a comparison of both strands. For amino acid sequences, the BLASTP program uses as defaults a word length of 3, and expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff & Henikoff, Proc. Natl. Acad. Sci. USA 89:10915 (1989)) alignments (B) of 50, expectation (E) of 10, M=5, N=−4, and a comparison of both strands.
  • The BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, e.g., Karlin & Altschul, Proc. Nat'l. Acad. Sci. USA 90:5873-5787 (1993)). One measure of similarity provided by the BLAST algorithm is the smallest sum probability (P(N)), which provides an indication of the probability by which a match between two nucleotide or amino acid sequences would occur by chance. For example, a nucleic acid is considered similar to a reference sequence if the smallest sum probability in a comparison of the test nucleic acid to the reference nucleic acid is less than about 0.2, more preferably less than about 0.01, and most preferably less than about 0.001.
  • An indication that two nucleic acid sequences or polypeptides are substantially identical is that the polypeptide encoded by the first nucleic acid is immunologically cross reactive with the antibodies raised against the polypeptide encoded by the second nucleic acid, as described below. Thus, a polypeptide is typically substantially identical to a second polypeptide, for example, where the two peptides differ only by conservative substitutions. Another indication that two nucleic acid sequences are substantially identical is that the two molecules or their complements hybridize to each other under stringent conditions, as described below. Yet another indication that two nucleic acid sequences are substantially identical is that the same primers can be used to amplify the sequence.
  • The phrase “selectively (or specifically) hybridizes to” refers to the binding, duplexing, or hybridizing of a molecule only to a particular nucleotide sequence under stringent hybridization conditions when that sequence is present in a complex mixture (e.g., total cellular or library DNA or RNA).
  • By “host cell” is meant a cell that contains an expression vector and supports the replication or expression of the expression vector. Host cells may be, for example, prokaryotic cells such as E. coli or eukaryotic cells such as yeast cells or mammalian cells such as CHO cells.
  • “Inhibitors,” “activators,” and “modulators” of expression or of activity are used to refer to inhibitory, activating, or modulating molecules, respectively, identified using in vitro and in vivo assays for expression or activity, e.g., ligands, agonists, antagonists, and their homologs and mimetics. The term “modulator” includes inhibitors and activators. Inhibitors are agents that, e.g., inhibit expression of a polypeptide or polynucleotide of the invention or bind to, partially or totally block stimulation or enzymatic activity, decrease, prevent, delay activation, inactivate, desensitize, or down regulate the activity of a polypeptide or polynucleotide of the invention, e.g., antagonists. Activators are agents that, e.g., induce or activate the expression of a polypeptide or polynucleotide of the invention or bind to, stimulate, increase, open, activate, facilitate, enhance activation or enzymatic activity, sensitize or up regulate the activity of a polypeptide or polynucleotide of the invention, e.g., agonists. Modulators include naturally occurring and synthetic ligands, antagonists, agonists, small chemical molecules and the like. Assays to identify inhibitors and activators include, e.g., applying putative modulator compounds to cells, in the presence or absence of a polypeptide or polynucleotide of the invention and then determining the functional effects on a polypeptide or polynucleotide of the invention activity. Samples or assays comprising a polypeptide or polynucleotide of the invention that are treated with a potential activator, inhibitor, or modulator are compared to control samples without the inhibitor, activator, or modulator to examine the extent of effect. Control samples (untreated with modulators) are assigned a relative activity value of 100%. Inhibition is achieved when the activity value of a polypeptide or polynucleotide of the invention relative to the control is about 80%, optionally 50% or 25-1%. Activation is achieved when the activity value of a polypeptide or polynucleotide of the invention relative to the control is 110%, optionally 150%, optionally 200-500%, or 1000-3000% higher.
  • The term “test compound” or “drug candidate” or “modulator” or grammatical equivalents as used herein describes any molecule, either naturally occurring or synthetic, e.g., protein, oligopeptide (e.g., from about 5 to about 25 amino acids in length, preferably from about 10 to 20 or 12 to 18 amino acids in length, preferably 12, 15, or 18 amino acids in length), small organic molecule, polysaccharide, lipid, fatty acid, polynucleotide, RNAi, oligonucleotide, etc. The test compound can be in the form of a library of test compounds, such as a combinatorial or randomized library that provides a sufficient range of diversity. Test compounds are optionally linked to a fusion partner, e.g., targeting compounds, rescue compounds, dimerization compounds, stabilizing compounds, addressable compounds, and other functional moieties. Conventionally, new chemical entities with useful properties are generated by identifying a test compound (called a “lead compound”) with some desirable property or activity, e.g., inhibiting activity, creating variants of the lead compound, and evaluating the property and activity of those variant compounds. Often, high throughput screening (HTS) methods are employed for such an analysis.
  • A “small organic molecule” refers to an organic molecule, either naturally occurring or synthetic, that has a molecular weight of more than about 50 Daltons and less than about 2500 Daltons, preferably less than about 2000 Daltons, preferably between about 100 to about 1000 Daltons, more preferably between about 200 to about 500 Daltons.
  • III. Diagnosis of Ischemia
  • The invention provides methods for diagnosing ischemia (e.g., stroke or transient ischemic attacks) or a predisposition for developing ischemia by detecting the expression of a plurality of ischemia-associated genes in a sample (e.g., a blood sample) from a subject. In some embodiments of the invention, expression of a plurality of the genes set forth in Table 1, 2, 3, 4, 5, 6, or 7 is detected. In one preferred embodiment, expression of a plurality of the genes set forth in Table 1 is detected. In one embodiment, at least about a 1.3 fold increase in expression of the following genes: LEPROT, PCGF3, PPP3R1, PVRL2, INSR, BIRC1, TSHZ3, DF, FBN2, IER3, NUMB, and LAK when compared to the normal control level, and at least about a 1.3 fold decrease in expression of the following genes: CD8B1 and RRAS2 when compared to the normal control level indicates that the subject has experienced or is at risk for a cardioembolic stroke. In another embodiment, at least about a 1.3 fold decrease in expression of the following genes: C21orf7, DAB2, JAM3, ITGA2B, PPBP, SYNJ2, SLC25A37, ZNF185, C7orf41, and LAK when compared to the normal control level indicates that the subject has experienced or is at risk for an atherothrombotic stroke or atheroembolic stroke.
  • Gene expression may be measured using any method known in the art. One of skill in the art will appreciate that the means of measuring gene expression is not a critical aspect of the invention. A variety of methods of specific DNA and RNA measurement using nucleic acid hybridization techniques are known to those of skill in the art (see, Sambrook, supra and Ausubel, supra) and may be used to detect the expression of the genes set forth in Table 1, 2, 3, 4, 5, 6, or 7. Some methods involve an electrophoretic separation (e.g., Southern blot for detecting DNA, and Northern blot for detecting RNA), but measurement of DNA and RNA can also be carried out in the absence of electrophoretic separation (e.g., by dot blot). Southern blot of genomic DNA (e.g., from a human) can be used for screening for restriction fragment length polymorphism (RFLP) to detect the presence of a genetic disorder affecting a polypeptide of the invention.
  • The selection of a nucleic acid hybridization format is not critical. A variety of nucleic acid hybridization formats are known to those skilled in the art. For example, common formats include sandwich assays and competition or displacement assays. Hybridization techniques are generally described in Hames and Higgins Nucleic Acid Hybridization, A Practical Approach, IRL Press (1985); Gall and Pardue, Proc. Natl. Acad. Sci. U.S.A., 63:378-383 (1969); and John et al. Nature, 223:582-587 (1969).
  • Detection of a hybridization complex may require the binding of a signal-generating complex to a duplex of target and probe polynucleotides or nucleic acids. Typically, such binding occurs through ligand and anti-ligand interactions as between a ligand-conjugated probe and an anti-ligand conjugated with a signal. The binding of the signal generation complex is also readily amenable to accelerations by exposure to ultrasonic energy.
  • The label may also allow indirect detection of the hybridization complex. For example, where the label is a hapten or antigen, the sample can be detected by using antibodies. In these systems, a signal is generated by attaching fluorescent or enzyme molecules to the antibodies or in some cases, by attachment to a radioactive label (see, e.g., Tijssen, “Practice and Theory of Enzyme Immunoassays,” Laboratory Techniques in Biochemistry and Molecular Biology, Burdon and van Knippenberg Eds., Elsevier (1985), pp. 9-20).
  • The probes are typically labeled either directly, as with isotopes, chromophores, lumiphores, chromogens, or indirectly, such as with biotin, to which a streptavidin complex may later bind. Thus, the detectable labels used in the assays of the present invention can be primary labels (where the label comprises an element that is detected directly or that produces a directly detectable element) or secondary labels (where the detected label binds to a primary label, e.g., as is common in immunological labeling). Typically, labeled signal nucleic acids are used to detect hybridization. Complementary nucleic acids or signal nucleic acids may be labeled by any one of several methods typically used to detect the presence of hybridized polynucleotides. The most common method of detection is the use of autoradiography with 3H, 125I, 35S, 14C. or 32P-labeled probes or the like.
  • Other labels include, e.g., ligands that bind to labeled antibodies, fluorophores, chemiluminescent agents, enzymes, and antibodies which can serve as specific binding pair members for a labeled ligand. An introduction to labels, labeling procedures and detection of labels is found in Polak and Van Noorden Introduction to Immunocytochemistry, 2nd ed., Springer Verlag, NY (1997); and in Haugland Handbook of Fluorescent Probes and Research Chemicals, a combined handbook and catalogue Published by Molecular Probes, Inc. (1996).
  • In general, a detector which monitors a particular probe or probe combination is used to detect the detection reagent label. Typical detectors include spectrophotometers, phototubes and photodiodes, microscopes, scintillation counters, cameras, film and the like, as well as combinations thereof. Examples of suitable detectors are widely available from a variety of commercial sources known to persons of skill in the art. Commonly, an optical image of a substrate comprising bound labeling moieties is digitized for subsequent computer analysis.
  • Most typically, the amount of RNA is measured by quantifying the amount of label fixed to the solid support by binding of the detection reagent. Typically, the presence of a modulator during incubation will increase or decrease the amount of label fixed to the solid support relative to a control incubation which does not comprise the modulator, or as compared to a baseline established for a particular reaction type. Means of detecting and quantifying labels are well known to those of skill in the art.
  • In preferred embodiments, the target nucleic acid or the probe is immobilized on a solid support. Solid supports suitable for use in the assays of the invention are known to those of skill in the art. As used herein, a solid support is a matrix of material in a substantially fixed arrangement.
  • For example, in one embodiment of the invention, microarrays are used to detect the pattern of gene expression. Microarrays provide one method for the simultaneous measurement of the expression levels of large numbers of genes. Each array consists of a reproducible pattern of a plurality of nucleic acids (e.g., a plurality of nucleic acids that hybridize to a plurality of the genes set forth in Table 1, 2, 3, 4, 5, 6, or 7) attached to a solid support. In one embodiment, the array contains a plurality of nucleic acids that hybridize to a plurality of the genes listed in Table 1. Labeled RNA or DNA is hybridized to complementary probes on the array and then detected by laser scanning. Hybridization intensities for each probe on the array are determined and converted to a quantitative read-out of relative gene expression levels in ischemia (e.g., stroke or transient ischemic attacks).
  • In some embodiments, a sample is obtained from a subject, total mRNA is isolated from the sample and is converted to labeled cRNA and then hybridized to an array. Relative transcript levels are calculated by reference to appropriate controls present on the array and in the sample. See Mahadevappa and Warrington, Nat. Biotechnol. 17, 1134-1136 (1999).
  • A variety of automated solid-phase assay techniques are also appropriate. For instance, very large scale immobilized polymer arrays (VLSIPS™), available from Affymetrix, Inc. (Santa Clara, Calif.) can be used to detect changes in expression levels of a plurality of genes involved in the same regulatory pathways simultaneously. See, Tijssen, supra, Fodor et al. (1991) Science, 251: 767-777; Sheldon et al. (1993) Clinical Chemistry 39(4): 718-719, and Kozal et al. (1996) Nature Medicine 2(7): 753-759.
  • Detection can be accomplished, for example, by using a labeled detection moiety that binds specifically to duplex nucleic acids (e.g., an antibody that is specific for RNA-DNA duplexes). One preferred example uses an antibody that recognizes DNA-RNA heteroduplexes in which the antibody is linked to an enzyme (typically by recombinant or covalent chemical bonding). The antibody is detected when the enzyme reacts with its substrate, producing a detectable product. Coutlee et al. (1989) Analytical Biochemistry 181:153-162; Bogulavski (1986) et al. J. Immunol. Methods 89:123-130; Prooijen-Knegt (1982) Exp. Cell Res. 141:397-407; Rudkin (1976) Nature 265:472-473, Stollar (1970) Proc. Nat'l Acad. Sci. USA 65:993-1000; Ballard (1982) Mol. Immunol. 19:793-799; Pisetsky and Caster (1982) Mol. Immunol. 19:645-650; Viscidi et al. (1988) J. Clin. Microbial. 41:199-209; and Kiney et al. (1989) J. Clin. Microbiol. 27:6-12 describe antibodies to RNA duplexes, including homo and heteroduplexes. Kits comprising antibodies specific for DNA:RNA hybrids are available, e.g., from Digene Diagnostics, Inc. (Beltsville, Md.).
  • In addition to available antibodies, one of skill in the art can easily make antibodies specific for nucleic acid duplexes using existing techniques, or modify those antibodies that are commercially or publicly available. In addition to the art referenced above, general methods for producing polyclonal and monoclonal antibodies are known to those of skill in the art (see, e.g., Paul (3rd ed.) Fundamental Immunology Raven Press, Ltd., NY (1993); Coligan, et al., Current Protocols in Immunology, Wiley Interscience (1991-2008); Harlow and Lane, Antibodies: A Laboratory Manual Cold Spring Harbor Press, NY (1988); Harlow and Lane, Using Antibodies, Cold Spring Harbor Press, NY (1999); Stites et al. (eds.) Basic and Clinical Immunology (4th ed.) Lange Medical Publications, Los Altos, Calif., and references cited therein; Goding Monoclonal Antibodies: Principles and Practice (2d ed.) Academic Press, New York, N.Y., (1986); and Kohler and Milstein Nature 256: 495-497 (1975)). Other suitable techniques for antibody preparation include selection of libraries of recombinant antibodies in phage or similar vectors (see, Huse et al. Science 246:1275-1281 (1989); and Ward et al. Nature 341:544-546 (1989)). Specific monoclonal and polyclonal antibodies and antisera will usually bind with a KD of at least about 0.1 μM, preferably at least about 0.01 μM or better, and most typically and preferably, 0.001 μM or better.
  • The nucleic acids used in this invention can be either positive or negative probes. Positive probes bind to their targets and the presence of duplex formation is evidence of the presence of the target. Negative probes fail to bind to the suspect target and the absence of duplex formation is evidence of the presence of the target. For example, the use of a wild type specific nucleic acid probe or PCR primers may serve as a negative probe in an assay sample where only the nucleotide sequence of interest is present.
  • The sensitivity of the hybridization assays may be enhanced through use of a nucleic acid amplification system that multiplies the target nucleic acid being detected. Examples of such systems include the polymerase chain reaction (PCR) system, in particular RT-PCR or real time PCR, and the ligase chain reaction (LCR) system. Other methods recently described in the art are the nucleic acid sequence based amplification (NASBA, Cangene, Mississauga, Ontario) and Q Beta Replicase systems. These systems can be used to directly identify mutants where the PCR or LCR primers are designed to be extended or ligated only when a selected sequence is present. Alternatively, the selected sequences can be generally amplified using, for example, nonspecific PCR primers and the amplified target region later probed for a specific sequence indicative of a mutation.
  • An alternative means for determining the level of expression of the nucleic acids of the present invention is in situ hybridization. In situ hybridization assays are well known and are generally described in Angerer et al., Methods Enzymol. 152:649-660 (1987). In an in situ hybridization assay, cells, preferentially human cells from the cerebellum or the hippocampus, are fixed to a solid support, typically a glass slide. If DNA is to be probed, the cells are denatured with heat or alkali. The cells are then contacted with a hybridization solution at a moderate temperature to permit annealing of specific probes that are labeled. The probes are preferably labeled with radioisotopes or fluorescent reporters.
  • In one embodiment of the invention, microarrays are used to detect the pattern of gene expression. Microarrays provide one method for the simultaneous measurement of the expression levels of large numbers of genes. Each array consists of a reproducible pattern of a plurality of nucleic acids (e.g., a plurality of nucleic acids that hybridize to a plurality of the genes set forth in Table 1, 2, 3, 4, 5, 6 or 7) attached to a solid support. In one embodiment, the array contains a plurality of nucleic acids that hybridize to a plurality of the genes listed in Table 1. Labeled RNA or DNA is hybridized to complementary probes on the array and then detected by laser scanning. Hybridization intensities for each probe on the array are determined and converted to a quantitative read-out of relative gene expression levels in ischemia (e.g., stroke or transient ischemic attacks)
  • In some embodiments, a sample is obtained from a subject, total mRNA is isolated from the sample and is converted to labeled cRNA and then hybridized to an array. Relative transcript levels are calculated by reference to appropriate controls present on the array and in the sample. See Mahadevappa and Warrington, Nat. Biotechnol. 17, 1134-1136 (1999).
  • In other embodiments, quantitative RT-PCR is used to detect the expression of a plurality of the genes set forth in Tables 1, 2, 3, 4, 5, 6 or 7. In one embodiment, quantitative RT-PCR is used to detect a plurality of the genes listed in Table 1. A general overview of the applicable technology can be found, for example, in A-Z of Quantitative PCR, Bustin, ed., 2004, International University Line; Quantitative PCR Protocols, Kochanowski and Reischl, eds., 1999, Humana Press; Clinical Applications of PCR, Lo, ed., 2006, Humana Press; PCR Protocols: A Guide to Methods and Applications (Innis et al. eds. (1990)) and PCR Technology: Principles and Applications for DNA Amplification (Erlich, ed. (1992)). In addition, amplification technology is described in U.S. Pat. Nos. 4,683,195 and 4,683,202. Methods for multiplex PCR, known in the art, are applicable to the present invention.
  • Accordingly, in one embodiment of the invention provides a reaction mixture comprising a plurality of polynucleotides which specifically hybridize (e.g., primers) to a plurality of nucleic acid sequences of the genes set forth in Table 1, 2, 3, 4, 5, 6 or 7. In some embodiments, the invention provides a reaction mixture comprising a plurality of polynucleotides which specifically hybridize (e.g., primers) to a plurality of nucleic acid sequences of the genes set forth in Table 1. In some embodiments, the reaction mixture is a PCR mixture, for example, a multiplex PCR mixture.
  • This invention relies on routine techniques in the field of recombinant genetics. Generally, the nomenclature and the laboratory procedures in recombinant DNA technology described below are those well known and commonly employed in the art. Standard techniques are used for cloning, DNA and RNA isolation, amplification and purification. Generally enzymatic reactions involving DNA ligase, DNA polymerase, restriction endonucleases and the like are performed according to the manufacturer's specifications. Basic texts disclosing the general methods of use in this invention include Sambrook et al., Molecular Cloning, A Laboratory Manual (3rd ed. 2001); Kriegler, Gene Transfer and Expression: A Laboratory Manual (1990); and Current Protocols in Molecular Biology (Ausubel et al., eds., 1994-2008, Wiley Interscience)).
  • For nucleic acids, sizes are given in either kilobases (kb) or base pairs (bp). These are estimates derived from agarose or acrylamide gel electrophoresis, from sequenced nucleic acids, or from published DNA sequences. For proteins, sizes are given in kilodaltons (kDa) or amino acid residue numbers. Proteins sizes are estimated from gel electrophoresis, from sequenced proteins, from derived amino acid sequences, or from published protein sequences.
  • Oligonucleotides that are not commercially available can be chemically synthesized according to the solid phase phosphoramidite triester method first described by Beaucage & Caruthers, Tetrahedron Letts. 22:1859-1862 (1981), using an automated synthesizer, as described in Van Devanter et. al., Nucleic Acids Res. 12:6159-6168 (1984). Purification of oligonucleotides is by either native acrylamide gel electrophoresis or by anion-exchange HPLC as described in Pearson & Reanier, J. Chrom. 255:137-149 (1983).
  • IV. Ischemia Reference Profiles
  • The invention also provides ischemia reference profiles. The reference profiles comprise information correlating the expression levels of a plurality of ischemia-associated genes (i.e., a plurality of the genes set forth in Table 1, 2, 3, 4, 5, 6, or 7) to particular types of ischemia. In one embodiment, the ischemia reference profile correlates the expression levels of a plurality of the genes listed in Table 1 to particular types of ischemia. The profiles can conveniently be used to diagnose, monitor and prognose ischemia.
  • One embodiment of the invention provides an ischemia reference profile for subjects who have experienced or are at risk for experiencing cardioembolic stroke. Accordingly, the ischemia reference profile correlates the expression levels of a plurality of the genes selected from LEPROT, PCGF3, PPP3R1, PVRL2, INSR, BIRC1, TSHZ3, DF, FBN2, IER3, NUMB, LAK, CD8B1 and RRAS2. For example, an expression profile exhibiting at least about a 1.3 fold increase in expression of the following genes: LEPROT, PCGF3, PPP3R1, PVRL2, INSR, BIRC1, TSHZ3, DF, FBN2, IER3, NUMB, and LAK when compared to the normal control level, and at least about a 1.3 fold decrease in expression of the following genes: CD8B1 and RRAS2 when compared to the normal control level is a reference profile for a subject who has experienced or is at risk for a cardioembolic stroke.
  • One embodiment of the invention provides an ischemia reference profile for subjects who have experienced or are at risk for experiencing atherothrombotic stroke. Accordingly, the ischemia reference profile correlates the expression levels of a plurality of the genes selected from C21orf7, DAB2, JAM3, ITGA2B, PPBP, SYNJ2, SLC25A37, ZNF185, C7orf41, and LAK. An expression profile exhibiting at least about a 1.3 fold decrease in expression of the following genes: C21orf7, DAB2, JAM3, ITGA2B, PPBP, SYNJ2, SLC25A37, ZNF185, C7orf41, and LAK when compared to the normal control level is a reference profile for a subject who has experienced or is at risk for an atherothrombotic stroke.
  • The reference profiles can be entered into a database, e.g., a relational database comprising data fitted into predefined categories. Each table, or relation, contains one or more data categories in columns. Each row contains a unique instance of data for the categories defined by the columns. For example, a typical database for the invention would include a table that describes a sample with columns for age, gender, reproductive status, expression profile and so forth. Another table would describe a disease: symptoms, level, sample identification, expression profile and so forth. In one embodiment, the invention matches the experimental sample to a database of reference samples. The database is assembled with a plurality of different samples to be used as reference samples. An individual reference sample in one embodiment will be obtained from a patient during a visit to a medical professional. Information about the physiological, disease and/or pharmacological status of the sample will also be obtained through any method available. This may include, but is not limited to, expression profile analysis, clinical analysis, medical history and/or patient interview. For example, the patient could be interviewed to determine age, sex, ethnic origin, symptoms or past diagnosis of disease, and the identity of any therapies the patient is currently undergoing. A plurality of these reference samples will be taken. A single individual may contribute a single reference sample or more than one sample over time. One skilled in the art will recognize that confidence levels in predictions based on comparison to a database increase as the number of reference samples in the database increases.
  • The database is organized into groups of reference samples. Each reference sample contains information about physiological, pharmacological and/or disease status. In one aspect the database is a relational database with data organized in three data tables, one where the samples are grouped primarily by physiological status, one where the samples are grouped primarily by disease status and one where the samples are grouped primarily by pharmacological status. Within each table the samples can be further grouped according to the two remaining categories. For example the physiological status table could be further categorized according to disease and pharmacological status.
  • As will be appreciated by one of skill in the art, the present invention may be embodied as a method, data processing system or program products. Accordingly, the present invention may take the form of data analysis systems, methods, analysis software, etc. Software written according to the present invention is to be stored in some form of computer readable medium, such as memory, hard-drive, DVD ROM or CD ROM, or transmitted over a network, and executed by a processor. The present invention also provides a computer system for analyzing physiological states, levels of disease states and/or therapeutic efficacy. The computer system comprises a processor, and memory coupled to said processor which encodes one or more programs. The programs encoded in memory cause the processor to perform the steps of the above methods wherein the expression profiles and information about physiological, pharmacological and disease states are received by the computer system as input. Computer systems may be used to execute the software of an embodiment of the invention (see, e.g., U.S. Pat. No. 5,733,729).
  • V. Methods of Identifying Compounds for Treating or Preventing Ischemia
  • The invention also provides methods of identifying compounds for treating or preventing ischemia. Compounds for treating or preventing ischemia can be readily identified according to methods well known to those of skill in the art.
  • A number of different screening protocols can be utilized to identify agents that modulate the level of activity or expression of ischemia-associated genes (i.e., agents that decrease the activity or expression of genes overexpressed in ischemia and increase the activity or expression of genes underexpressed in ischemia).
  • Preliminary screens can be conducted by screening for agents that modulate expression of ischemia-associated genes. The screening methods of the invention can be performed as in vitro or cell-based assays. Cell based assays can be performed in any cells which express one or more ischemia-associated genes. One of skill in the art will appreciate that ischemia-associated genes can be expressed in cells that do not contain endogenous ischemia-associated genes. Cell-based assays may involve whole cells or cell fractions to screen for agent binding or modulation of ischemia-associated genes Suitable cell-based assays are described in, e.g., DePaola et al., Annals of Biomedical Engineering 29: 1-9 (2001).
  • In vivo assays can also be used to identify agents that can be used to treat or prevent ischemia. The basic format of such methods involves administering a lead compound identified during an initial screen to an animal that serves as a model for ischemia and then determining if in fact the ischemia is ameliorated. The animal models utilized in validation studies generally are mammals of any kind. Specific examples of suitable animals include, but are not limited to, primates (e.g., chimpanzees, monkeys, and the like) and rodents (e.g., mice, rats, guinea pigs, rabbits, and the like).
  • The agents tested as potential modulators of ischemia-associated gene expression can be any small chemical compound, or a biological entity, such as a polypeptide, sugar, nucleic acid or lipid. Essentially any chemical compound can be used as a potential modulator in the assays of the invention, although most often compounds that can be dissolved in aqueous or organic (especially DMSO-based) solutions are used. The assays are designed to screen large chemical libraries by automating the assay steps and providing compounds from any convenient source to assays, which are typically run in parallel (e.g., in microtiter formats on microtiter plates in robotic assays).
  • In one embodiment, high throughput screening methods involve providing a combinatorial chemical or peptide library containing a large number of potential therapeutic compounds (potential modulator or ligand compounds). Such “combinatorial chemical libraries” or “ligand libraries” are then screened in one or more assays, as described herein, to identify those library members (particular chemical species or subclasses) that display a desired characteristic activity. The compounds thus identified can serve as conventional “lead compounds” or can themselves be used as potential or actual therapeutics.
  • A combinatorial chemical library is a collection of diverse chemical compounds generated by either chemical synthesis or biological synthesis, by combining a number of chemical “building blocks” such as reagents. For example, a linear combinatorial chemical library such as a polypeptide library is formed by combining a set of chemical building blocks (amino acids) in every possible way for a given compound length (i.e., the number of amino acids in a polypeptide compound). Millions of chemical compounds can be synthesized through such combinatorial mixing of chemical building blocks.
  • Preparation and screening of combinatorial chemical libraries is well known to those of skill in the art. Such combinatorial chemical libraries include, but are not limited to, peptide libraries (see, e.g., U.S. Pat. No. 5,010,175, Furka, Int. J. Pept. Prot. Res. 37:487-493 (1991) and Houghton et al., Nature 354:84-88 (1991)). Other chemistries for generating chemical diversity libraries can also be used. Such chemistries include, but are not limited to: peptoids (e.g., PCT Publication No. WO 91/19735), encoded peptides (e.g., PCT Publication WO 93/20242), random bio-oligomers (e.g., PCT Publication No. WO 92/00091), benzodiazepines (e.g., U.S. Pat. No. 5,288,514), diversomers such as hydantoins, benzodiazepines and dipeptides (Hobbs et al., Proc. Nat. Acad. Sci. USA 90:6909-6913 (1993)), vinylogous polypeptides (Hagihara et al., J. Amer. Chem. Soc. 114:6568 (1992)), nonpeptidal peptidomimetics with glucose scaffolding (Hirschmann et al., J. Amer. Chem. Soc. 114:9217-9218 (1992)), analogous organic syntheses of small compound libraries (Chen et al., J. Amer. Chem. Soc. 116:2661 (1994)), oligocarbamates (Cho et al., Science 261:1303 (1993)), and/or peptidyl phosphonates (Campbell et al., J. Org. Chem. 59:658 (1994)), nucleic acid libraries (see Ausubel, Berger and Sambrook, all supra), peptide nucleic acid libraries (see, e.g., U.S. Pat. No. 5,539,083), antibody libraries (see, e.g., Vaughn et al., Nature Biotechnology, 14(3):309-314 (1996) and PCT/US96/10287), carbohydrate libraries (see, e.g., Liang et al., Science, 274:1520-1522 (1996) and U.S. Pat. No. 5,593,853), small organic molecule libraries (see, e.g., benzodiazepines, Baum C&EN, January 18, page 33 (1993); isoprenoids, U.S. Pat. No. 5,569,588; thiazolidinones and metathiazanones, U.S. Pat. No. 5,549,974; pyrrolidines, U.S. Pat. Nos. 5,525,735 and 5,519,134; morpholino compounds, U.S. Pat. No. 5,506,337; benzodiazepines, U.S. Pat. No. 5,288,514, and the like).
  • Devices for the preparation of combinatorial libraries are commercially available (see, e.g., ECIS™, Applied BioPhysics Inc., Troy, N.Y., MPS, 390 MPS, Advanced Chem Tech, Louisville Ky., Symphony, Rainin, Woburn, Mass., 433A Applied Biosystems, Foster City, Calif., 9050 Plus, Millipore, Bedford, Mass.). In addition, numerous combinatorial libraries are themselves commercially available (see, e.g., ComGenex, Princeton, N.J., Tripos, Inc., St. Louis, Mo., 3D Pharmaceuticals, Exton, Pa., Martek Biosciences, Columbia, Md., etc.).
  • VI. Kits
  • The invention also provides kits for diagnosing ischemia or a predisposition for developing ischemia. For example, the invention provides kits that include one or more reaction vessels that have aliquots of some or all of the reaction components of the invention in them. Aliquots can be in liquid or dried form. Reaction vessels can include sample processing cartridges or other vessels that allow for the containment, processing and/or amplification of samples in the same vessel. The kits may comprise a plurality of nucleic acid probes that hybridize to a plurality the genes set forth in Table 1, 2, 3, 4, 5, 6, or 7. In one embodiment, the kits comprise a plurality of nucleic acid probes that hybridize to a plurality of the genes set forth in Table 1. The probes may be immobilized on an array as described herein. In addition, the kit can comprise appropriate buffers, salts and other reagents to facilitate amplification and/or detection reactions (e.g., primers) for determining the expression levels of a plurality of the genes set forth in Table 1, 2, 3, 4, 5, 6, or 7. In one embodiment, the kit comprises appropriate buffers, salts and other reagents to facilitate amplification and/or detection reactions (e.g., primers) for determining the expression levels of a plurality of the genes set forth in Table 1. The kits can also include written instructions for the use of the kit.
  • EXAMPLES
  • The following examples are offered to illustrate, but not to limit the claimed invention.
  • Materials and Methods Human Subjects:
  • Acute ischemic stroke patients (n=45 samples from 15 patients) were enrolled in the CLEAR trial. The Institutional Review Boards at the participating institutions approved the study protocols and consent forms. Stroke patients were diagnosed clinically and computed tomography brain scans performed to exclude hemorrhage. Following informed consent, patients were randomized to receive either standard-dose r-tPA (Activase) or a combination of eptifibatide and low-dose r-tPA (Activase) in a 1:3 ratio in a double-blinded manner within 3 hr of the onset of stroke. Blood (15 ml) was drawn from each patient into PAXgene tubes before the treatment (“<3 hr samples”), approximately 2 hours after the thrombolysis treatment (“5 hr samples”) and 24 hours after the stroke onset (“24 hr samples”), respectively. A total of 45 blood samples were collected from the subjects with stroke. For additional information see ClinicalTrials.gov under identifier NCT00250991.
  • The etiology of the strokes was assessed using the TOAST criteria (Adams et al. Stroke (1993) 24:35-41) and classified as: Atherosclerotic stroke, Cardioembolic stroke and Stroke with undetermined etiology. Patients with small artery lacunar stroke were generally excluded from the CLEAR trial because of the study design, and none of the patients reported here had lacunar stroke.
  • Control peripheral blood samples were drawn from 8 healthy volunteers (n=16 samples). Each volunteer contributed two independent blood samples one day apart. Healthy controls had no history of cardiovascular or cerebral vascular disease, recent infection or hematological disease.
  • Sample Processing
  • Whole blood (15 ml) was collected into 6 PAXgene vacutainers (PreAnalytiX, Hilden, Germany) via antecubital fossa venipuncture from each subject. PAXgene tubes were frozen at −80° C. after 2 hr at room temperature. Total RNA was isolated (PAXgene blood RNA kit, PreAnalytiX, Germany) according to the manufacturer's protocol. The RNA is from PMNs (Neutrophils, basophils and eosinophils), mononuclear cells (PBMC-lymphocytes, macrophage/monocytes), platelets and red blood cell precursors.
  • Microarray Hybridization and RT-PCR
  • RNA samples were labeled, hybridized and scanned according to standard Affymetrix Protocols (Affymetrix Expression Analysis Technical Manual). 10 μg total RNA was labeled using the One-Cycle Target Labeling protocol. Affymetrix Human U133 Plus 2 arrays that contain more that 54,000 probe sets were used for each RNA sample. The RNA samples are also subject to RT-PCR.
  • Microarray Data Analysis
  • Probe-level data was saved in Affymetrix.cel files and summarized with Robust Multi-array Average (RMA) software (on the worldwide web at bioconductor.org/). Statistical analyses including a one-way analysis of variance (ANOVA) for cardioembolic stroke, atherosclerotic stroke, Stroke of undetermined etiology and controls) were performed using Genespring software (Silicon Genetics, Redwood City, Calif.). The Benjamini-Hochberg false discovery rate (FDR) was used to control for multiple comparisons with a 5% FDR (<0.05) being considered significant. Different fold change filters were applied to minimize type-two error. Direct comparison between cardioembolic stroke and atherosclerotic stroke was also performed (Student's t-test) to compare with the ANOVA analysis. Demographic data were analyzed with the Student T test or Fisher's exact test. The methods have been described in detail in our previous studies. See, e.g., Tang et al., Brain Res Mol Brain Res (2004) 132:155-167; Tang et al., Ann Neurol (2004) 56:808-814; and Tang et al., J Cereb Blood Flow Metab (2006) 26(8):1089-102.
  • Example 1 Identification of Genes Differentially Expressed in Cardioembolic Strokes and Atherothrombotic Strokes Demographic Data for Cardioembolic and Atherosclerotic Stroke Patients
  • There were no significant age, gender or race differences and no differences in history of hypercholesterolemia or hypertension between the groups. Many of the cardioembolic stroke patients had a history of heart disease while none of the atherosclerotic stroke patients did (p=0.06).
  • Differential Expression Profiles of Cardioembolic Stroke and Atherosclerotic Stroke
  • The one-way ANOVA (FDR<0.05, Student-Newman-Keuls post hoc test, equal variance) yielded 660 genes that were differentially regulated for cardioembolic vs. atherosclerotic stroke. The Student t-test (p<0.001) yielded 135 genes that were differentially regulated for cardioembolic stroke vs atherosclerotic stroke. Of these 135 genes identified using the t-test, 95 of these were also identified using the one-way ANOVA. Using a 1.5 fold change filter, a total of 77 genes were significantly regulated between cardioembolic stroke and atherosclerotic stroke (significant using ANOVA or T-test; fold change>1.5). A Pearson cluster analysis using these 77 genes showed clear segregation of samples from controls and samples from subjects with cardioembolic stroke compared with subjects with atherosclerotic stroke at each of the times following stroke (FIG. 1). This also held true whether cluster analysis was performed using the 660 genes from the ANOVA analysis or the 135 genes from the t-test.
  • We next examined possible confounding factors on the identified etiology-related genes. Of the 54 genes identified as race-related (white/black, t-test. FDR<0.05, fold change>1.5), none are among the 77 etiology-related genes. Of the 424 genes identified as being regulated by aspirin in patients on aspirin prior to the stroke, only 5 were among the 77 etiology-related genes (6.5%) (Tang et al., Med Hypotheses (2006) 67:462-466).
  • Etiology Prediction of Undetermined Patients
  • Prediction Analysis of Microarrays (PAM) was used to determine the minimum number of genes that differentiate cardioembolic from atherosclerotic stroke. PAM employs shrunken nearest centroids to find the most reliable genes that differentiate two or more classes. (Tang et al., 2006, supra; Tibshirani et al., 2002, Proc Natl Acad Sci USA 99:6567-6572) PAM identified a minimum of 23 genes that best differentiated cardioembolic from atherosclerotic stroke. A 10 fold cross validation with a leave-one-out approach showed that these 23 genes correctly classified 32 of 33 samples from subjects with known causes of stroke (Table 1).
  • With regard to healthy controls, the 23 genes can be classified into 3 subgroups, using a 1.3 fold change in expression as a significant change. LEPROT, PCGF3, PPP3R1, PVRL2, INSR, BIRC1, TSHZ3, DF, FBN2, IER3, NUMB, and LAK exhibit at least a 1.3 fold increase in expression in subjects with cardioembolic stroke versus control subjects and RRAS2 and CD8B1 exhibit at least a 1.3 fold decrease in expression in subjects with cardioembolic stroke versus control subjects. C21orf7, DAB2, JAM3, ITGA2B, PPBP, SYNJ2, SLC25A37, ZNF185, C7orf41, and LAK exhibit at least 1.3 fold decrease in expression in subjects with atherothrombotic stroke versus control subjects.
  • Thus, by examining the expression level of 23 genes, we can achieve 95.2% sensitivity and 100% specificity for the diagnosis of cardioembolic stroke, 100% sensitivity and 95.2% specificity for atherothrombotic stroke, respectively. Thus, only a short list of genes needs to be screened for a single patient and this can be done simultaneously on a single real time PCR panel. The power of this list of genes was shown by predicting the cause of stroke in six additional patients with an unknown cause of stroke. All six of these six patients were diagnosed as having cardioembolic stroke, which would mean that they should be treated with Coumadin rather than other types of therapy to prevent future strokes.
  • By examining the blood gene expression of as few as 23 genes, we are able to differentiate cardioembolic stroke from atherothrombotic stroke in an objective manner as early as three hours after onset of stroke. As noted, the gene expression profiles disclosed herein can be used to determine the cause of the stroke or TIA in those patients who have an unknown etiology.
  • PAM and the minimum set of 23 genes were used to predict the etiology of the subjects whose cause of stroke could not be determined based upon clinical TOAST criteria. PAM classified all 12 of the unknown samples as being cardioembolic stroke with probabilities over 90% (92.9-99.9%, FIG. 2).
  • Function Analysis of Atherosclerotic and Cardioembolism Regulated Genes
  • The differentially regulated genes between cardioembolic stroke and atherosclerotic stroke were then classified by cluster analysis. Two subgroups of genes were identified: one is mainly regulated in cardioembolic stroke relative to healthy control (281 genes at 1.2 fold filter or 148 genes at 1.3 fold filter), the other is mainly regulated in atherosclerotic stroke relative to healthy control (84 genes at 1.2 fold filter or 63 genes at 1.3 fold filter). The functions of the two etiology-specific gene lists were then explored in the Nextbio System (Cupertino, Calif., USA), a web-based data search and analysis engine. The genes were ranked according to fold change and then queried against GO, KEGG pathways and REACTOME databases in Nextbio with p value 0.05 cut off. This analysis found that the genes regulated by cardioembolic stroke were mainly involved in response to pathogens, including immune cell activation, defense response, proliferation and apoptosis. In contrast, the genes mainly regulated by atherosclerotic stroke were related to hemostasis, cytokines and chemokines (FIG. 3). For many of the functional pathways represented, there is little overlap between the pathways related to atherosclerotic versus cardioembolic stroke.
  • Comparison of all the high throughput studies deposited in the Nextbio system (currently 6000 studies) to our study showed that atherosclerotic-specific expression profiles shared the most genes with Crohn's disease (28 genes in common)(GEO Series GSE3365), (Burczynski et al., J Mol Diagn (2006) 8:51-61) ulcerative colitis (14 genes in common) (GEO Series GSE3365), (Burczynski et al., 2006, supra) and rheumatoid arthritis (26 genes in common)(GEO Series GSE4588). On the other hand, cardioembolism-specific expression profiles were most similar to those from patients with sepsis and septic shock (105 genes and 109 genes in common at day 1, respectively)(GEO Series GSE4607). (Wong et al., Physiol Genomics (2007) 30(2):146-55).
  • Cell Type Sources of the Stroke Etiology Regulated Genes
  • The genes regulated in cardioembolic versus atherosclerotic stroke might or might not be expressed in restricted cell types in blood. Using our reference gene list derived from healthy controls, (Du et al., Genomics (2006) 87(6):693-703) most of the genes regulated in atherosclerotic stroke appear to be regulated in platelets and monocytes (FIG. 4a ) whereas most of the genes regulated in cardioembolic stroke appear to be expressed in neutrophils (FIG. 4b ).
  • Example 2 Diagnosis of Stroke
  • A blood sample will be obtained. RNA is isolated from the blood sample and the RNA labeled and applied to a microarray or similar platform to examine all expressed genes in blood (including, e.g., the genes set forth in Tables 1, 2, 3, 4, 5, or 6). From the microarray the expression of every gene in blood can then be calculated. Suitable software such as Prediction Analysis of Microarrays (PAM) is then used to calculate the probability that the changes of gene expression in the patient are due to a stroke. A probability of 85% of more that the changes represent a stroke is used to confirm the diagnosis of stroke.
  • The next step is to then determine the cause of the stroke. This is important because strokes from atherosclerosis may require surgery or vascular stenting; and strokes from cardioembolism require anti-coagulation with suitable mediacations including, e.g., Coumadin, Warfarin, and the like; and strokes from lacunar disease/hypertension require treatment with aspirin and other anti-platelet agents combined with drugs for the hypertension. From the same microarray used to make the diagnosis of a stroke, the expression of the genes listed in Table 1 is assessed in the patient's blood sample. The expression of these genes is compared to a control or reference sample, or to a combination of genes on the array that serve as control genes. As shown in Table 1, the genes that increase in stroke due to atherosclerosis are decreased in stroke due to cardioembolism; and the genes that increase in stroke due to cardioembolism decrease in stroke due to atherosclerosis; and some genes only change either in stroke due to cardioembolism or only change in stroke due to atherosclerosis. The profile of expression of all 23 genes is again entered into PAM, and PAM calculates the probability that the stroke in a given patient is either cardioembolic, atherosclerotic or due to some other cause. If the probability is 85% or greater for a given cause of stroke, then the cause of stroke will be reported. If the probability is 50% for any cause of stroke then the gene expression profile will not have been able to determine the cause of stroke.
  • It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, patent applications and accession numbers cited herein are hereby incorporated by reference in their entirety for all purposes.
  • TABLE 1
    Fold Difference
    Human Gene (Cardioembolic vs.
    GenBank ID UniGene ID Symbol Gene description Atherothrombotic)
    BC003064 481980 DAB2 disabled homolog 2, mitogen-responsive 1.449
    phosphoprotein (Drosophila)
    NM_001343 481980 DAB2 disabled homolog 2, mitogen-responsive 1.531
    phosphoprotein (Drosophila)
    NM_003897 591785 IER3 immediate early response 3 1.421
    NM_017526 23581 LEPROT leptin receptor overlapping transcript 1.464
    NM_001999 519294 FBN2 fibrillin 2 (congenital contractural 1.64
    arachnodactyly)
    NM_007150 16622 ZNF185 zinc finger protein 185 (LIM domain) 1.544
    NM_000945 280604 PPP3R1 protein phosphatase 3 (formerly 1.503
    2B), regulatory subunit B,
    19 kDa, alpha isoform (calcineurin B, type I)
    NM_004536 191356 BIRC1 NLR family, apoptosis inhibitory 1.417
    (NAIP /// protein /// similar to Baculoviral IAP
    LOC728519) repeat-containing protein 1 (Neuronal
    apoptosis inhibitory protein)
    NM_001928 155597 CFD complement factor D (adipsin) 1.542
    NM_000419 411312 ITGA2B integrin, alpha 2b (platelet glycoprotein 2.146
    IIb of IIb/IIIa complex, antigen CD41)
    NM_004931 405667 CD8B CD8b molecule −1.785714286
    AI753792 502004 RRAS2 related RAS viral (r-ras) oncogene homolog 2 −1.736111111
    AA149644 150718 JAM3 junctional adhesion molecule 3 1.424
    R64130 2164 PPBP pro-platelet basic protein (chemokine 1.75
    (C-X-C motif) ligand 7)
    AW296309 405667 CD8B CD8b molecule −1.526717557
    NM_020152 222802 C21orf7 chromosome 21 open reading frame 7 1.527
    BG251467 122514 SLC25A37 solute carrier family 25, member 37 1.444
    AL136805 278436 TSHZ3 teashirt family zinc finger 3 1.439
    AI520949 110675 PVRL2 poliovirus receptor-related 2 1.64
    (herpesvirus entry mediator B)
    W73230 200100 C7orf41 chromosome 7 open reading frame 41 1.489
    AI215106 591381 INSR Insulin receptor 1.501
    AW270105 144309 PCGF3 Polycomb group ring finger 3 1.495
    BE867789 110675 PVRL2 poliovirus receptor-related 2 1.561
    (herpesvirus entry mediator B)
    BE867789 110675 PVRL2 poliovirus receptor-related 2 2.028
    (herpesvirus entry mediator B)
    AW167424 585653 NUMB Numb homolog (Drosophila) 1.896
    AI971212 434494 SYNJ2 synaptojanin 2 1.443
    AA521086 99691 ALPK1 alpha-kinase 1 1.952
  • TABLE 2
    GenBank ID Unigene Common Name Gene description
    AA167449 Hs.529901 XIST MRNA; cDNA DKFZp686K10163
    (from clone DKFZp686K10163)
    AV646597 Hs.529901 MRNA; cDNA DKFZp686K10163
    (from clone DKFZp686K10163)
    NM_000607 Hs.567311 ORM1 orosomucoid 1
    BE644917 Hs.529901 XIST MRNA; cDNA DKFZp686K10163
    (from clone DKFZp686K10163)
    AA628440 Hs.529901 XIST MRNA; cDNA DKFZp686K10163
    (from clone DKFZp686K10163)
    AI733564 Hs.478588 Transcribed sequence with weak similarity to protein pir:
    A40138 (H. sapiens) A40138 glycogen phosphorylase
    NM_000419 Hs.411312 ITGA2B integrin, alpha 2b (platelet glycoprotein IIb
    of IIb/IIIa complex, antigen CD41B)
    BE867789 Hs.110675 PVRL2 poliovirus receptor-related 2 (herpesvirus entry mediator B)
    AA521086 Hs.99691 LAK lymphocyte alpha-kinase
    AB023212 Hs.158722 PCNX pecanex homolog (Drosophila)
    AL109714 Hs.459049 LOC283687 hypothetical protein LOC283687
    L10343 PI3 elafin has been sequenced at the protein level;
    pre-elafin has not; its existence is
    assumed from its molecular weight
    (PAGE analysis); putative; Homo sapiens
    elafin precursor, gene, complete cds.
    AW167424 Hs.585653 NUMB numb homolog (Drosophila)
    M35999 Hs.218040 ITGB3 integrin, beta 3 (platelet glycoprotein IIIa, antigen CD61)
    NM_002638 Hs.112341 PI3 protease inhibitor 3, skin-derived (SKALP)
    AI929792 Hs.21374 Transcribed sequences
    NM_000607 Hs.567311 ORM2 orosomucoid 1
    R64130 Hs.2164 PPBP pro-platelet basic protein (chemokine (C-X-C motif) ligand 7)
    NM_003118 Hs.111779 SPARC secreted protein, acidic, cysteine-rich (osteonectin)
    NM_002736 Hs.433068 PRKAR2B protein kinase, cAMP-dependent, regulatory, type II, beta
    AA703239 Hs.159430 Transcribed sequence with weak similarity
    to protein prf: 1303335A (H. sapiens)
    1303335A decay accelerating factor long [Homo sapiens]
    NM_004666 Hs.12114 VNN1 vanin 1
    NM_016348 Hs.519694 C5orf4 chromosome 5 open reading frame 4
    BI868572 DKFZp686115217 603392679F1 NIH_MGC_90 Homo sapiens cDNA
    clone IMAGE: 5402706 5′, mRNA sequence.
    AW205418 Hs.495097 KIAA2025 KIAA2025 protein
    NM_001999 Hs.519294 FBN2 fibrillin 2 (congenital contractural arachnodactyly)
    AI520949 Hs.110675 PVRL2 poliovirus receptor-related 2 (herpesvirus entry mediator B)
    M25915 Hs.436657 CLU clusterin (complement lysis inhibitor,
    SP-40, 40, sulfated glycoprotein 2,
    testosterone-repressed prostate message 2, apolipoprotein J)
    BF055462 Hs.164226 THBS1 thrombospondin 1
    AI679555 Hs.527653 Transcribed sequence with weak similarity
    to protein ref: NP_060312.1 (H. sapiens)
    hypothetical protein FLJ20489 [Homo sapiens]
    AW051321 Hs.464137 CDNA FLJ30303 fis, clone BRACE2003269
    NM_000129 Hs.335513 F13A1 coagulation factor XIII, A1 polypeptide
    BE896490 Hs.595327 SNAP29 synaptosomal-associated protein, 29 kDa
    NM_000697 Hs.422967 ALOX12 arachidonate 12-lipoxygenase
    AA181060 Hs.349283 Clone IMAGE: 5288883, mRNA
    NM_002619 Hs.81564 PF4 platelet factor 4 (chemokine (C-X-C motif) ligand 4)
    AU157823 PYGL AU157823 PLACE1 Homo sapiens cDNA clone
    PLACE1009595 3′, mRNA sequence.
    BE867789 Hs.110675 PVRL2 poliovirus receptor-related 2 (herpesvirus entry mediator B)
    AA526844 Hs.556600 MYLK MSTP083 mRNA, complete cds
    BF435438 Hs.80720 Full length insert cDNA YH93B03
    NM_005231 Hs.632133 EMS1 ems1 sequence (mammary tumor and squamous cell
    carcinoma-associated (p80/85 src substrate)
    NM_007150 Hs.16622 ZNF185 zinc finger protein 185 (LIM domain)
    NM_001928 Hs.155597 DF D component of complement (adipsin)
    NM_003831 Hs.445511 RIOK3 RIO kinase 3 (yeast)
    NM_022763 Hs.159430 FAD104 FAD104
    NM_001343 Hs.481980 DAB2 disabled homolog 2, mitogen-responsive
    phosphoprotein (Drosophila)
    NM_020152 Hs.222802 C21orf7 chromosome 21 open reading frame 7
    BC029493 Hs.369265 IRAK3 interleukin-1 receptor-associated kinase 3
    BF976693 Hs.376675 CDNA FLJ34100 fis, clone FCBBF3007597
    NM_000945 Hs.280604 PPP3R1 protein phosphatase 3 (formerly 2B), regulatory
    subunit B, 19 kDa, alpha isoform (calcineurin B, type I)
    AI215106 Hs.591381 INSR insulin receptor
    X82240 Hs.2484 TCL1A T-cell leukemia/lymphoma 1A
    AW296309 Hs.405667 CD8B1 CD8 antigen, beta polypeptide 1 (p37)
    M85256 Hs.554197 IGKC Isolate donor Z clone Z55K immunoglobulin kappa
    light chain variable region mRNA, partial cds
    AF439512 Hs.387787 KLRK1 killer cell lectin-like receptor subfamily K, member 1
    NM_005442 Hs.591663 EOMES eomesodermin homolog (Xenopus laevis)
    AI424825 Hs.435052 ATP8A1 ATPase, aminophospholipid transporter
    (APLT), Class I, type 8A, member 1
    NM_006159 Hs.505326 NELL2 NEL-like 2 (chicken)
    BI547087 603190322F1 NIH_MGC_95 Homo sapiens cDNA
    clone IMAGE: 5261717 5′, mRNA sequence.
    BC001872 Hs.510635 IGHM synonym: MU; Homo sapiens immunoglobulin
    heavy constant mu, mRNA
    (cDNA clone MGC: 1228 IMAGE: 3544448), complete cds.
    AW006735 Hs.85258 CD8A CD8 antigen, alpha polypeptide (p32)
    NM_007360 Hs.387787 KLRK1 killer cell lectin-like receptor subfamily K, member 1
    NM_002261 Hs.74082 KLRC3 synonyms: NKG2E, NKG2-E; isoform
    NKG2-E is encoded by transcript variant
    NKG2-E; go_component: integral to membrane
    [goid 0016021] [evidence IEA];
    go_function: transmembrane receptor activity
    [goid 0004888] [evidence TAS]
    [pmid 9683661]; go_function: lectin
    [goid 0005530] [evidence IEA];
    go_function: sugar binding [goid 0005529]
    [evidence IEA]; go_process: cellular
    defense response [goid 0006968] [evidence TAS]
    [pmid 9683661]; go_process:
    heterophilic cell adhesion [goid 0007157]
    [evidence IEA]; Homo sapiens killer
    cell lectin-like receptor subfamily C, member 3
    (KLRC3), transcript variant NKG2-E, mRNA.
    M13231 Hs.534032 TRGV9 T cell receptor gamma locus
    AI753792 Hs.502004 RRAS2 related RAS viral (r-ras) oncogene homolog 2
    M16768 Hs.534032 TRGV9 T-cell receptor (V-J-C) precursor; Human
    T-cell receptor gamma chain VJCI-
    CII-CIII region mRNA, complete cds.
    NM_003175 Hs.458346 XCL1 chemokine (C motif) ligand 2
    U96394 Hs.449601 IGL@ Clone P2-147 anti-oxidized LDL immunoglobulin
    light chain Fab mRNA, partial cds
    M27331 Hs.534032 TRGV9 T cell receptor gamma locus
    U23772 Hs.546295 XCL1 chemokine (C motif) ligand 1
    NM_004931 Hs.405667 CD8B1 CD8 antigen, beta polypeptide 1 (p37)
    NM_006275 Hs.6891 SFRS6 splicing factor, arginine/serine-rich 6
    BC020552 Hs.379186 PDCD6 programmed cell death 6
    NM_001548 Hs.20315 IFIT1 interferon-induced protein with tetratricopeptide repeats 1
    BC005248 Hs.461178 EIF1AY eukaryotic translation initiation factor 1A, Y-linked
    NM_004660 Hs.99120 DDX3Y DEAD (Asp-Glu-Ala-Asp) box polypeptide 3, Y-linked
    NM_001008 Hs.282376 RPS4Y1 ribosomal protein S4, Y-linked
  • TABLE 3
    GenBank ID Unigene Common Name Gene description
    AI733564 Hs.478588 Transcribed sequence with weak similarity
    to protein pir: A40138 (H. sapiens)
    A40138 glycogen phosphorylase
    NM_000419 Hs.411312 ITGA2B integrin, alpha 2b (platelet glycoprotein
    IIb of IIb/IIIa complex, antigen CD41B)
    BE867789 Hs.110675 PVRL2 poliovirus receptor-related 2
    (herpesvirus entry mediator B)
    AA521086 Hs.99691 LAK lymphocyte alpha-kinase
    AW167424 Hs.585653 NUMB numb homolog (Drosophila)
    R64130 Hs.2164 PPBP pro-platelet basic protein (chemokine
    (C-X-C motif) ligand 7)
    BI868572 DKFZp686I15217 603392679F1 NIH_MGC_90 Homo sapiens
    cDNA clone IMAGE: 5402706 5′,
    mRNA sequence.
    NM_001999 Hs.519294 FBN2 fibrillin 2 (congenital contractural arachnodactyly)
    AI520949 Hs.110675 PVRL2 poliovirus receptor-related 2
    (herpesvirus entry mediator B)
    AW051321 Hs.464137 CDNA FLJ30303 fis, clone BRACE2003269
    BE896490 Hs.595327 SNAP29 synaptosomal-associated protein, 29 kDa
    AA181060 Hs.349283 Clone IMAGE: 5288883, mRNA
    BE867789 Hs.110675 PVRL2 poliovirus receptor-related 2
    (herpesvirus entry mediator B)
    NM_007150 Hs.16622 ZNF185 zinc5t finger protein 185 (LIM domain)
    NM_001928 Hs.155597 DF D component of complement (adipsin)
    NM_001343 Hs.481980 DAB2 disabled homolog 2, mitogen-responsive
    phosphoprotein (Drosophila)
    NM_020152 Hs.222802 C21orf7 chromosome 21 open reading frame 7
    BF976693 Hs.376675 CDNA FLJ34100 fis, clone FCBBF3007597
    NM_000945 Hs.280604 PPP3R1 protein phosphatase 3 (formerly 2B), regulatory
    subunit B, 19 kDa, alpha isoform (calcineurin B, type I)
    AI215106 Hs.591381 INSR insulin receptor
    AW270105 Hs.643902 RNF3 ring finger protein 3
    W73230 Hs.200100 Ells1 zd56c09.s1 Soares_fetal_heart_NbHH19W
    Homo sapiens cDNA clone IMAGE:
    344656 3′ similar to contains element
    MER10 repetitive element;, mRNA sequence.
    NM_017526 Hs.23581 OBRGRP leptin receptor
    AW205122 Hs.496572 FLJ22679 hypothetical protein FLJ22679
    BC003064 Hs.481980 DAB2 disabled homolog 2, mitogen-responsive
    phosphoprotein (Drosophila)
    N63920 Hs.596025 CDNA clone IMAGE: 5294823, partial cds
    BG251467 Hs.122514 MSCP mitochondrial solute carrier protein
    AI971212 Hs.434494 SYNJ2 synaptojanin 2
    AL136805 Hs.278436 ZNF537 zinc finger protein 537
    AA149644 Hs.150718 JAM3 junctional adhesion molecule 3
    AW665656 Hs.633892 GLUL glutamate-ammonia ligase (glutamine synthase)
    NM_003897 Hs.591785 IER3 immediate early response 3
    NM_004536 Hs.191356 BIRC1 baculoviral IAP repeat-containing 1
    AI719730 Hs.24258 GUCY1A3 guanylate cyclase 1, soluble, alpha 3
    AW796364 Hs.371594 MKNK1 Transcribed sequence with weak
    similarity to protein ref: NP_060265.1
    (H. sapiens) hypothetical protein
    FLJ20378 [Homo sapiens]
    BC043380 Hs.468274 CDNA clone IMAGE: 5223469, partial cds
    AA482548 Hs.497873 WDR26 zt34b03.s1 Soares ovary tumor NbHOT
    Homo sapiens cDNA clone
    IMAGE: 724205 3′, mRNA sequence.
    AI476341 Hs.93825 CDNA FLJ39784 fis, clone SPLEN2002314
    NM_009590 Hs.143102 AOC2 amine oxidase, copper containing 2 (retina-specific)
    AA218974 LOC158563 zr02g12.s1 Stratagene NT2 neuronal
    precursor 937230 Homo sapiens cDNA
    clone IMAGE: 650374 3′, mRNA sequence.
    AA010315 Hs.60371 Transcribed sequences
    BE439987 Hs.462214 GAS7 growth arrest-specific 7
    AI356228 Hs.515351 KIAA1533 KIAA1533
    AK023845 USP34 ubiquitin specific protease 34
    AI650285 Hs.287299 Transcribed sequence with weak
    similarity to protein ref: NP_060312.1
    (H. sapiens) hypothetical protein
    FLJ20489 [Homo sapiens]
    BE221883 Hs.11184 UBE2R2 ubiquitin-conjugating enzyme E2R 2
    BG337478 Hs.128037 CDNA FLJ38117 fis, clone D3OST2003797
    AV723666 EFCBP2 AV723666 HTB Homo sapiens cDNA
    clone HTBABA11 5′, mRNA sequence.
    BG334495 Hs.631749 LOC284021 hypothetical protein LOC284021
    AI962978 Hs.469244 WASF2 WAS protein family, member 2
    AW297879 Hs.436271 Transcribed sequences
    NM_000313 Hs.64016 PROS1 protein S (alpha)
    BF446281 Hs.433307 BCKDHA branched chain keto acid dehydrogenase E1, alpha
    polypeptide (maple syrup urine disease)
    AI476341 Hs.93825 CDNA FLJ39784 fis, clone SPLEN2002314
    NM_002413 Hs.81874 MGST2 microsomal glutathione S-transferase 2
    AI698731 Hs.202238 Transcribed sequences
    BM849515 Hs.636486 LRRK1 leucine-rich repeat kinase 1
    AK096134 Hs.378150 Chromosome 4 unknown transcript 1 variant 2 mRNA,
    partial sequence, alternatively spliced
    AV700946 Hs.432337 Transcribed sequence with weak similarity
    to protein pir: 149130 (M.musculus)
    149130 reverse transcriptase-mouse
    BE083088 Hs.591602 SSFA2 RC2-BT0642-030400-021-c05 BT0642
    Homo sapiens cDNA, mRNA sequence.
    AF315688 Hs.591083 IFNK interferon, kappa
    BC013319 Hs.506381 FGD6 FYVE, RhoGEF and PH domain containing 6
    NM_018407 Hs.492314 LAPTM4B lysosomal associated protein transmembrane 4 beta
    BC026969 Hs.492716 MGC21654 Homo sapiens unknown MGC21654 product, mRNA
    (cDNA clone IMAGE: 5116073), partial cds.
    BC015590 Hs.382046 CDNA clone IMAGE: 4643842, partial cds
    NM_014015 Hs.592051 DEXI dexamethasone-induced transcript
    AW572279 Hs.515840 DNMT3A DNA (cytosine-5-)-methyltransferase 3 alpha
    AL359941 Hs.593311 programmed cell death 6
    BC019022 Hs.531856 dJ383J4.3 hypothetical gene supported by BC007071
    AI692169 Hs.379186 PDCD6 wd37e07.x1 Soares_NFL_T_GBC_S1
    Homo sapiens cDNA clone
    IMAGE: 2330340 3′, mRNA sequence.
    AC006033 Homo sapiens, Similar to steroidogenic
    acute regulatory protein related, clone
    MGC: 3251 IMAGE: 3505985, mRNA,
    complete cds.; H_NH0121A08.9 This
    gene was based on gi(13111773 13543614 14042926);
    Homo sapiens BAC clone
    RP11-121A8 from 7, complete sequence.
    AL521959 Hs.487479 PSCD3 pleckstrin homology, Sec7 and coiled-coil domains 3
    W67995 Hs.54943 FXC1 fracture callus 1 homolog (rat)
    AW083371 Hs.173878 NIPSNAP1 nipsnap homolog 1 (C. elegans)
    AF044954 Hs.513266 NDUFB10 NADH dehydrogenase (ubiquinone)
    1 beta subcomplex, 10, 22 kDa
    AI347139 Hs.8162 MGC39372 hypothetical protein MGC39372
    AK074465 Hs.462833 FLJ31952 hypothetical protein FLJ31952
    AI609285 Hs.503891 USP28 tw83h09.x1 NCI_CGAP_HN5 Homo sapiens
    cDNA clone IMAGE: 2266337 3′
    similar to contains Alu repetitive
    element; contains element MER29 repetitive
    element;, mRNA sequence.
    NM_000107 Hs.643521 DDB2 damage-specific DNA binding protein 2, 48 kDa
    NM_005317 Hs.465511 GZMM granzyme M (lymphocyte met-ase 1)
    BC040914 Hs.322462 Clone IMAGE: 5745627, mRNA
    AK001164 Hs.599785 CDNA FLJ10302 fis, clone NT2RM2000042
    NM_005608 Hs.155975 PTPRCAP protein tyrosine phosphatase, receptor
    type, C-associated protein
    NM_013330 Hs.642710 NA4E7 non-metastatic cells 7, protein expressed
    in (nucleoside-diphosphate kinase)
    AB020630 Hs.45719 PPP1R16B protein phosphatase 1, regulatory (inhibitor) subunit 16B
    AB020630 Hs.45719 PPP1R16B protein phosphatase 1, regulatory (inhibitor) subunit 16B
    AF298547 Hs.369279 NALP2 NACHT, leucine rich repeat and PYD containing 2
    AW157571 Hs.479066 MARLIN1 multiple coiled-coil GABABR1-binding protein
    AA767131 Hs.121432 KIAA0073 KIAA0073 protein
    NM_004356 Hs.54457 CD81 CD81 antigen (target of antiproliferative antibody 1)
    AI702465 Hs.23606 Transcribed sequences
    U90339 Hs.584739 ADK adenosine kinase
    AW296309 Hs.405667 CD8B1 CD8 antigen, beta polypeptide 1 (p37)
    AI753792 Hs.502004 RRAS2 related RAS viral (r-ras) oncogene homolog 2
    NM_004931 Hs.405667 CD8B1 CD8 antigen, beta polypeptide 1 (p37)
  • TABLE 4
    GenBank Unigene
    ID ID Common Name Gene Description
    AA167449 Hs.529901 XIST MRNA; cDNA DKFZp686K10163
    (from clone DKFZp686K10163)
    AV646597 Hs.529901 MRNA; cDNA DKFZp686K10163
    (from clone DKFZp686K10163)
    NM_000607 Hs.567311 ORM1 orosomucoid 1
    BE644917 Hs.529901 XIST MRNA; cDNA DKFZp686K10163
    (from clone DKFZp686K10163)
    AA628440 Hs.529901 XIST MRNA; cDNA DKFZp686K10163
    (from clone DKFZp686K10163)
    AI733564 Hs.478588 Transcribed sequence with weak similarity
    to protein pir: A40138 (H. sapiens)
    A40138 glycogen phosphorylase
    NM_000419 Hs.411312 ITGA2B integrin, alpha 2b (platelet glycoprotein IIb
    of IIb/IIIa complex, antigen CD41B)
    BE867789 Hs.110675 PVRL2 poliovirus receptor-related 2 (herpesvirus entry mediator B)
    AA521086 Hs.99691 LAK lymphocyte alpha-kinase
    AB023212 Hs.158722 PCNX pecanex homolog (Drosophila)
    AL109714 Hs.459049 LOC283687 hypothetical protein LOC283687
    L10343 PI3 elafin has been sequenced at the protein level; pre-elafin
    has not; its existence is assumed from its molecular
    weight (PAGE analysis); putative; Homo sapiens
    elafin precursor, gene, complete cds.
    AW167424 Hs.585653 NUMB numb homolog (Drosophila)
    M35999 Hs.218040 ITGB3 integrin, beta 3 (platelet glycoprotein IIIa, antigen CD61)
    NM_002638 Hs.112341 PI3 protease inhibitor 3, skin-derived (SKALP)
    AI929792 Hs.21374 Transcribed sequences
    NM_000607 Hs.567311 ORM2 orosomucoid 1
    R64130 Hs.2164 PPBP pro-platelet basic protein (chemokine (C-X-C motif) ligand 7)
    NM_003118 Hs.111779 SPARC secreted protein, acidic, cysteine-rich (osteonectin)
    NM_002736 Hs.433068 PRKAR2B protein kinase, cAMP-dependent, regulatory, type II, beta
    AA703239 Hs.159430 Transcribed sequence with weak similarity
    to protein prf: 1303335A (H. sapiens)
    1303335A decay accelerating factor long [Homo sapiens]
    NM_004666 Hs.12114 VNN1 vanin 1
    NM_016348 Hs.519694 C5orf4 chromosome 5 open reading frame 4
    BI868572 DKFZp686I15217 603392679F1 NIH_MGC_90 Homo sapiens cDNA
    clone IMAGE: 5402706 5′, mRNA sequence.
    AW205418 Hs.495097 KIAA2025 KIAA2025 protein
    NM_001999 Hs.519294 FBN2 fibrillin 2 (congenital contractural arachnodactyly)
    AI520949 Hs.110675 PVRL2 poliovirus receptor-related 2 (herpesvirus entry mediator B)
    M25915 Hs.436657 CLU clusterin (complement lysis inhibitor, SP-40,
    40, sulfated glycoprotein 2, testosterone-repressed
    prostate message 2, apolipoprotein J)
    BF055462 Hs.164226 THBS1 thrombospondin 1
    AI679555 Hs.527653 Transcribed sequence with weak similarity
    to protein ref: NP_060312.1
    (H. sapiens) hypothetical protein FLJ20489 [Homo sapiens]
    AW051321 Hs.464137 CDNA FLJ30303 fis, clone BRACE2003269
    NM_000129 Hs.335513 F13A1 coagulation factor XIII, A1 polypeptide
    BE896490 Hs.595327 SNAP29 synaptosomal-associated protein, 29 kDa
    NM_000697 Hs.422967 ALOX12 arachidonate 12-lipoxygenase
    AA181060 Hs.349283 Clone IMAGE: 5288883, mRNA
    NM_002619 Hs.81564 PF4 platelet factor 4 (chemokine (C-X-C motif) ligand 4)
    AU157823 PYGL AU157823 PLACE1 Homo sapiens cDNA clone
    PLACE1009595 3′, mRNA sequence.
    BE867789 Hs.110675 PVRL2 poliovirus receptor-related 2 (herpesvirus entry mediator B)
    AA526844 Hs.556600 MYLK MSTP083 mRNA, complete cds
    BF435438 Hs.80720 Full length insert cDNA YH93B03
    NM_005231 Hs.632133 EMS1 ems1 sequence (mammary tumor and squamous cell
    carcinoma-associated (p80/85 src substrate)
    NM_007150 Hs.16622 ZNF185 zinc finger protein 185 (LIM domain)
    NM_001928 Hs.155597 DF D component of complement (adipsin)
    NM_003831 Hs.445511 RIOK3 RIO kinase 3 (yeast)
    NM_022763 Hs.159430 FAD104 FAD104
    NM_001343 Hs.481980 DAB2 disabled homolog 2, mitogen-responsive
    phosphoprotein (Drosophila)
    NM_020152 Hs.222802 C21orf7 chromosome 21 open reading frame 7
    BC029493 Hs.369265 IRAK3 interleukin-1 receptor-associated kinase 3
    BF976693 Hs.376675 CDNA FLJ34100 fis, clone FCBBF3007597
    NM_000945 Hs.280604 PPP3R1 protein phosphatase 3 (formerly 2B), regulatory
    subunit B, 19 kDa, alpha isoform (calcineurin B, type I)
    AI215106 Hs.591381 INSR insulin receptor
    AI817801 Hs.191356 BIRC1 Transcribed sequence with strong similarity
    to protein sp: Q13075 (H. sapiens)
    BIR1_HUMAN Baculoviral IAP repeat-containing protein 1
    AW270105 Hs.643902 RNF3 ring finger protein 3
    BG913589 Hs.59214 LOC144871 DnaJ (Hsp40) homolog, subfamily C, member 3
    W73230 Hs.200100 Ells1 zd56c09.s1 Soares_fetal_heart_NbHH19W
    Homo sapiens cDNA clone IMAGE: 344656 3′ similar
    to contains element MER10 repetitive element;,
    mRNA sequence.
    BF691447 Hs.644051 B4GALT5 UDP-Gal: betaGlcNAc beta 1,4-galactosyltransferase,
    polypeptide 5
    NM_005502 Hs.429294 ABCA1 ATP-binding cassette, sub-family A (ABC1), member 1
    NM_000361 Hs.2030 THBD thrombomodulin
    AK024569 Hs.195403 DOCKS dedicator of cytokinesis 5
    AB051833 Hs.123239 ACRBP acrosin binding protein
    NM_004126 Hs.83381 GNG11 guanine nucleotide binding protein (G protein), gamma 11
    Y07846 Hs.322852 GAS2L1 growth arrest-specific 2 like 1
    BE327727 Hs.443301 Transcribed sequences
    M36532 Hs.155097 CA2 carbonic anhydrase II
    NM_017526 Hs.23581 OBRGRP leptin receptor
    AW205122 Hs.496572 FLJ22679 hypothetical protein FLJ22679
    AI141116 Hs.123239 ACRBP acrosin binding protein
    AW293296 Hs.163893 Transcribed sequences
    N63244 Hs.592143 TUBB1 tubulin, beta 1
    BG120535 VNN1 602346858F1 NIH_MGC_90 Homo sapiens cDNA
    clone IMAGE: 4441695 5′, mRNA sequence.
    AU152763 Hs.586165 CDNA FLJ10742 lis, clone NT2RP3001629
    BC003064 Hs.481980 DAB2 disabled homolog 2, mitogen-responsive
    phosphoprotein (Drosophila)
    N63920 Hs.596025 CDNA clone IMAGE: 5294823, partial cds
    BG251467 Hs.122514 MSCP mitochondrial solute carrier protein
    AF237762 Hs.306199 GPR84 G protein-coupled receptor 84
    AW206560 Hs.609146 Transcribed sequences
    AI971212 Hs.434494 SYNJ2 synaptojanin 2
    AL136805 Hs.278436 ZNF537 zinc finger protein 537
    BC026299 Hs.518727 Clone IMAGE: 4275461, mRNA
    BE675324 Hs.200770 Transcribed sequences
    NM_021647 Hs.178121 KIAA0626
    NM_018482 Hs.106015 DDEF1 synonyms: PAP, PAG2, ASAP1, ZG14P,
    KIAA1249; Homo sapiens development and
    differentiation enhancing factor 1 (DDEF1), mRNA.
    AA149644 Hs.150718 JAM3 junctional adhesion molecule 3
    AF325460 Hs.351812 CLECSF7 C-type (calcium dependent, carbohydrate-recognition domain)
    lectin, superfamily member 7
    AW665656 Hs.633892 GLUL glutamate-ammonia ligase (glutamine synthase)
    AA417099 Hs.465709 Transcribed sequences
    NM_003897 Hs.591785 IER3 immediate early response 3
    AF275260 Hs.592117 CXCL16 chemokine (C-X-C motif) ligand 16
    AF001540 MALAT-1 PRO1073 protein
    AI640434 Hs.601545 FLJ10357 hypothetical protein FLJ10357
    AW043859 Hs.235795 Clone IMAGE: 5263020, mRNA
    H68759 Hs.122514 Transcribed sequences
    NM_004536 Hs.191356 BIRC1 baculoviral IAP repeat-containing 1
    AF086010 Hs.335205 Full length insert cDNA clone YW04H08
    NM_003189 Hs.73828 TAL1 T-cell acute lymphocytic leukemia 1
    AW138767 Hs.274256 ELOVL7 hypothetical protein FLJ23563
    NM_003693 Hs.534497 SCARF1 scavenger receptor class F, member 1
    BG177759 Hs.497873 WDR26 WD repeat domain 26
    U49396 Hs.408615 P2RX5 purinergic receptor P2X, ligand-gated ion channel, 5
    AA781795 Hs.546467 EPSTI1 epithelial stromal interaction 1 (breast)
    BF433219 Transcribed sequences
    BC003574 Hs.2484 TCL1A T-cell leukemia/lymphoma 1A
    AB051458 Hs.419171 KIAA1671 KIAA1671 protein
    NM_004114 Hs.6540 FGF13 fibroblast growth factor 13
    BF446578 Hs.125293 RASGEF1A RasGEF domain family, member 1A
    AA931562 Hs.444049 Transcribed sequence with weak similarity
    to protein ref: NP_060312.1
    (H. sapiens) hypothetical protein FLJ20489 [Homo sapiens]
    BF514552 Hs.292449 FCRH3 Fc receptor-like protein 3
    X82240 Hs.2484 TCL1A T-cell leukemia/lymphoma 1A
    AW296309 Hs.405667 CD8B1 CD8 antigen, beta polypeptide 1 (p37)
    M85256 Hs.554197 IGKC Isolate donor Z clone Z55K immunoglobulin kappa
    light chain variable region mRNA, partial cds
    AF439512 Hs.387787 KLRK1 killer cell lectin-like receptor subfamily K, member 1
    NM_005442 Hs.591663 EOMES eomesodermin homolog (Xenopus laevis)
    AI424825 Hs.435052 ATP8A1 ATPase, aminophospholipid transporter (APLT),
    Class I, type 8A, member 1
    NM_006159 Hs.505326 NELL2 NEL-like 2 (chicken)
    BI547087 603190322F1 NIH_MGC_95 Homo sapiens cDNA
    clone IMAGE: 5261717 5′, mRNA sequence.
    BC001872 Hs.510635 IGHM synonym: MU; Homo sapiens immunoglobulin
    heavy constant mu, mRNA
    (cDNA clone MGC: 1228 IMAGE: 3544448), complete cds.
    AW006735 Hs.85258 CD8A CD8 antigen, alpha polypeptide (p32)
    NM_007360 Hs.387787 KLRK1 killer cell lectin-like receptor subfamily K, member 1
    NM_002261 Hs.74082 KLRC3 synonyms: NKG2E, NKG2-E; isoform NKG2-E is
    encoded by transcript variant NKG2-E; go_component:
    integral to membrane [goid 0016021] [evidence IEA];
    go_function: transmembrane receptor activity
    [goid 0004888] [evidence TAS] [pmid 9683661];
    go_function: lectin [goid 0005530] [evidence IEA];
    go_function: sugar binding [goid 0005529] [evidence IEA];
    go_process: cellular defense response [goid 0006968]
    [evidence TAS] [pmid 9683661]; go_process:
    heterophilic cell adhesion [goid 0007157] [evidence
    IEA]; Homo sapiens killer cell lectin-like receptor
    subfamily C, member 3 (KLRC3), transcript variant
    NKG2-E, mRNA.
    M13231 Hs.534032 TRGV9 T cell receptor gamma locus
    AI753792 Hs.502004 RRAS2 related RAS viral (r-ras) oncogene homolog 2
    M16768 Hs.534032 TRGV9 T-cell receptor (V-J-C) precursor; Human
    T-cell receptor gamma chain VJCI-
    CII-CIII region mRNA, complete cds.
    NM_003175 Hs.458346 XCL1 chemokine (C motif) ligand 2
    U96394 Hs.449601 IGL@ Clone P2-147 anti-oxidized LDL immunoglobulin light
    chain Fab mRNA, partial cds
    M27331 Hs.534032 TRGV9 T cell receptor gamma locus
    U23772 Hs.546295 XCL1 chemokine (C motif) ligand 1
    NM_004931 Hs.405667 CD8B1 CD8 antigen, beta polypeptide 1 (p37)
    NM_006275 Hs.6891 SFRS6 splicing factor, arginine/serine-rich 6
    BC020552 Hs.379186 PDCD6 programmed cell death 6
    NM_001548 Hs.20315 IFIT1 interferon-induced protein with tetratricopeptide repeats 1
    BC005248 Hs.461178 EIF1AY eukaryotic translation initiation factor 1A, Y-linked
    NM_004660 Hs.99120 DDX3Y DEAD (Asp-Glu-Ala-Asp) box polypeptide 3, Y-linked
    NM_001008 Hs.282376 RPS4Y1 ribosomal protein S4, Y-linked
  • TABLE 5
    GenBank Unigene
    ID ID Common Name Gene Description
    AA167449 Hs.529901 XIST MRNA; cDNA DKFZp686K10163
    (from clone DKFZp686K10163)
    AV646597 Hs.529901 MRNA; cDNA DKFZp686K10163
    (from clone DKFZp686K10163)
    NM_000607 Hs.567311 ORM1 orosomucoid 1
    BE644917 Hs.529901 XIST MRNA; cDNA DKFZp686K10163
    (from clone DKFZp686K10163)
    AA628440 Hs.529901 XIST MRNA; cDNA DKFZp686K10163
    (from clone DKFZp686K10163)
    AI733564 Hs.478588 Transcribed sequence with weak similarity to protein
    pir: A40138 (H. sapiens) A40138 glycogen phosphorylase
    NM_000419 Hs.411312 ITGA2B integrin, alpha 2b (platelet glycoprotein IIb of
    IIb/IIIa complex, antigen CD41B)
    BE867789 Hs.110675 PVRL2 poliovirus receptor-related 2 (herpesvirus entry mediator B)
    AA521086 Hs.99691 LAK lymphocyte alpha-kinase
    AB023212 Hs.158722 PCNX pecanex homolog (Drosophila)
    AL109714 Hs.459049 LOC283687 hypothetical protein LOC283687
    L10343 PI3 elafin has been sequenced at the protein level;
    pre-elafin has not; its existence is assumed from its molecular
    weight (PAGE analysis); putative; Homo sapiens elafin
    precursor, gene, complete cds.
    AW167424 Hs.585653 NUMB numb homolog (Drosophila)
    M35999 Hs.218040 ITGB3 integrin, beta 3 (platelet glycoprotein IIIa, antigen CD61)
    NM_002638 Hs.112341 PI3 protease inhibitor 3, skin-derived (SKALP)
    AI929792 Hs.21374 Transcribed sequences
    NM_000607 Hs.567311 ORM2 orosomucoid 1
    R64130 Hs.2164 PPBP pro-platelet basic protein (chemokine (C-X-C motif) ligand 7)
    NM_003118 Hs.111779 SPARC secreted protein, acidic, cysteine-rich (osteonectin)
    NM_002736 Hs.433068 PRKAR2B protein kinase, cAMP-dependent, regulatory, type II, beta
    AA703239 Hs.159430 Transcribed sequence with weak similarity
    to protein prf: 1303335A (H. sapiens)
    1303335A decay accelerating factor long [Homo sapiens]
    NM_004666 Hs.12114 VNN1 vanin 1
    NM_016348 Hs.519694 C5orf4 chromosome 5 open reading frame 4
    BI868572 DKFZp686I15217 603392679F1 NIH_MGC_90 Homo sapiens cDNA
    clone IMAGE: 5402706 5′, mRNA sequence.
    AW205418 Hs.495097 KIAA2025 KIAA2025 protein
    NM_001999 Hs.519294 FBN2 fibrillin 2 (congenital contractural arachnodactyly)
    AI520949 Hs.110675 PVRL2 poliovirus receptor-related 2 (herpesvirus entry mediator B)
    M25915 Hs.436657 CLU clusterin (complement lysis inhibitor, SP-40, 40,
    sulfated glycoprotein 2, testosterone-
    repressed prostate message 2, apolipoprotein J)
    BF055462 Hs.164226 THBS1 thrombospondin 1
    AI679555 Hs.527653 Transcribed sequence with weak similarity
    to protein ref: NP_060312.1 (H. sapiens)
    hypothetical protein FLJ20489 [Homo sapiens]
    AW051321 Hs.464137 CDNA FLJ30303 fis, clone BRACE2003269
    NM_000129 Hs.335513 F13A1 coagulation factor XIII, A1 polypeptide
    BE896490 Hs.595327 SNAP29 synaptosomal-associated protein, 29 kDa
    NM_000697 Hs.422967 ALOX12 arachidonate 12-lipoxygenase
    AA181060 Hs.349283 Clone IMAGE: 5288883, mRNA
    NM_002619 Hs.81564 PF4 platelet factor 4 (chemokine (C-X-C motif) ligand 4)
    AU157823 PYGL AU157823 PLACE1 Homo sapiens cDNA clone
    PLACE1009595 3′, mRNA sequence.
    BE867789 Hs.110675 PVRL2 poliovirus receptor-related 2 (herpesvirus entry mediator B)
    AA526844 Hs.556600 MYLK MSTP083 mRNA, complete cds
    BF435438 Hs.80720 Full length insert cDNA YH93B03
    NM_005231 Hs.632133 EMS1 ems1 sequence (mammary tumor and squamous cell
    carcinoma-associated (p80/85 src substrate)
    NM_007150 Hs.16622 ZNF185 zinc finger protein 185 (LIM domain)
    NM_001928 Hs.155597 DF D component of complement (adipsin)
    NM_003831 Hs.445511 RIOK3 RIO kinase 3 (yeast)
    NM_022763 Hs.159430 FAD104 FAD104
    NM_001343 Hs.481980 DAB2 disabled homolog 2, mitogen-responsive
    phosphoprotein (Drosophila)
    NM_020152 Hs.222802 C21orf7 chromosome 21 open reading frame 7
    BC029493 Hs.369265 IRAK3 interleukin-1 receptor-associated kinase 3
    BF976693 Hs.376675 CDNA FLJ34100 fis, clone FCBBF3007597
    NM_000945 Hs.280604 PPP3R1 protein phosphatase 3 (formerly 2B), regulatory subunit B,
    19 kDa, alpha isoform (calcineurin B, type I)
    AI215106 Hs.591381 INSR insulin receptor
    AI817801 Hs.191356 BIRC1 Transcribed sequence with strong similarity to protein
    sp: Q13075 (H. sapiens) BIR1_HUMAN
    Baculoviral IAP repeat-containing protein 1
    AW270105 Hs.643902 RNF3 ring finger protein 3
    BG913589 Hs.59214 LOC144871 DnaJ (Hsp40) homolog, subfamily C, member 3
    W73230 Hs.200100 Ells1 zd56c09.s1 Soares_fetal_heart_NbHH19W
    Homo sapiens cDNA clone IMAGE: 344656 3′ similar to
    contains element MER10 repetitive element;, mRNA
    sequence.
    BF691447 Hs.644051 B4GALT5 UDP-Gal: betaGlcNAc beta 1,4-galactosyltransferase,
    polypeptide 5
    NM_005502 Hs.429294 ABCA1 ATP-binding cassette, sub-family A (ABC1), member 1
    NM_000361 Hs.2030 THBD thrombomodulin
    AK024569 Hs.195403 DOCK5 dedicator of cytokinesis 5
    AB051833 Hs.123239 ACRBP acrosin binding protein
    NM_004126 Hs.83381 GNG11 guanine nucleotide binding protein (G protein), gamma 11
    Y07846 Hs.322852 GAS2L1 growth arrest-specific 2 like 1
    BE327727 Hs.443301 Transcribed sequences
    M36532 Hs.155097 CA2 carbonic anhydrase II
    NM_017526 Hs.23581 OBRGRP leptin receptor
    AW205122 Hs.496572 FLJ22679 hypothetical protein FLJ22679
    AI141116 Hs.123239 ACRBP acrosin binding protein
    AW293296 Hs.163893 Transcribed sequences
    N63244 Hs.592143 TUBB1 tubulin, beta 1
    BG120535 VNN1 602346858F1 NIH_MGC_90 Homo sapiens cDNA clone
    IMAGE: 4441695 5′, mRNA sequence.
    AU152763 Hs.586165 CDNA FLJ10742 fis, clone NT2RP3001629
    BC003064 Hs.481980 DAB2 disabled homolog 2, mitogen-responsive
    phosphoprotein (Drosophila)
    N63920 Hs.596025 CDNA clone IMAGE: 5294823, partial cds
    BG251467 Hs.122514 MSCP mitochondrial solute carrier protein
    AF237762 Hs.306199 GPR84 G protein-coupled receptor 84
    AW206560 Hs.609146 Transcribed sequences
    AI971212 Hs.434494 SYNJ2 synaptojanin 2
    AL136805 Hs.278436 ZNF537 zinc finger protein 537
    BC026299 Hs.518727 Clone IMAGE: 4275461, mRNA
    BE675324 Hs.200770 Transcribed sequences
    NM_021647 Hs.178121 KIAA0626
    NM_018482 Hs.106015 DDEF1 synonyms: PAP, PAG2, ASAP1,
    ZG14P, KIAA1249; Homo sapiens development
    and differentiation enhancing factor 1 (DDEF1), mRNA.
    AA149644 Hs.150718 JAM3 junctional adhesion molecule 3
    AF325460 Hs.351812 CLECSF7 C-type (calcium dependent, carbohydrate-recognition
    domain) lectin, superfamily member 7
    AW665656 Hs.633892 GLUL glutamate-ammonia ligase (glutamine synthase)
    AA417099 Hs.465709 Transcribed sequences
    NM_003897 Hs.591785 IER3 immediate early response 3
    AF275260 Hs.592117 CXCL16 chemokine (C-X-C motif) ligand 16
    AF001540 MALAT-1 PRO1073 protein
    AI640434 Hs.601545 FLJ10357 hypothetical protein FLJ10357
    AW043859 Hs.235795 Clone IMAGE: 5263020, mRNA
    H68759 Hs.122514 Transcribed sequences
    NM_004536 Hs.191356 BIRC1 baculoviral IAP repeat-containing 1
    AF086010 Hs.335205 Full length insert cDNA clone YW04H08
    NM_003189 Hs.73828 TAL1 T-cell acute lymphocytic leukemia 1
    AW138767 Hs.274256 ELOVL7 hypothetical protein FLJ23563
    NM_003693 Hs.534497 SCARF1 scavenger receptor class F, member 1
    BG177759 Hs.497873 WDR26 WD repeat domain 26
    AW264036 Hs.478588 BCL6 B-cell CLL/lymphoma 6 (zinc finger protein 51)
    AL119957 Hs.59214 DNAJC3 DnaJ (Hsp40) homolog, subfamily C, member 3
    NM_018388 Hs.105134 MBNL3 muscleblind-like 3 (Drosophila)
    AI640434 Hs.601545 FLJ10357 hypothetical protein FLJ10357
    AI332764 Hs.516646 Transcribed sequences
    AI719730 Hs.24258 GUCY1A3 guanylate cyclase 1, soluble, alpha 3
    NM_130441 Hs.351812 CLECSF7 C-type (calcium dependent, carbohydrate-recognition
    domain) lectin, superfamily member 7
    AW796364 Hs.371594 MKNK1 Transcribed sequence with weak similarity
    to protein ref: NP_060265.1 (H. sapiens)
    hypothetical protein FLJ20378 [Homo sapiens]
    BC043380 Hs.468274 CDNA clone IMAGE: 5223469, partial cds
    NM_017698 FLJ22679
    AW069181 Hs.603149 ZAK cr43e01.x1 Human bone marrow stromal cells Homo sapiens
    cDNA clone HBMSC_cr43e01 3′, mRNA sequence.
    AF350881 Hs.272225 TRPM6 transient receptor potential cation channel,
    subfamily M, member 6
    AA082707 Hs.592262 MLL5 myeloid/lymphoid or mixed-lineage leukemia 5
    (trithorax homolog, Drosophila)
    AL035700 SH3BGRL2 continued from bA177G23.1 in Em: AL451064 match:
    proteins: Tr: O75368 Sw: P55822 Tr: Q9BPY5 Tr: Q9BRB8
    Sw: Q9WUZ7; Human DNA sequence from
    clone RP1-75K24 on chromosome 6q13-15 Contains
    the the 3′ end of the SH3BGRL2 gene for SH3 domain
    binding glutamic acid-rich protein-like 2, complete
    sequence.
    N66571 Hs.501898 MRVI1 murine retrovirus integration site 1 homolog
    AA482548 Hs.497873 WDR26 zt34b03.s1 Soares ovary tumor NbHOT Homo sapiens
    cDNA clone IMAGE: 724205 3′, mRNA sequence.
    AI052659 Hs.334019 Transcribed sequences
    AF074331 PAPSS2 Homo sapiens PAPS synthetase-2 (PAPSS2)
    mRNA, complete cds.
    AI682905 Hs.280342 PRKAR1A protein kinase, cAMP-dependent, regulatory, type I, alpha
    (tissue specific extinguisher 1)
    AI022066 Hs.480763 Transcribed sequences
    AI953847 Hs.148741 IBRDC2 IBR domain containing 2
    NM_000361 Hs.2030 THBD thrombomodulin
    AY151286 Hs.196384 PTGS2 prostaglandin-endoperoxide synthase 2 (prostaglandin
    G/H synthase and cyclooxygenase)
    AL713724 Hs.487994 MRNA; cDNA DKFZp667O0416 (from clone DKFZp667O0416)
    AI831952 Hs.567518 NDE1 nudE nuclear distribution gene E homolog 1 (A. nidulans)
    N45231 Hs.513053 DNAJA4 DnaJ (Hsp40) homolog, subfamily A, member 4
    AA044825 Hs.520757 TBXAS1 thromboxane A synthase 1 (platelet, cytochrome
    P450, family 5, subfamily A)
    AI476341 Hs.93825 CDNA FLJ39784 fis, clone SPLEN2002314
    BF195718 Hs.221889 CSDA cold shock domain protein A
    AL833423 Hs.379548 MRNA; cDNA DKFZp313H2139 (from clone DKFZp313H2139)
    NM_009590 Hs.143102 AOC2 amine oxidase, copper containing 2 (retina-specific)
    AA770170 Hs.499489 MIR c-mir, cellular modulator of immune recognition
    BE965029 Hs.501928 MICAL2 601658812R1 NIH_MGC_69 Homo sapiens cDNA clone
    IMAGE: 3886131 3′, mRNA sequence.
    BC018042 Hs.279815 CSAD cysteine sulfinic acid decarboxylase
    AA218974 LOC158563 zr02g12.s1 Stmtagene NT2 neuronal precursor 937230
    Homo sapiens cDNA clone IMAGE: 650374 3′, mRNA sequence.
    AF188298 Hs.481980 DAB2 disabled homolog 2, mitogen-responsive
    phosphoprotein (Drosophila)
    NM_005906 Hs.446125 MAK male germ cell-associated kinase
    BC002716 Hs.496572 FLJ22679 hypothetical protein FLJ22679
    AK023512 Hs.463439 SPAG9 sperm associated antigen 9
    AA010315 Hs.60371 Transcribed sequences
    AF051151 Hs.135853 TLR5 toll-like receptor 5
    BU929456 OSTF1 AGENCOURT_10424238 NIH_MGC_79 Homo sapiens
    cDNA clone IMAGE: 6663343 5′, mRNA sequence.
    NM_002607 Hs.535898 PDGFA platelet-derived growth factor alpha polypeptide
    AK024748 Hs.297343 CAMKK2 calcium/calmodulin-dependent protein kinase kinase 2, beta
    U76248 Hs.477959 SIAH2 seven in absentia homolog 2 (Drosophila)
    AI819198 Hs.208229 GPR54 G protein-coupled receptor 54
    AI452469 Hs.605187 Transcribed sequence with weak similarity to protein
    ref: NP_009032.1 (H. sapiens) sarcosine dehydrogenase;
    dimethylglycine dehydrogenase-like 1 [Homo sapiens]
    AA037483 Hs.458395 HIST1H2BC zk34a02.s1 Soares pregnant_uterus_NbHPU Homo sapiens
    cDNA clone IMAGE: 484682 3′, mRNA sequence.
    U56237 Hs.631534 FCAR Fc fragment of IgA, receptor for
    N66045 Hs.29189 Transcribed sequences
    AW299958 Hs.524491 PAPSS2 3′-phosphoadenosine 5′-phosphosulfate synthase 2
    AK021983 Hs.106015 CDNA FLJ11921 fis, clone HEMBB1000318
    NM_002398 Hs.526754 MEIS1 Meis1, myeloid ecotropic viral integration
    site
    1 homolog (mouse)
    AV725666 Hs.220950 FOXO3A CDNA clone IMAGE: 4814010, partial cds
    AK026714 Hs.7886 PELI1 pellino homolog 1 (Drosophila)
    NM_005373 Hs.82906 MPL CDC20 cell division cycle 20 homolog (S. cerevisiae)
    AK024382 unnamed protein product; Homo sapiens
    cDNA FLJ14320 fis, clone PLACE3000455.
    AA702409 Hs.592017 Transcribed sequences
    AI074467 Hs.593643 Transcribed sequences
    AI368358 Hs.496969 NPL N-acetylneuraminate pyruvate lyase
    (dihydrodipicolinate synthase)
    H28667 Hs.444451 ZAK sterile alpha motif and leucine zipper containing kinase AZK
    AL544951 Hs.280604 PPP3R1 AL544951 Homo sapiens PLACENTA
    COT 25-NORMALIZED Homo sapiens
    cDNA clone CS0DI012YC11 5-PRIME, mRNA sequence.
    AL050388 Hs.487046 SOD2 superoxide dismutase 2, mitochondrial
    AI829674 Hs.584845 Transcribed sequences
    NM_018324 Hs.24309 THEDC1 hypothetical protein FLJ11106
    AA362254 Hs.529633 Transcribed sequences
    AW130600 Hs.99472 MRNA; cDNA DKFZp564O0862 (from clone DKFZp564O0862)
    N25732 Hs.591328 FOXO3A yx83c03.s1 Soares melanocyte 2NbHM Homo sapiens cDNA
    clone IMAGE: 268324 3′, mRNA sequence.
    NM_017815 Hs.442782 C14orf94 chromosome 14 open reading frame 94
    AK055448 ZNF587 Homo sapiens cDNA FLJ30886 fis, clone FEBRA2005014,
    weakly similar to ZINC FINGER PROTEIN 84.
    S69189 Hs.464137 ACOX1 acyl-Coenzyme A oxidase 1, palmitoyl
    AU146027 Hs.592326 AU146027 HEMBA1 Homo sapiens cDNA clone
    HEMBA1006595 3′, mRNA sequence.
    BE439987 Hs.462214 GAS7 growth arrest-specific 7
    AI363213 Hs.381058 KIAA0146 KIAA0146 protein
    BF508786 Hs.613959 MRNA; cDNA DKFZp686J24234
    (from clone DKFZp686J24234)
    BF680284 Hs.34558 CDNA: FLJ21199 fis, clone COL00235
    H93077 Hs.519694 C5orf4 chromosome 5 open reading frame 4
    AI798924 Hs.191850 Transcribed sequences
    W19983 Hs.370725 OSBPL1A oxysterol binding protein-like 1A
    AA057437 Hs.458747 Transcribed sequences
    NM_024565 Hs.14070 FLJ14166 hypothetical protein FLJ14166
    AI356228 Hs.515351 KIAA1533 KIAA1533
    AI937121 Hs.29282 Transcribed sequences
    AI806045 Hs.61438 Transcribed sequences
    N24643 Hs.446017 WSB1 WD repeat and SOCS box-containing 1
    AU122258 AU122258 MAMMA1 Homo sapiens cDNA clone
    MAMMA1002009 5′, mRNA sequence.
    AI278204 Hs.99472 MRNA; cDNA DKFZp564O0862 (from clone DKFZp564O0862)
    AW450374 Hs.593734 Clone IMAGE: 4824518, mRNA
    BE888885 Hs.220950 FOXO3A CDNA clone IMAGE: 4814010, partial cds
    AK023845 USP34 ubiquitin specific protease 34
    BF511336 Hs.591641 Transcribed sequences
    R12665 Hs.11594 CDNA FLJ27273 fis, clone TMS00761
    BC006428 Hs.189119 CXXC5 CXXC finger 5
    AI354636 Hs.586401 qu95c03.x1 NCI_CGAP_Gas4 Homo sapiens cDNA clone
    IMAGE: 1979812 3′, mRNA sequence.
    AK025248 Hs.546419 FLJ13220 hypothetical protein FLJ13220
    BE675549 Hs.79170 TTC9 tetratricopeptide repeat domain 9
    NM_000579 Hs.450802 CCR5 chemokine (C-C motif) receptor 5
    AB020630 Hs.45719 PPP1R16B protein phosphatase 1, regulatory (inhibitor) subunit 16B
    NM_002985 Hs.514821 CCL5 chemokine (C-C motif) ligand 5
    NM_014392 Hs.518595 D4S234E DNA segment on chromosome 4 (unique) 234 expressed sequence
    AI821566 Hs.642748 TTC16 torsin family 2, member A
    AA771779 Hs.461074 ZFP90 zinc finger protein 90 homolog (mouse)
    AI084226 Hs.58831 TOSO regulator of Fas-induced apoptosis
    AF057557 Hs.58831 TOSO regulator of Fas-induced apoptosis
    NM_005356 Hs.470627 LCK lymphocyte-specific protein tyrosine kinase
    BC041468 Hs.434746 LOC339988 Hypothetical protein LOC339988 (LOC339988), mRNA
    BC002556 RAB3IP
    NM_002002 Hs.465778 FCER2 Fc fragment of IgE, low affinity II, receptor for (CD23A)
    NM_018556 Hs.590883 SIRPB2 signal-regulatory protein beta 2
    AB020630 Hs.45719 PPP1R16B protein phosphatase 1, regulatory (inhibitor) subunit 16B
    AF298547 Hs.369279 NALP2 NACHT, leucine rich repeat and PYD containing 2
    AW157571 Hs.479066 MARLIN1 multiple coiled-coil GABABR1-binding protein
    AA767131 Hs.121432 KIAA0073 KIAA0073 protein
    M21121 Hs.514821 CCL5 chemokine (C-C motif) ligand 5
    NM_004356 Hs.54457 CD81 CD81 antigen (target of antiproliferative antibody 1)
    BF432238 Hs.585799 ZNF286 CDNA FLJ31089 fis, clone IMR321000092
    NM_004310 Hs.160673 RHOH ras homolog gene family, member H
    BC000533 Hs.567374 EIF3S8 eukaryotic translation initiation factor 3, subunit 8, 110 kDa
    U07236 Hs.470627 LCK lymphocyte-specific protein tyrosine kinase
    AI702465 Hs.23606 Transcribed sequences
    AU155091 Hs.633678 Clone IMAGE: 4814008, mRNA
    U90339 Hs.584739 ADK adenosine kinase
    AW575245 Hs.266331 FREB Fc receptor homolog expressed in B cells
    NM_030915 Hs.567598 LBH likely ortholog of mouse limb-bud and heart gene
    AI524095 Hs.403857 LY9 lymphocyte antigen 9
    AW204712 Hs.385493 C10orf128 hypothetical protein LOC170371
    U49396 Hs.408615 P2RX5 purinergic receptor P2X, ligand-gated ion channel, 5
    AA781795 Hs.546467 EPSTI1 epithelial stromal interaction 1 (breast)
    BF433219 Transcribed sequences
    BC003574 Hs.2484 TCL1A T-cell leukemia/lymphoma 1A
    AB051458 Hs.419171 KIAA1671 KIAA1671 protein
    NM_004114 Hs.6540 FGF13 fibroblast growth factor 13
    BF446578 Hs.125293 RASGEF1A RasGEF domain family, member 1A
    AA931562 Hs.444049 Transcribed sequence with weak similarity to protein ref:
    NP_060312.1 (H. sapiens) hypothetical
    protein FLJ20489 [Homo sapiens]
    BF514552 Hs.292449 FCRH3 Fc receptor-like protein 3
    X82240 Hs.2484 TCL1A T-cell leukemia/lymphoma 1A
    AW296309 Hs.405667 CD8B1 CD8 antigen, beta polypeptide 1 (p37)
    M85256 Hs.554197 IGKC Isolate donor Z clone Z55K immunoglobulin kappa light
    chain variable region mRNA, partial cds
    AF439512 Hs.387787 KLRK1 killer cell lectin-like receptor subfamily K, member 1
    NM_005442 Hs.591663 EOMES eomesodermin homolog (Xenopus laevis)
    AI424825 Hs.435052 ATP8A1 ATPase, aminophospholipid transporter
    (APLT), Class I, type 8A, member 1
    NM_006159 Hs.505326 NELL2 NEL-like 2 (chicken)
    BI547087 603190322F1 NIH_MGC_95 Homo sapiens cDNA
    clone IMAGE: 5261717 5′, mRNA sequence.
    BC001872 Hs.510635 IGHM synonym: MU; Homo sapiens immunoglobulin
    heavy constant mu, mRNA (cDNA
    clone MGC: 1228 IMAGE: 3544448), complete cds.
    AW006735 Hs.85258 CD8A CD8 antigen, alpha polypeptide (p32)
    NM_007360 Hs.387787 KLRK1 killer cell lectin-like receptor subfamily K, member 1
    NM_002261 Hs.74082 KLRC3 synonyms: NKG2E, NKG2-E; isoform NKG2-E is
    encoded by transcript variant NKG2-E; go_component:
    integral to membrane [goid 0016021] [evidence IEA];
    go_function: transmembrane receptor activity [goid 0004888]
    [evidence TAS] [pmid 9683661]; go_function: lectin
    [goid 0005530] [evidence IEA]; go_function: sugar
    binding [goid 0005529] [evidence IEA]; go_process:
    cellular defense response [goid 0006968] [evidence TAS]
    [pmid 9683661]; go_process: heterophilic cell adhesion
    [goid 0007157] [evidence IEA]; Homo sapiens killer
    cell lectin-like receptor subfamily C, member 3
    (KLRC3), transcript variant NKG2-E, mRNA.
    M13231 Hs.534032 TRGV9 T cell receptor gamma locus
    AI753792 Hs.502004 RRAS2 related RAS viral (r-ras) oncogene homolog 2
    M16768 Hs.534032 TRGV9 T-cell receptor (V-J-C) precursor; Human T-cell receptor
    gamma chain VJCI-CII-CIII region mRNA, complete cds.
    NM_003175 Hs.458346 XCL1 chemokine (C motif) ligand 2
    U96394 Hs.449601 IGL4 Clone P2-147 anti-oxidized LDL immunoglobulin
    light chain Fab mRNA, partial cds
    M27331 Hs.534032 TRGV9 T cell receptor gamma locus
    U23772 Hs.546295 XCL1 chemokine (C motif) ligand 1
    NM_004931 Hs.405667 CD8B1 CD8 antigen, beta polypeptide 1 (p37)
    NM_006275 Hs.6891 SFRS6 splicing factor, arginine/serine-rich 6
    BC020552 Hs.379186 PDCD6 programmed cell death 6
    NM_001548 Hs.20315 IFIT1 interferon-induced protein with tetratricopeptide repeats 1
    BC005248 Hs.461178 EIF1AY eukaryotic translation initiation factor 1A, Y-linked
    NM_004660 Hs.99120 DDX3Y DEAD (Asp-Glu-Ala-Asp) box polypeptide 3, Y-linked
    NM_001008 Hs.282376 RPS4Y1 ribosomal protein S4, Y-linked
  • TABLE 6
    GenBank Unigene
    ID ID Common Name Gene Description
    AA167449 Hs.529901 XIST MRNA; cDNA DKFZp686K10163
    (from clone DKFZp686K10163)
    AV646597 Hs.529901 MRNA; cDNA DKFZp686K10163
    (from clone DKFZp686K10163)
    NM_000607 Hs.567311 ORM1 orosomucoid 1
    BE644917 Hs.529901 XIST MRNA; cDNA DKFZp686K10163
    (from clone DKFZp686K10163)
    AA628440 Hs.529901 XIST MRNA; cDNA DKFZp686K10163
    (from clone DKFZp686K10163)
    AI733564 Hs.478588 Transcribed sequence with weak similarity to protein
    pir: A40138 (H. sapiens) A40138 glycogen phosphorylase
    NM_000419 Hs.411312 ITGA2B integrin, alpha 2b (platelet glycoprotein IIb
    of IIb/IIIa complex, antigen CD41B)
    BE867789 Hs.110675 PVRL2 poliovirus receptor-related 2 (herpesvirus entry mediator B)
    AA521086 Hs.99691 LAK lymphocyte alpha-kinase
    AB023212 Hs.158722 PCNX pecanex homolog (Drosophila)
    AL109714 Hs.459049 LOC283687 hypothetical protein LOC283687
    L10343 PI3 elafin has been sequenced at the protein level; pre-elafin
    has not; its existence is assumed from its molecular weight
    (PAGE analysis); putative; Homo sapiens elafin
    precursor, gene, complete cds.
    AW167424 Hs.585653 NUMB numb homolog (Drosophila)
    M35999 Hs.218040 ITGB3 integrin, beta 3 (platelet glycoprotein IIIa, antigen CD61)
    NM_002638 Hs.112341 PI3 protease inhibitor 3, skin-derived (SKALP)
    AI929792 Hs.21374 Transcribed sequences
    NM_000607 Hs.567311 ORM2 orosomucoid 1
    R64130 Hs.2164 PPBP pro-platelet basic protein (chemokine (C-X-C motif) ligand 7)
    NM_003118 Hs.111779 SPARC secreted protein, acidic, cysteine-rich (osteonectin)
    NM_002736 Hs.433068 PRKAR2B protein kinase, cAMP-dependent, regulatory, type II, beta
    AA703239 Hs.159430 Transcribed sequence with weak similarity
    to protein prf: 1303335A (H. sapiens)
    1303335A decay accelerating factor long [Homo sapiens]
    NM_004666 Hs.12114 VNN1 vanin 1
    NM_016348 Hs.519694 C5orf4 chromosome 5 open reading frame 4
    BI868572 DKFZp686I15217 603392679F1 NIH_MGC_90 Homo sapiens cDNA clone
    IMAGE: 5402706 5′, mRNA sequence.
    AW205418 Hs.495097 KIAA2025 KIAA2025 protein
    NM_001999 Hs.519294 FBN2 fibrillin 2 (congenital contractural arachnodactyly)
    AI520949 Hs.110675 PVRL2 poliovirus receptor-related 2 (herpesvirus entry mediator B)
    M25915 Hs.436657 CLU clusterin (complement lysis inhibitor, SP-40, 40,
    sulfated glycoprotein 2, testosterone-
    repressed prostate message 2, apolipoprotein J)
    BF055462 Hs.164226 THBS1 thrombospondin 1
    AI679555 Hs.527653 Transcribed sequence with weak similarity to
    protein ref: NP_060312.1 (H. sapiens)
    hypothetical protein FLJ20489 [Homo sapiens]
    AW051321 Hs.464137 CDNA FLJ30303 fis, clone BRACE2003269
    NM_000129 Hs.335513 F13A1 coagulation factor XIII, A1 polypeptide
    BE896490 Hs.595327 SNAP29 synaptosomal-associated protein, 29 kDa
    NM_000697 Hs.422967 ALOX12 arachidonate 12-lipoxygenase
    AA181060 Hs.349283 Clone IMAGE: 5288883, mRNA
    NM_002619 Hs.81564 PF4 platelet factor 4 (chemokine (C-X-C motif) ligand 4)
    AU157823 PYGL AU157823 PLACE1 Homo sapiens cDNA clone
    PLACE1009595 3′, mRNA sequence.
    BE867789 Hs.110675 PVRL2 poliovirus receptor-related 2 (herpesvirus entry mediator B)
    AA526844 Hs.556600 MYLK MSTP083 mRNA, complete cds
    BF435438 Hs.80720 Full length insert cDNA YH93B03
    NM_005231 Hs.632133 EMS1 ems1 sequence (mammary tumor and squamous cell
    carcinoma-associated (p80/85 src substrate)
    NM_007150 Hs.16622 ZNF185 zinc finger protein 185 (LIM domain)
    NM_001928 Hs.155597 DF D component of complement (adipsin)
    NM_003831 Hs.445511 RIOK3 RIO kinase 3 (yeast)
    NM_022763 Hs.159430 FAD104 FAD104
    NM_001343 Hs.481980 DAB2 disabled homolog 2, mitogen-responsive
    phosphoprotein (Drosophila)
    NM_020152 Hs.222802 C21orf7 chromosome 21 open reading frame 7
    BC029493 Hs.369265 IRAK3 interleukin-1 receptor-associated kinase 3
    BF976693 Hs.376675 CDNA FLJ34100 fis, clone FCBBF3007597
    NM_000945 Hs.280604 PPP3R1 protein phosphatase 3 (formerly 2B), regulatory
    subunit B, 19 kDa, alpha isoform (calcineurin B, type I)
    AI215106 Hs.591381 INSR insulin receptor
    AI817801 Hs.191356 BIRC1 Transcribed sequence with strong similarity
    to protein sp: Q13075 (H. sapiens)
    BIR1_HUMAN Baculoviral IAP repeat-containing protein 1
    AW270105 Hs.643902 RNF3 ring finger protein 3
    BG913589 Hs.59214 LOC144871 DnaJ (Hsp40) homolog, subfamily C, member 3
    W73230 Hs.200100 Ells1 zd56c09.s1 Soares_fetal_heart_NbHH19W Homo sapiens
    cDNA clone IMAGE: 344656 3′ similar to contains element
    MER10 repetitive element;, mRNA sequence.
    BF691447 Hs.644051 B4GALT5 UDP-Gal: betaGlcNAc beta 1,4-galactosyltransferase,
    polypeptide 5
    NM_005502 Hs.429294 ABCA1 ATP-binding cassette, sub-family A (ABC1), member 1
    NM_000361 Hs.2030 THBD thrombomodulin
    AK024569 Hs.195403 DOCK5 dedicator of cytokinesis 5
    AB051833 Hs.123239 ACRBP acrosin binding protein
    NM_004126 Hs.83381 GNG11 guanine nucleotide binding protein (G protein), gamma 11
    Y07846 Hs.322852 GAS2L1 growth arrest-specific 2 like 1
    BE327727 Hs.443301 Transcribed sequences
    M36532 Hs.155097 CA2 carbonic anhydrase II
    NM_017526 Hs.23581 OBRGRP leptin receptor
    AW205122 Hs.496572 FLJ22679 hypothetical protein FLJ22679
    AI141116 Hs.123239 ACRBP acrosin binding protein
    AW293296 Hs.163893 Transcribed sequences
    N63244 Hs.592143 TUBB1 tubulin, beta 1
    BG120535 VNN1 602346858F1 NIH_MGC_90 Homo sapiens cDNA clone
    IMAGE: 4441695 5′, mRNA sequence.
    AU152763 Hs.586165 CDNA FLJ10742 fis, clone NT2RP3001629
    BC003064 Hs.481980 DAB2 disabled homolog 2, mitogen-responsive
    phosphoprotein (Drosophila)
    N63920 Hs.596025 CDNA clone IMAGE: 5294823, partial cds
    BG251467 Hs.122514 MSCP mitochondrial solute carrier protein
    AF237762 Hs.306199 GPR84 G protein-coupled receptor 84
    AW206560 Hs.609146 Transcribed sequences
    AI971212 Hs.434494 SYNJ2 synaptojanin 2
    AL136805 Hs.278436 ZNF537 zinc finger protein 537
    BC026299 Hs.518727 Clone IMAGE: 4275461, mRNA
    BE675324 Hs.200770 Transcribed sequences
    NM_021647 Hs.178121 KIAA0626
    NM_018482 Hs.106015 DDEF1 synonyms: PAP, PAG2, ASAP1, ZG14P,
    KIAA1249; Homo sapiens development
    and differentiation enhancing factor 1 (DDEF1), mRNA.
    AA149644 Hs.150718 JAM3 junctional adhesion molecule 3
    AF325460 Hs.351812 CLECSF7 C-type (calcium dependent, carbohydrate-recognition
    domain) lectin, superfamily member 7
    AW665656 Hs.633892 GLUL glutamate-ammonia ligase (glutamine synthase)
    AA417099 Hs.465709 Transcribed sequences
    NM_003897 Hs.591785 IER3 immediate early response 3
    AF275260 Hs.592117 CXCL16 chemokine (C-X-C motif) ligand 16
    AF001540 MALAT-1 PRO1073 protein
    AI640434 Hs.601545 FLJ10357 hypothetical protein FLJ10357
    AW043859 Hs.235795 Clone IMAGE: 5263020, mRNA
    H68759 Hs.122514 Transcribed sequences
    NM_004536 Hs.191356 BIRC1 baculoviral IAP repeat-containing 1
    AF086010 Hs.335205 Full length insert cDNA clone YW04H08
    NM_003189 Hs.73828 TAL1 T-cell acute lymphocytic leukemia 1
    AW138767 Hs.274256 ELOVL7 hypothetical protein FLJ23563
    NM_003693 Hs.534497 SCARF1 scavenger receptor class F, member 1
    BG177759 Hs.497873 WDR26 WD repeat domain 26
    AW264036 Hs.478588 BCL6 B-cell CLL/lymphoma 6 (zinc finger protein 51)
    AL119957 Hs.59214 DNAJC3 DnaJ (Hsp40) homolog, subfamily C, member 3
    NM_018388 Hs.105134 MBNL3 muscleblind-like 3 (Drosophila)
    AI640434 Hs.601545 FLJ10357 hypothetical protein FLJ10357
    AI332764 Hs.516646 Transcribed sequences
    AI719730 Hs.24258 GUCY1A3 guanylate cyclase 1, soluble, alpha 3
    NM_130441 Hs.351812 CLECSF7 C-type (calcium dependent, carbohydrate-recognition
    domain) lectin, superfamily member 7
    AW796364 Hs.371594 MKNK1 Transcribed sequence with weak similarity
    to protein ref: NP_060265.1 (H. sapiens)
    hypothetical protein FLJ20378 [Homo sapiens]
    BC043380 Hs.468274 CDNA clone IMAGE: 5223469, partial cds
    NM_017698 FLJ22679
    AW069181 Hs.603149 ZAK cr43e01.x1 Human bone marrow stromal cells Homo sapiens
    cDNA clone HBMSC_cr43e01 3′, mRNA sequence.
    AF350881 Hs.272225 TRPM6 transient receptor potential cation channel,
    subfamily M, member 6
    AA082707 Hs.592262 MLL5 myeloid/lymphoid or mixed-lineage leukemia 5
    (trithorax homolog, Drosophila)
    AL035700 SH3BGRL2 continued from bA177G23.1 in Em: AL451064 match:
    proteins: Tr: O75368 Sw: P55822 Tr: Q9BPY5
    Tr: Q9BRB8 Sw: Q9WUZ7; Human DNA sequence from
    clone RP1-75K24 on chromosome 6q13-15 Contains
    the the 3′ end of the SH3BGRL2 gene for SH3 domain
    binding glutamic acid-rich protein-like 2, complete
    sequence.
    N66571 Hs.501898 MRVI1 murine retrovirus integration site 1 homolog
    AA482548 Hs.497873 WDR26 zt34b03.s1 Soares ovary tumor NbHOT Homo sapiens cDNA
    clone IMAGE: 724205 3′, mRNA sequence.
    AI052659 Hs.334019 Transcribed sequences
    AF074331 PAPSS2 Homo sapiens PAPS synthetase-2 (PAPSS2)
    mRNA, complete cds.
    AI682905 Hs.280342 PRKAR1A protein kinase, cAMP-dependent, regulatory, type I, alpha
    (tissue specific extinguisher 1)
    AI022066 Hs.480763 Transcribed sequences
    AI953847 Hs.148741 IBRDC2 IBR domain containing 2
    NM_000361 Hs.2030 THBD thrombomodulin
    AY151286 Hs.196384 PTGS2 prostaglandin-endoperoxide synthase 2 (prostaglandin
    G/H synthase and cyclooxygenase)
    AL713724 Hs.487994 MRNA; cDNA DKFZp667O0416
    (from clone DKFZp667O0416)
    AI831952 Hs.567518 NDE1 nudE nuclear distribution gene E homolog 1 (A. nidulans)
    N45231 Hs.513053 DNAJA4 DnaJ (Hsp40) homolog, subfamily A, member 4
    AA044825 Hs.520757 TBXAS1 thromboxane A synthase 1 (platelet, cytochrome
    P450, family 5, subfamily A)
    AI476341 Hs.93825 CDNA FLJ39784 fis, clone SPLEN2002314
    BF195718 Hs.221889 CSDA cold shock domain protein A
    AL833423 Hs.379548 MRNA; cDNA DKFZp313H2139
    (from clone DKFZp313H2139)
    NM_009590 Hs.143102 AOC2 amine oxidase, copper containing 2 (retina-specific)
    AA770170 Hs.499489 MIR c-mir, cellular modulator of immune recognition
    BE965029 Hs.501928 MICAL2 601658812R1 NIH_MGC_69 Homo sapiens cDNA clone
    IMAGE: 3886131 3′, mRNA sequence.
    BC018042 Hs.279815 CSAD cysteine sulfinic acid decarboxylase
    AA218974 LOC158563 zr02g12.s1 Stmtagene NT2 neuronal precursor
    937230 Homo sapiens cDNA clone
    IMAGE: 650374 3′, mRNA sequence.
    AF188298 Hs.481980 DAB2 disabled homolog 2, mitogen-responsive
    phosphoprotein (Drosophila)
    NM_005906 Hs.446125 MAK male germ cell-associated kinase
    BC002716 Hs.496572 FLJ22679 hypothetical protein FLJ22679
    AK023512 Hs.463439 SPAG9 sperm associated antigen 9
    AA010315 Hs.60371 Transcribed sequences
    AF051151 Hs.135853 TLR5 toll-like receptor 5
    BU929456 OSTF1 AGENCOURT_10424238 NIH_MGC_79 Homo sapiens
    cDNA clone IMAGE: 6663343 5′, mRNA sequence.
    NM_002607 Hs.535898 PDGFA platelet-derived growth factor alpha polypeptide
    AK024748 Hs.297343 CAMKK2 calcium/calmodulin-dependent protein kinase kinase 2, beta
    U76248 Hs.477959 SIAH2 seven in absentia homolog 2 (Drosophila)
    AI819198 Hs.208229 GPR54 G protein-coupled receptor 54
    AI452469 Hs.605187 Transcribed sequence with weak similarity to protein
    ref: NP_009032.1 (H. sapiens) sarcosine dehydrogenase;
    dimethylglycine dehydrogenase-like 1 [Homo sapiens]
    AA037483 Hs.458395 HIST1H2BC zk34a02.s1 Soares_pregnant_uterus_NbHPU Homo sapiens
    cDNA clone IMAGE: 484682 3′, mRNA sequence.
    U56237 Hs.631534 FCAR Fc fragment of IgA, receptor for
    N66045 Hs.29189 Transcribed sequences
    AW299958 Hs.524491 PAPSS2 3′-phosphoadenosine 5′-phosphosulfate synthase 2
    AK021983 Hs.106015 CDNA FLJ11921 fis, clone HEMBB1000318
    NM_002398 Hs.526754 MEIS1 Meis1, myeloid ecotropic viral integration
    site
    1 homolog (mouse)
    AV725666 Hs.220950 FOXO3A CDNA clone IMAGE: 4814010, partial cds
    AK026714 Hs.7886 PELI1 pellino homolog 1 (Drosophila)
    NM_005373 Hs.82906 MPL CDC20 cell division cycle 20 homolog (S. cerevisiae)
    AK024382 unnamed protein product; Homo sapiens cDNA
    FLJ14320 fis, clone PLACE3000455.
    AA702409 Hs.592017 Transcribed sequences
    AI074467 Hs.593643 Transcribed sequences
    AI368358 Hs.496969 NPL N-acetylneuraminate pyruvate lyase
    (dihydrodipicolinate synthase)
    H28667 Hs.444451 ZAK sterile alpha motif and leucine zipper containing kinase AZK
    AL544951 Hs.280604 PPP3R1 AL544951 Homo sapiens PLACENTA
    COT 25-NORMALIZED Homo sapiens
    cDNA clone CSODI012VC11 5-PRIME, mRNA sequence.
    AL050388 Hs.487046 SOD2 superoxide dismutase 2, mitochondrial
    AI829674 Hs.584845 Transcribed sequences
    NM_018324 Hs.24309 THEDC1 hypothetical protein FLJ11106
    AA362254 Hs.529633 Transcribed sequences
    AW130600 Hs.99472 MRNA; cDNA DKFZp564O0862
    (from clone DKFZp564O0862)
    N25732 Hs.591328 FOXO3A yx83c03.s1 Soares melanocyte 2NbHM Homo sapiens cDNA
    clone IMAGE: 268324 3′, mRNA sequence.
    NM_017815 Hs.442782 C14orf94 chromosome 14 open reading frame 94
    AK055448 ZNF587 Homo sapiens cDNA FLJ30886 fis, clone FEBRA2005014,
    weakly similar to ZINC FINGER PROTEIN 84.
    S69189 Hs.464137 ACOX1 acyl-Coenzyme A oxidase 1, palmitoyl
    AU146027 Hs.592326 AU146027 HEMBA1 Homo sapiens cDNA clone
    HEMBA1006595 3′, mRNA sequence.
    BE439987 Hs.462214 GAS7 growth arrest-specific 7
    AI363213 Hs.381058 KIAA0146 KIAA0146 protein
    BF508786 Hs.613959 MRNA; cDNA DKFZp686J24234
    (from clone DKFZp686J24234)
    BF680284 Hs.34558 CDNA: FLJ21199 fis, clone COL00235
    H93077 Hs.519694 C5orf4 chromosome 5 open reading frame 4
    AI798924 Hs.191850 Transcribed sequences
    W19983 Hs.370725 OSBPL1A oxysterol binding protein-like 1A
    AA057437 Hs.458747 Transcribed sequences
    NM_024565 Hs.14070 FLJ14166 hypothetical protein FLJ14166
    AI356228 Hs.515351 KIAA1533 KIAA1533
    AI937121 Hs.29282 Transcribed sequences
    AI806045 Hs.61438 Transcribed sequences
    N24643 Hs.446017 WSB1 WD repeat and SOCS box-containing 1
    AU122258 AU122258 MAMMAL Homo sapiens cDNA clone
    MAMMA1002009 5′, mRNA sequence.
    AI278204 Hs.99472 MRNA; cDNA DKFZp564O0862
    (from clone DKFZp564O0862)
    AW450374 Hs.593734 Clone IMAGE: 4824518, mRNA
    BE888885 Hs.220950 FOXO3A CDNA clone IMAGE: 4814010, partial cds
    AK023845 USP34 ubiquitin specific protease 34
    BF511336 Hs.591641 Transcribed sequences
    NM_007199 Hs.369265 IRAK3 interleukin-1 receptor-associated kinase 3
    AI056872 Hs.591328 Transcribed sequences
    BG251467 Hs.122514 MSCP mitochondrial solute carrier protein
    NM_022083 C1orf24 chromosome 1 open reading frame 24
    AW057518 Hs.608694 ELL2 elongation factor, RNA polymerase II, 2
    AI650285 Hs.287299 Transcribed sequence with weak similarity
    to protein ref: NP_060312.1 (H. sapiens)
    hypothetical protein FLJ20489 [Homo sapiens]
    AU147506 Hs.7886 PELI1 pellino homolog 1 (Drosophila)
    BF435852 Hs.464137 ACOX1 acyl-Coenzyme A oxidase 1, palmitoyl
    W03103 Hs.106015 DDEF1 za04b05.r1 Soares melanocyte 2NbHM Homo sapiens
    cDNA clone IMAGE: 291537 5′, mRNA sequence.
    AI458949 Hs.5204141 INGR1 interferon gamma receptor 1
    AB030034 Hs.444451 ZAK sterile alpha motif and leucine zipper containing kinase AZK
    BC011877 Hs.195403 DOCK5 Hypothetical protein LOC286061 (LOC286061), mRNA
    AL137028
    NM_007219 Hs.589884 RNF24 ring finger protein 24
    AA868809 Hs.25447 CDNA FLJ43180 fis, clone FCBBF3013846
    NM_012329 Hs.463483 MMD monocyte to macrophage differentiation-associated
    AA778783 Hs.420024 Transcribed sequence with weak similarity
    to protein ref: NP_055301.1 (H. sapiens)
    neuronal thread protein [Homo sapiens]
    NM_030918 Hs.192326 SNX27 sorting nexin family member 27
    T79640 Hs.174312 Transcribed sequences
    R91734 yp98f04.r1 Soares fetal liver spleen 1NFLS Homo sapiens
    cDNA clone IMAGE: 195487 5′, mRNA sequence.
    U44403 Hs.75367 SLA Src-like-adaptor
    BF591270 Hs.595473 KLHL8 7h44e04.x1 NCI_CGAP_Co16 Homo sapiens cDNA
    clone IMAGE: 3318846 3′, mRNA sequence.
    BC042590 Hs.434241 LOC404636 Homo sapiens cDNA clone IMAGE: 4821044, partial cds.
    NM_018586 MSCP
    BE221883 Hs.11184 UBE2R2 ubiquitin-conjugating enzyme E2R 2
    BG337478 Hs.128037 CDNA FLJ38117 fis, clone D3OST2003797
    AV723666 EFCBP2 AV723666 HTB Homo sapiens cDNA clone
    HTBABA11 5′, mRNA sequence.
    AK025898 Hs.525232 LRP10 low density lipoprotein receptor-related protein 10
    AB062477 Homo sapiens OK/SW-c1.41 mRNA, complete cds.
    AW467357 Hs.371720 SYK spleen tyrosine kinase
    AI808120 Hs.479766 RRM1 TPA regulated locus
    BE966748 ERO1L 601661247R1 NIH_MGC_72 Homo sapiens cDNA
    clone IMAGE: 3916235 3′, mRNA sequence.
    AK024677 Hs.632602 ASAHL N-acylsphingosine amidohydrolase (acid ceramidase)-like
    AL038191 Hs.474536 DKFZp566P1724_s1 566 (synonym: hfkd2) Homo sapiens
    cDNA clone DKFZp566P1724 3′, mRNA sequence.
    BG432887 Hs.442789 Transcribed sequence with weak similarity to protein
    ref: NP_005210.1 (H. sapiens) diaphanous 1; Diaphanous,
    Drosophila, homolog of, 1; deafness, autosomal dominant
    1; diaphanous
    BF516252 Hs.528703 ANKRD13 ankyrin repeat domain 13
    AA576497 Hs.492740 ATF6 activating transcription factor 6
    NM_017593 Hs.146551 BMP2K BMP2 inducible kinase
    NM_003105 Hs.368592 SORL1 sortilin-related receptor, L(DLR class) A repeats-containing
    AA706922 Hs.517034 Transcribed sequences
    AI963142 Hs.48353 CDNA FLJ32274 fis, clone PROST2000036
    AI735391 Hs.146551 BMP2K at10e09.x1 Barstead aorta HPLRB6 Homo sapiens cDNA
    clone IMAGE: 2354728 3′, mRNA sequence.
    AI807658 Hs.192326 Transcribed sequences
    BE693389 Transcribed sequences
    N32832 Hs.159430 FAD104 FAD104
    AF015452 Hs.390736 CFLAR CASP8 and FADD-like apoptosis regulator
    AL049273 Hs.429434 MRNA; cDNA DKFZp564H023 (from clone DKFZp564H023)
    BC039388 Hs.237886 Clone IMAGE: 5298774, mRNA
    AA382004 Hs.122514 MSCP EST95296 Activated T-cells II Homo sapiens
    cDNA 5′ end, mRNA sequence.
    BG334495 Hs.631749 LOC284021 hypothetical protein LOC284021
    AW367571 Hs.438673 LOC338692 hypothetical protein LOC338692
    AI084056 Hs.464217 PGS1 phosphatidylglycerophosphate synthase
    AK054840 Hs.106015 CDNA FLJ30278 fis, clone BRACE2002755
    AI051950 Hs.99472 MRNA; cDNA DKFZp564O0862
    (from clone DKFZp564O0862)
    BF724303 Hs.412293 Transcribed sequences
    AK000794 Hs.520757 CDNA FLJ20787 fis, clone COL02178
    AF153820 Hs.1547 KCNJ2 potassium inwardly-rectifying channel, subfamily J, member 2
    BE671084 Hs.293593 ARHGAP26 GTPase regulator associated with focal
    adhesion kinase pp125(FAK)
    AU146685 Hs.126667 CDNA FLJ11971 fis, clone HEMBB1001208
    AI962978 Hs.469244 WASF2 WAS protein family, member 2
    AI634046 Hs.390736 CFLAR CASP8 and FADD-like apoptosis regulator
    AW297879 Hs.436271 Transcribed sequences
    AK025534 Hs.588289 CDNA: FLJ21881 fis, clone HEP02746
    N72610 Hs.484363 Transcribed sequence with strong similarity to protein
    pdb: 1BGM (E. coli) O Chain O, Beta-Galactosidase
    BF056507 Hs.372000 NSMAF neutral sphingomyelinase (N-SMase)
    activation associated factor
    W87434 Hs.106015 Transcribed sequence with moderate similarity
    to protein sp: P39188 (H. sapiens) ALU1_HUMAN
    Alu subfamily J sequence contamination warning entry
    AF085978 Hs.474596 Homo sapiens full length insert cDNA clone YT87E05.
    N63821 Hs.175437 DKFZp434C184 za26c12.s1 Soares fetal liver spleen 1NFLS Homo sapiens
    cDNA clone IMAGE: 293686 3′, mRNA sequence.
    AV700891 Hs.517296 v-ets erythroblastosis virus E26 oncogene homolog 2 (avian)
    AI692401 Hs.29282 Transcribed sequences
    N52625 Hs.603141 ZRANB1 yv37f12.s1 Soares fetal liver spleen 1NFLS Homo sapiens
    cDNA clone IMAGE: 244943 3′ similar to contains element
    MER22 repetitive element;, mRNA sequence.
    R45471 Hs.479396 RBPSUH recombining binding protein suppressor of hairless (Drosophila)
    H67156 Hs.122514 Transcribed sequences
    BF724558 Hs.636976 Transcribed sequence with moderate similarity
    to protein pir: T02670 (H. sapiens)
    T02670 probable thromboxane A2 receptor isoform beta-human
    BE551054 Hs.279583 DREV1 DORA reverse strand protein 1
    NM_021213 Hs.285218 PCTP phosphatidylcholine transfer protein
    N93399 Hs.494406 LOC349236 CDNA FLJ46484 fis, clone THYMU3026350
    BF668314 Hs.221497 PRO0149 PRO0149 protein
    NM_002213 Hs.536663 ITGB5 integrin, beta 5
    AW974609 Hs.136398 ZCCHC6 zinc finger, CCHC domain containing 6
    AK001393 Hs.134857 MGC12458 hypothetical protein MGC12458
    NM_000313 Hs.64016 PROS1 protein S (alpha)
    AW027474 Hs.446678 NCOA2 nuclear receptor coactivator 2
    AI422414 Hs.484551 Transcribed sequences
    NM_004196 Hs.280881 CDKL1 cyclin-dependent kinase-like 1 (CDC2-related kinase)
    AI374686 Hs.122523 Transcribed sequences
    AW184034 Hs.600998 BRAF v-raf murine sarcoma viral oncogene homolog B1
    BC025707 Hs.484099 KCNMB1 potassium large conductance calcium-activated
    channel, subfamily M, beta member 1
    AA815354 Hs.520684 Hypothetical LOC284527 (LOC284527), mRNA
    AF306674 Hs.132050 MGC40368 hypothetical protein MGC40368
    W93728 Hs.77890 GUCY1B3 guanylate cyclase 1, soluble, beta 3
    NM_003326 Hs.181097 TNFSF4 tumor necrosis factor (ligand) superfamily, member 4
    (tax-transcriptionally activated glycoprotein 1, 34 kDa)
    R62432 Hs.211252 SLC24A3 solute carrier family 24 (sodium/potassium/
    calcium exchanger), member 3
    AI821895 Hs.433060 Transcribed sequences
    AW051591 Hs.388364 LOC285533 hypothetical protein LOC285533
    NM_000187 Hs.368254 HGD homogentisate 1,2-dioxygenase (homogentisate oxidase)
    AK023837 Hs.159799 THRAP2 thyroid hormone receptor associated protein 2
    BF446281 Hs.433307 BCKDHA branched chain keto acid dehydrogenase E1, alpha
    polypeptide (maple syrup urine disease)
    BE046521 Hs.191482 CUTL1 cut-like 1, CCAAT displacement protein (Drosophila)
    AW006409 Hs.532144 histone 1, H3d
    AI476341 Hs.93825 CDNA FLJ39784 fis, clone SPLEN2002314
    BF512068 Hs.575090 Transcribed sequences
    AA488687 Hs.390594 SLC7A11 solute carrier family 7, (cationic amino acid transporter,
    y+ system) member 11
    NM_002413 Hs.81874 MGST2 microsomal glutathione S-transferase 2
    R64696 CD58 yi22f12.r1 Soares placenta Nb2HP Homo sapiens
    cDNA clone IMAGE: 140015 5′
    similar to contains Alu repetitive element;, mRNA sequence.
    AV699911 Hs.310421 Transcribed sequence with weak similarity
    to protein sp: P23961 (H. sapiens)
    ALUC_HUMAN !!!! ALU CLASS C WARNING ENTRY !!!!
    NM_002350 Hs.491767 LYN v-yes-1 Yamaguchi sarcoma viral related oncogene homolog
    AI698731 Hs.202238 Transcribed sequences
    AA215519 zr97a07.r1 NCI_CGAP_GCB1 Homo sapiens cDNA clone
    IMAGE: 683604 5′, mRNA sequence.
    BC000195 Hs.279583 DREV1 DORA reverse strand protein 1
    AW304786 Hs.507260 SLC15A4 solute carrier family 15, member 4
    AA705029 Hs.529488 Transcribed sequence with strong similarity to protein
    pdb: 1BGM (E. coli) O Chain O, Beta-Galactosidase
    BC020868 Hs.632256 STAT5B signal transducer and activator of transcription 5B
    BM849515 Hs.636486 LRRK1 leucine-rich repeat kinase 1
    AW269743 Hs.254477 CDNA FLJ20182 fis, clone COLF0190
    BC039825 Hs.446125 MAK male germ cell-associated kinase
    NM_014339 Hs.129751 IL17R interleukin 17 receptor
    AW196696 Hs.484363 Transcribed sequence with strong similarity to protein
    ref: NP_060904.1 (H. sapiens) goliath protein; likely ortholog
    of mouse g1-related zinc finger protein [Homo
    sapiens]
    AI583964 Hs.544636 Transcribed sequences
    BE552138 Hs.632488 CR1 complement component (3b/4b) receptor 1-like
    AI738802 Hs.644106 CDK11 cyclin-dependent kinase (CDC2-like) 11
    BC025708 Hs.592017 FLJ11175 hypothetical protein FLJ11175
    BE327650 Hs.369978 FLJ11753 hypothetical protein FLJ11753
    AI972498 Hs.97469 a1/3GTP Clone IMAGE: 4812754, mRNA
    AI668625 Hs.380094 Full length insert cDNA YO61D09
    AI342132 Hs.485241 qt26c08.x1 Soares_pregnant_uterus_NbHPU Homo sapiens
    cDNA clone IMAGE: 1949102 3′, mRNA sequence.
    AF350251 Hs.132868 USP32 ubiquitin specific protease 32
    BC038707 Hs.420559 Homo sapiens, Similar to neuronal thread protein,
    clone IMAGE: 3932744, mRNA.
    AK022004 Hs.106015 CDNA FLJ11942 fis, clone HEMBB1000652
    BF512846 Hs.471461 ACSL3 acyl-CoA synthetase long-chain family member 3
    NM_014450 Hs.88012 SIT SHP2-interacting transmembrane adaptor protein
    BF345244 Hs.378501 LOC283989 hypothetical protein LOC283989
    AI057637 Hs.234898 LOC283445 acetyl-Coenzyme A carboxylase beta
    BC002918 Hs.213088 CHST12 carbohydrate (chondroitin 4) sulfotransferase 12
    X79782 Hs.449601 IGLJ3 H. sapiens (T1.1) mRNA for IG lambda light chain
    NM_024310 Hs.466383 PLEKHF1 pleckstrin homology domain containing, family
    F (with FYVE domain) member 1
    BF116060 Hs.519783 FLJ44216 FLJ44216 protein
    Y11339 Hs.105352 SIAT7A sialyltransferase 7 ((alpha-N-acetylneuraminyl-
    2,3-beta-galactosyl-1,3)-N-acetyl
    galactosaminide alpha-2,6-sialyltransferase) A
    BC003379 Hs.632714 L0057228 hypothetical protein from clone 643
    NM_024947 Hs.529592 PHC3 polyhomeotic like 3 (Drosophila)
    NM_000878 Hs.474787 IL2RB interleukin 2 receptor, beta
    AF031138 Hs.509513 NCR3 natural cytotoxicity triggering receptor 3
    NM_014914 Hs.435039 CENTG2 centaurin, gamma 2
    NM_030978 Hs.132499 ARPC5L actin related protein ⅔ complex, subunit 5-like
    NM_004758 Hs.112499 BZRAP1 benzodiazapine receptor (peripheral) associated protein 1
    AW338214 Hs.437696 Clone IMAGE: 5275753, mRNA
    AJ238374 TH1L Homo sapiens mRNA for putative protein
    TH1, partial, clone IMAGE ID 785447.
    AF288573 Hs.2007 TNFSF6 tumor necrosis factor (ligand) superfamily, member 6
    NM_031213 Hs.465542 C19orf27 hypothetical protein MGC5244
    AF044954 Hs.513266 NDUFB10 NADH dehydrogenase (ubiquinone) 1 beta
    subcomplex, 10, 22 kDa
    BE671663 Hs.592102 EVER2 epidermodysplasia verruciformis 2
    NM_007237 Hs.632549 SP140 SP140 nuclear body protein
    AI003777 Hs.632176 1-Sep septin 1
    AI421559 Hs.106185 RALGDS ral guanine nucleotide dissociation stimulator
    NM_020886 Hs.503891 USP28 ubiquitin specific protease 28
    AI042377 Hs.470457 Transcribed sequences
    AA742584 Hs.125914 C8orf5 chromosome 8 open reading frame 5
    BG231773 Hs.371680 CDNA FLJ46579 fis, clone THYMU3042758
    BE788984 GALM 601481076F1 NIH_MGC_68 Homo sapiens cDNA clone
    IMAGE: 3883818 5′, mRNA sequence.
    AA135722 Hs.597962 Transcribed sequences
    NM_014349 Hs.474737 APOL3 apolipoprotein L, 3
    AW268594 Hs.374421 C9orf81 chromosome 9 open reading frame 81
    NM_018641 Hs.213088 CHST12 carbohydrate (chondroitin 4) sulfotransferase 12
    BF678830 LOC152485 hypothetical protein LOC152485
    NM_006117 Hs.15250 PECI peroxisomal D3,D2-enoyl-CoA isomerase
    AW977516 Hs.592755 Transcribed sequences
    BF984830 Hs.190284 RAI1 retinoic acid induced 1
    NM_005263 Hs.73172 GFI1 growth factor independent 1
    AI347139 Hs.8162 MGC39372 hypothetical protein MGC39372
    NM_002832 Hs.402773 PTPN7 protein tyrosine phosphatase, non-receptor type 7
    NM_003362 Hs.191334 UNG uracil-DNA glycosylase
    AA679705 Hs.535464 EIF3S8 eukaryotic translation initiation factor 3, subunit 8, 110 kDa
    AY007128 Hs.469728 CDNA FLJ26765 fis, clone PRS02774
    AK074465 Hs.462833 FLJ31952 hypothetical protein FLJ31952
    NM_001504 Hs.198252 CXCR3 chemokine (C-X-C motif) receptor 3
    NM_005715 Hs.557541 UST uronyl-2-sulfotransferase
    AA683481 Hs.22546 MGC20446 hypothetical protein MGC20446
    AI829961 Hs.36972 CD7 CD7 antigen (p41)
    AI609285 Hs.503891 USP28 tw83h09.x1 NCI_CGAP_HN5 Homo sapiens
    cDNA clone IMAGE: 2266337 3′
    similar to contains Alu repetitive element; contains
    element MER29 repetitive element;, mRNA sequence.
    AL582804 Hs.403857 LY9 lymphocyte antigen 9
    NM_000107 Hs.643521 DDB2 damage-specific DNA binding protein 2, 48 kDa
    AL833685 Hs.440508 MRNA; cDNA DKFZp667O0522
    (from clone DKFZp667O0522)
    BE568184 15E1.2 cytochrome c oxidase subunit VIa polypeptide 1
    BG250907 Hs.591503 Clone IMAGE: 5178133, mRNA
    NM_018281 Hs.476319 FLJ10948 hypothetical protein FLJ10948
    BG542955 Hs.133916 LOC152485 hypothetical protein LOC152485
    AK024386 Hs.155742 GRHPR glyoxylate reductase/hydroxypyruvate reductase
    NM_024070 Hs.521075 STAG3 stromal antigen 3
    AB014719 Hs.618112 APBA2 amyloid beta (A4) precursor protein-binding,
    family A, member 2 (X11-like)
    D42043 Hs.98910 RAFTLIN raft-linking protein
    AY043466 Hs.292449 FCRH3 Fc receptor-like protein 3
    AI017564 Hs.492716 MGC21654 unknown MGC21654 product
    NM_005317 Hs.465511 GZMM granzyme M (lymphocyte met-ase 1)
    AL527430 Hs.2006 GSTM3 glutathione S-transferase M3 (brain)
    NM_014767 Hs.523009 SPOCK2 synonym: testican-2; go_component: extracellular
    matrix [goid 0005578] [evidence NAS] [pmid 10386950];
    go_function: calcium ion binding [goid 0005509] [evidence
    IDA] [pmid 10386950]; go_process: synaptogenesis
    [goid 0007416] [evidence NAS] [pmid 10386950]; go_process:
    extracellular matrix organization and biogenesis [goid
    0030198] [evidence NAS] [pmid 10386950];
    go_process: regulation of cell differentiation [goid 0045595]
    [evidence NAS] [pmid 10386950]; Homo sapiens
    sparc/osteonectin, cwcv and kazal-like domains
    proteoglycan (testican) 2 (SPOCK2), mRNA.
    BC040914 Hs.322462 Clone IMAGE: 5745627, mRNA
    AK001164 Hs.599785 CDNA FLJ10302 fis, clone NT2RM2000042
    AK097515 Hs.120250 FLJ40597 hypothetical protein FLJ40597
    NM_005608 Hs.155975 PTPRCAP protein tyrosine phosphatase, receptor type,
    C-associated protein
    AI457120 Hs.331420 PPAT phosphoribosyl pyrophosphate amidotransferase
    AA541630 Hs.170019 RUNX3 runt-related transcription factor 3
    NM_024709 Hs.519839 FLJ14146 hypothetical protein FLJ14146
    NM_013330 Hs.642710 NME7 non-metastatic cells 7, protein expressed in
    (nucleoside-diphosphate kinase)
    AL520200 Hs.420796 MGC15429 hypothetical protein MGC15429
    NM_003752 Hs.567374 EIF3S8 eukaryotic translation initiation factor 3, subunit 8, 110 kDa
    BE259729 Hs.438429 RPS19 ribosomal protein S19
    AW043830 Hs.471441 Transcribed sequences
    R12665 Hs.11594 CDNA FLJ27273 fis, clone TMS00761
    BC006428 Hs.189119 CXXC5 CXXC finger 5
    AI354636 Hs.586401 qu95c03.x1 NCI_CGAP_Gas4 Homo sapiens cDNA
    clone IMAGE: 1979812 3′, mRNA sequence.
    AK025248 Hs.546419 FLJ13220 hypothetical protein FLJ13220
    BE675549 Hs.79170 TTC9 tetratricopeptide repeat domain 9
    NM_000579 Hs.450802 CCR5 chemokine (C-C motif) receptor 5
    AB020630 Hs.45719 PPP1R16B protein phosphatase 1, regulatory (inhibitor) subunit 16B
    NM_002985 Hs.514821 CCL5 chemokine (C-C motif) ligand 5
    NM_014392 Hs.518595 D4S234E DNA segment on chromosome 4 (unique)
    234 expressed sequence
    AI821566 Hs.642748 TTC16 torsin family 2, member A
    AA771779 Hs.461074 ZFP90 zinc finger protein 90 homolog (mouse)
    AI084226 Hs.58831 TOSO regulator of Fas-induced apoptosis
    AF057557 Hs.58831 TOSO regulator of Fas-induced apoptosis
    NM_005356 Hs.470627 LCK lymphocyte-specific protein tyrosine kinase
    BC041468 Hs.434746 LOC339988 Hypothetical protein LOC339988 (LOC339988), mRNA
    BC002556 RAB3IP
    NM_002002 Hs.465778 FCER2 Fc fragment of IgE, low affinity II, receptor for (CD23A)
    NM_018556 Hs.590883 SIRPB2 signal-regulatory protein beta 2
    AB020630 Hs.45719 PPP1R16B protein phosphatase 1, regulatory (inhibitor) subunit 16B
    AF298547 Hs.369279 NALP2 NACHT, leucine rich repeat and PYD containing 2
    AW157571 Hs.479066 MARLIN1 multiple coiled-coil GABABR1-binding protein
    AA767131 Hs.121432 KIAA0073 KIAA0073 protein
    M21121 Hs.514821 CCL5 chemokine (C-C motif) ligand 5
    NM_004356 Hs.54457 CD81 CD81 antigen (target of antiproliferative antibody 1)
    BF432238 Hs.585799 ZNF286 CDNA FLJ31089 fis, clone IMR321000092
    NM_004310 Hs.160673 RHOH ras homolog gene family, member H
    BC000533 Hs.567374 EIF3S8 eukaryotic translation initiation factor 3, subunit 8, 110 kDa
    U07236 Hs.470627 LCK lymphocyte-specific protein tyrosine kinase
    AI702465 Hs.23606 Transcribed sequences
    AU155091 Hs.633678 Clone IMAGE: 4814008, mRNA
    U90339 Hs.584739 ADK adenosine kinase
    AW575245 Hs.266331 FREB Fc receptor homolog expressed in B cells
    NM_030915 Hs.567598 LBH likely ortholog of mouse limb-bud and heart gene
    AI524095 Hs.403857 LY9 lymphocyte antigen 9
    AW204712 Hs.385493 C10orf128 hypothetical protein LOC170371
    U49396 Hs.408615 P2RX5 purinergic receptor P2X, ligand-gated ion channel, 5
    AA781795 Hs.546467 EPSTI1 epithelial stromal interaction 1 (breast)
    BF433219 Transcribed sequences
    BC003574 Hs.2484 TCL1A T-cell leukemia/lymphoma 1A
    AB051458 Hs.419171 KIAA1671 KIAA1671 protein
    NM_004114 Hs.6540 FGF13 fibroblast growth factor 13
    BF446578 Hs.125293 RASGEF1A RasGEF domain family, member 1A
    AA931562 Hs.444049 Transcribed sequence with weak similarity
    to protein ref: NP_060312.1 (H. sapiens)
    hypothetical protein FLJ20489 [Homo sapiens]
    BF514552 Hs.292449 FCRH3 Fc receptor-like protein 3
    X82240 Hs.2484 TCL1A T-cell leukemia/lymphoma 1A
    AW296309 Hs.405667 CD8B1 CD8 antigen, beta polypeptide 1 (p37)
    M85256 Hs.554197 IGKC Isolate donor Z clone Z55K immunoglobulin kappa light chain
    variable region mRNA, partial cds
    AF439512 Hs.387787 KLRK1 killer cell lectin-like receptor subfamily K, member 1
    NM_005442 Hs.591663 EOMES eomesodermin homolog (Xenopus laevis)
    AI424825 Hs.435052 ATP8A1 ATPase, aminophospholipid transporter (APLT),
    Class I, type 8A, member 1
    NM_006159 Hs.505326 NELL2 NEL-like 2 (chicken)
    BI547087 603190322F1 NIH_MGC_95 Homo sapiens cDNA clone
    IMAGE: 5261717 5′, mRNA sequence.
    BC001872 Hs.510635 IGHM synonym: MU; Homo sapiens immunoglobulin
    heavy constant mu, mRNA (cDNA
    clone MGC: 1228 IMAGE: 3544448), complete cds.
    AW006735 Hs.85258 CD8A CD8 antigen, alpha polypeptide (p32)
    NM_007360 Hs.387787 KLRK1 killer cell lectin-like receptor subfamily K, member 1
    NM_002261 Hs.74082 KLRC3 synonyms: NKG2E, NKG2-E; isoform NKG2-E is
    encoded by transcript variant NKG2-E; go_component:
    integral to membrane [goid 0016021] [evidence IEA];
    go_function: transmembrane receptor activity
    [goid 0004888] [evidence TAS] [pmid 9683661]; go_function:
    lectin [goid 0005530] [evidence IEA]; go_function: sugar
    binding [goid 0005529] [evidence IEA]; go_process:
    cellular defense response [goid 0006968] [evidence TAS]
    [pmid 9683661]; go_process: heterophilic cell adhesion
    [goid 0007157] [evidence IEA]; Homo sapiens
    killer cell lectin-like receptor subfamily C, member 3
    (KLRC3), transcript variant NKG2-E, mRNA.
    M13231 Hs.534032 TRGV9 T cell receptor gamma locus
    AI753792 Hs.502004 RRAS2 related RAS viral (r-ras) oncogene homolog 2
    M16768 Hs.534032 TRGV9 T-cell receptor (V-J-C) precursor; Human T-cell receptor
    gamma chain VJCI-CII-CIII region mRNA, complete cds.
    NM_003175 Hs.458346 XCL1 chemokine (C motif) ligand 2
    U96394 Hs.449601 IGL1 Clone P2-147 anti-oxidized LDL immunoglobulin
    light chain Fab mRNA, partial cds
    M27331 Hs.534032 TRGV9 T cell receptor gamma locus
    U23772 Hs.546295 XCL1 chemokine (C motif) ligand 1
    NM_004931 Hs.405667 CD8B1 CD8 antigen, beta polypeptide 1 (p37)
    NM_006275 Hs.6891 SFRS6 splicing factor, arginine/serine-rich 6
    BC020552 Hs.379186 PDCD6 programmed cell death 6
    NM_001548 Hs.20315 IFIT1 interferon-induced protein with tetratricopeptide repeats 1
    BC005248 Hs.461178 EIF1AY eukaryotic translation initiation factor 1A, Y-linked
    NM_004660 Hs.99120 DDX3Y DEAD (Asp-Glu-Ala-Asp) box polypeptide 3, Y-linked
    NM_001008 Hs.282376 RPS4Y1 ribosomal protein S4, Y-linked
  • TABLE 7
    GenBank Unigene
    ID ID Gene Description
    AA167449 Hs.529901 MRNA; cDNA DKFZp686K10163 (from clone DKFZp686K10163)
    AV646597 Hs.529901 MRNA; cDNA DKFZp686K10163 (from clone DKFZp686K10163)
    NM_000607 Hs.567311 orosomucoid 1
    BE644917 Hs.529901 MRNA; cDNA DKFZp686K10163 (from clone DKFZp686K10163)
    AA628440 Hs.529901 MRNA; cDNA DKFZp686K10163 (from clone DKFZp686K10163)
    AI733564 Hs.478588 Transcribed sequence with weak similarity to protein pir:A40138 (H. sapiens) A40138 glycogen
    phosphorylase
    NM_000419 Hs.411312 “integrin, alpha 2b (platelet glycoprotein IIb of IIb/IIIa complex, antigen CD41B)”
    BE867789 Hs.110675 poliovirus receptor-related 2 (herpesvirus entry mediator B)
    AA521086 Hs.99691 lymphocyte alpha-kinase
    AB023212 Hs.158722 pecanex homolog (Drosophila)
    AL109714 Hs.459049 hypothetical protein LOC283687
    L10343 “elafin has been sequenced at the protein level; pre-elafin has not; its existence is assumed from its
    molecular weight (PAGE analysis); putative; Homo sapiens elafin precursor, gene, complete cds.”
    AW167424 Hs.585653 numb homolog (Drosophila)
    M35999 Hs.218040 “integrin, beta 3 (platelet glycoprotein IIIa, antigen CD61)”
    NM_002638 Hs.112341 “protease inhibitor 3, skin-derived (SKALP)”
    AI929792 Hs.21374 Transcribed sequences
    NM_000607 Hs.567311 orosomucoid 1
    R64130 Hs.2164 pro-platelet basic protein (chemokine (C-X-C motif) ligand 7)
    NM_003118 Hs.111779 “secreted protein, acidic, cysteine-rich (osteonectin)”
    NM_002736 Hs.433068 “protein kinase, cAMP-dependent, regulatory, type II, beta”
    AA703239 Hs.159430 Transcribed sequence with weak similarity to protein prf:1303335A (H. sapiens) 1303335A decay
    accelerating factor long [Homo sapiens]
    NM_004666 Hs.12114 vanin 1
    NM_016348 Hs.519694 chromosome 5 open reading frame 4
    BI868572 “603392679F1 NIH_MGC_90 Homo sapiens cDNA clone IMAGE:5402706 5′, mRNA sequence.”
    AW205418 Hs.495097 KIAA2025 protein
    NM_001999 Hs.519294 fibrillin 2 (congenital contractural arachnodactyly)
    AI520949 Hs.110675 poliovirus receptor-related 2 (herpesvirus entry mediator B)
    M25915 Hs.436657 “clusterin (complement lysis inhibitor, SP-40,40, sulfated glycoprotein 2, testosterone-repressed prostate
    message
    2, apolipoprotein J)”
    BF055462 Hs.164226 thrombospondin 1
    AI679555 Hs.527653 Transcribed sequence with weak similarity to protein ref:NP_060312.1 (H. sapiens) hypothetical protein
    FLJ20489 [Homo sapiens]
    AW051321 Hs.464137 “CDNA FLJ30303 fis, clone BRACE2003269”
    NM_000129 Hs.335513 “coagulation factor XIII, A1 polypeptide”
    BE896490 Hs.595327 “synaptosomal-associated protein, 29 kDa”
    NM_000697 Hs.422967 arachidonate 12-lipoxygenase
    AA181060 Hs.349283 “Clone IMAGE:5288883, mRNA”
    NM_002619 Hs.81564 platelet factor 4 (chemokine (C-X-C motif) ligand 4)
    AU157823 “AU157823 PLACE1 Homo sapiens cDNA clone PLACE1009595 3′, mRNA sequence.”
    BE867789 Hs.110675 poliovirus receptor-related 2 (herpesvirus entry mediator B)
    AA526844 Hs.556600 “MSTP083 mRNA, complete cds”
    BF435438 Hs.80720 Full length insert cDNA YH93B03
    NM_005231 Hs.632133 ems1 sequence (mammary tumor and squamous cell carcinoma-associated (p80/85 src substrate)
    NM_007150 Hs.16622 zinc finger protein 185 (LIM domain)
    NM_001928 Hs.155597 D component of complement (adipsin)
    NM_003831 Hs.445511 RIO kinase 3 (yeast)
    NM_022763 Hs.159430 FAD 104
    NM_001343 Hs.481980 disabled homolog 2, mitogen-responsive phosphoprotein (Drosophila)”
    NM_020152 Hs.222802 chromosome 21 open reading frame 7
    BC029493 Hs.369265 interleukin-1 receptor-associated kinase 3
    BF976693 Hs.376675 “CDNA FLJ34100 fis, clone FCBBF3007597”
    NM_000945 Hs.280604 “protein phosphatase 3 (formerly 2B), regulatory subunit B, 19 kDa, alpha isoform (calcineurin B, type I)”
    AI215106 Hs.591381 insulin receptor
    AI817801 Hs.191356 Transcribed sequence with strong similarity to protein sp:Q13075 (H. sapiens) BIR1_HUMAN Baculoviral
    IAP repeat-containing protein 1
    AW270105 Hs.643902 ring finger protein 3
    BG913589 Hs.59214 “DnaJ (Hsp40) homolog, subfamily C, member 3”
    W73230 Hs.200100 “zd56c09.s1 Soares_fetal_heart_NbHH19W Homo sapiens cDNA clone IMAGE:344656 3′ similar to
    contains element MER10 repetitive element;, mRNA sequence.”
    BF691447 Hs.644051 “UDP-Gal:betaGlcNAc beta 1,4-galactosyltransferase, polypeptide 5”
    NM_005502 Hs.429294 “ATP-binding cassette, sub-family A (ABC1), member 1”
    NM_000361 Hs.2030 thrombomodulin
    AK024569 Hs.195403 dedicator of cytokinesis 5
    AB051833 Hs.123239 acrosin binding protein
    NM_004126 Hs.83381 “guanine nucleotide binding protein (G protein), gamma 11”
    Y07846 Hs.322852 growth arrest-specific 2 like 1
    BE327727 Hs.443301 Transcribed sequences
    M36532 Hs.155097 carbonic anhydrase II
    NM_017526 Hs.23581 leptin receptor
    AW205122 Hs.496572 hypothetical protein FLJ22679
    AI141116 Hs.123239 acrosin binding protein
    AW293296 Hs.163893 Transcribed sequences
    N63244 Hs.592143 “tubulin, beta 1“
    BG120535 “602346858F1 NIH_MGC_90 Homo sapiens cDNA clone IMAGE:4441695 5′, mRNA sequence.”
    AU152763 Hs.586165 “CDNA FLJ10742 fis, clone NT2RP3001629”
    BC003064 Hs.481980 disabled homolog 2, mitogen-responsive phosphoprotein (Drosophila)”
    N63920 Hs.596025 “CDNA clone IMAGE:5294823, partial cds”
    BG251467 Hs.122514 mitochondrial solute carrier protein
    AF237762 Hs.306199 G protein-coupled receptor 84
    AW206560 Hs.609146 Transcribed sequences
    AI971212 Hs.434494 synaptojanin 2
    AL136805 Hs.278436 zinc finger protein 537
    BC026299 Hs.518727 “Clone IMAGE:4275461, mRNA”
    BE675324 Hs.200770 Transcribed sequences
    NM_021647 Hs.178121
    NM_018482 Hs.106015 “synonyms: PAP, PAG2, ASAP1, ZG14P, KIAA1249; Homo sapiens development and differentiation
    enhancing factor 1 (DDEF1), mRNA.”
    AA149644 Hs.150718 junctional adhesion molecule 3
    AF325460 Hs.351812 “C-type (calcium dependent, carbohydrate-recognition domain) lectin, superfamily member 7”
    AW665656 Hs.633892 glutamate-ammonia ligase (glutamine synthase)
    AA417099 Hs.465709 Transcribed sequences
    NM_003897 Hs.591785 immediate early response 3
    AF275260 Hs.592117 chemokine (C-X-C motif) ligand 16
    AF001540 PRO1073 protein
    AI640434 Hs.601545 hypothetical protein FLJ10357
    AW043859 Hs.235795 “Clone IMAGE:5263020, mRNA”
    H68759 Hs.122514 Transcribed sequences
    NM_004536 Hs.191356 baculoviral IAP repeat-containing 1
    AF086010 Hs.335205 Full length insert cDNA clone YW04H08
    NM_003189 Hs.73828 T-cell acute lymphocytic leukemia 1
    AW138767 Hs.274256 hypothetical protein FLJ23563
    NM_003693 Hs.534497 “scavenger receptor class F, member 1”
    BG177759 Hs.497873 WD repeat domain 26
    AW264036 Hs.478588 B-cell CLL/lymphoma 6 (zinc finger protein 51)
    AL119957 Hs.59214 “DnaJ (Hsp40) homolog, subfamily C, member 3”
    NM_018388 Hs.105134 muscleblind-like 3 (Drosophila)
    AI640434 Hs.601545 hypothetical protein FLJ10357
    AI332764 Hs.516646 Transcribed sequences
    AI719730 Hs.24258 “guanylate cyclase 1, soluble, alpha 3”
    NM_130441 Hs.351812 “C-type (calcium dependent, carbohydrate-recognition domain) lectin, superfamily member 7”
    AW796364 Hs.371594 Transcribed sequence with weak similarity to protein ref:NP_060265.1 (H. sapiens) hypothetical protein
    FLJ20378 [Homo sapiens]
    BC043380 Hs.468274 “CDNA clone IMAGE:5223469, partial cds”
    NM_017698
    AW069181 Hs.603149 “cr43e01.x1 Human bone marrow stromal cells Homo sapiens cDNA clone HBMSC_cr43e01 3′, mRNA
    sequence.”
    AF350881 Hs.272225 “transient receptor potential cation channel, subfamily M, member 6”
    AA082707 Hs.592262 “myeloid/lymphoid or mixed-lineage leukemia 5 (trithorax homolog, Drosophila)”
    AL035700 “continued from bA177G23.1 in Em:AL451064 match: proteins: Tr:O75368 Sw:P55822 Tr:Q9BPY5
    Tr:Q9BRB8 Sw:Q9WUZ7; Human DNA sequence from clone RP1-75K24 on chromosome 6q13-15
    Contains the the 3′ end of the SH3BGRL2 gene for SH3 domain binding glutamic acid-rich protein-like 2,
    complete sequence.”
    N66571 Hs.501898 murine retrovirus integration site 1 homolog
    AA482548 Hs.497873 “zt34b03.s1 Soares ovary tumor NbHOT Homo sapiens cDNA clone IMAGE:724205 3′, mRNA
    sequence.”
    AI052659 Hs.334019 Transcribed sequences
    AF074331 Homo sapiens PAPS synthetase-2 (PAPSS2) mRNA, complete cds.”
    AI682905 Hs.280342 “protein kinase, cAMP-dependent, regulatory, type I, alpha (tissue specific extinguisher 1)”
    AI022066 Hs.480763 Transcribed sequences
    AI953847 Hs.148741 IBR domain containing 2
    NM_000361 Hs.2030 thrombomodulin
    AY151286 Hs.196384 prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase)
    AL713724 Hs.487994 MRNA; cDNA DKFZp667O0416 (from clone DKFZp667O0416)
    AI831952 Hs.567518 nudE nuclear distribution gene E homolog 1 (A. nidulans)
    N45231 Hs.513053 “DnaJ (Hsp40) homolog, subfamily A, member 4”
    AA044825 Hs.520757 “thromboxane A synthase 1 (platelet, cytochrome P450, family 5, subfamily A)”
    AI476341 Hs.93825 “CDNA FLJ39784 fis, clone SPLEN2002314”
    BF195718 Hs.221889 cold shock domain protein A
    AL833423 Hs.379548 MRNA; cDNA DKFZp313H2139 (from clone DKFZp313H2139)
    NM_009590 Hs.143102 “amine oxidase, copper containing 2 (retina-specific)”
    AA770170 Hs.499489 “c-mir, cellular modulator of immune recognition”
    BE965029 Hs.501928 “601658812R1 NrH_MGC_69 Homo sapiens cDNA clone IMAGE:3886131 3′, mRNA sequence.”
    BC018042 Hs.279815 cysteine sulfinic acid decarboxylase
    AA218974 “zr02g12.s1 Stratagene NT2 neuronal precursor 937230 Homo sapiens cDNA clone IMAGE:650374 3′,
    mRNA sequence.”
    AF188298 Hs.481980 disabled homolog 2, mitogen-responsive phosphoprotein (Drosophila)”
    NM_005906 Hs.446125 male germ cell-associated kinase
    BC002716 Hs.496572 hypothetical protein FLJ22679
    AK023512 Hs.463439 sperm associated antigen 9
    AA010315 Hs.60371 Transcribed sequences
    AF051151 Hs.135853 toll-like receptor 5
    BU929456 “AGENCOURT_10424238 NrH_MGC_79 Homo sapiens cDNA clone IMAGE:6663343 5′, mRNA
    sequence.”
    NM_002607 Hs.535898 platelet-derived growth factor alpha polypeptide
    AK024748 Hs.297343 “calcium/calmodulin-dependent protein kinase kinase 2, beta”
    U76248 Hs.477959 seven in absentia homolog 2 (Drosophila)
    AI819198 Hs.208229 G protein-coupled receptor 54
    AI452469 Hs.605187 Transcribed sequence with weak similarity to protein ref:NP_009032.1 (H. sapiens) sarcosine
    dehydrogenase; dimethylglycine dehydrogenase-like 1 [Homo sapiens]
    AA037483 Hs.458395 “zk34a02.s1 Soares_pregnant_uterus_NbHPU Homo sapiens cDNA clone IMAGE:484682 3′, mRNA
    sequence.”
    U56237 Hs.631534 “Fc fragment of IgA, receptor for”
    N66045 Hs.29189 Transcribed sequences
    AW299958 Hs.524491 3′-phosphoadenosine 5′-phosphosulfate synthase 2
    AK021983 Hs.106015 “CDNA FLJ11921 fis, clone HEMBB1000318”
    NM_002398 Hs.526754 “Meis1, myeloid ecotropic viral integration site 1 homolog (mouse)”
    AV725666 Hs.220950 “CDNA clone IMAGE:4814010, partial cds”
    AK026714 Hs.7886 pellino homolog 1 (Drosophila)
    NM_005373 Hs.82906 CDC20 cell division cycle 20 homolog (S. cerevisiae)
    AK024382 “unnamed protein product; Homo sapiens cDNA FLJ14320 fis, clone PLACE3000455.”
    AA702409 Hs.592017 Transcribed sequences
    AI074467 Hs.593643 Transcribed sequences
    AI368358 Hs.496969 N-acetylneuraminate pyruvate lyase (dihydrodipicolinate synthase)
    H28667 Hs.444451 sterile alpha motif and leucine zipper containing kinase AZK
    AL544951 Hs.280604 “AL544951 Homo sapiens PLACENTA COT 25-NORMALIZED Homo sapiens cDNA clone
    CS0DI012YC11 5-PRIME, mRNA sequence.”
    AL050388 Hs.487046 superoxide dismutase 2, mitochondrial”
    AI829674 Hs.584845 Transcribed sequences
    NM_018324 Hs.24309 hypothetical protein FLJ11106
    AA362254 Hs.529633 Transcribed sequences
    AW130600 Hs.99472 MRNA; cDNA DKFZp564O0862 (from clone DKFZp564O0862)
    N25732 Hs.591328 “yx83c03.s1 Soares melanocyte 2NbHM Homo sapiens cDNA clone IMAGE:268324 3′, mRNA
    sequence.”
    NM_017815 Hs.442782 chromosome 14 open reading frame 94
    AK055448 Homo sapiens cDNA FLJ30886 fis, clone FEBRA2005014, weakly similar to ZINC FINGER PROTEIN
    84.”
    S69189 Hs.464137 “acyl-Coenzyme A oxidase 1, palmitoyl”
    AU146027 Hs.592326 “AU146027 HEMBA1 Homo sapiens cDNA clone HEMBA1006595 3′, mRNA sequence.”
    BE439987 Hs.462214 growth arrest-specific 7
    AI363213 Hs.381058 KIAA0146 protein
    BF508786 Hs.613959 MRNA; cDNA DKFZp686J24234 (from clone DKFZp686J24234)
    BF680284 Hs.34558 “CDNA: FLJ21199 fis, clone COL00235”
    H93077 Hs.519694 chromosome 5 open reading frame 4
    AI798924 Hs.191850 Transcribed sequences
    W19983 Hs.370725 oxysterol binding protein-like 1A
    AA057437 Hs.458747 Transcribed sequences
    NM_024565 Hs.14070 hypothetical protein FLJ14166
    AI356228 Hs.515351 KIAA1533
    AI937121 Hs.29282 Transcribed sequences
    AI806045 Hs.61438 Transcribed sequences
    N24643 Hs.446017 WD repeat and SOCS box-containing 1
    AU122258 “AU122258 MAMMA1 Homo sapiens cDNA clone MAMMA1002009 5′, mRNA sequence.”
    AI278204 Hs.99472 MRNA; cDNA DKFZp564O0862 (from clone DKFZp564O0862)
    AW450374 Hs.593734 “Clone IMAGE:4824518, mRNA”
    BE888885 Hs.220950 “CDNA clone IMAGE:4814010, partial cds”
    AK023845 ubiquitin specific protease 34
    BF511336 Hs.591641 Transcribed sequences
    NM_007199 Hs.369265 interleukin-1 receptor-associated kinase 3
    AI056872 Hs.591328 Transcribed sequences
    BG251467 Hs.122514 mitochondrial solute carrier protein
    NM_022083 chromosome
    1 open reading frame 24
    AW057518 Hs.608694 “elongation factor. RNA polymerase II, 2”
    AI650285 Hs.287299 Transcribed sequence with weak similarity to protein ref:NP_060312.1 (H. sapiens) hypothetical protein
    FLJ20489 [Homo sapiens]
    AU147506 Hs.7886 pellino homolog 1 (Drosophila)
    BF435852 Hs.464137 “acyl-Coenzyme A oxidase 1, palmitoyl”
    W03103 Hs.106015 “za04b05.r1 Soares melanocyte 2NbHM Homo sapiens cDNA clone IMAGE:291537 5′, mRNA
    sequence.”
    AI458949 Hs.520414 interferon gamma receptor 1
    AB030034 Hs.444451 sterile alpha motif and leucine zipper containing kinase AZK
    BC011877 Hs.195403 “Hypothetical protein LOC286061 (LOC286061), mRNA”
    AL137028
    NM_007219 Hs.589884 ring finger protein 24
    AA868809 Hs.25447 “CDNA FLJ43180 fis, clone FCBBF3013846”
    NM_012329 Hs.463483 monocyte to macrophage differentiation-associated
    AA778783 Hs.420024 Transcribed sequence with weak similarity to protein ref:NP_055301.1 (H. sapiens) neuronal thread
    protein [Homo sapiens]
    NM_030918 Hs.192326 sorting nexin family member 27
    T79640 Hs.174312 Transcribed sequences
    R91734 “yp98f04.r1 Soares fetal liver spleen 1NFLS Homo sapiens cDNA clone IMAGE:195487 5′, mRNA
    sequence.”
    U44403 Hs.75367 Src-like-adaptor
    BF591270 Hs.595473 “7h44e04.x1 NCI_CGAP_Co16 Homo sapiens cDNA clone IMAGE:3318846 3′, mRNA sequence.”
    BC042590 Hs.434241 Homo sapiens cDNA clone IMAGE:4821044, partial cds.”
    NM_018586
    BE221883 Hs.11184 ubiquitin-conjugating enzyme E2R 2
    BG337478 Hs.128037 “CDNA FLJ38117 fis, clone D3OST2003797”
    AV723666 “AV723666 HTB Homo sapiens cDNA clone HTBABA11 5′, mRNA sequence.”
    AK025898 Hs.525232 low density lipoprotein receptor-related protein 10
    AB062477 Homo sapiens OK/SW-cl.41 mRNA, complete cds.”
    AW467357 Hs.371720 spleen tyrosine kinase
    AI808120 Hs.479766 TPA regulated locus
    BE966748 “601661247R1 NIH_MGC_72 Homo sapiens cDNA clone IMAGE:3916235 3′, mRNA sequence.”
    AK024677 Hs.632602 N-acylsphingosine amidohydrolase (acid ceramidase)-like
    AL038191 Hs.474536 “DKFZp566P1724_s1 566 (synonym: hfkd2) Homo sapiens cDNA clone DKFZp566P1724 3′, mRNA
    sequence.”
    BG432887 Hs.442789 “Transcribed sequence with weak similarity to protein ref:NP_005210.1 (H. sapiens) diaphanous 1;
    Diaphanous, Drosophila, homolog of, 1; deafness, autosomal dominant 1; diaphanous”
    BF516252 Hs.528703 ankyrin repeat domain 13
    AA576497 Hs.492740 activating transcription factor 6
    NM_017593 Hs.146551 BMP2 inducible kinase
    NM_003105 Hs.368592 “sortilin-related receptor, L(DLR class) A repeats-containing”
    AA706922 Hs.517034 Transcribed sequences
    AI963142 Hs.48353 “CDNA FLJ32274 fis, clone PROST2000036”
    AI735391 Hs.146551 “at10e09.x1 Barstead aorta HPLRB6 Homo sapiens cDNA clone IMAGE:2354728 3′, mRNA sequence.”
    AI807658 Hs.192326 Transcribed sequences
    BE693389 Transcribed sequences
    N32832 Hs.159430 FAD 104
    AF015452 Hs.390736 CASP8 and FADD-like apoptosis regulator
    AL049273 Hs.429434 MRNA; cDNA DKFZp564H023 (from clone DKFZp564H023)
    BC039388 Hs.237886 “Clone IMAGE:5298774, mRNA“
    AA382004 Hs.122514 “EST95296 Activated T-cells II Homo sapiens cDNA 5′ end, mRNA sequence.”
    BG334495 Hs.631749 hypothetical protein LOC284021
    AW367571 Hs.438673 hypothetical protein LOC338692
    AI084056 Hs.464217 phosphatidylglycerophosphate synthase
    AK054840 Hs.106015 “CDNA FLJ30278 fis, clone BRACE2002755”
    AI051950 Hs.99472 MRNA; cDNA DKFZp564O0862 (from clone DKFZp564O0862)
    BF724303 Hs.412293 Transcribed sequences
    AK000794 Hs.520757 “CDNA FLJ20787 fis, clone COL02178”
    AF153820 Hs.1547 “potassium inwardly-rectifying channel, subfamily J, member 2”
    BE671084 Hs.293593 GTPase regulator associated with focal adhesion kinase pp125(FAK)
    AU146685 Hs.126667 “CDNA FLJ11971 fis, clone HEMBB1001208“
    AI962978 Hs.469244 “WAS protein family, member 2”
    AI634046 Hs.390736 CASP8 and FADD-like apoptosis regulator
    AW297879 Hs.436271 Transcribed sequences
    AK025534 Hs.588289 “CDNA: FLJ21881 fis, clone HEP02746”
    N72610 Hs.484363 “Transcribed sequence with strong similarity to protein pdb:1BGM (E. coli) O Chain O, Beta-
    Galactosidase”
    BF056507 Hs.372000 neutral sphingomyelinase (N-SMase) activation associated factor
    W87434 Hs.106015 Transcribed sequence with moderate similarity to protein sp:P39188 (H. sapiens) ALU1_HUMAN Alu
    subfamily J sequence contamination warning entry
    AF085978 Hs.474596 Homo sapiens full length insert cDNA clone YT87E05.
    N63821 Hs.175437 “za26c12.s1 Soares fetal liver spleen 1NFLS Homo sapiens cDNA clone IMAGE:293686 3′, mRNA
    sequence.”
    AV700891 Hs.517296 v-ets erythroblastosis virus E26 oncogene homolog 2 (avian)
    AI692401 Hs.29282 Transcribed sequences
    N52625 Hs.603141 “yv37f12.s1 Soares fetal liver spleen 1NFLS Homo sapiens cDNA clone IMAGE:244943 3′ similar to
    contains element MER22 repetitive element;, mRNA sequence.”
    R45471 Hs.479396 recombining binding protein suppressor of hairless (Drosophila)
    H67156 Hs.122514 Transcribed sequences
    BF724558 Hs.636976 Transcribed sequence with moderate similarity to protein pir:T02670 (H. sapiens) T02670 probable
    thromboxane A2 receptor isoform beta - human
    BE551054 Hs.279583 DORA reverse strand protein 1
    NM_021213 Hs.285218 phosphatidylcholine transfer protein
    N93399 Hs.494406 “CDNA FLJ46484 fis, clone THYMU3026350”
    BF668314 Hs.221497 PRO0149 protein
    NM_002213 Hs.536663 “integrin, beta 5”
    AW974609 Hs.136398 “zinc finger, CCHC domain containing 6”
    AK001393 Hs.134857 hypothetical protein MGC12458
    NM_000313 Hs.64016 protein S (alpha)
    AW027474 Hs.446678 nuclear receptor coactivator 2
    AI422414 Hs.484551 Transcribed sequences
    NM_004196 Hs.280881 cyclin-dependent kinase-like 1 (CDC2-related kinase)
    AI374686 Hs.122523 Transcribed sequences
    AW184034 Hs.600998 v-raf murine sarcoma viral oncogene homolog B1
    BC025707 Hs.484099 “potassium large conductance calcium-activated channel, subfamily M, beta member 1”
    AA815354 Hs.520684 “Hypothetical LOC284527 (LOC284527), mRNA”
    AF306674 Hs.132050 hypothetical protein MGC40368
    W93728 Hs.77890 “guanylate cyclase 1, soluble, beta 3”
    NM_003326 Hs.181097 “tumor necrosis factor (ligand) superfamily, member 4 (tax-transcriptionally activated glycoprotein 1,
    34 kDa)”
    R62432 Hs.211252 “solute carrier family 24 (sodium/potassium/calcium exchanger), member 3”
    AI821895 Hs.433060 Transcribed sequences
    AW051591 Hs.388364 hypothetical protein LOC285533
    NM_000187 Hs.368254 “homogentisate 1,2-dioxygenase (homogentisate oxidase)”
    AK023837 Hs.159799 thyroid hormone receptor associated protein 2
    BF446281 Hs.433307 “branched chain keto acid dehydrogenase E1, alpha polypeptide (maple syrup urine disease)”
    BE046521 Hs.191482 “cut-like 1, CCAAT displacement protein (Drosophila)”
    AW006409 Hs.532144 “histone 1, H3d”
    AI476341 Hs.93825 “CDNA FLJ39784 fis, clone SPLEN2002314”
    BF512068 Hs.575090 Transcribed sequences
    AA488687 Hs.390594 “solute carrier family 7, (cationic amino acid transporter, y+ system) member 11”
    NM_002413 Hs.81874 microsomal glutathione S-transferase 2
    R64696 “yi22f12.r1 Soares placenta Nb2HP Homo sapiens cDNA clone IMAGE:140015 5′ similar to contains Alu
    repetitive element;, mRNA sequence.”
    AV699911 Hs.310421 Transcribed sequence with weak similarity to protein sp:P23961 (H. sapiens) ALUC_HUMAN!!!! ALU
    CLASS C WARNING ENTRY!!!!
    NM_002350 Hs.491767 v-yes-1 Yamaguchi sarcoma viral related oncogene homolog
    AI698731 Hs.202238 Transcribed sequences
    AA215519 “zr97a07.r1 NCI_CGAP_GCB1 Homo sapiens cDNA clone IMAGE:683604 5′, mRNA sequence.”
    BC000195 Hs.279583 DORA reverse strand protein 1
    AW304786 Hs.507260 “solute carrier family 15, member 4”
    AA705029 Hs.529488 “Transcribed sequence with strong similarity to protein pdb:1BGM (E. coli) O Chain O, Beta-
    Galactosidase”
    BC020868 Hs.632256 signal transducer and activator of transcription 5B
    BM849515 Hs.636486 leucine-rich repeat kinase 1
    AW269743 Hs.254477 “CDNA FLJ20182 fis, clone COLF0190”
    BC039825 Hs.446125 male germ cell-associated kinase
    NM_014339 Hs.129751 interleukin 17 receptor
    AW196696 Hs.484363 Transcribed sequence with strong similarity to protein ref:NP_060904.1 (H. sapiens) goliath protein; likely
    ortholog of mouse g1-related zinc finger protein [Homo sapiens]
    AI583964 Hs.544636 Transcribed sequences
    BE552138 Hs.632488 complement component (3b/4b) receptor 1-like
    AI738802 Hs.644106 cyclin-dependent kinase (CDC2-like) 11
    BC025708 Hs.592017 hypothetical protein FLJ11175
    BE327650 Hs.369978 hypothetical protein FLJ11753
    AI972498 Hs.97469 “Clone IMAGE:4812754, mRNA”
    AI668625 Hs.380094 Full length insert cDNA YO61D09
    AI342132 Hs.485241 “qt26c08.x1 Soares_pregnant_uterus_NbHPU Homo sapiens cDNA clone IMAGE:1949102 3′, mRNA
    sequence.”
    AF350251 Hs. 132868 ubiquitin specific protease 32
    BC038707 Hs.420559 Homo sapiens, Similar to neuronal thread protein, clone IMAGE:3932744, mRNA.”
    AK022004 Hs.106015 “CDNA FLJ11942 fis, clone HEMBB1000652”
    BF512846 Hs.471461 acyl-CoA synthetase long-chain family member 3
    AW450403 Hs.97270 “family with sequence similarity 13, member A1”
    AW268357 Hs. 132868 ubiquitin specific protease 32
    AF207547 Hs.78960 “LATS, large tumor suppressor, homolog 2 (Drosophila)”
    AK025759 Hs.592692 Clone 23872 mRNA sequence
    AW002073 Hs.606630 Transcribed sequences
    AW974815 Hs.444451 Transcribed sequences
    AW294022 Hs.308710 KIAA1718 protein
    AI740571 Hs.159130 Transcribed sequence with weak similarity to protein sp:P39188 (H. sapiens) ALU1_HUMAN Alu
    subfamily J sequence contamination warning entry
    AI290654 Hs.26403 hypothetical protein LOC283578
    AW119113 Hs.2030 thrombomodulin
    R71245 “yi54e05.s1 Soares placenta Nb2HP Homo sapiens cDNA clone IMAGE:143072 3′ similar to gb:M21121
    T-CELL SPECIFIC RANTES PROTEIN PRECURSOR (HUMAN);, mRNA sequence.”
    BF357738 Hs.584811 Transcribed sequences
    AW020871 Hs.499209 “CDNA FLJ90139 fis, clone HEMBB1001026, weakly similar to ENDOSOMAL P24A PROTEIN
    PRECURSOR.”
    BE962615 Hs.643691 sorting nexin 3
    NM_144665 Hs.191599 sestrin 3
    AA252762 Hs.505516 KIAA1463 protein
    AI023699 Hs.371594 MAP kinase-interacting serine/threonine kinase 1
    AW502463 Hs.504096 Cas-Br-M (murine) ecotropic retroviral transforming sequence
    AK096134 Hs.378150 “Chromosome 4 unknown transcript 1 variant 2 mRNA, partial sequence, alternatively spliced”
    AW291297 Hs.420272 “H2A histone family, member Y”
    AA524299 Hs.525232 Transcribed sequence with moderate similarity to protein sp:P39192 (H. sapiens) ALU5_HUMAN Alu
    subfamily SC sequence contamination warning entry
    BE503981 Hs.420272 “H2A histone family, member Y”
    BE894882 Hs.130853 “601434066F1 NIH_MGC_72 Homo sapiens cDNA clone IMAGE:3919073 5′, mRNA sequence.”
    AV700946 Hs.432337 Transcribed sequence with weak similarity to protein pir:I49130 (M. musculus) I49130 reverse
    transcriptase - mouse
    BF002625 Hs.612374 Transcribed sequences
    AW295340 Hs.99691 Transcribed sequence with weak similarity to protein sp:P39192 (H. sapiens) ALU5_HUMAN Alu
    subfamily SC sequence contamination warning entry
    BF062244 Hs.144333 lin-7 homolog A (C. elegans)
    AF050145 Hs.460960 iduronate 2-sulfatase (Hunter syndrome)
    AK091836 Hs.484678 MRNA; cDNA DKFZp686I05132 (from clone DKFZp686I05132)
    AI939422 Hs.461253 Transcribed sequences
    D29805 Hs.272011 “UDP-Gal:betaGlcNAc beta 1,4-galactosyltransferase, polypeptide 1”
    NM_025158 Hs.306769 RUN and FYVE domain containing 1
    AA195936 Hs.82719 hypothetical protein MGC21416
    AI079521 Hs.594059 fring
    AF130091 Hs.72071 potassium channel tetramerisation domain containing 9
    BC020843 Hs.616365 hepatitis A virus cellular receptor 2
    AW301766 Hs.527653 “decay accelerating factor for complement (CD55, Cromer blood group system)”
    BC035084 Hs.536364 Full length insert cDNA clone ZD78D03
    BC008306 Hs.287471 NICE-3 protein
    M24779 Hs.81170 pim-1 oncogene
    BM014995 “603640947F1 NIH_MGC_87 Homo sapiens cDNA clone IMAGE:5417266 5′, mRNA sequence.”
    BC020868 Hs.632256 signal transducer and activator of transcription 5B
    T83380 “ye03h05.s1 Soares fetal liver spleen 1NFLS Homo sapiens cDNA clone IMAGE:116697 3′, mRNA
    sequence.”
    N39126 Hs.191346 Transcribed sequences
    AB053312 Hs.390736 “ALS2CR10 mRNA,.”
    BF223935 Hs.268774 Transcribed sequences
    X62009 Hs.519294 fibrillin 2 (congenital contractural arachnodactyly)
    BF508977 Hs.463059 signal transducer and activator of transcription 3 (acute-phase response factor)
    BF510533 Hs.642655 Transcribed sequences
    AK024177 Hs.529860 Homo sapiens CDNA FLJ14115 fis, clone MAMMA1001760.”
    AI754064 Hs.532315 “solute carrier family 31 (copper transporters), member 1”
    BC016012 Hs.471492 “eukaryotic translation initiation factor 2C, 4”
    BE083088 Hs.591602 “RC2-BT0642-030400-021-C05 BT0642 Homo sapiens cDNA, mRNA sequence.”
    BC040178 Homo sapiens GTP binding protein 5 (putative), mRNA (cDNA clone IMAGE:4797390), with apparent
    retained intron.”
    AL039447 Hs.642739 chromosome 9 open reading frame 48
    AL832141 Hs.369592 thyroid adenoma associated
    AL555336 Hs.380635 Transcribed sequence with moderate similarity to protein pir:B28096 (H. sapiens) B28096 line-1 protein
    ORF2 - human
    AF315688 Hs.591083 “interferon, kappa”
    AI749193 Hs.374067 ubiquitin protein ligase E3B
    AI201594 Hs.568928 MRNA; cDNA DKFZp762M127 (from clone DKFZp762M127)
    NM_004488 glycoprotein V (platelet)
    BC013319 Hs.506381 “FYVE, RhoGEF and PH domain containing 6”
    NM_002359 Hs.252229 v-maf musculoaponeurotic fibrosarcoma oncogene homolog G (avian)
    AI357616 Hs.127934 hypothetical protein LOC90133
    AU146585 Hs.386168 “CDNA FLJ10258 fis, clone HEMBB1000908”
    M62762 “Human vacuolar H+ ATPase proton channel subunit mRNA, complete cds.”
    BG109846 Hs.616796 protein x 013
    NM_005890 “synonyms: MGC1348, KIAA0394; isoform b is encoded by transcript variant b; go_component: kinesin
    complex [goid 0005871] [evidence IEA]; go_function: transcription factor activity [goid 0003700]
    [evidence TAS] [pmid 9736752]; go_process: cell cycle arrest [goid 0007050] [evidence TAS] [pmid
    9736752]; go_process: cell growth and/or maintenance [goid 0008151] [evidence IEA]; go_process:
    development [goid 0007275] [evidence IEA]; go_process: neurogenesis [goid 0007399] [evidence IEA];
    Homo sapiens growth arrest-specific 7 (GAS7), transcript variant b, mRNA.”
    AB040966 Hs.515351 KIAA1533
    AI652645 Hs.475506 KIAA0763 gene product
    AK022387 Hs.491682 “protein kinase, DNA-activated, catalytic polypeptide”
    AK023308 “unnamed protein product; Homo sapiens CDNA FLJ13246 fis, clone OVARC1000682, highly similar to
    PROCESSING ALPHA-1,2-MANNOSIDASE (EC 3.2.1.—).”
    BE855963 Hs.508725 hypothetical protein FLJ12118
    NM_005955 Hs.591505 metal-regulatory transcription factor 1
    AF132033 “intelligence reducing insertion protein INGRIN; Homo sapiens OPA-containing protein (HOPA) gene,
    complete cds.”
    NM_024822 “synonyms: FLJ22601, dJ1158H2.1; Homo sapiens hypothetical protein FLJ22843 (FLJ22843), mRNA.”
    BE856376 Hs.250616 lipidosin
    AI684710 Hs.514920 nuclear domain 10 protein
    NM_018407 Hs.492314 lysosomal associated protein transmembrane 4 beta
    AF086079 Hs.231895 Full length insert cDNA clone YZ82H07
    BC026969 Hs.492716 Homo sapiens unknown MGC21654 product, mRNA (cDNA clone IMAGE:5116073), partial cds.”
    AK000834 Hs.449434 Homo sapiens CDNA FLJ20827 fis, clone ADKA03543.”
    AF086444 Hs.390420 Full length insert cDNA clone ZD81E01
    NM_015322 Hs.362733 fem-1 homolog b (C. elegans)
    NM_016172 Hs.9194 ubiquitin associated domain containing 1
    AL713719 Hs.29189 MRNA; cDNA DKFZp667K1916 (from clone DKFZp667K1916)
    AA897191 Hs.279245 “transforming, acidic coiled-coil containing protein 1”
    R91245 “yp94d10.s1 Soares fetal liver spleen 1NFLS Homo sapiens cDNA clone IMAGE:195091 3′, mRNA
    sequence.”
    AI867175 Hs.504907 chromosome 20 open reading frame 106
    BG149547 Hs.408458 Transcribed sequences
    NM_012204 Hs.22302 “general transcription factor IIIC, polypeptide 4, 90 kDa”
    NM_025244 Hs.120267 “testis specific, 10”
    BF433757 Hs.528993 ralA binding protein 1
    BC026007 Hs.41735 “Clone IMAGE:4704511, mRNA”
    BC014891 Hs.620701 KIAA0701 protein
    AW590925 Hs.419240 Transcribed sequences
    AL080215 Hs.516578 MRNA; cDNA DKFZp586J0323 (from clone DKFZp586J0323)
    X13230 Hs.387262 MCF.2 cell line derived transforming sequence
    AI821782 Hs.97858 Transcribed sequences
    BI869014 Hs.627200 “CDNA FLJ33783 fis, clone BRSSN2007504”
    BF434655 Hs.6734 “7p02f01.x1 NCI_CGAP_Ov18 Homo sapiens cDNA clone IMAGE:3644688 3′, mRNA sequence.”
    AK026026 Hs.474150 BH3 interacting domain death agonist
    AI819386 Hs.634057 MRNA; cDNA DKFZp686B 14224 (from clone DKFZp686B14224)
    BF969352 Hs.195080 “CDNA clone IMAGE:4152985, partial cds”
    AU145749 Hs.20516 “CDNA FLJ11764 fis, clone HEMBA1005685”
    NM_006547 Hs.432616 IGF-II mRNA-binding protein 3
    L11702 Hs.591810 glycosylphosphatidylinositol specific phospholipase D1
    BE326728 Hs.642633 hypothetical protein MGC11266
    AW379790 Hs.200063 “RC3-HT0253-181099-011-c03 HT0253 Homo sapiens cDNA, mRNA sequence.”
    NM_023034 Hs.608111 Wolf-Hirschhorn syndrome candidate 1-like 1
    AI936976 Hs.509017 “glycine-, glutamate-, thienylcyclohexylpiperidine-binding protein”
    BC033224 Hs.207457 DKFZP434L187 protein
    BC015590 Hs.382046 “CDNA clone IMAGE:4643842, partial cds”
    AU144449 Transcribed sequence with moderate similarity to protein ref:NP_071431.1 (H. sapiens) cytokine receptor-
    like factor 2; cytokine receptor CRL2 precusor [Homo sapiens]
    AB029030 Hs.21554 KIAA1107 protein
    AI935717 Hs.471637 hypothetical protein MGC42174
    AL050042 Hs.538604 Homo sapiens mRNA; cDNA DKFZp566L0824 (from clone DKFZp566L0824).
    NM_024743 Hs.122583 hypothetical protein FLJ21934
    BC017894 Hs.420024 chromosome 10 open reading frame 46
    NM_024516 Hs.632177 hypothetical protein MGC4606
    AI214466 Hs.283011 “qg69b04.x1 Soares_NFL_T_GBC_S1 Homo sapiens cDNA clone IMAGE:1840399 3′ similar to
    TR:Q13443 Q13443 METALLOPROTEASE/DISINTEGRIN/CYSTEINE-RICH PROTEIN
    PRECURSOR.;, mRNA sequence.”
    BC039406 Hs.623811 “Clone IMAGE:5300951, mRNA”
    AI280108 Hs.487511 chromosome 7 open reading frame 26
    AL031228
    AL139228 “match: proteins: Sw:P51151 Sw:P24408; Human DNA sequence from clone RP4-540A13 on
    chromosome Xq22.1-22.3 Contains the gene for a novel protein similar to RAB9 (member RAS oncogene
    family), ESTs, STSS and GSSs, complete sequence.”
    BC001793 Hs.412468 kelch domain containing 3
    AV741657 Hs.633089 amine oxidase (flavin containing) domain 2
    AF078842 Hs.323342 “hqp0207; similar to bovine and pig tubulin-tyrosine ligase (TTL): Swiss-Prot Accession Numbers P38584
    and P38160; Homo sapiens HOTTL protein mRNA, complete cds.”
    NM_017686 Hs.632427 ganglioside induced differentiation associated protein 2
    AL390171 Hs.480356 vacuolar protein sorting 52 (yeast)
    AI796581 Hs.438550 KIAA0056 protein
    BE781103 Hs.43619 lung cancer metastasis-related protein 1
    NM_024531 Hs.6459 putative G-protein coupled receptor GPCR41
    AW628835 Hs.444950 “TBC1 domain family, member 10”
    NM_017876 Hs.69554 ring finger protein 126
    AB011117 Hs.128627 signal-induced proliferation-associated 1 like 3
    NM_016579 Hs.558499 8D6 antigen
    NM_016292 Hs.30345 heat shock protein 75
    AA534894 Hs.162659 chromosome 9 open reading frame 28
    NM_006876 Hs.8526 “UDP-GlcNAc:betaGal beta-1,3-N-acetylglucosaminyltransferase 6”
    R67325 Hs.588291 “Hypothetical protein LOC255512, mRNA (cDNA clone IMAGE:5274144), partial cds”
    AL050022 Hs.438991 DKFZP564D116 protein
    AF219116 Hs.415299 inosine triphosphatase (nucleoside triphosphate pyrophosphatase)
    NM_020153 Hs.533738 hypothetical protein FLJ21827
    NM_145315 Hs.259666 lactation elevated 1
    BC005133 Hs.326586 tRNA splicing 2′ phosphotransferase 1
    AA514326 Hs.334684 hypothetical protein MGC10485
    M99436 Hs.332173 “transducin-like enhancer of split 2 (E(sp1) homolog, Drosophila)”
    NM_012236 Hs.571874 sex comb on midleg homolog 1 (Drosophila)
    H07095 “yl81h11.s1 Soares infant brain 1NIB Homo sapiens cDNA clone IMAGE:44797 3′, mRNA sequence.”
    AK000185 Hs.306389 “CDNA FLJ20178 fis, clone COL09990”
    BE677453 Hs.91531 “myeloid/lymphoid or mixed-lineage leukemia (trithorax homolog, Drosophila); translocated to, 6”
    AA425633 “zv47a01.s1 Soares ovary tumor NbHOT Homo sapiens cDNA clone IMAGE:756744 3′, mRNA
    sequence.”
    W22625 “71E5 Human retina cDNA Tsp509I-cleaved sublibrary Homo sapiens cDNA not directional, mRNA
    sequence.”
    N21279 “yx53c01.s1 Soares melanocyte 2NbHM Homo sapiens cDNA clone IMAGE:265440 3′, mRNA
    sequence.”
    M77171 “Human zinc finger protein gene, partial cds.”
    NM_014015 Hs.592051 dexamethasone-induced transcript
    AW016250 Hs.604838 “UI-H-BI0p-abl-c-02-0-UI.s1 NCI_CGAP_Sub2 Homo sapiens cDNA clone IMAGE:2712171 3′, mRNA
    sequence.”
    AB011173 Hs.591518 amine oxidase (flavin containing) domain 2
    NM_001667 Hs.502836 sorting nexin 15
    NM_017514 Hs.632839 likely ortholog of mouse plexin 3
    AK026088 Hs.493739 ubiquitin associated protein 2
    AA404269 Hs.524348 prickle-like 1 (Drosophila)
    NM_017637 Hs.435309
    BC001745 DNA segment on chromosome 4 (unique) 234 expressed sequence
    D38122 Hs.2007 “tumor necrosis factor (ligand) superfamily, member 6”
    AI096888 Hs.475334 KIAA0280 protein
    AV702405 Hs.632801 emopamil binding protein (sterol isomerase)
    NM_015540 Hs.371045 DKFZP727M111 protein
    NM_012222 Hs.271353 mutY homolog (E. coli)
    NM_000386 Hs.371914 bleomycin hydrolase
    NM_014593 Hs.180933 CXXC finger 1 (PHD domain)
    NM_024096 Hs.632191 XTP3-transactivated protein A
    AI885290 Hs.445818 spondin 1, extracellular matrix protein”
    AK002076 Hs.517948 DEAH (Asp-Glu-Ala-His) box polypeptide 30
    NM_018127 Hs.434232 elaC homolog 2 (E. coli)
    AF190863 Hs.460336 “golgi associated, gamma adaptin ear containing, ARF binding protein 2”
    BE646227 Hs.613098 “protein tyrosine phosphatase, non-receptor type 23”
    AW572279 Hs.515840 DNA (cytosine-5-)-methyltransferase 3 alpha
    N49268 Hs.373857 Kruppel-like factor 12
    D26351 Hs.65758 inositol 1,4,5-triphosphate receptor, type 3”
    BG149482 “nad29d02.x1 NCI_CGAP_Lu24 Homo sapiens cDNA clone IMAGE:3366939 3′ similar to contains L1.t1
    L1 L1 repetitive element;, mRNA sequence.”
    NM_024102 Hs.204773 MEP50 protein
    NM_001610 Hs.532492 acid phosphatase 2, lysosomal”
    NM_024765
    BF110434 Hs.562802 hypothetical protein R29124_1
    BC030552 Hs.302963 “Clone IMAGE:5223566, mRNA”
    AW571582 Hs.618112 “amyloid beta (A4) precursor protein-binding, family A, member 2 (X11-like)”
    BC000638 Hs.514151 gasdermin-like
    M57707 Hs.1497 “retinoic acid receptor, gamma”
    NM_024092 Hs.13662 hypothetical protein MGC5508
    AB011087 Hs.495349 KIAA0515
    AK094684 Hs.363407 “LOC401124 (LOC401124), mRNA”
    BC003170 Hs.490551 NICE-4 protein
    AB033832 Hs.352298 platelet derived growth factor D
    AL359941 Hs.593311 programmed cell death 6
    NM_015185 Hs.54697
    BC019022 Hs.531856 hypothetical gene supported by BC007071
    AU154785 Hs.31532 “AU154785 NT2RP4 Homo sapiens cDNA clone NT2RP4002888 3′, mRNA sequence.”
    BF508604 Hs.632709 regulator of nonsense transcripts 1
    AF308301 Hs.18946 mitochondrial ribosomal protein S26
    AA634138 Hs.593575 chromosome 6 open reading frame 49
    BF339831 Hs.239500 hypothetical protein MGC13114
    AI952009 Hs.523009 “sparc/osteonectin, cwcv and kazal-like domains proteoglycan (testican) 2”
    N29877 Hs.596783 taxilin
    AW190316 Hs.221447 NADH:ubiquinone oxidoreductase MLRQ subunit homolog
    N62126 Hs.32374 deltex 3 homolog (Drosophila)
    BF447901 Hs.97837 “Similar to Group X secretory phospholipase A2 precursor (Phosphatidylcholine 2-acylhydrolase GX)
    (GX sPLA2) (SPLA2-X) (LOC388229), mRNA”
    NM_022743 Hs.567571 SET and MYND domain containing 3
    AL133055 Hs.636446 hypothetical protein DKFZp434J1015
    D49958 Hs.75819 glycoprotein M6A
    U37012 Hs.493202 “cleavage and polyadenylation specific factor 1, 160 kDa”
    AI692169 Hs.379186 “wd37e07.x1 Soares_NFL_T_GBC_S1 Homo sapiens cDNA clone IMAGE:2330340 3′, mRNA
    sequence.”
    AK024800 Hs.612887 “CDNA: FLJ21147 fis, clone CAS09371”
    NM_002378 Hs.631845 megakaryocyte-associated tyrosine kinase
    BF057784 Hs.187884 G protein-coupled receptor 114
    BF038366 Hs.199695 hypothetical protein MAC30
    U92706 “Human rearranged immunoglobulin heavy chain (A1VH3) gene, partial cds.”
    AA833716 Hs.460336 KIAA1970 protein
    M98528 Homo sapiens neuron-specific protein gene, last exon, clone D4S234.”
    NM_007181 mitogen-activated protein kinase kinase kinase kinase 1
    AF054994 Hs.31290 Clone 23832 mRNA sequence
    NM_006255 Hs.333907 “protein kinase C, eta”
    AC006033 Homo sapiens, Similar to steroidogenic acute regulatory protein related, clone MGC:3251
    IMAGE:3505985, mRNA, complete cds.; H_NH0121A08.9 This gene was based on gi(13111773
    13543614 14042926); Homo sapiens BAC clone RP11-121A8 from 7, complete sequence.”
    AF016535 Hs.489033 “ATP-binding cassette, sub-family B (MDR/TAP), member 1”
    AA744529 Hs.95424 mitogen-activated protein kinase kinase kinase kinase 1
    AU145682 Hs.308048 early B-cell factor
    U76542 Hs.500645 pyrroline-5-carboxylate synthetase (glutamate gamma-semialdehyde synthetase)
    AA723370 Hs.546387 CGI-105 protein
    AL521959 Hs.487479 “pleckstrin homology, Sec7 and coiled-coil domains 3”
    W67995 Hs.54943 fracture callus 1 homolog (rat)
    NM_020187 Hs.458320 DC12 protein
    NM_052931 Hs.492348 SLAM family member 6
    AW083371 Hs.173878 nipsnap homolog 1 (C. elegans)
    AL049942 Hs.213735 zinc finger protein 337
    AV700174 Hs.292580 hypothetical protein LOC283551
    NM_017773 Hs.272794 hypothetical protein FLJ20340
    NM_001628 Hs.521212 “aldo-keto reductase family 1, member B1 (aldose reductase)”
    AF225422 Homo sapiens AD023 mRNA, complete cds.”
    X02189 H. sapiens adenosine deaminase (ADA) gene 5′ flanking region and exon 1 (and joined CDS).
    NM_014450 Hs.88012 SHP2-interacting transmembrane adaptor protein
    BF345244 Hs.378501 hypothetical protein LOC283989
    AI057637 Hs.234898 acetyl-Coenzyme A carboxylase beta
    BC002918 Hs.213088 carbohydrate (chondroitin 4) sulfotransferase 12
    X79782 Hs.449601 H. sapiens (T1.1) mRNA for IG lambda light chain
    NM_024310 Hs.466383 “pleckstrin homology domain containing, family F (with FYVE domain) member 1”
    BF116060 Hs.519783 FLJ44216 protein
    Y11339 Hs.105352 “sialyltransferase 7 ((alpha-N-acetylneuraminyl-2,3-beta-galactosyl-1,3)-N-acetyl galactosaminide alpha-
    2,6-sialyltransferase) A”
    BC003379 Hs.632714 hypothetical protein from clone 643
    NM_024947 Hs.529592 polyhomeotic like 3 (Drosophila)
    NM_000878 Hs.474787 interleukin 2 receptor, beta”
    AF031138 Hs.509513 natural cytotoxicity triggering receptor 3
    NM_014914 Hs.435039 “centaurin, gamma 2”
    NM_030978 Hs.132499 “actin related protein 2/3 complex, subunit 5-like”
    NM_004758 Hs.112499 benzodiazapine receptor (peripheral) associated protein 1
    AW338214 Hs.437696 “Clone IMAGE:5275753, mRNA”
    AJ238374 Homo sapiens mRNA for putative protein TH1, partial, clone IMAGE ID 785447.”
    AF288573 Hs.2007 “tumor necrosis factor (ligand) superfamily, member 6”
    NM_031213 Hs.465542 hypothetical protein MGC5244
    AF044954 Hs.513266 “NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 10, 22 kDa”
    BE671663 Hs.592102 epidermodysplasia verruciformis 2
    NM_007237 Hs.632549 SP140 nuclear body protein
    AI003777 Hs.632176 septin 1
    AI421559 Hs.106185 ral guanine nucleotide dissociation stimulator
    NM_020886 Hs.503891 ubiquitin specific protease 28
    AI042377 Hs.470457 Transcribed sequences
    AA742584 Hs.125914 chromosome 8 open reading frame 5
    BG231773 Hs.371680 “CDNA FLJ46579 fis, clone THYMU3042758”
    BE788984 “601481076F1 NIH_MGC_68 Homo sapiens cDNA clone IMAGE:3883818 5′, mRNA sequence.”
    AA135722 Hs.597962 Transcribed sequences
    NM_014349 Hs.474737 “apolipoprotein L, 3”
    AW268594 Hs.374421 chromosome 9 open reading frame 81
    NM_018641 Hs.213088 carbohydrate (chondroitin 4) sulfotransferase 12
    BF678830 hypothetical protein LOC152485
    NM_006117 Hs.15250 “peroxisomal D3,D2-enoyl-CoA isomerase”
    AW977516 Hs.592755 Transcribed sequences
    BF984830 Hs.190284 retinoic acid induced 1
    NM_005263 Hs.73172 growth factor independent 1
    AI347139 Hs.8162 hypothetical protein MGC39372
    NM_002832 Hs.402773 “protein tyrosine phosphatase, non-receptor type 7”
    NM_003362 Hs.191334 uracil-DNA glycosylase
    AA679705 Hs.535464 “eukaryotic translation initiation factor 3, subunit 8, 110 kDa”
    AY007128 Hs.469728 “CDNA FLJ26765 fis, clone PRS02774”
    AK074465 Hs.462833 hypothetical protein FLJ31952
    NM_001504 Hs.198252 chemokine (C-X-C motif) receptor 3
    NM_005715 Hs.557541 uronyl-2-sulfotransferase
    AA683481 Hs.22546 hypothetical protein MGC20446
    AI829961 Hs.36972 CD7 antigen (p41)
    AI609285 Hs.503891 “tw83h09.x1 NCI_CGAP_HN5 Homo sapiens cDNA clone IMAGE:2266337 3′ similar to contains Alu
    repetitive element; contains element MER29 repetitive element;, mRNA sequence.”
    AL582804 Hs.403857 lymphocyte antigen 9
    NM_000107 Hs.643521 “damage-specific DNA binding protein 2, 48 kDa”
    AL833685 Hs.440508 MRNA; cDNA DKFZp667O0522 (from clone DKFZp667O0522)
    BE568184 cytochrome c oxidase subunit VIa polypeptide 1
    BG250907 Hs.591503 “Clone IMAGE:5178133, mRNA”
    NM_018281 Hs.476319 hypothetical protein FLJ10948
    BG542955 Hs.133916 hypothetical protein LOC152485
    AK024386 Hs.155742 glyoxylate reductase/hydroxypyruvate reductase
    NM_024070 Hs.521075 stromal antigen 3
    AB014719 Hs.618112 “amyloid beta (A4) precursor protein-binding, family A, member 2 (X11-like)”
    D42043 Hs.98910 raft-linking protein
    AY043466 Hs.292449 Fc receptor-like protein 3
    AI017564 Hs.492716 unknown MGC21654 product
    NM_005317 Hs.465511 granzyme M (lymphocyte met-ase 1)
    AL527430 Hs.2006 glutathione S-transferase M3 (brain)
    NM_014767 Hs.523009 “synonym: testican-2; go_component: extracellular matrix [goid 0005578] [evidence NAS] [pmid
    10386950]; go_function: calcium ion binding [goid 0005509] [evidence IDA] [pmid 10386950];
    go_process: synaptogenesis [goid 0007416] [evidence NAS] [pmid 10386950]; go_process: extracellular
    matrix organization and biogenesis [goid 0030198] [evidence NAS] [pmid 10386950]; go_process:
    regulation of cell differentiation [goid 0045595] [evidence NAS] [pmid 10386950]; Homo sapiens
    sparc/osteonectin, cwcv and kazal-like domains proteoglycan (testican) 2 (SPOCK2), mRNA.”
    BC040914 Hs.322462 “Clone IMAGE:5745627, mRNA”
    AK001164 Hs.599785 “CDNA FLJ10302 fis, clone NT2RM2000042”
    AK097515 Hs.120250 hypothetical protein FLJ40597
    NM_005608 Hs.155975 “protein tyrosine phosphatase, receptor type, C-associated protein”
    AI457120 Hs.331420 phosphoribosyl pyrophosphate amidotransferase
    AA541630 Hs.170019 runt-related transcription factor 3
    NM_024709 Hs.519839 hypothetical protein FLJ14146
    NM_013330 Hs.642710 “non-metastatic cells 7, protein expressed in (nucleoside-diphosphate kinase)”
    AL520200 Hs.420796 hypothetical protein MGC15429
    NM_003752 Hs.567374 “eukaryotic translation initiation factor 3, subunit 8, 110 kDa”
    BE259729 Hs.438429 ribosomal protein S19
    AW043830 Hs.471441 Transcribed sequences
    R12665 Hs.11594 “CDNA FLJ27273 fis, clone TMS00761”
    BC006428 Hs.189119 CXXC finger 5
    AI354636 Hs.586401 “qu95c03.x1 NCI_CGAP_Gas4 Homo sapiens cDNA clone IMAGE:1979812 3′, mRNA sequence.”
    AK025248 Hs.546419 hypothetical protein FLJ13220
    BE675549 Hs.79170 tetratricopeptide repeat domain 9
    NM_000579 Hs.450802 chemokine (C-C motif) receptor 5
    AB020630 Hs.45719 protein phosphatase 1, regulatory (inhibitor) subunit 16B”
    NM_002985 Hs.514821 chemokine (C-C motif) ligand 5
    NM_014392 Hs.518595 DNA segment on chromosome 4 (unique) 234 expressed sequence
    AI821566 Hs.642748 torsin family 2, member A”
    AA771779 Hs.461074 zinc finger protein 90 homolog (mouse)
    AI084226 Hs.58831 regulator of Fas-induced apoptosis
    AF057557 Hs.58831 regulator of Fas-induced apoptosis
    NM_005356 Hs.470627 lymphocyte-specific protein tyrosine kinase
    BC041468 Hs.434746 “Hypothetical protein LOC339988 (LOC339988), mRNA”
    BC002556
    NM_002002 Hs.465778 “Fc fragment of IgE, low affinity II, receptor for (CD23A)”
    NM_018556 Hs.590883 signal-regulatory protein beta 2
    AB020630 Hs.45719 protein phosphatase 1, regulatory (inhibitor) subunit 16B”
    AF298547 Hs.369279 “NACHT, leucine rich repeat and PYD containing 2”
    AW157571 Hs.479066 multiple coiled-coil GABABR1-binding protein
    AA767131 Hs.121432 KIAA0073 protein
    M21121 Hs.514821 chemokine (C-C motif) ligand 5
    NM_004356 Hs.54457 CD81 antigen (target of antiproliferative antibody 1)
    BF432238 Hs.585799 “CDNA FLJ31089 fis, clone IMR321000092”
    NM_004310 Hs.160673 “ras homolog gene family, member H”
    BC000533 Hs.567374 “eukaryotic translation initiation factor 3, subunit 8, 110 kDa”
    U07236 Hs.470627 lymphocyte-specific protein tyrosine kinase
    AI702465 Hs.23606 Transcribed sequences
    AU155091 Hs.633678 “Clone IMAGE:4814008, mRNA“
    U90339 Hs.584739 adenosine kinase
    AW575245 Hs.266331 Fc receptor homolog expressed in B cells
    NM_030915 Hs.567598 likely ortholog of mouse limb-bud and heart gene
    AI524095 Hs.403857 lymphocyte antigen 9
    AW204712 Hs.385493 hypothetical protein LOC170371
    U49396 Hs.408615 “purinergic receptor P2X, ligand-gated ion channel, 5”
    AA781795 Hs.546467 epithelial stromal interaction 1 (breast)
    BF433219 Transcribed sequences
    BC003574 Hs.2484 T-cell leukemia/lymphoma 1A
    AB051458 Hs.419171 KIAA1671 protein
    NM_004114 Hs.6540 fibroblast growth factor 13
    BF446578 Hs.125293 “RasGEF domain family, member 1A”
    AA931562 Hs.444049 Transcribed sequence with weak similarity to protein ref:NP_060312.1 (H. sapiens) hypothetical protein
    FLJ20489 [Homo sapiens]
    BF514552 Hs.292449 Fc receptor-like protein 3
    X82240 Hs.2484 T-cell leukemia/lymphoma 1A
    AW296309 Hs.405667 “CD8 antigen, beta polypeptide 1 (p37)”
    M85256 Hs.554197 “Isolate donor Z clone Z55K immunoglobulin kappa light chain variable region mRNA, partial cds”
    AF439512 Hs.387787 “killer cell lectin-like receptor subfamily K, member 1”
    NM_005442 Hs.591663 eomesodermin homolog (Xenopus laevis)
    AI424825 Hs.435052 “ATPase, aminophospholipid transporter (APLT), Class I, type 8A, member 1”
    NM_006159 Hs.505326 NEL-like 2 (chicken)
    BI547087 “603190322F1 NIH_MGC_95 Homo sapiens cDNA clone IMAGE:5261717 5′, mRNA sequence.”
    BC001872 Hs.510635 “synonym: MU; Homo sapiens immunoglobulin heavy constant mu, mRNA (cDNA clone MGC:1228
    IMAGE:3544448), complete cds.”
    AW006735 Hs.85258 “CD8 antigen, alpha polypeptide (p32)”
    NM_007360 Hs.387787 “killer cell lectin-like receptor subfamily K, member 1”
    NM_002261 Hs.74082 “synonyms: NKG2E, NKG2-E; isoform NKG2-E is encoded by transcript variant NKG2-E;
    go_component: integral to membrane [goid 0016021] [evidence IEA]; go_function: transmembrane
    receptor activity [goid 0004888] [evidence TAS] [pmid 9683661]; go_function: lectin [goid 0005530]
    [evidence IEA]; go_function: sugar binding [goid 0005529] [evidence IEA]; go_process: cellular defense
    response [goid 0006968] [evidence TAS] [pmid 9683661]; go_process: heterophilic cell adhesion [goid
    0007157] [evidence IEA]; Homo sapiens killer cell lectin-like receptor subfamily C, member 3 (KLRC3),
    transcript variant NKG2-E, mRNA.”
    M13231 Hs.534032 T cell receptor gamma locus
    AI753792 Hs.502004 related RAS viral (r-ras) oncogene homolog 2
    M16768 Hs.534032 “T-cell receptor (V-J-C) precursor; Human T-cell receptor gamma chain VJCI-CII-CIII region mRNA,
    complete cds.”
    NM_003175 Hs.458346 chemokine (C motif) ligand 2
    U96394 Hs.449601 “Clone P2-147 anti-oxidized LDL immunoglobulin light chain Fab mRNA, partial cds”
    M27331 Hs.534032 T cell receptor gamma locus
    U23772 Hs.546295 chemokine (C motif) ligand 1
    NM_004931 Hs.405667 “CD8 antigen, beta polypeptide 1 (p37)”
    NM_006275 Hs.6891 “splicing factor, arginine/serine-rich 6”
    BC020552 Hs.379186 programmed cell death 6
    NM_001548 Hs.20315 interferon-induced protein with tetratricopeptide repeats 1
    BC005248 Hs.461178 “eukaryotic translation initiation factor 1A, Y-linked”
    NM_004660 Hs.99120 “DEAD (Asp-Glu-Ala-Asp) box polypeptide 3, Y-linked”
    NM_001008 Hs.282376 “ribosomal protein S4, Y-linked”
  • TABLE 8
    Atheroembolic/ Cardioembolic/ Cardioembolic/
    Common Name control control Atheroembolic
    DAB2 −1.754 −1.21 1.449
    DAB2 −1.751 −1.142 1.531
    ZNF185 −1.416 1.09 1.544
    ITGA2B −2.32 −1.081 2.146
    JAM3 −1.694 −1.19 1.424
    PPBP −1.886 −1.077 1.75
    C21orf7 −2.293 −1.503 1.527
    SLC25A37 −1.326 1.089 1.444
    C7orf41 −1.324 1.125 1.489
    SYNJ2 −1.331 1.083 1.443
  • TABLE 9
    Atheroembolic/ Cardioembolic/ Cardioembolic/
    Common Name control control Atheroembolic
    LAK 1.42 −1.375 1.952
    PVRL2 1.357 −1.15 1.561
    PVRL2 1.432 −1.145 1.64
    PCGF3 1.323 −1.129 1.495
    PPP3R1 1.34 −1.122 1.503
    LEPROT 1.314 −1.114 1.464
    INSR 1.369 −1.096 1.501
    PVRL2 1.859 −1.09 2.028
    NUMB 1.821 −1.041 1.896
    FBN2 1.622 −1.011 1.64
    BIRC1 1.426 1.007 1.417
    TSHZ3 1.457 1.013 1.439
    DF 1.595 1.034 1.542
    IER3 1.701 1.197 1.421
    RRAS2 −1.449 1.198 −1.736
    CD8B1 −1.259 1.213 −1.526
    CD8B1 −1.447 1.234 −1.785
  • TABLE 10
    Fold Fold Fold
    (Cardio- (Cardio- (Athero-
    embolic/ embolic/ embolic/ Human
    Athero- healthy healthy GenBank UniGene
    Gene Symbol embolic) control) control) ID ID Gene description
    PVRL2 2.028 1.859 −1.09 BE867789 110675 poliovirus receptor-related 2 (herpesvirus entry mediator B)
    NUMB 1.896 1.821 −1.041 AW167424 585653 Numb homolog (Drosophila)
    IER3 1.421 1.701 1.197 NM_003897 591785 immediate early response 3
    FBN2 1.64 1.622 −1.011 NM_001999 519294 fibrillin 2 (congenital contractural amchnodactyly)
    CFD 1.542 1.595 1.034 NM_001928 155597 complement factor D (adipsin)
    TSHZ3 1.439 1.457 1.013 AL136805 278436 teashirt family zinc finger 3
    PVRL2 1.64 1.432 −1.145 AI520949 110675 poliovirus receptor-related 2 (herpesvirus entry mediator B)
    NAIP /// 1.417 1.426 1.007 NM_004536 191356 “NLR family, apoptosis inhibitory protein /// similar to Baculoviral
    LOC728519 IAP repeat-containing protein 1 (Neuronal apoptosis inhibitory
    protein)”
    ALPK1 1.952 1.42 −1.375 AA521086 99691 alpha-kinase 1
    INSR 1.501 1.369 −1.096 AI215106 591381 Insulin receptor
    PVRL2 1.561 1.357 −1.15 BE867789 110675 poliovirus receptor-related 2 (herpesvirus entry mediator B)
    PPP3R1 1.503 1.34 −1.122 NM_000945 280604 “protein phosphatase 3 (formerly 2B), regulatory subunit B, 19 kDa,
    alpha isoform (calcineurin B, type I)”
    PCGF3 1.495 1.323 −1.129 AW270105 144309 Polycomb group ring finger 3
    LEPROT 1.464 1.314 −1.114 NM_017526 23581 leptin receptor overlapping transcript
    C7orf41 1.489 1.125 −1.324 W73230 200100 chromosome 7 open reading frame 41
    ZNF185 1.544 1.09 −1.416 NM_007150 16622 zinc finger protein 185 (LIM domain)
    SLC25A37 1.444 1.089 −1.326 BG251467 122514 “solute carrier family 25, member 37”
    SYNJ2 1.443 1.083 −1.331 AI971212 434494 synaptojanin 2
    PPBP 1.75 −1.077 −1.886 R64130 2164 pro-platelet basic protein (chemokine (C-X-C motif) ligand 7)
    ITGA2B 2.146 −1.081 −2.32 NM_000419 411312 “integrin, alpha 2b (platelet glycoprotein IIb of IIb/IIIa complex,
    antigen CD41)”
    DAB2 1.531 −1.142 −1.751 NM_001343 481980 disabled homolog 2, mitogen-responsive phosphoprotein
    (Drosophila)”
    JAM3 1.424 −1.19 −1.694 AA149644 150718 junctional adhesion molecule 3
    DAB2 1.449 −1.21 −1.754 BC003064 481980 disabled homolog 2, mitogen-responsive phosphoprotein
    (Drosophila)”
    CD8B −1.526 −1.259 1.213 AW296309 405667 CD8b molecule
    CD8B −1.785 −1.447 1.234 NM_004931 405667 CD8b molecule
    RRAS2 −1.736 −1.449 1.198 AI753792 502004 related RAS viral (r-ras) oncogene homolog 2
    C21orf7 1.527 −1.503 −2.293 NM_020152 222802 chromosome 21 open reading frame 7

Claims (21)

What is claimed is:
1. A method for diagnosing an ischemia or a predisposition for developing an ischemia, the method comprising: determining a level of expression of a plurality of ischemia-associated genes in a biological sample from a mammalian subject, wherein an increase or decrease of said level compared to a normal control level of said genes indicates that said subject suffers from or is at risk of developing ischemia, wherein said plurality of ischemia-associated genes is selected from the genes set forth in Table 1, 2, 3, 4, 5, 6, or 7.
2. The method of claim 1, wherein said plurality of ischemia-associated genes is selected from the genes set forth in Table 1.
3. The method of claim 1, wherein said increase is at least about 1.3 fold higher than said normal control level and said decrease is at least about 1.3 fold lower than said normal control level.
4. The method of claim 3, wherein at least about a 1.3 fold increase in expression of the following genes: LEPROT, PCGF3, PPP3R1, PVRL2, INSR, BIRC1, TSHZ3, DF, FBN2, IER3, NUMB, and LAK when compared to the normal control level, and at least about a 1.3 fold decrease in expression of the following genes: CD8B1 and RRAS2 when compared to the normal control level indicates that the subject has experienced or is at risk for a cardioembolic stroke.
5. The method of claim 3, wherein at least about a 1.3 fold decrease in expression of the following genes: C21orf7, DAB2, JAM3, ITGA2B, PPBP, SYNJ2, SLC25A37, ZNF185, C7orf41, and LAK when compared to the normal control level indicates that the subject has experienced or is at risk for an atherothrombotic stroke.
6. The method of claim 1, wherein said ischemia is a member selected from the group consisting of: embolic stroke, thrombotic stroke, and transient ischemic attack.
7. The method of claim 1, wherein said ischemia is cardioembolic stroke.
8. The method of claim 1, wherein said ischemia is atherothrombotic stroke.
9. The method of claim 1, wherein said sample is blood.
10. The method of claim 1, wherein said level of expression is determined by detecting hybridization of an ischemia-associated gene probe to a gene transcript of said biological sample.
11. The method of claim 10, wherein said hybridization step is carried out on a nucleic acid array.
12. An ischemia reference expression profile, comprising a pattern of gene expression of a plurality of the genes set forth in Table 1, 2, 3, 4, 5, 6, or 7.
13. An ischemia reference expression profile, comprising a pattern of gene expression of a plurality of the genes set forth in Table 1.
14. The ischemia reference expression profile of claim 13, wherein at least about a 1.3 fold increase in expression of the following genes: LEPROT, PCGF3, PPP3R1, PVRL2, INSR, BIRC1, TSHZ3, DF, FBN2, IER3, NUMB, and LAK when compared to the normal control level, and at least about a 1.3 fold decrease in expression of the following genes: CD8B1 and RRAS2 when compared to the normal control level is a reference expression profile for cardioembolic stroke.
15. The ischemia reference expression profile of claim 13, wherein at least about a 1.3 fold decrease in expression of the following genes: C21orf7, DAB2, JAM3, ITGA2B, PPBP, SYNJ2, SLC25A37, ZNF185, C7orf41, and LAK when compared to the normal control level is a reference expression profile for atherothrombotic stroke.
16. A method of screening for a compound for treating or preventing ischemia, said method comprising the steps of:
a) contacting a candidate compound with a cell expressing one or more genes set forth in Table 1, 2, 3, 4, 5, 6, or 7; and
b) selecting a compound that modulates the expression level of one or more genes set forth in Table 1, 2, 3, 4, 5, 6, or 7.
17. The method of claim 16, wherein a compound that decreases the expression of at least one gene selected from the group consisting of: LEPROT, PCGF3, PPP3R1, PVRL2, INSR, BIRC1, TSHZ3, DF, FBN2, IER3, NUMB, and LAK when compared to the normal control level, or increases the expression of at least one gene selected from the group consisting of: CD8B1 and RRAS2 relative to a control level is identified as a compound useful for treating or preventing ischemia.
18. The method of claim 17, wherein the ischemia is cardioembolic stroke.
19. The method of claim 16, wherein a compound that increases the expression of at least one gene selected from the group consisting of: C21orf7, DAB2, JAM3, ITGA2B, PPBP, SYNJ2, SLC25A37, ZNF185, C7orf41, and LAK is identified as a compound useful for treating or preventing ischemia.
20. The method of claim 19 wherein the ischemia is atherothrombotic stroke.
21. An array comprising a nucleic acid which binds to a plurality of nucleic acid sequences set forth in Table 1, 2, 3, 4, 5, 6, or 7.
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