14

Personalized Medicine
And

Pharmacogenetics

Q603
Medical Genetics
2014
 Objectives!

Define/describe personalized medicine and how it

could be and is used, including Direct to
Consumer (DTC) testing!
!
Describe factors contributing to drug responses!
!
List and describe examples of how genetic
polymorphisms effect drug metabolism (e.g.,
genetic differences in the cytochrome P450
genes)!
 Personalized Medicine !

Customized healthcare tailored to individual

patients in whatever ways possible

From a genetic perspective: Screening to identify genetic

predisposing risk factors in order to reduce the risk by
changing: ? diet, ?behavior, ?life style, ?environmental
exposures, ?medications.!
!
We have discussed this some at various times in the
course. Already happening and expected to increase.!
 Direct To Consumer (DTC) Testing!
• Direct to consumer genetic testing refers to genetic tests that
are marketed directly to consumers (e.g. via the Internet,
television, print or advertisements.). May also be called other
things such as at-home genetic testing, etc.!

• Raises multiple issues.!

• Does not necessarily involve a doctor in the process.!

• A number of organizations have raised concerns about DTC

testing, such as the American College of Medical Genetics
(ACMG); the College of American Pathologists (CAP), etc…!
 American College of Medical Genetics (ACMG)!
Policy statement on DTC testing (2008).!
…it is critical for the public to realize that genetic testing is
only one part of a complex process which has the potential for
both positive and negative impact on health and well being. !
!

Minimum requirements!
!

• A knowledgeable professional should be involved in the process of

ordering and interpreting a genetic test!
• The consumer should be fully informed regarding what the test can and
cannot say about his or her health!
• The scientific evidence on which a test is based should be clearly stated!
• The clinical testing laboratory must be accredited by CLIA, the State and/
or other applicable accrediting agencies!
• Privacy concerns must be addressed !
 Some DTC Testing Questions!

• What is the disorder for which the test is being used?!

• What is the test?!
• What evidence links the test to the disorder?!
• How is the disorder usually diagnosed? !!
• What are the implications of a positive test result vs. a
negative test result on medical management? Personal
decision-making? Risks to other family members?!
• Who is going to help explain the results to all the
family members who need to know?!
 Patient evaluated by our cytogenetics laboratory
• Found to have deletion associated with Wolf Hirschorn syndrome.
• Clinical features not all typical so family thought patient may be mosaic.
• Family sent buccal swab to DTC company for testing.
• Results came back with a number of increased and decreased
estimates related to a variety of diseases.
• The company did not identify the deletion found by cytogenetics lab, so,
the family decided that this was evidence for mosaicism.
 Goggle now

How It Works – 23andMe

https://www.23andme.com/howitworks/

23andMe provides ancestry-related genetic

reports and raw genetic data. At this time we
do not offer health-related genetic reports. If
you are a current customer …
?
 Drug%Response%
%Response rate of most drugs is 25-75%. Thus, use of drugs
in non-responders increases occurrence of side effects
and health care costs.

About 15% of prescribed drugs have severe adverse

effects. Some side effects can be so severe that individuals
can be hospitalized, even when the drugs are prescribed
and administered according to established protocols.

%Over 2 million people are hospitalized each year for

adverse reactions to prescription drugs, most of which are
avoidable.*

*Wilkinson. G.R. N. Engl. J. Med. (2005) 352(21): 2211-2221

Percent of Population in Which Drug is Ineffective

www.personalizedmedicinecoalition.org
 Diagnosis

Treatment /
4 possible results
Drug

Effective Not effective Effective Not effective

No toxic/adverse No toxic/adverse Toxic/adverse Toxic/adverse

effect(s) effect(s) effect(s) effect(s)
OPTIMAL RESULT
 Pharmacogene+cs:. goal is to get effective & non-toxic
dosing

%Concerned%with%the%impact%of%gene6c%varia6on%on%
drug%response%and%metabolism%

Pharmacogenomics: Application of genomic

information or methods to pharmacogenetic problems

The promise/hope is that the

knowledge of a patient's DNA
sequence could be used to
optimize drug efficacy and
reduce adverse effects.
 Genetic changes that impact drug
response/reaction may be

Constitutional (e.g., inherited): Variant present in

all cells. Passed from parent or occurred during
gametogenesis.

Somatic (e.g., .tumor-specific): In a particular

group/subgroup of cells.
FACTORS%WHICH%CAN%CONTRIBUTE%TO%%DRUG%
RESPONSIVENESS%%
• Drug%metabolism%(pharmacokine6cs)%%
• Drug%target%reac6vity%(pharmacodynamics)%
• Environmental%condi6ons%
• Acquired%problems%(pathological%processes)%
• General%health,%race,%age,%and%gender%
• Gene6c/genomic%factors%
• Combina6ons%of%factors%
 Pharmacokine6cs%&%Pharmacodynamics%
• Pharmacokine6cs%explores%what%the%body%does%to%the%drug%
how is the drug metabolized by the body?
• Pharmacodynamics%explores%what%a%drug%does%to%the%body%
how does the drug act on the target?

(metabolism)

(target)
 DRUG%METABOLISM%
• Varia6on%in%drug%responses%oUen%due%to%
gene6c%varia6on%in%drug%metabolism%enzymes%

• Almost%all%of%the%major%enzymes%involved%in%
drug%metabolism%display%clinically%significant%
gene6c%polymorphisms/variants.%
 HYPOTHETICAL%SCENARIO%
• AUer%a%surgery,%your%surgeon%prescribes%codeine%to%treat%
your%post[surgical%pain.%
• Two%hours%post%ini6a6on%of%treatment,%you%are%s6ll%
experiencing%excrucia6ng%pain!%%
• Why%isn t%codeine%working%the%way%an6cipated/desired?%

• To%be%an%effec6ve%analgesic,%codeine%must%be%converted%
to%morphine.%

http://www.pharmgkb.org/resources/education/cyp2d6.jsp
 CYP2D6%
• Cytochrome%P450%2D6%(CYP2D6)%is%
a%drug%metabolizing%enzyme:%
– Predominantly%expressed%in%the%liver%%
– Metabolizes%20[25%%of%commonly%
prescribed%drugs%
– Varia6on%in%ac6vity%can%lead%to%%
serious%drug%reac6ons%
– Catalyzes%conversion%of%codeine%to%
morphine%
• 10%,%no%pain%relief%from%codeine%
Text

Beta.Blockers. An+depressants. An+psycho+cs. An+7cancer. Opioids. Others.

agents.
carvedilol% amitriptyline% haloperidol% SERM:%tamoxifen% codeine% amphetamine%
S[metoprolol% clomipramine% perphenazine% Vinca%alkaloids:% dextromethorphan% bufuralol%
propafenone% desipramine% risperidone% vincris6ne% oxycodone% debrisoquine%
6molol% fluoxe6ne% thioridazine% % dextromethorphan%
imipramine% zuclopenthixol% % fluvoxamine%
paroxe6ne% % lidocaine%
nortriptyline%
20
 Gene+c.varia+ons.of.the.CYP2D6.gene.
• Highly%polymorphic%%
– SNPs%(point%muta6ons),%dele6ons,%inser6ons,%copy%number%
polymorphisms%[%>100%iden6fied%alleles%
• Allelic%frequencies%vary%in%different%ethnic%popula6ons%
– Can%be%divided%into%subpopula6ons%based%on%the%
ac6vity%of%the%resul6ng%proteins,%i.e.,%poor,%extensive,%
and%ultrarapid.metabolizers.%
– Normal%response%is%rapid%conversion%of%codeine%to%
morphine%%
• Normal%CYP2D6%→%extensive.metabolizers.(EM).%%
• Pain%relief%with%codeine%is%effec6ve%
• Much%less%likely%to%develop%toxicity%with%standard%dose%
of%codeine.%%
 CYP2D6.Alleles.
=poor metabolizers
Inadequate%expression%→%↓%conversion%of%
codeine%to%morphine.%%
• These%people%are%poor.metabolizers.(PM).
• Results%in%decreased%produc6on%of%morphine%→%
poor%pain%relief%from%codeine%
• Can%develop%adverse%effects,%e.g.,%nausea,%due%to%
↑codeine%
variation in suppression of
• 24%alleles%have%no%ac6vity% activity exists
• 6%alleles%have%decreased%ac6vity%
• 5[10%%of%Caucasians%are%homozygous%for%
recessive%(low%or%no%ac6vity)%alleles%
 CYP2D6%Alleles%
Overexpression%→%↑%conversion%of%codeine%to%
morphine.%%
• These%people%are%ultrametabolizers.(UM)%%
• Results%in%increased%produc6on%of%morphine%→%adverse%
effects%and%toxicity,%e.g.%impaired%respira6on%and%
seda6on.%%
• Alleles%*1,%*2,%*4%and%others%have%copy%number%
polymorphisms%
• The%*2%variant%can%have%1,%2,%3,%4,%5%or%13%copies,%i.e.%
increased%ac6vity% overall—problem is too much production of the protein
• Hyperac6ve%in%up%to%30%%of%East%Africans%
Variability%exists%in%CYP2D6%drug%metabolism%
overexpression inadequate expression
Extensive.
Ultra7rapid. Intermediate. Poor..
metabolizer.
metabolizer.. metabolizer.. metabolizer..
( normal )..
(UM). (IM). (PM).
(EM).
More%than%2% 2%copies%of% Decreased% Inac6ve%or%
func6onal% func6onal% func6onal% null%alleles%
genes% gene% alleles%

Decreased.enzyme.ac+vity.

Faster%drug% Severely%
metabolism% compromised%drug%
metabolism%
Consequence:%therapeu6c%failure%or%adverse%drug%reac6on%
24
• Although%gene6c%tes6ng%is%has%not%been%
rou6nely%done,%it%is%possible%to%test%for%
varia6ons%in%the%gene%for%the%CYP2D6%enzyme.%%

• In%the%future,%it%should%be%possible%to%
determine%what%gene6c%varia6ons%exist%in%
CYP2D6%gene%before%prescribing%a%pain%
reliever.%%
 Breast Cancer Revisited
Assessing Risk!
(Have already talked about BRCA1 and 2)

Breast Cancer

High! Low!

Pre-emptive treatment! Avoid Mammogram!

Avoid Radiation Risk!
High cost saving to society!
Medium!
Continue screening mammograms!
and self exams.!

What if cancer occurs? >> Her2/Neu and Trastuzumab (Herceptin) ?

can treat w/ drugs
 tx: Tamoxifen
(Breast Cancer Revisited Again)

Tamoxifen can block the action of estrogen.

Used to treat estrogen receptor positive (ER+) breast

cancer for over 30 years
Approved by the FDA

Metabolized by CYP2D6 to active forms, endoxifen and

4-hydroxy-tamoxifen
Some studies have found a correlation between
CYP2D6 genotype and endoxifen levels
∴ CYP2D6 genotype impacts the effectiveness of endoxifen
Utility of CYP2D6 testing in relation to breast cancer
and treatment? still being studied as to whether genotyping
for CYP2D6 is worthwhile prior to use of tamoxifen
 TPMT%%(Thiopurine%Methyltransferase)%

• TPMT%breaks%down%a%class%of%chemotherapeu6c%compounds%
called%thiopurines%
How much breakdown occurs
• Influences%the%outcome%of%chemotherapy%for%leukemia%in%
children%

• Thiopurines%can%reach%toxic%levels%if%the%drug%is%eliminated%too%
slowly%
∴
• The%dose%must%be%adjusted%according%to%an%individual's%TPMT%
speed ,%which%has%drama6cally%improved%the%survival%rate%of%
affected%children.%%
 TPMT%
• 90%%homozygous%for%wild%type%allele%and%metabolize%product%
normally%
– Toxicity%is%low,%but%relapse%is%high.%
• Some%are%poor%metabolizers%
– Toxicity%is%high.%%
– Children%are%at%risk%of%dying%
• 0.3%%are%homozygous%for%low%ac6vity%variants%
– Mostly%TPMT*3A%allele%homozygotes%%
must be determined before
– High%risk%of%myelosuppression% dosing begins
– Treat%with%1/10%to%1/15%the%standard%dose%

• Label:' Recommenda6on%to%use%pharmacogene6c%tes6ng%to%
guide%dosing .%
 Warfarin%%
• One%of%the%most%widely%prescribed%oral%
an6coagulants.%%

• Has%a%narrow%therapeu6c%window%and%wide%
interindividual%variability,%dosing%problema6c.%%

• If%the%dose%is%too%low%(under[an6coagula6on),%can%
result%in%thromboembolic%stroke%

• If%too%high%(over[an6coagula6on),%can%result%in%
bleeding%complica6ons%(intracranial%hemorrhage).%%
 Warfarin%%
%%% With%30%million%prescrip6ons%wrimen%annually%
for%warfarin%in%the%United%States%and%nearly%
43,000%reported%annually%as%being%seen%in%
emergency%rooms%for%adverse%side%effects,%the%
poten6al%for%gene6c%tes6ng%to%minimize%pain%
and%suffering%is%tremendous, %said%Joe%Leigh%
Simpson,%MD,%FACMG,%President%of%the%
American%College%of%Medical%Gene6cs.%
Wall Street Journal AUGUST 16, 2007
 Warfarin%

• Warfarin%stops%the%
forma6on%of%ac6ve%
cloong%factors%by%
MOA: inhibi6on%of%vitamin%K%
epoxide%reductase%
complex%subunit%1%
(VKORC1)%
%
• S[Warfarin%is%
metabolized%by%CYP2C9%

• Warfarin%ac6vity%is%
determined%par6ally%by% active form is S-warfarin
gene6c%factors.%%
 CYP2C9..(and.Warfarin).
• The%variant%alleles%*2%and%*3%have%much%lower%
ac6vity%than%the%wild[type%allele%*1.%%(doesn t%
metabolize%as%fast)%
• Require%less%warfarin%to%achieve%an%an6coagulant%
effect%but%have%increased%risk%for%hemorrhage%(need%
less%to%overdose).%%
• Variants%mainly%among%Caucasian%pa6ents%
• Rare%in%African%American%and%most%Asian%pa6ents.%

• However,%this%pharmacokine6c%varia6on%does%not%
explain%all%of%the%variance%in%the%therapeu6c%warfarin%
dose,%there%is%also%a%pharmacodynamic%component%
∴ look at target (reductase)
 Warfarin s%Target%
• Inhibits%VKORC1%so%it%doesn t%recycle%cofactors%
for%cloong%factors%
• There%are%two%main%haplotypes:%
– %haplotype%group%(A),%low[dose%
– %haplotype%group%(B),%high[dose%
– %if%A/B,%intermediate[dose%
• Asian%Americans%are%generally%more%sensi6ve%
to%warfarin%(group%A%haplotypes).%%

• African%Americans%are%on%average%rela6vely%
resistant%(group%B%haplotypes)%
 Gene6cs%of%Warfarin s%Dose%
Variability%
• The%CYP2C9'variants%are%in%the%coding%region%and%
alter%enzyme%ac6vity%

• The%VKORC1'variants%are%noncoding%and%are%thought%
to%alter%expression%of%the%protein.%%

• The%varia6ons%responsible%for%approximately%30%%to%
45%%of%the%differences%in%warfarin%dose.%%
The warfarin drug
labeling was revised on
August 16, 2007 by the
FDA to include genetic
information.

The new label states

that lower initial doses
should be considered
for patients with genetic
variations in CYP2C9
and VKORC1.
 Some.Pharmacogene+cs.Ethical.Issues.
1. Not%giving%a%nonresponder%a%certain%drug%which%works%in%
others,%pa6ent%may%feel%discriminated%against%(direct%to%
consumer%marke6ng)%
2. Falsely%accusing%pa6ent%of%being%noncompliant%or%having%
drug[seeking%behavior%due%to%increased%clearance%
3. Nonresponder%status%influencing%risk%calcula6on%made%by%
insurance%companies%(agreeing%to%cover%expensive,%toxic%or%
ineffec6ve%drug)%
4. Do%you%want%to%be%contacted%if%your%genotype%is%found%at%a%
later%6me%to%be%associated%with%a%condi6on%you%weren t%
originally%tested%for? %
– Issues:%%Referrals?,%Privacy?,%Who%contacts%the%pa6ents?,%………..%
 Diagnosis

Treatment / Drug

Effective Not effective Effective Not effective

No toxic/adverse No toxic/adverse Toxic/adverse Toxic/adverse

effect(s) effect(s) effect(s) effect(s)
Goal Diagnosis
DNA is just
one part of it
Obtain individual/personal data (DNA,
blood biomarker(s), urine, etc ….. )

Personalized treatment plan (e.g., drug)

Plan A Plan B Plan C Plan D

Effective
? Whole genome/exome sequencing ?
END.