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7
Pharmacogenomics
IsabelleMercierandAmaliaM.Issa
LearningObjective
1.Explainthebasicconceptsofpharmacogenomicsandbefamiliarwithitsterminology.
2.Discusshowgeneticsaffecttheactivityofdrug-metabolizingenzymes.
3.Considerhowpharmacogenomicsmayplayaroleindrugtherapyselectiongivenaspecificcase.
INTRODUCTION
PharmacogenomicsandPrecisionMedicine
Interpatientvariabilityindrugtherapyresponseisawell-knownpharmacotherapeuticconcept.Indeed,as
farbackas1892,WilliamOslerisreputedtohavesaid,“Ifitwere notforthegreatvariabilityamong
individuals,medicinemightbeascienceandnotanart”(Golden,2004).Inadditiontofactorssuchas
age,sex,drug–druginteractions,andcomorbidities,geneticsalsoisknowntoplayaroleininterpatient
variabilityofdrugresponse.
Theabilityofgeneticvariability(inheriteddifferences) toinfluencetherapeutic drugresponseisthe
basisofpharmacogeneticsandpharmacogenomics.Generally,pharmacogeneticsreferstosingleorafew
genevariations(calledpolymorphisms),whereaspharmacogenomicsrefersmorebroadlytothegenomewide (or an individual’s entire deoxyribonucleic acid [DNA] sequence) effects on drug therapy.
Precision medicine is a more recently coined term thatincludes pharmacogenetics/pharmacogenomics
and refers to “an emerging approach for disease treatment and prevention that takes into account
individualvariabilityingenes,environment,andlifestyleforeachperson”(NationalLibraryofMedicine
(2020).
Wecanthinkofpharmacogenomicsasthebasicscienceofprecisionmedicine,andindeed,muchofthe
progress that has been made in the field of precision medicine to date has been largely focused on
pharmacogenomics.
This chapter is geared toward future clinicians, particularly nurse practitioners and physician
assistants, to provide them with an overview of pharmacogenomics, the current state of the science,
including some pertinent examples, some relevant applications, and promises, pitfalls and policy
implications.
BASICCONCEPTS
Because pharmacogenomics is rootedingenetics, itis helpful toreview some basicgenetic concepts.
Severalofthedefinitionsofkeytermsthatareassociatedwithgeneticsandpharmacogenomicscanbe
foundinBox7.1.
Thehumangenomeistheunderpinningofeveryhuman’sindividuality.Withtheexceptionofidentical
twins,thegenomeisdifferentforeveryindividual,althoughinthegrandschemeofthings,thereareonly
smalldifferencesamongpeople’sDNAthatmakeusunique.Thehumangenomeconsistsofapproximately
threebillionbasepairs,99.9%ofwhicharethesameamongallhumans,withonly0.1%variationamong
individuals.ThevariationsthatoccurwithDNA(polymorphisms),alongwithenvironmentalanddietary
factors,createapatient’sindividuality,susceptibilitytodisease,andresponsetotreatments.Includedin
thisindividualityisaperson’sabilitytoabsorb,distribute,metabolize,andexcretedrugs.Understanding
thegeneticcomponentsaffectingthesepharmacokineticprocessescanhelpthecliniciantailortreatment
forapatient.
Box7.1 Definitions
Adenine(A)—Oneofthefournucleotidebases.Pairswiththymine.
Alleles—Multipleversions of a gene. Each person typically inherits two alleles ofeachgene, one
fromthemotherandonefromthefather.
Autosomal—Pertainstoanychromosomethatisnotasexchromosome. Humanshave22autosomal
pairs(i.e.,44autosomes)ineachcell.
Biomarkers—Moleculesthatindicatethestatusofabiologicalprocess.
Chromosome—TheorganizedstructureofDNAandproteins,thedouble-helix.Itcontainsgenesand
nucleotidesequences.
Cytosine(C)—Oneofthefournucleotidebases.Pairswithguanine.
DNA—Deoxyribonucleic acid, a nucleic acid that contains genetic information and/or instructions
usedinthefunctionoflivingorganisms.Exon—Theportionofagenethatcodesforaminoacids.
Gene—AsequenceofDNAthatcodesforatypeofproteinorRNA,servingaparticularfunctionin
acell.Genome—Allofthegeneticmaterialinchromosomesofanorganism.
Guanine(G)—Oneofthefournucleotidebases.Pairswithcytosine.
Haplotype—Acombinationofalleles.Ahaplotypemaybeasinglelocusofalleles,multipleloci,or
evenanentirechromosome.
Nucleotide—MoleculesthatmakeupthestructuralunitsofDNAandRNA.ThefourDNAnucleotides
areadenine,cytosine,guanine,andthymine.ForRNA,uracilissubstitutedforthymine.
Precisionmedicine—Amorerecentlycoinedtermthatincludespharmacogenetics/pharmacogenomics
andrefers to“anemergingapproachfordiseasetreatment andpreventionthat takes intoaccount
individual variability in genes, environment,and lifestyle for each person” (National Library of
Medicine,2020).
Pharmacogenetics—Refers to the study of inherited differences in single gene variations (called
polymorphisms)orafewgenes,indrugmetabolismandresponse.
Pharmacogenomics—Referstotheeffectsofgenome-widesequence(oranindividual’sentireDNA
sequence)ondrugtherapy.
Polymorphism—DNAsequencevariation.
RNA—Ribonucleicacid,anucleicacidthatcarriesgeneticinformationandproducesproteinsusedin
thefunctionoflivingorganisms.
SNP—Single-nucleotidepolymorphism,aDNAsequencevariationoccurringwhenasinglenucleotide
differsamongmembersofaspecies.
Thymine(T)—Oneofthefournucleotidebases.Pairswithadenine.
Wild-type—Thenormal,asopposedtothemutant,geneorallele.
Eachhumanhas23pairsofchromosomes—22areautosomalandlookthesameinmalesandfemales,
and1pairisthesexchromosome,inwhichfemaleshavetwoXchromosomesandmaleshaveanXanda
Ychromosome.Thesechromosomesreside inthenucleusofacell(Figure7.1). Eachchromosome is
composedofDNA,whichcarriesthegeneticinformationfortheindividual.Eachchromosomecanhave
hundreds or thousands of genes; it is estimated that there are more than 25,000 genes on the human
genome.However,genesonlymakeupabout1%ofthetotalDNAfoundinhumans.
Genesfunctiontoproduceproteinsinvolvedinthemillionsofbiological processes thatsupportthe
functionofthebodyeveryday.Genesthatmutateormalfunctioncanhaveprofoundeffectsonthebody.In
thecaseinwhichasinglegenemutatesormalfunctions,theresultisamonogenicdisease,suchassickle
cellanemiaor cysticfibrosis.Inmostcases,however,therearemultiplegenesinvolvedinthedisease
process.Thesearereferredtoaspolygenicdisorders.
Polygenicdisordersmayappearasasingleclinicaldisorderbutatthemolecularlevelhavemultiple
biomarkers. Biomarkers are molecules that indicate the status of a biological process. Examples of
biomarkers include prostate-specific antigen for prostate cancer or hemoglobin A1c (HbA1c), now
considered more reliable thanglucose tests as a marker of hyperglycemia. HbA1chas been added as
standard of care accordingto therecommendations of the American Diabetes Association not only to
detectdiabetesbutalso toinform abouttheprediabetic status, whichis a powerful predictive tool to
manage this disease in high-risk patients (Lyons & Basu, 2012). Genetic biomarkers, specific DNA
sequences,arealsobeingdiscovered.
ThebuildingblocksofDNAare thefournucleotide bases,includingthetwo purines—adenine (A)
andguanine (G)—and the two pyrimidines—thymine (T) and cytosine (C). DNA strands are linked
throughbasepairingofthepyrimidineswiththepurines(AwithT;GwithC),conceptuallyformingthe
well-knowndoublehelix(SeeFigure7.1).Thearrangementofthesebasepairsalongeachchromosome
iscalledtheDNAsequence.Variationsinthebasepairingsrangefromsinglenucleotidepolymorphisms
(SNPs),insertions,ordeletionsofanucleotidebasetochangesinthenumberofcopiesofgenes.These
variationscanaltertheproductionorfunctionofproteins,thuscreatingthevariationintheexpressionofa
diseaseortheresponsetodrugtherapy.
FIGURE7–1Relationship amonghumancell, chromosome,genes,andDNA.DNA,deoxyribonucleic
acid.
SingleNucleotidePolymorphisms
A SNP is a variation in the DNA sequence that differs among members of a species or paired
chromosomes in an individual. For example, the following are two sequenced DNA fragments from
differentindividuals:AAGCTAandAAGTTA.Notethattheonlydifferencebetweenthesesequencesis
thesubstitutionofthymidine(T)forcytosine(C).Inthiscase,therearetwoversions(oralleles)ofthis
gene.Eachpersontypicallyinheritstwoallelesofeachgene:onefromthemotherandonefromthefather.
Therecanbeupto10millionSNPsinhumans,butonlythoseSNPsoncodingregionsofthegeneorthe
areaoftheDNAresponsibleforturninggenesonoroffhaveaneffectonhumans.ThisconceptofSNPs
anddifferingallelesisimportantinthestudyofpharmacogenomics,asmanyofthegenesresponsiblefor
drugactivityandmetabolism(e.g., cytochrome P450 [CYP]) have differentalleles on the same gene,
producingdifferentmetaboliceffects.
CLINICALAPPLICATIONSOFPHARMACOGENOMICS
Amajorcurrentissueinmedicalcareisthatmanytherapiesgiventopatientstotreattheirdiseases(e.g.,
cardiovascular,cancer,diabetes)aremisalignedwiththepatient’sgeneticmakeup.Therearetwomain
consequencesthatdirectlyresultfromthislackofmolecularknowledgeatthetimeofdrugtreatment:(1)
Patients can be given a therapy that inefficiently treats the underlying cause of the disease (lack of
therapeutic effect)and(2) patients canbe givena medicationthat can lead to adverse drugreactions
(ADRs)thatcanbeharmfulorevenfatalduetoadifferenceintheirgeneticmakeup.Cliniciansandhealth
careprofessionalsmustunderstandandacknowledgethatsomepatientscouldbegeneticallypredisposed
toresponddifferentlytoagivendrug.Thisgeneticinformationshouldthenbeutilizedtoassuretailored
therapyandsafety.
Themainorganinvolvedindetoxification/metabolism ofdrugsistheliver.TheCYPsuperfamilyof
liver enzymes is a key player in drug metabolism as these enzymes are directly involved in the
modification and processing of approximately 75% of all medications taken (Di, 2014; Tornio &
Backman,2018).TheimpactofgeneticmodificationsintheseCYPenzymeshasthereforeanimportant
impact on patient treatment. The following examples are focused on genetic alterations in these CYP
enzymesandtheirclinicalimplicationsfocusedoncommonlyusedcardiovascularmedicationsaswellas
aspecificclassofcommonlyusedantibiotics.
Clopidogrel:MetabolismandPolymorphism
TheP4502C19(CYP2C19)liverenzymeisoneofthebestcharacterizedP450isoenzymeswithclinical
implications linked to this genetic polymorphism. The CYP2C19 gene has 9 exons and is situated on
chromosome 10. Todate,morethan30 differentSNPshavebeenidentifiedforthisgene.Interestingly,
several years ago, reports emerged that not all patients metabolized clopidogrel in a similar manner,
regardlessoftheirageorweight,suggestingthatadditionalcomponentsmightbeinvolved.
Clopidogrel is a very common medication that is prescribed to patients undergoing acute coronary
syndrome(ACS). When patients arrive at the hospital withapartial coronaryobstruction,antiplatelet
agents are the gold standard in preventing irreversible cardiac ischemia. Clopidogrel is given as an
inactive prodrug that is rapidly converted to its active metabolite via hepatic bioactivation through
CYP2C19enzymes(seeChapters2and3forareviewofprodrugsandbiotransformation).Clopidogrel
inhibits ADP-mediated platelet activation and aggregation by irreversibly binding to the platelet
purinergicreceptorP2RY12.About15%ofclopidogrelismodifiedintoanactivecompoundand85%is
hydrolyzedtoinactiveformstobeexcreted.
Duetoitspotentnature,atimelyinterventionwiththispharmacologicagentisessentialtopreventing
furtherblockageanddeath,makingdosagekeytoattainingefficaciousandsafetreatment.Themetabolism
of clopidogrel to its active metabolite is critical to successful treatment, and thus inherited genetic
polymorphisms associated with CYP2C19 have a high impact on the physiological responses to
clopidogrel in patients. Genetic variants of the CYP2C19 gene result in normal, reduced, or absent
enzyme activity or candirectlylead toanoveractive enzyme. As summarizedin Figure 7.2, different
mutationsareresponsiblefortheselevelsofenzymatic activity. Inpharmacogenomics,geneticvariants
are identified using a special nomenclature (see Box 7.2). While CYP2C19*1 is the wild-type allele
resulting in normal enzyme activity, the most common loss-of-function variant is referred to as
CYP2C19*2(681G>A)(Schuldineretal.,2009).TheCYP2C19*2allele isinheritedasanautosomal
codominanttraitthatco-segregatesmostlytotheAsianpopulationandislesscommoninCaucasianand
Africans(Scottetal.,2011).Amuchlesscommonvariantassociatedwithareducedorabsentfunctionof
thisenzymeisreferredtoasCYP2C19*3(636G>A),whichisdetectedonlyinlessthan10%oftheAsian
population.Thedistributionofthesemutationsinpatientsdictateshowpatientsmetabolizeclopidogrel.
Around 2% to 15% of patients carry loss-of-function mutations (*2/*2,*2/*3,*3/*3) on both alleles,
resultinginsignificantlyreducedorlackofCYP2C19activity,andthesepatientsarereferredtoaspoor
metabolizers (PMs). Otherindividuals carrya gain-of-functionmutation,whichmakesCYP2C19more
active(*1/*17,*17/*17);thesepatientsarereferredtoasultrarapidmetabolizers(URMs)andcomprise
about5%to30%ofpatientpopulations.Mostpatients,however,haveanormalCYP2C19genewithout
anymutations, who are called extensive metabolizers (EMs), or with onlyone loss-of-function allele
(*1/*2,*1/*3),whoarereferred toas intermediatemetabolizers (IMs).EMsandIMscomprise 35% to
50%and18%to45%ofagivenpopulation,respectively.
FIGURE7–2ClopidogreltherapyandCYP2C19.CYP,cytochromeP450.
Warfarin:MetabolismandPolymorphism
Warfarinis acommonlyprescribedbloodthinnerusedtopreventatrialfibrillation–inducedstrokes,as
well as permanent damage following the onset of venous thromboembolism or pulmonary embolism.
Warfarinexists as aracemic mixture ofR-warfarin andS-warfarin(Qayyum etal.,2015). S-warfarin
possessesthemostanticoagulantpropertiesthroughitsactionasavitaminKantagonist.VitaminKplays
a crucial role in the coagulation cascade as its reduced form acts as a cofactor of gamma-glutamyl
carboxylase,animportantenzymethatrendersthecoagulationfactorsII,VII,IX,andXfunctionalthrough
post-ribosomalsynthesis(Figure7.3).Importantly,inorderforthecoagulationcascadetobefullyactive,
vitaminKneedstobeinitsreducedform.Thisisaccomplishedbyanupstreamenzymecalledthevitamin
Kepoxidereductasecomplex,subunit1(VKORC1).VKORC1isthetherapeutictargetofwarfarin,and
its inhibition results in decreased amounts of vitamin K, preventing coagulation factors from being
activated(Figure7.3;Panetal.,2015).Onceitstherapeuticwindowisachieved,S-warfarinisrapidly
metabolizedthroughtheP450liverenzymeCYP2C9toitsinactiveoxidizedform(7-hydroxywarfarin).
TherateatwhichS-warfarinismetabolizedishighlydependentontheenzymaticactivityofCYP2C9.As
onemightexpect,alessefficientmetabolismandclearanceofwarfarincouldleadtoaccumulationofits
activeformsystemicallyleadingtosustainedanticoagulationeffects.Indeed,severalincidentshavebeen
reportedwhereaccidentaldeathshaveoccurredduetoexcessivebleedingfollowingwarfarintreatment.
ItwaslaterdiscoveredthatsomepatientsdonothaveafullyfunctionalCYP2C9enzymeduetoalleles
containingmutations,preventingtheproper inactivationof thepotentactive S-warfarin.There are two
mainCYP2C9SNPs foundinpatients, *2(R144C) and*3(I359L);*1isreferred toasthe wild-type
allelewithoutmutations.TheCYP2C9*1individualspossessnormalenzymeactivitywhile CYP2C9*2
carriersexhibita30%decreaseinactivityandCYP2C9*3patientshaveasmuchasa90%decreasein
theirenzymaticactivity.PatientscanexpressafunctionalCYP2C9enzymebycarryingtwonormalcopies
ofthegeneanormalcopyandapolymorphic*1/*2,orcouldhavebothcopieswithpolymorphism*2/*3.
Clinicalimplicationwillbediscussedinthefollowing.ThetargetenzymeVKORC1hasalsoshownthe
presenceofinactivatingmutation,themostcommonbeing–1639G>A.
Box7.2 PharmacogenomicsandtheStarAlleleNomenclature:ABriefOverview
Pharmacogenomics uses a special nomenclature to identify alleles rather than by their cDNA or
genomicpositions(asinotherareasofgenetics).Forpharmacogenomics,variantsareidentifiedusing
a simple system of numbers and letters divided by a star. Consider the following as an example:
CYP3A5*2. This common example is pronounced or spoken as “sip-3-A-5-star-2.” Itrefers to the
alleleorvariantintheCYP3A5genelocatedatpositiong.27289C>A,whichleadstothesubstitutionin
theaminoacidp.T398N.Thestar nomenclature wasfirstused toidentify variationsintheCYP450
genesandthenwasadoptedforuseinotherpharmacogenomicgenes.
From a clinical perspective, the CYP450 genetic variations are particularly interesting as they
signifyfourdifferentphenotypicstatesofdrugmetabolism:
•AnURM
•AnEM
•AnIM
•APM
Individuals with two standard copies of the normally functioning allele are called extensive drug
metabolizers.Usingthestarnomenclature,thiswild-typeallelecorrespondsto*1.Anindividualwith
double or multiple copies of an allele, called an ultrarapid metabolizer, typically has increased
functionality.Ontheotherhand,personsconsideredintermediateorpoordrugmetabolizershaveone
ormoreallelesharboringreducedfunctionality.Thestarnomenclature*2,*3,*4,andsoonisusedto
denotealleleswithalteredfunctionality(i.e.,increasedorreduceddrugmetabolism).
CYP,cytochromeP450;DNA,deoxyribonucleicacid;EM,extensivemetabolizer;IM,intermediatemetabolizer;PM,poormetabolizer;URM,
ultrarapidmetabolizer.
FIGURE7–3WarfarintherapyandVKORC1/CYP2C9polymorphism.
CYP,cytochromeP450;VKORC1,vitaminKepoxidereductasecomplex,subunit1.
MitochondrialMutationLinkedtoAntibiotics-InducedOtotoxicity
Aminoglycosidesareaclassofantibioticsthatarestillcurrentlyusedtotreatgram-negativeinfections.
Antibioticswithinthisclassareassociatedwithincreasedriskofbothnephrotoxicityandototoxicityin
bothyoungandadultpatients.Damagetotheearrangesfromtinnitustoirreversiblehearingloss,which
hasbeenlinkedbothinanimalmodelsandinhumanstudiestodoses,frequency,andlengthoftreatment
(Bitner-Glindzicz&Rahman,2007;Hutchinetal., 1993).However,thereseemstobeasegregationof
mitochondrial mutations that have been identified that correlate with hypersensitivity of aminoglycosides-inducedototoxicityinpatients(Bitner-Glindzicz&Rahman,2007;Hutchinetal.,1993).Atthe
molecular level, aminoglycosides are designed to bind bacterial ribosomes to halt protein synthesis.
However,aninheritedmutationinthemitochondrialDNA(transferredmaternally)increasestheaffinity
bywhichaminoglycosides bindtomitochondrial ribosomes,resultinginanincreasedhalf-lifeofthese
antibioticsinthehaircellsoftheinnerear(Bitner-Glindzicz&Rahman,2007).Thisincreasedpresence
ofaminoglycoside-bindingaffinityintheearofgeneticallypredisposedindividualsisspecificallythought
toaffectmitochondrialproteinsynthesisanddisruptadenosinetriphosphateproductionandiongradients
intheear,leadingtohearingimpairment(Hutchinetal.,1993).
GeneticTestingtoPredictDrugEfficacyandAdverseResponse
The active metabolite of clopidogrel dictates its therapeutic efficacy. Therefore, the degree to which
patients are capable of effectively producing these active metabolites through their liver CYP2C19
enzymes is directly linked to their treatment success and recovery from an ACS. In the case of
clopidogrel,thePMsarethosewhocouldbenefitthemostfromgenetictestingpriortotherapy,asstated
onpackageinsertsandassuggestedbytheU.S.FoodandDrugAdministration(FDA).ThesePMsare
incapableofproducingtheactivemetaboliteofclopidogrel,duetoinactivatingmutationsinCYP2C19
liverenzymeresponsibletoconvertclopidogreltoitsactivemetabolite.IfaPMpatientsuddenlysuffers
acoronaryblockageandisadministeredclopidogrel,thiswouldresultinanunsuccessfultreatmentofthe
patient’s coronary blockage. The Clinical Pharmacogenetics Implementation Consortium also
recommendsthatspecialattentionbegiventoURMsandthatalternativetherapiesbeusedinPMstotreat
their coronary obstruction (Scott et al., 2011). In addition, IMs are also challenging to treat with
clopidogrel, as thesepatients havea highernumberof residual platelets,whichcouldlead to adverse
cardiovascularoutcomes(Shirasakaetal.,2015),andmightalsobenefitfromotherformsoftherapy.
For patients receivingwarfarintreatment,genetictestingis recommendedinorder topredictwhich
patients are carrying these mutations who would be at higher risk for bleeding (Maluso, 2015). For
example,thosewhocarrytheVKORC1mutation–1639G>AproducelessVKORC1(referredtoasA
haplotype)thanthosewiththeregularGallele(Ghaplotype).Consequently,theAhaplotypeindividual
wouldrequirelesswarfarintoinhibitVKORC1toproducesimilaranticoagulanteffects.Thesameistrue
for patients who carry CYP2C9 *2 and *3, where the active form of warfarin does not go through
clearancenormally,leadingtoimmediateexcessivebleeding.Asaconsequence,thetherapeuticindexof
thisbloodthinnerisextremelynarrowandneedstobecarefullyassessed.Genetictestingisthushighly
suggested to assess those patients who are genetically predisposed to metabolize clopidogrel and
warfarindifferently.Genetictestingoffersknowledgeofthisgeneticinformationaheadoftimetopredict
theefficacyoftheselifesavingdrugsandguidethetherapeuticwindowtowardmoresuccessfultherapy.
In theory, hearing loss associated with possible mitochondrial mutations inherited by the mother
followingaminoglycoside treatmentcould beapreventableadverse event.Theextensive rehabilitation
requiredforchildrenaffectedbythisirreversiblehearinglossshouldmotivategeneticscreeningpriorto
aminoglycoside therapy. Such genetic testing would identify early on which patients should not be
receivingthisantibioticorprovideinformationaboutdosage.
PROMISES,PITFALLS,ANDPOLICYIMPLICATIONS
In addition to pharmacogenomics, progress is being made with newer technologies such as next
generation sequencing, including whole genome sequencing (WGS), exome sequencing, and targeted
ribonucleic acid (RNA) sequencing,as well as CRISPR-Cas9 genome editing. One new trendthat is
increasingwithinthepharmaceuticalindustryistousepharmacogenomicsfordrugre-purposingandrepositioning(Ferrero&Agarwal,2018).Collectively,therapidscientificdevelopmentsareleadingtoa
number ofimplicationsfor policy,includingbothopportunities andchallenges (Issa, 2015;Issa et al.,
2019;Jolyetal.,2020).
Pharmacogenomics andpersonalized medicine provide both economic opportunities andchallenges.
Thecostofdifferentpharmacogenomictestscontinuestodecline,andthereisincreasingevidenceforthe
cost-effectivenessofpharmacogenomicsaswellasitspotentialtoreduceADRs.Itisalsoimportantto
consider how pharmacogenomics might increase costs, including the storage of genetic samples,
resourcesforcomputationalanalysis, andinterpretationofthefindings.Whileelectronichealthrecords
(EHRs)andclinical decisionsupport(CDS)systemsaregettingbetterandmoreuser-friendly,theyare
generallynotyetwell equipped for thelargeamountofdata thatis beinggenerated bytheincreasing
amountofgenomicinformation,particularlyfrom WGS.InorderforEHRandCDSsystems tobecome
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