PHARMACOGENOMIC

SJARIFISMAIL
Personalized medicine
Personalizedmedicinetakesintoaccountindividualgenetic

differences

Traditionally,doctorsused:

Familyhistory

Socioeconomiccircumstances

Environmentalfactors

Now:

genomic/genetictesting

proteomicprofiling

metabolomic

analysis(studymetabolites)
Effectiveness of drugs:
Danger of drugs:

6.7% of patients in hospitals experience serious drug
reactions
Old Paradigm:
New Paradigm:
Future Paradigm:
Personalized Medicine Today
The Plan
The Plan:
The Plan:
P.M.
Gene

Sequencing/Testing

RFLPanalysis

SNPs

(singlenucleotidepolymorphisms)

Morethan1.4millionSNPs

wereidentifiedinthe

initialsequencingofthehumangenome,withover

60,000oftheminthecodingregionofgenes(Evans

andMcLeod2003).
(butevensilentmutationscanaffectphenotype)
TheaccuracyofDTCgenomescantestshas

beenquestioned,butVenteretal.foundthat

thegenotypes,orparticularDNAbases

observed,agreedmorethan99.7%ofthetime.
Dopredicteddiseaseriskshaveanyclinical

validity?
Genotypephenotypecorrelation?
Certaindiseaseriskscanbebetterpredicted

thanothers.
Whatthetestsdodisagreeon,

however,isthediseaserisk
Pharmacogenetics

Studyofgeneticvariationthatgivesrisetodifferent

responsestodrugs

Itisestimatedthatgeneticscanaccountfor20to95

percentofvariabilityindrugmetabolism

andeffects.

Nongenetic

factorsinclude:age,organfunction,

concomitanttherapy,druginteractions,andthenature

ofthedisease.
Pharmacogenomics Under the PM Umbrella

Better medication choices

100,000 Americans die annually and 2,000,000+ are
hospitalized due to adverse reactions to medications

Predict individual reactions to dugs

Safer dosing options

More exact dosing, optimum result/side effect balance

Improvements in drug development

Exclude genetic variations from certain clinical trials, speeding
up drug design time
Back to the drugs

The utility of pharmacogenetics:

Determining appropriate dosing

Avoiding unnecessary toxic treatments

Ensuring maximal efficacy

Reducing adverse side effects

Developing or choosing novel treatments

Can also explain variable response to illicit drugs
ProteomicProfiling

Relevant in the identification and predisposition to
disease

Joshs presentation
Metabolomic

Analysis

Firstfromurineanalysis

Networksofmetabolitefeedbackpathwaysregulate
geneandproteinexpression.Metabolitesalsocan
mediatesignalingbetweenorganisms.

Biomarkersofdisease(diagnostics)

Themetabolome

isthereforemostpredictiveof
phenotype(Fiehn

2002;Weckwerth

2003).

However,anunderstandingoftheresultingdatais
limitedowingtoafundamentallackofbiochemicaland
physiologicalknowledgeaboutnetworkorganization
Metabolite

targetanalysis
Metabolic

profiling
Metabolomics Metabolite

fingerprinting
allmetabolites,

presentinacellor

sample.

Comprehensive
analysisofentire

metabolome

underagivenset

ofconditions.
theintentionis

nottoidentify

eachobserved

compoundbutto
comparepatterns

orfingerprintsof
metabolitesthat

changein

responseto

diseaseortoxin

exposure.Use

statisticaltoolsto

lookformajor

differences.
focusonone

specific

metabolite
groupofmetabolites,

i.e

thoseassociated

withaspecific

pathway.
Extractionmethod

(capillary

electrophoresis,gas

orliquid

chromatography)

speciallydesignedfor

compoundsinclassto

eliminate
unwanted/irrelevant

metabolites.
http://swift.cmbi.ru.nl/euroschool/meta_seminar1.pdf
Metabolomic

Analysis
static
dynamic
ApplicationsofPersonalized

Medicine

Cytochrome P450 genotyping test

Enzyme group cytochrome P450 (CYP450

Many types of medications(including antidepressents, anticoagulants,
proton pump inhibitors, etc)

Determine dosing and effects of these drugs.

Thiopurine methyltransferase test

Thiopurine

Thiopurine methyltransferase (TPMT)

UGT1A1 TA repeat genotype test

Irinotecan (Camptosar)

UGT1A1 enzyme

Dihydropyrimidine dehydrogenase test

5-flourouracil (5-FU)

Dihydropyrimidine dehydrogenase enzyme

Responsible for breaking down 5-FU
UsesinMuscularDystrophy:

BeckerandDuchenne

MD samefamilyofdisease;Duchennes

moreseverethanBeckersbecausegenerallythereadingframe

ispreservedinBMDwhileitisnotinDMD.

DMD deatharoundage20;BMD

lifeexpectancymaybe

reduced,butsomehaveanormallifespan.Severitypartially

dependsonmutation.

Dystrophin

isthelargestknowngeneinthehumanbody,

locatedontheXchromosome.

79exons

~15%causedbypremature

stopcodons

Phenotypegenotype

correlationstudies
Gentamicin

treatmentinDMD/BMD

Aminoglycoside

antibioticsynthesizedbyMicromonospora

Worksbybindingthe30Ssubunit(inhibitionsite)ofthe

bacterialribosome,interruptingproteinsynthesis(stopcodon

readthrough)
Gentamicin

treatmentofDuchenne

andBeckermuscular

dystrophyduetononsensemutations.(Wagneretal2001)

Somesuccessinmdx

mousemodel

suppressedtruncationof

proteinandimprovedphenotype.

Cons:highlynephrotoxic;canhavepsychiatricsideeffects.
Irinotecan

Treatmentforcancerthatworksbyinhibiting

topoisomerase

1,whichpreventsDNAfromunwinding.

Clinicalstudieshaverevealedsignificantassociations

betweenUGT1A1*28andirinotecan

toxicity.

Arecommendedstrategyforirinotecandose

adjustmentsbasedonindividualgeneticfactorshasnot

yetbeenfullyestablished.
Selzentry (Pfizer)

CCR5-tropic HIV treatment (CD4 immune cells)

Ineffective for CXCR4-tropic strains of HIV

Trofile assay to determine patients strain of HIV

Detect virus that does not act through CCR5 at levels as low as
0.3% of a viral population

Clinical trial patients selected with Trofile assay
Warfarin: A dosage story

Most widely used anticoagulant in
the world

A blood thinner

Prescribed doses vary widely (1-
40mg / daily)

Therapuetic index is very low

High risk of bleeding early in
treatment

Two genes involved in
metabolism: CYP2C9 and
VKORC1
HomozygouswildtypeCYP2C9

andVKORC1
CarrierofCYP2C9mutantallele
CarrierofVKORC1mutantallele
CYP2C9 genotype Time to stable dose
*1/*1 extensive(normal) metabolizer 4 - 5 days
*1/*2 intermediate metabolizer 8 -10 days
*1/*3, *2/*2, *3/*3 intermediate or
poor metabolizer
12-15 days
Plavix: A story about effectiveness

Anti-clotting drug

Prescribed for coronary
artery disease and those
who have suffered a heart
attack or stroke or have a
stent

A pro-drug

Converted to active form in
the liver by CYP2C19
CYP2C19mutantcarriershadreducedpresence

oftheactiveingredient(pharmacokinetics)and

reducedthinning

(pharmacodynamics
Cancer Treatments: A story about the future?
Personalized Medicine

There is an emerging goal among translational
scientists to make medical practice more personalized

Pharmacogenetics is
an important step
towards that goal

The effects of this
movement are seen in
many aspects of society
Direct to consumer genetic testing

Companies now offer genetic testing services
directly to customers

Pharmacogenetic testing is becoming an important
aspect of this service

Controversy about whether this should be
available to anyone or only doctors and about its
accuracy

https://www.navigenics.com/member
Economic investment is huge

Roche is a Swiss
pharmaceutical company

Illumina is the worlds
largest supplier of
genome sequencing (San
Diego based!)

Interested in sequencing
applications to drug
development and
diagnostics
http://money.howstuffworks.com/hostiletakeover.htm
Concerns with this approach?

How reliable are the tests?

Are health care providers prepared to use this
information?

Will Insurance companies pay for the tests?

Will tailor made medicine lead to discrimination?

Will ethnic biases in science bias treatment
developments?

Will this affect peoples privacy?
OR IS IT JUST THE BEGINNING?...
The End