Journal of Infection and Molecular Biology 1 (2): 20 – 26.

http://www.nexusacademicpublishers.com/journal/2

Review Article
Cytokine Genes Polymorphism and Potential use as Bio-Markers
Atiya Yasmeen1, Tanveer Hussain*1, Ali Ahmad Sheikh2, Muti-ur-Rehman Khan3, Muhammad Nauman Zahid4,
Ziaullah Mughal5, Sikander Khan Sherwani6, Syed Mubasher Hussain7, Muhammad Intizar7
1
Institute of Biochemistry & Biotechnology, University of Veterinary and Animal Sciences Lahore 54000, Pakistan; 2University
Diagnostic Laboratory, University of Veterinary and Animal Sciences Lahore 54000, Pakistan; 3Department of Pathology, University of
Veterinary and Animal Sciences Lahore 54000, Pakistan, 4 Quality Operations Laboratory, University of Veterinary and Animal Sciences
Lahore 54000, Pakistan; 5Pet Centre, University of Veterinary and Animal Sciences Lahore 54000, Pakistan; 6Federal Urdu University,
Karachi; 7Remount Veterinary and Farm Corps, Pakistan Army
*
Corresponding author: tanveer.hussain@uvas.edu.pk

ARTICLE HISTORY ABSTRACT

Received: 2013-04-10 Cytokines, which are recognized as signaling proteins are essential for both innate and adaptive
Revised: 2013-06-15 immune response for their development and functioning, are produced by different types of cells.
Accepted: 2013-06-24 The expression of the cytokine gene is highly regulated and its expression and genetic
polymorphisms have been applied in a variety of diseases, in treatments and in infection
susceptibility. Recently it has been shown that the cytokines and their receptors are polymorphic
Key Words: Cytokines, genes, in nature, and plays a significant role in regulating functions of normal immune system. The
SNPs, Markers polymorphism that occurs in these genes are linked with a variety of immune diseases and to
complications related to organ transplant. Currently the data related to disease is much
contradictory and confusing, while in the analysis of cytokine the predominant form is single locus
analysis. The use of polymorphic haplotype has become common as this gives the clear view about
immune disfunction and the polymorphism associated the cytokine. For immune system and the
traits of disease resistance, major histocompatibility complex i.e. MHC gene is considered very
important. The associations of the polymorphism in autoimmune diseases, in cytokine gene,
outcome of transplantation have been described. For the typing of single nucleotide polymorphism
there exist several methods which could be applied for the typing of cytokine as well as variations
of cytokine gene receptor. A method adopted in current study to type multiple cytokines and
polymorphisms of receptor gene was SNaPshot, which is also called primer extension method.
With the development we can apply this method in different laboratories in order to type cytokine
SNPs in various populations and this helps in research.
All copyrights reserved to Nexus® academic publishers
ARTICLE CITATION: Yasmeen A, Hussain T, Sheikh AA, Khan MR, Zahid MN, Mughal Z, Sherwani SK, Hussain SM, Intizar M
(2013). Cytokine genes polymorphism and potential use as bio-markers. J. Inf. Mol. Biol. 1 (2): 20 – 26.

INTRODUCTION macrophages and also participate in organ structure

Cytokines are a family of more than hundred small proteins maintenance and during para inflammatory state of the cells
which functions as short range mediators, hence involved in stress, restores homeostasis (Tarrant, 2010). All cells could
every biological process. The cytokine field came in late 1970s produce and respond the cytokines except red blood cells.
when biological approaches that are molecular were introduced Today cytokines are studied in every biological discipline,
, which first resulted in the cloning of interferons ( IFNs ), hence cytokine mediated effects dominate over the different
initially IFNβ by Tada Taniguchi and then IFNα by David fields of immunology, inflammation, cancer and atherosclerosis
Goeddel’s colleagues together with Charles Weissman’s group (Dinarello, 2011).These regulatory cytokines could be used as
(Feldmann, 2008).Cytokines that are secreted by cells are biomarkers for the detection and treatment of the diseases so
protein that are soluble and transmit the signals to other cells the more complete knowledge about the cytokines signaling is
by acting as a messenger (Loo et al, 2012).There is a significant fundamental in the process of inflammation in order to find
role which Cytokines plays in an immune system, and the more effective clinical strategies (Van, 2009). For disease
balance between humoral Th2 and cell mediated Th1 resistance traits and immune system the major
responsiveness.Th1 cells perform its role in cellular immunity in histocompatibility complex, MHC gene is considered very
order so they can fight against pathogens that are intracellular significant. But the functions of these genes are different on
which includes viruses and removal of cancerous cells can traits that are economically important (Supakorn, 2009).The
occur. While in humoral immunity Th2 cells are important genes which encode MHC molecules are the most polymorphic
through the up regulation of the production of antibody, so genes that have been described in vertebrates with
provide protection against pathogens that are extracellular polymorphism that occurs at the peptide binding sites
(Lan et al, 2006). Cytokines plays a significant role in the predominantly. There occurs an association between types of
physiological processes as well as mediating the immune MHC and pathogen susceptibility (De et al, 2011). Cell surface
response. Cytokines functions by the tissue resident proteins encoded by MHC genes are classified into three

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Yasmeen et al (2013). Cytokines Gene Polymorphism and Potential use as Bio-markers
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Journal of Infection and Molecular Biology 1 (2): 20 – 26.
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categories based on molecular weight, function, and their immune functions and some others that’s immune function is
differences in the cellular distribution (Mohammadi, unknown. The gene products of MHC class I and II play a
2010).Traditionally we divide the MHC genes into three classes significant role in immune response and in antigen presentation
that is the MHC class I genes, class II genes and the antigen and in vertebrates the MHC coding genes are highly variable
presenting MHC molecules are encoded by them and the next (Faruk et al, 2007).
is class III genes, that encodes molecules that are important in

(Figure 1 : Common categories of Cytokines, www.systemicenzymesupport.org)

CHARACTERISTICS AND CLASSIFICATION OF CLASSIFICATION OF CYTOKINES (Ikram et al., 2004)

CYTOKINES The growth factors include the following
Cytokines are involved in communication of cells, as they act as  Haemopoietic growth factors
signaling proteins as well as glycoprotein. Cytokines produced  Epidermal growth factors
by different cells are basically divided into two types i.e. Th1  Platelet derived growth factors
and Th2. For good health there should be a balance between  Transforming growth factor β
Th1 & Th2.Pro inflammatory response that are involved in
 Fibroblast factors
antiviral and antibacterial responses are produced by Th1
cytokines. Uncontrolled damage of tissue could occur in case of  Insulin like factors for growth
excessive responses of Th1.In acute inflammation excess Th1  Nerve growth factors
can be observed. Whereas anti inflammatory responses are  Interleukins
produced by Th2 cytokines, as they can counteract the o IL1 to IL18
mediated Th1 microbicidal actions. Atopy (eczema, allergic  Interferons
conjunctivitis, asthma & allergic rhinitis) and allergies are o IFN- α
associated with excessive Th2 responses. In chronic o IFN- β
inflammation excess Th2 could be observed o IFN- γ
(www.systemicenzymesupport.org).  Tumour Necrosis factor(TNF) etc
Cytokines consists of a large family of proteins,  Miscellaneous
glycoprotein or peptides that are used in cellular
communication (Olson et al, 2009). The activation, growth and IMPORTANCE OF MHC FOR ANIMAL BREEDERS
differentiation of different cells are influenced by Cytokines. A family of genes called Major histocompatibility complex
Cytokines exhibit less restricted tissue specificity as compared
(MHC) found in vertebrates mostly. MHC plays very significant
to hormones, so produced by a variety of cells types (Lumachi et
role in reproductive success, immune system and in
al, 2010).
autoimmunity.
Cytokines have the following properties which give the
MHC encodes the protein from this gene that expressed on cell
shape to the nature of network (Watanabe et al, 1997)
surface; these proteins display the antigen to a type of white
 Pleiotropy, means single cytokine having multiple blood cell. These white blood cells are able to coordinate in
biological activities. killing or kill the pathogens, malfunction or infect the cells
 Redundancy, multiple cytokines has activities of (Supakorn , 2009). MHC is divided into the 3 main subgroups
overlapping. named as MHC class I genes, MHC class II genes and MHC
 Cross-talk, single cell have interactions with multiple class III genes. Heterodimeric peptide binding proteins are
cytokines with seems identical responses. encoded by MHC I and MHC II , the proteins that modulate
Other classifications are done based on structural or functional antigens loading in the lysosomal compartments are encoded by
groupings. Cytokines work in a network that is highly complex MHC class II. Other immune compartments such as heat shock
and coordinated, in which they repress or induce the synthesis proteins complement components and cytokines are encoded
of their own as well as cytokine receptors and other cytokines by MHC class III. In goat 1,077bp is the length of MHC I that
(Bidwell et al, 1999). encodes protein with 337 amino acids (Supakorn, 2009).

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Yasmeen et al (2013). Cytokines Gene Polymorphism and Potential use as Bio-markers
ISSN Online: 2307 – 5465, Print: 2307 – 5716
Journal of Infection and Molecular Biology 1 (2): 20 – 26.
http://www.nexusacademicpublishers.com/journal/2

The proteins encoded by MHC-I are highly involved in to regulate and mediate inflammatory and immune responses
presentation of peptides that are intra cellularly derived to the (Chun, 2012). The production of the cytokines is stimulated by
cytotoxic T cell. In the host control viral infection the cellular primary events in the response of immune system that directs
immunity is critical , an event that’s highly attributable to the the development of T helper (Th) with cytokines that are
antigen presentation through the pathway of MHC class I, produced in discrete patterns (Garra, 1998).The expression of
whose genes are activated transcriptionally by different the Cytokine gene is highly aberrant and regulated from genetic
cytokines or by interferons (IFN) (Jorgensen et al , 2006). and environmental polymorphism has been applied in
Mostly the MHC genes are of particular interest for the susceptibility to infections, in a variety of diseases and response
veterinary geneticists and animal breeders because they are to the treatment (Smith et al, 2009). In malfunctioning or
linked with susceptibility to a wide array of diseases and infecting cell or in the killing of pathogens the MHC gene is
genetic resistance (Supakorn , 2009). In the genome of human thought to be very significant gene for system of immune. By
the MHC, genes depends on the other genes and interacts with analyzing the polymorphisms of the fragments that are
the other MHC as well as with non MHC genes that are located regulatory fragments will gave us a significant data related to
outside of the MHC region (Debnath et al, 2012). gene expression and regulation. The variation of quantitative
traits that controlled genetically could affect the phenotypic
CYTOKINES IN IMMUNITY performance (Supakorn, 2009).Cytokines are known as
Cytokines are polypeptide, regulatory hormones that Biomarkers of immunotoxcity and they regulate the responses
constitutes the signaling system of cells and are produced of immune system so pleiotropic functions are performed by
during the effector phases and activation of innate and specific them (Elsabahy and Wooley, 2013).
immunity. They have many roles that are functional and serve

(Figure 2: Cytokines as Biomarkers of immunotoxcity, Elsabahy and Wooley, 2013).

CYTOKINE POLYMORPHISM/CYTOKINE SNP disease and those involving in vitro gene expression. Only very
POLYMORPHISM few studies have been done related to these both approaches
A series of SNPs or individual SNPs analysis in a variety of (Lan et al, 2006). In human the SNP polymorphism results in
cytokine genes are involved in the disease association studies. A the various levels of expression in the individuals which are
given cytokine is represented by single SNP through the usage healthy and has associations with autoimmunity,
of this approach. This sort of choice could be made on a number cardiovascular disease, susceptibility to infection and cancer.
of different criteria’s such as the effect on the production of The polymorphisms related cytokine genes are not well
cytokine, frequency in the study control population, or in other described. We were failed to show a relationship, when we
cases, the reagents availability or scientifically done prior compare the polymorphisms across the regulatory regions of
findings. Mostly the study done of a single polymorphic locus TNF- a gene and in vitro TNF-a release to the splenocyte in rat.
predominates (Keen, 2002). Most of the polymorphisms that Cytokine genes have various conservations across the species
were reported within the cytokine genes occur within the (Tarrant, 2010). A high rate of polymorphism as well as the
regulatory or putative regions. In research, the influence of the associations with disease have been found using these variants
cytokine gene polymorphisms on disease and gene expression in the coding region and in non coding region of cytokine gene
occurs at two stages that studies using in vivo association of (Smith et al, 2009).We know that Cytokines and receptors of

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Yasmeen et al (2013). Cytokines Gene Polymorphism and Potential use as Bio-markers
ISSN Online: 2307 – 5465, Print: 2307 – 5716
Journal of Infection and Molecular Biology 1 (2): 20 – 26.
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them are highly polymorphic. There are main three forms of the immunological action of a specific cytokine could be
poplymorphism named as microsatellites, SNPs and VNTRs. masked or enhanced. Hence, there exists such a complexity in
The variation occurs in polymorphism is very high. This could cytokine biology that suggests that CNS action of a specific
be easily described through the frequency by which a cytokine cytokine should not be considered in isolation (Quan et al,
has been studied. The well characterize genes like IL10 and 2002). Juvenile idiopathic arthritis (JIA) is a disorder that is
TNFa have a variety of microsatellites and single nucleotide caused by the combination of certain genetic and environmental
polymorphisms (SNP), whereas the cytokines such as IL2 and factors, and the all types of JIA are characterized by
IL12 previously were thought non polymorphic. Well, now in inflammation of the joints, hence locally the inflammation
these genes polymorphism is being found (Keen, 2002).The reaction is controlled by infiltration of immune cells in
activities of transcription are effected by Polymorphisms that combination with various other cytokines. It is reported that
are in many cytokine genes which results in the individual cytokines plays significant roles in the recovery from disease
variations in the activity as well as the production of cytokines (Van et al, 2009).
which ultimately affect the transplanted grafts (Brunet, 2012). The rapid cellular division is very rare during adult life,
Gene transcription is affected by a number of polymorphisms of and mostly it occurs as a result of an injury such as during
the cytokine genes or gene promoters that influence the in vitro repair of wound. The up regulation that we saw with a number
and in vivo production of cytokines (Adamopoulos et al, 2011). of cytokines, if contrast with down regulation of cellular
This review not only describes the associations of diseases replication repressors like p53, occur in a wound. The cytokine
but also related to cytokine functions and to the receptors of expression is suppressed as the healing progresses, hence p53 is
cytokine gene polymorphism. Functional SNPs that affect gene increased again. In malignant tumors there is an occurrence of
expression, mRNA stability or structure of protein ultimately rapid uncontrolled cell division (SLAVIN, 1996). During an
are associated with disease, and to study the controversial inflammatory state the production of cytokine is mostly
results related to function is also the main objective of this regulated by the activation of other cells which results in a
review (Smith et al, 2009). Polymorphisms may affect the complex cytokine cascade. The limited information is obtained
structure of protein and if it is located in the region of by measuring single assay of cytokine, while if we want to
regulation it may alter the protein production. In few genes achieve more information then there is a need to be analyzed
small numbers of SNPs were investigated through the studies of multiple cytokines. Now with the development in technology
candidate gene, previously, it is an approach that overlooks the multiplexing of cytokines has become more fast, simple and
polymorphisms that are potentially important. For the typing of reproducible (Vistnes et al, 2010). The abnormal productions of
SNPs at large scale an approach is used that will allow the cytokines have been discussed in disorders of neuropsychiatric
much detailed polymorphisms throughout the candidate gene for instance Obsessive compulsive, attention deficit
and the false positive results could be found due to the hyperactivity and anorexia nervosa like disorder. Cytokines
increased number of SNPs typed if the data were not corrected play an important role in Alzheimer’s disease, schizophrenia
sufficiently (Turner et al, 2002). Among individuals in pathogen and depression and there is a common link between depression
resistance and in immune function, an important source of and insomnia. Cytokines are also involved in anhedonia i.e. the
variation is represented by Cytokine polymorphism. This inability to experience pleasure and learned helplessness
variation can be maintained like genotype conferred resistance (Spelman et al, 2006).
to one species of pathogen and may confer the increased
susceptibility to the second by exposure to a number of CYTOKINES IN CANCER IMMUNOTHERAPY
pathogen species. Antagonistic pleiotropy represents an Progress in the field of biotechnology has revealed that there are
example of this type of association that has been presented as a some substances which take part in immunological process
mechanism by which the genetic diversity could be found between the host and the cancer, and they are monoclonal
within a population (Turner et al, 2011). One host antibodies, Cytokines and the immunomodulating agents
immunogenetic variation represents Cytokine gene single which are produced by effector cells and called as macrophages,
nucleotide polymorphisms (SNPs) and they are associated with lymphocytes and NK cells of the patients of cancer (Urushizaki
autoimmune disorders, other diseases and response to the 1989). The risk of cancer is enhanced by the conditions of
treatment, susceptibility to infections etc (Cano et al, 2012). inflammation in some tissues, and there is an involvement of
The SNPs that are present in the region of regulation of the cytokines in cancer related inflammation that represents a goal
genes and code for cytokines could be modifiers of disease and for therapeutic and diagnostic strategies as well as challenge for
also impact the expression levels. Traditionally the techniques future scientists (Germano et al, 2008). The production as well
named as PCR-RFLP were used for cytokine SNP genotyping as release of cytokine in cancer is affected by tumor itself or by
but at large scale it is not amenable for cytokine SNP therapeutic intervention. In fact the organ confined and
association related studies hence is a low throughput systemic toxic symptoms both are mediated by the release of
technique. Now for discrimination assay of alleles currently we cytokines and there is a link between various types of cancer
use a technique called Taqman real time PCR (Johnson et al, treatment which includes chemotherapy, radiation therapy, and
2004). hormonal therapy. So finally we conclude that cytokines play
very important role in the anticancer activities. We can analyze
CYTOKINES AS DIAGNOSTIC TOOL their potential in therapeutics by this way that the direct
From inflammation to immune response, cell migration, cell injection of cytokines into tumors could be curative (Ronca et
growth, angiogensis, fibrosis, there is the involvement of al, 2009). With the advancement of cytokine immunotherapy
Cytokines especially in every biological process, so we can say that is particularly done in combination with the
that in every disease there are multiple cytokines that are chemotherapy, hence collectively called as biochemotherapy
involved (Feldmann, 2008). There is a production of multiple has significant improved outcome for the metastatic diseases.
cytokines in parallel or sequentially in order to coordinate Now as a post surgical adjuvant Cytokines with vaccines of
evolution, initiation, and for the resolution of an immune cancer are under trials and considered as an important part in
response. Sharing bioactivities of multiple cytokines in therapy of cancer so we can achieve beneficial and long term
peripheral of immune system can result in fundamental survival rates from disease (Dezfouli et al, 2005). The
redundancy. Depending upon the presence of other cytokines, advancement in molecular biology, microsequencing, and

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ISSN Online: 2307 – 5465, Print: 2307 – 5716
Journal of Infection and Molecular Biology 1 (2): 20 – 26.
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monoclonal antibodies has made it possible to achieve the pure Dendritic cells are produced from monocytes of the
preparation of recombinant cytokine for the applications like patients and are used in cancer vaccines. From the expression of
therapeutics and for experimental purposes. There is a number MHC I class and MHC II class, DCs get their potential. Henc,
of cytokines that perform the function of pathophysiological. in designing vaccines for cancer immunotherapy DCs play
The genes that are regulated by cytokines could be detected by major role (Koido et al, 2011).
gene chip microarray (Oppenheim, 2000).

Figure 3: Role of DCs in designing vaccines for cancer immunotherapy, www.hindawi.com

CYTOKINES AS THERAPEUTIC TARGETS behavior, periodontitis susceptibility and severity. This

The research of cytokine has introduced us with new therapies detection offers an induction of prophylaxis and early diagnosis
that has recognized in treating many important diseases. These to other members of the family against the progression of
therapeutic advances result in two types of strategies, the first disease (Loo et al, 2012). By studying the results of these
among those embodies the administration of recombinant, biomarker gave us the evidence of that the change of levels of
purified cytokines while the second strategy is the serum cytokines are linked with depression, pain, fatigue,
administration of therapeutics that will inhibit dangerous disturbance in sleep with severity of pain and analgesic intake
affects of the up regulated and endogenous cytokines. (Miaskowski et al, 2012). Cytokines act as very useful serum
Interferons and the Hematopoietic growth factors are the biomarkers in the patients with thyroid cancer (Lumachi et al,
examples of successful cytokine therapeutics (Vilcek et al., 2010). The chemokines, cytokines and the growth factors as
2004). Cytokines are one of the best targets for the products in biomarkers have been aided by exploratory and mechanistic
biotechnology industry, they are important extracellular studies of biomarker that insinuate repair process and
molecules that are rate limiting and these cytokines form very inflammatory in toxicity. The cytokines are used as biomarkers
specific therapeutics; they are more specific as compared to because they are sensitive, specific and show temporal kinetics
small chemicals organic in nature due to wide surface that permits persistence, detection, and resolution of toxicity.
interaction of receptors as well as antibody with the targets The use of cytokines is more useful when they derive acute
(Feldmann, 2008). Cytokines has potential to be used in toxicity named “asimmunostimulation” (Tarrant, 2010). In
therapeutics or immune adjuvants for certain diseases; they may livestock and in human, in immune response genes the single
be used as therapeutic targets in various diseases (Xing et al., nucleotide polymorphism (SNPs) has been recognized as
2000). The current review shows that the in certain markers to infectious diseases for susceptibility (Kongchum et
pathological conditions which also includes autoimmune al, 2010).
disease, auto-antibodies could be produced against the For genotyping we need a technology that should be
cytokines and that could be detected in healthy individuals. In economical and for association studies large sample size is
the autoimmune diseases, these AutoAbs are prognostic required as well as increased number of SNP markers in
markers which may be positive or negative. High levels of cytokine genes that should be functional. For a number of
autoantibodies against the cytokines may cause significant functionally polymorphisms of cytokine in TNFa,
immunodeficiency (Cappellano et al, 2012). TNFb, IL10, and IL1 genes which are associated with many
inflammatory and immune diseases, Taqman real time PCR
CYTOKINES AS BIOMARKERS genotyping assay are validated designed (Johnson et al, 2004).
A biomarker can be defined as any measureable characteristics For the functional analysis, the selections of SNPs were based
encompass the detection of pharmacologic, pathologic and on the proximity of a SNP to the site of transcription or
physiologic process (Tarrant, 2010). The polymorphisms of association studies that were unreliable in the past. Since the
cytokine gene could be used as markers for the clinical studies of the functionality of SNP, the knowledge related to
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Yasmeen et al (2013). Cytokines Gene Polymorphism and Potential use as Bio-markers
ISSN Online: 2307 – 5465, Print: 2307 – 5716
Journal of Infection and Molecular Biology 1 (2): 20 – 26.
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