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www.genetics.edu.au The Australasian Genetics Resource Book – © 2007 1 PHARMACOGENETICS/PHARMACOGENOMICS 25 FACT SHEET Produced by the Centre for Genetics Education. Internet: http://www.genetics.edu.au Important points • Pharmacogenetics is the science that underpins understanding the role that an individual’s genetic make-up plays in how well a medicine works, as well as what side effects are likely to occur (personalised medicine) • Potential benefits include: – Development of drugs that maximise therapeutic effects but decrease damage to nearby healthy cells – Prescription of drugs based on a patient’s genetic profile versus trial and error decreasing the likelihood of adverse reactions – More accurate methods of determining dosages – Development of vaccines made of genetic material could activate the immune system to have all the benefits of existing vaccines but with reduced risks of infections • Pharmacogenetics is currently being used to: – Determine drug responses in the treatment of cardiac, respiratory and psychiatric conditions – Understand how some people metabolise codeine in the liver faster than others do – Develop targeted drugs in areas such as psychiatry, dementia, cardiac conditions and in the treatment of breast and other cancers • Limitations include: – Many genes are likely to be involved in how someone reacts to a drug, making targeting different drugs very complex – Identification of the small variations in everyone’s genes that may influence drug metabolism or how the condition develops is very difficult and time consuming – The interactions with other drugs and environmental factors will need to be determined before any conclusions are made about the genetic influence on how the drug is working • Ethical issues include: – Personalised medicine is likely to be very expensive and may adversely impact on equity and access to drugs. This may mean that the development of drugs will be targeted to those that work well with certain population groups; any such targeting will need to be carefully implemented to avoid a perception of stigma based on ethnicity – The assumption that an individual’s race can indicate their genetic profile for drug response is itself problematic since not all people who belong to a particular ethnic group will have the same genetic variations • Regulation will be needed if the techniques are to be widely used including prescription guidelines, testing and usage labels Findings from the Human Genome Project (see Genetics Fact Sheet 24) made it clear that 99.9% of the information in the estimated 20,000 human genes is identical from one person to the next. The small differences in the remaining 0.1% of genes present in the human cells are key to each individual. Usually these differences do not cause any problem with how their body grows, develops or works although they may influence an individual’s susceptibility to certain health problems or determine how an individual’s body reacts to different treatments – in particular, how different medicines are metabolised. The study of the interaction between genetics and therapeutic drugs is variously called pharmacogenetics or pharmacogenomics. The differences between the two are the initial approach of the science: • Pharmacogenetics starts with an unexpected drug response result and looks for a genetic cause • Pharmacogenomics on the other hand begins with looking for genetic differences within a population that explain certain observed responses to a drug or susceptibility to a health problem These terms are used interchangeably so the term used in this Fact Sheet is pharmacogenetics. Pharmacogenetics The term pharmacogenetics comes from the combination of two words: pharmacology and genetics. • Pharmacology is the study of how drugs work in the body and genetics is the study of how characteristics that result from the action of a single gene or of several genes acting together are inherited and how they work in the cells of the body • Therefore, pharmacogenetics is the study of genetic factors that influence how a drug works Factors that influence how an individual responds to medication include their external and internal environments and overall health, as well as their genetic make-up. The goal of pharmacogenetics is to understand the role that an individual’s genetic make-up plays in how well a medicine works, as well as what side effects are likely to occur in the individual’s body. Understanding this can help tailor drugs in the future best suited for a particular individual (personalised medicine) or group. The small differences in the genes between different population groups, or some families within a population group,

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Page 1: Genomics

www.genetics.edu.au The Australasian Genetics Resource Book – © 2007 1

PHARMACOGENETICS/PHARMACOGENOMICS 25F A C T S H E E T

Produced by the Centre for Genetics Education. Internet: http://www.genetics.edu.au

Important points

• Pharmacogeneticsisthesciencethatunderpinsunderstandingtherolethatanindividual’sgeneticmake-upplaysinhowwellamedicineworks,aswellaswhatsideeffectsarelikelytooccur(personalised medicine)

• Potentialbenefitsinclude:– Developmentofdrugsthatmaximisetherapeuticeffectsbutdecreasedamagetonearbyhealthycells– Prescriptionofdrugsbasedonapatient’sgeneticprofileversustrialanderrordecreasingthelikelihoodofadverse

reactions– Moreaccuratemethodsofdeterminingdosages– Developmentofvaccinesmadeofgeneticmaterialcouldactivatetheimmunesystemtohaveallthebenefitsofexisting

vaccinesbutwithreducedrisksofinfections• Pharmacogeneticsiscurrentlybeingusedto:

– Determinedrugresponsesinthetreatmentofcardiac,respiratoryandpsychiatricconditions– Understandhowsomepeoplemetabolisecodeineintheliverfasterthanothersdo– Developtargeteddrugsinareassuchaspsychiatry,dementia,cardiacconditionsandinthetreatmentofbreastandother

cancers• Limitationsinclude:

– Manygenesarelikelytobeinvolvedinhowsomeonereactstoadrug,makingtargetingdifferentdrugsverycomplex– Identificationofthesmallvariationsineveryone’sgenesthatmayinfluencedrugmetabolismorhowthecondition

developsisverydifficultandtimeconsuming– Theinteractionswithotherdrugsandenvironmentalfactorswillneedtobedeterminedbeforeanyconclusionsaremade

aboutthegeneticinfluenceonhowthedrugisworking• Ethicalissuesinclude:

– Personalisedmedicineislikelytobeveryexpensiveandmayadverselyimpactonequityandaccesstodrugs.Thismaymeanthatthedevelopmentofdrugswillbetargetedtothosethatworkwellwithcertainpopulationgroups;anysuchtargetingwillneedtobecarefullyimplementedtoavoidaperceptionofstigmabasedonethnicity

– Theassumptionthatanindividual’sracecanindicatetheirgeneticprofilefordrugresponseisitselfproblematicsincenotallpeoplewhobelongtoaparticularethnicgroupwillhavethesamegeneticvariations

• Regulationwillbeneededifthetechniquesaretobewidelyusedincludingprescriptionguidelines,testingandusagelabels

FindingsfromtheHumanGenomeProject(seeGeneticsFactSheet24)madeitclearthat99.9%oftheinformationintheestimated20,000humangenesisidenticalfromonepersontothenext.Thesmalldifferencesintheremaining0.1%ofgenespresentinthehumancellsarekeytoeachindividual.

Usuallythesedifferencesdonotcauseanyproblemwithhowtheirbodygrows,developsorworksalthoughtheymayinfluenceanindividual’ssusceptibilitytocertainhealthproblemsordeterminehowanindividual’sbodyreactstodifferenttreatments–inparticular,howdifferentmedicinesaremetabolised.

Thestudyoftheinteractionbetweengeneticsandtherapeuticdrugsisvariouslycalledpharmacogeneticsorpharmacogenomics.Thedifferencesbetweenthetwoaretheinitialapproachofthescience:• Pharmacogeneticsstartswithanunexpecteddrugresponse

resultandlooksforageneticcause• Pharmacogenomicsontheotherhandbeginswithlooking

forgeneticdifferenceswithinapopulationthatexplaincertainobservedresponsestoadrugorsusceptibilitytoahealthproblem

ThesetermsareusedinterchangeablysothetermusedinthisFactSheetispharmacogenetics.

Pharmacogenetics Thetermpharmacogeneticscomesfromthecombinationoftwowords:pharmacologyandgenetics.• Pharmacologyisthestudyofhowdrugsworkinthebodyand

geneticsisthestudyofhowcharacteristicsthatresultfromtheactionofasinglegeneorofseveralgenesactingtogetherareinheritedandhowtheyworkinthecellsofthebody

• Therefore,pharmacogeneticsisthestudyofgeneticfactorsthatinfluencehowadrugworks

Factorsthatinfluencehowanindividualrespondstomedicationincludetheirexternalandinternalenvironmentsandoverallhealth,aswellastheirgeneticmake-up.

Thegoalofpharmacogeneticsistounderstandtherolethatanindividual’sgeneticmake-upplaysinhowwellamedicineworks,aswellaswhatsideeffectsarelikelytooccurintheindividual’sbody.Understandingthiscanhelptailordrugsinthefuturebestsuitedforaparticularindividual(personalisedmedicine)orgroup.

Thesmalldifferencesinthegenesbetweendifferentpopulationgroups,orsomefamilieswithinapopulationgroup,

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2 The Australasian Genetics Resource Book – © 2007 www.genetics.edu.au

PHARMACOGENETICS/PHARMACOGENOMICS 25F A C T S H E E T

thathavebuiltupoverthegenerationscanmeanthattheyreactdifferentlytomedicines.

Forexample,ifonegroupofpeoplebreakdownamedicineveryquicklyorveryslowlycomparedtoothers,thentheirgenesmayofferaclueastowhytheyrespondthatway.Ifsothenitmaybepredicted,basedonhisorhergenes,howsomeonewouldreacttoamedicinepriortogivingit.

Somepotentialbenefitsofpharmacogenetics• More powerful medicines: Drugsmaybedevelopedtargeting

specifichealthproblemsthatwillmaximisetherapeuticeffectsbutdecreasedamagetonearbyhealthycells

• Safer drugs the first time:Doctorscouldhaveanideawhichdrugtousebasedonageneticprofileversustrialanderrordecreasingthelikelihoodofadversereactions

• More accurate methods of determining dosages:Insteadofdosagesbeingbasedonbodyweightandage,itwouldbebasedonaindividual’sgenetics.Thiswoulddecreasethelikelihoodofanoverdose

• Better vaccines:Vaccinesmadeofgeneticmaterialcouldactivatetheimmunesystemtohaveallthebenefitsofexistingvaccinesbutwithreducedrisksofinfections

Pharmacogenetics in practice(a) Drug response

CommonvariationsinthegeneticinformationincludechangestoasingleletterofthefourlettersoftheDNAcode–A,T,CandG(seeGeneticsFactSheet1).Forexample,theDNAletter‘A’maybechangedtoa‘C’sothatthemessagefromthegenehasbeenslightlychanged.

Thesevariationsusuallycausenodirectproblem.However,insomepeopleitcanimpactontheirresponsetoadrug.ThisisbecausesmalldifferencesintheDNAcodegroupsthatinfluencearesponsetocertaindrugsaremorecommonincertainpopulationgroupsthanothers.

Forexample,theeffectsofdrugscalledACEinhibitors(angiotensin converting enzyme inhibitors)thatimprovesymptomsand survivalincasesofheartfailurehavebeenfoundtobegreaterinpeopleofEuropeanorUKancestrythanAfrican-Americans.Pre-treatmentgeneticscreeningofpatientswilleventuallyenablethisknowledgetobeappliedinclinicalpractice.

Somedrugsactbybindingtospecificchemicals,calledreceptorsites,onthesurfaceoforwithinbodycells.Variationinthegenesthatcodeforthereceptorsmaymeanthatsomepeoplemayproducereceptorsthatdonotinteractwellwiththedrug.

Forexample,somepeoplehavealackofresponsetothedrug salbutamol,usedinthetreatmentofasthma,duetogeneticvariationinthegenethatcodesareceptoronthesurfaceofsmoothmusclecellsliningairwaysofthelungs.

(b) Drug targets

Genesmayalsodeterminehowmanyofthereceptorsareproducedonorwithincellsandgeneticvariationmaymeanthatsomepeopleproducemoreofthesesitesthanothers.Forexample

• Psychiatry Theactionofthewidelyusedantipsychoticdrughaloperidol

(Haldol)dependsonitsabilitytobindtothedopamine(D2)receptorsite.Inonestudy:– 63%ofpatientswhosegeneticmake-upcausedalarge

numberofthesereceptorsitestobeproducedhadaresponsetotreatmentwithhaloperidol

– About29%ofpatientswithasmallernumberofdopamine(D2)receptorsitesdidwellonthedrug

• Breast cancer Researchhasshownthatwomenwithmetastaticbreastcancer

(cancerthatcanspreadtootherorgans)whoover-expresstheproteinproductofthegenecalledHER2haveaggressivediseaseandapoorprognosis.– TheHER2genenormallyproducesareceptorproteinon

thesurfaceofthebreastcellsthatisthoughttoplayaroleintheirnormalcellgrowthbysignallingthecelltodivideandmultiply

– WhentheHER2geneisover-expressed,extraproteinreceptorsareproducedonthecellsurface.Thisappearstotriggerthecelltogrowanddivideoutofcontrol,andthecellbecomescancerous(seeGeneticsFactSheet47)

– Twentytothirtypercentofallwomenwithmetastaticbreastcancerover-expresstheHER2protein

– ThedrugHerceptin®isanartificiallydevelopedantibodyagainsttheHER2geneproductandiscalledamonoclonalantibody.ItisthoughtthatHerceptin®worksbybindingtothereceptorsitesonthecellsurface,therebylimitingtheamountofcelldivisionthatoccursandpreventingthegrowthofthecancer

(c) Drug metabolism

Howpeopleabsorb,breakdownandeliminate(metabolise)drugsinthebodycanalsobeimpacteduponbytheirgeneticinformation.

Forexample,somepainreliefmedicationssuchascodeinerequireaprotein(anenzyme)producedinthelivercalledCYP2D6forthedrugtobeusedbythebody,breakitdownandremoveit.VariationsintheinformationcontainedintheCYP2D6genedeterminehowmuchofthisenzymeisproducedintheliver.• Peoplewhohavelowlevelsoftheenzymemetabolisecodeine

slowlyandsoitwillbeinthebodyforalongerperiodoftimethanifitwasmetabolisedquickly.Slowmetabolisersofcodeinearemorelikelytohaverespiratorysideeffects

• PeoplewhoproducelowlevelsofCYP2D6intheliverwillrequiresmallerdosesofthedrugsthatareeliminatedbythisenzyme,whilefastmetabolisers,peoplewhohavealotoftheenzyme,willneedlargerdrugdosestogetthesameeffects

(d) Drug development

Excludingfromclinicaltrialsthosepeoplewhosegeneticmake-upwouldmakethedrugbeingtestedharmfulorineffectiveforthemwillincreasethechancethatadrugwillshowitselfuseful

Page 3: Genomics

www.genetics.edu.au The Australasian Genetics Resource Book – © 2007 3

PHARMACOGENETICS/PHARMACOGENOMICS 25F A C T S H E E T

toaparticularpopulationgroup.Thiswouldincreasethechancethatthesamedrugwillmakeitintothemarketplace.Undertakingpre-geneticscreeningofthosepatientstakingpartinaclinicaltrialshouldalsomaketheclinicaltrialssmaller,faster,andthereforelessexpensive.

Forexample,asseeninclinicaltrialsfordevelopingdrugsforAlzheimerdiseaseandotherformsofdementia.• Thefirstgenetobeidentifiedthatisassociatedwith

AlzheimerdiseaseinlaterlifeiscalledAPOE(seeGeneticsFactSheet45).TheAPOEgeneoccursinthreeformsknownasE2,E3andE4

• HavingtheAPOE-4formofthegenehasbeenshowntobeassociatedwithAlzheimerdisease

• APOE-4isalsodistinctlyinvolvedindrugtreatmentforAlzheimerdisease.IndividualswithAlzheimerdiseasewhohaveE2andE3formsoftheAPOEgenesrespondwelltothedrugTacrine ®,whilethosewithAPOE-4donot

• KnowledgeoftheAPOEgeneticmake-upofanindividualwithAlzheimerdiseaseisimportantindrugtreatmenttrials

LimitationsManygenesarelikelytobeinvolvedinhowsomeonereactstoadrug.Itmeansthattargetingdifferentdrugsmaybeverycomplex.

Everyonehassmallvariationsintheirgenesthatdonotcauseanyproblemwiththewaythatthegeneworks.Sincethesedifferencesmayinfluencedrugmetabolismorhowtheconditiondevelops,thevariationswouldneedtobeidentified.Thisprocessisverydifficultandtimeconsuming.

Inadditionotherfactorsmayinfluenceaspecificdrugreactionsuchasinteractionswithotherdrugsandenvironmentalfactors.Theinfluenceofthesefactorswillneedtobedeterminedbeforeanyconclusionsaremadeaboutthegeneticinfluenceonhowthedrugisworking.

Ethical issuesTheideaofindividuallytargeteddrugtherapyisveryattractivebutislikelytobeveryexpensive,impactingonequityandaccesstodrugs.

Sothefutureofpharmacogeneticsismostlikelytobethedevelopmentofdrugsthatworkwellwithcertainpopulationgroups.Thetargetingofcertaingroupswithinpopulations,nomatterhowwell-intentioned,hasanunfortunatehistorysuchasthatseenwithtargetingsicklecelldiseasescreeningintheearly1970stotheAmericanBlackpopulationwithoutappropriateeducation.Anyprogramswillneedtobecarefullyimplementedtoavoidaperceptionofstigmabasedonethnicity.

Aswell,theassumptionthatanindividual’sracecanindicatetheirgeneticprofilefordrugresponseisitselfproblematicsincenotallpeoplewhobelongtoaparticularethnicgroupwillhavethesamegeneticvariations.Apossibleconsequenceofsuchgeneticprofilingisalsothedenialoftreatmentbasedonraceifapharmacogenetictestthatcoulddeterminemorepreciselyhowanindividualwouldreacttoadrugwasnotavailable.Itmaymeanthatpeoplefromdifferentethnicgroupswhoareaffectedbythesameconditionaregivendifferentaccesstotreatment.

RegulationsTodateregulationsrelatingspecificallytopharmacogeneticsorpharmacogenomicshavenotbeenestablishedinanycountry.Futureregulationwillbeneeded,however,ifthetechniquesaretobewidelyused.Thisregulationwouldlikelyinvolveprescriptionguidelines,testingandusagelabels.

Other Genetics Fact Sheets referred to in this Fact Sheet: 1, 24, 45, 47

Information in this Fact Sheet is sourced from:GillianMShenfield,DavidGLeCouteurandLaurentPRivory.(2002).Clinicalpharmacology.The Medical Journal of Australia1:9[online].

Availablefrom:http://www.mja.com.au.[AccessedJune2007]GulzarA.NiaziandS.Riaz-ud-Din.(2006).BiotechnologyandGenomicsinMedicine-AReviewWorldJournalofMedicalSciences1(2):72-81TheNationalCentreforBiotechnologyInformation(USA).Thepromiseofpharmacogenomics[online].Availablefrom:http://www.ncbi.nlm.

nih.gov/About/primer/pharm.html.[AccessedJune2007]UKNuffieldCouncilonBioethics.Ethicalissuesinpharmacogenomics[online].Availablefrom:http://www.nuffieldbioethics.org/publications/

pp_0000000018.asp.[AccessedJune2007]

Edit historyJune2007(2ndEd)Author/s:A/ProfKristineBarlow-StewartandMonaSalehAcknowledgementsthisedition:GayathriParasivamPreviouseditions:2004Acknowledgementspreviouseditions:Kimberly Strong, MonaSaleh,ProfLeslieBurnett


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