 Pharmacogenomics iiis iithe iibranch iiof iipharmacology iiwhich iideals iiwith iithe iiinfluence iiof iigenetic iivariation iion iidrug iiresponse iiin iipatients iiby iicorrelating iigene iiexpression iior iisingle-nucleotide iipolymorphisms iiwith iia iidrug’s iiefficacy iior iitoxicity.  iIt iiaims iito iidevelop iirational iimeans iito iioptimize iidrug iitherapy, iiwith iirespect iito iithe iipatient’s iigenotype, iito iiensure iimaximum iiefficacy iiwith iiminimal iiadverse iieffects. iiSuch iiapproaches iipromise iithe iiadvent iiof ii‘personalized iimedicine’, iiin iiwhich iidrugs iiand iidrug iicombinations iiare iioptimized iifor iieach iiindividual’s iiunique iigenetic iimakeup. iI

1. IIIIIIIIIIIPHARMACOGENOMICS
Whatiisipharmacogenomics?
 Pharmacogenomics i iis i ithei ibranchi iofi ipharmacologyi iwhichi idealsi iwithi ithei iinfluencei iof
iigenetic iivariation i ion i idrug i iresponse i iin i ipatients i iby i icorrelating i igene i iexpression i ior
iisingle-nucleotide iipolymorphisms iiwith iia iidrug’s iiefficacy iior iitoxicity.
 iIt i iaims i ito i idevelop i irational i imeans i ito i ioptimize iidrug iitherapy, i iwith i irespect iito iithe
iipatient’s i igenotype, iito iiensure i imaximumi iefficacyiiwithiiminimali iadverse i ieffects. i iSuch
iiapproaches i ipromise i ithe i iadvent i iofii‘personalized i imedicine’, iiini iwhichiidrugs i iand iidrug
iicombinations iiare iioptimized iifor iieach iiindividual’s iiunique iigenetic iimakeup. iI
 Pharmacogenomics iiis iithe i iwhole i igenome i iapplication i iof i ipharmacogenetics,
iiwhich iiexamines iithe iisingle iigene iiinteractions iiwith iidrugs.
INTRODUCTION:
 Pharmacogenomicsi iis i ithei istudyi iofi ihowi ianiiindividual’si igenetici iinheritancei iaffectsi ithe
iibody’s iiresponse iito iidrugs.
 iiThe i iterm i icomes i ifrom i ithe i iwords i ipharmacology i iand i igenomics i iand i iis i ithus i ithe
iiintersection iiof iipharmaceuticals iiand iigenetics.
 iiPharmacogenomics i iholds i ithe i ipromise i ithat i idrugs i imight i ione i idayi ibe i itailor-made i ifor
iiindividuals i iand i iadapted i ito i ieach i iperson’s iiown i igenetic i imakeup. i iEnvironment, i idiet,
iiage, iilifestyle, i iand i istate i iof i ihealth i iall i ican i iinfluence i ia i iperson’s i iresponse i ito
iimedicines, i ibut iiunderstanding i ian i iindividual’s i igenetic i imakeup i iis i ithought i ito iibe i ithe
iikey iito iicreating iipersonalized iidrugs iiwith iigreater iiefficacy iiand iisafety. i
 iThe i iway iia i iperson i iresponds iito i ia i idrug i i(this i iincludes i iboth iipositive i iand i inegative
iireactions)is iia iicomplex i itrait i ithat iiis i iinfluenced i iby iimany iidifferent iigenes. iiWithout

2. iiknowing i iall i iof i ithe iigenes i iinvolved iiin i idrug iiresponse, iiscientists i ihave i ifound i iit
iidifficult i ito i idevelop iigenetic iitests i ithat iicould i ipredict i ia i iperson’s i iresponse i ito i ia
iiparticular iidrug ii
 iiOnce i iscientists i idiscovered i ithat i ipeople’s i igenes iishow i ismall i ivariations i i(or i ichanges)
iiin i itheir i inucleotide i i(DNA i ibase) i icontent, i iall i iof i ithat i ichanged: i igenetic i itesting i ifor
iipredicting iidrug iiresponse iiis iinow iipossible. iI
 iPharmacogenomicsi icombinesi itraditionali ipharmaceuticali isciencesi isuchi iasi ibiochemistry
iiwith iiannotated iiknowledge iiof iigenes, iiproteins, iiand iisingle iinucleotide iipolymorphisms. i
 iThe i imost i icommon i ivariations i iin i ithe i ihuman i igenome i iare i icalled i isingle i inucleotide
iipolymorphisms ii.
 iiThere i iis i iestimated i ito i ibe i iapproximately i i11 iimillioni iSNPs iiin iithe iihuman iipopulation,
iiwith iianiiaverage iiofiione iievery ii1,300 iibase iipairs.
HISTORY:
 Genomics iiwas iiestablished iiby iiFred iiSanger iiwhen iihe iifirst iisequenced iithe iicomplete
iigenomes iiof iia iivirus iiand iia iimitochondrion. iiHis iigroup iiestablished iitechniques iiof
iisequencing, iigenome iimapping, iidata iistorage, iiand iibioinformatic iianalyses iiin iithe ii1970-
1980s.i
 iThe iiactual iiterm ii‘genomics’ iiis iithought iito iihave iibeen iicoined iiby iiDr. iiTomiiRoderick, iia
iigeneticist iiat iithe iiJackson iiLaboratory ii(Bar iiHarbor, iiME) iiover iibeer iiat iia iimeeting iiheld iiin
iiMaryland iion iithe iimapping iiof iithe iihuman iigenome iiin ii1986.
 In i i1972, i iWalter iiFiers i iand i ihis i iteam i iat i ithe i iLaboratory iiof iiMolecular i iBiology i iof i ithe
iiUniversityi iofi iGhenti i(Ghent,i iBel- i igium)i iwerei ithei ifirsti ito i ideterminei ithei isequencei iofi ia
iigene: iithe iigene iifor iiBacteriophage iiMS2 iicoat iiprotein. i

3.  iIni i1976,i ithei iteami ideterminedi ithei icompletei inucleotide-sequencei iofi ibacteriophagei iMS2-
RNA. i iThe i ifirst i iDNA-based i igenome i ito i ibe i isequenced i iin i iits i ientirety i iwas i ithat i iof
iibacteriophage iiΦ-X174 ii(5,368 iibp), iisequenced iiby iiFrederick iiSanger iiin ii1977.
 The iifirst iifree-living i iorganism iito iibe iisequenced iiwas iithat i iof i iHaemophilus i iinfluenzae iiin
ii1995, i iand i isince i itheniigenomes i iare i ibeingi isequenced i iat iia i irapid i ipace. iiA iiroughi idraft iiof
iithe iihu- i iman i igenome i iwas i icompleted i iby i ithe i iHuman i iGenome i iProject i iin i iearly i i2001,
iicreating iimuch iifanfare.
 Asiiof iiSeptember ii2007, iithe iicomplete iisequence iiwas iknown iiof iiabout ii1879 iiviruses, ii577
iibacterial iispecies i iand iiroughly ii23 iieukaryote iiorganisms, iiof iiwhich iiabout iihalf iiare iifungi.
 iiMost iiof iithe iibacteria iiwhose iigenomes iihave iibeen iicom- iipletely iisequenced iiare
iiproblematic iidisease-causing iiagents, iisuch iias iiHaemophilus iiinfluenzae. iI
 Pharmacogenomics iicombines iitraditional iipharmaceutical iisciences iisuch iiasiibiochemistry iiwith
iiannotated iiknowledge iiof iigenes, iiproteins, iiand iisingle iinucleotide iipolymorphisms ii.
IMPORTANCEIIOFIIPHARMACOGENOMIC:
 Adverse iiDrug iiReaction iiconveys iilittle iiof iithe iihorror iiof iia iisevere iinegative iireaction iito iia
iiprescribed iidrug. iiBut iisuch iinegative iireactions iicaniinonetheless iioccur.iI
 Aii1998 iistudyiiofiihospital- i iized iipatients iipublished iiiniithe iiJournali iofiithe iiAmericaniiMedical
iiAssociation iireported iithat iiin ii1994, iiadverse iidrug iireactions i iaccounted i ifor i imore i ithani i2.2
iimillioniiserious i icases i iand i iover i i100,000 i ideaths, i imakingi iadverse i idrugi ireactions i i(ADRs)
iione iiof iithe iileading iicauses iiof iihospitalization iiand iideath iiin iithe iiUnited iiStates ii.
 For iiinstance, i ithe i idailyi idoses i irequired i ito i itreat i ipatients i ivaryi ibyii20-fold iifor iithe iwarfarin,
iiby i i40-fold i ifor i ithe i iantihypertensive iidrug iipropranolol iiand iiby ii60-fold i ifor iiL-dopa i ifor
iiparkinson’s iidisease. iI

4.  Other i idrugs iihave iiclinical i iutility i iin iia i isubset i iof i ipatients iwith i igiven iipathology, i ie.g.,
iiantipsychotics i ithat iiare iiineffective iiin ii30% iiof iischizophrenics, iisuggesting iithat i isuch iidrugs
iiare iionly iieffective iiin iipatients iiwith iispecific iidisease iietiologies ii.
 iiMany i iof i ithe i ideaths i icould i ibe i iavoided i iif i ithe i iphysician i ihad iiprior i iknowledge i iof
iipatient’s i igenetic i iprofile, iiwhich i idetermines i ithe i idrug i iresponse. iiCurrently, iithere i iis iino
iisimple i iway i ito i idetermine iiwhether i ipeople i iwill i irespond iiwell, i ibadly, iior iinot iiat iiall iito iia
iimedication;iitherefore,iipharmaceuticali icompaniesi iarei ilimitedi itoi idevelopingi idrugsi iusingi ia
ii‘one iisize iifits iiall’ iisystem ii.
 iiThis iisystemi iallows i ifor i ithe i idevelopment i iof i idrugs i ito i iwhichi ithe i i‘average’ i ipatient i iwill
iirespond. iiBut, iias i ithe iistatistics iiabove iishow, iione iisize iidoes iinot iifit iiall, iisometimes i iwith
iidevastating iiresults. iI
 iWhat i iis i ineeded i iis iia i iway i ito iisolve iithe i iproblem i iof i iADRs i ibefore iithey i ihappen. iiThe
iisolution iiis iiin iisight iithough, iiand iiit iiis iicalled iipharmacogenomics.
Pharmacogenomics i ieventually i ican i ilead i ito i ian i ioverall idecrease i iini ithe i icost i iof i ihealth
i icare i ibecause i iof i idecreases i iin:
1. iThe iinumber iiof iiadverse iidrug iireactions
2. iThe iinumber iiof iifailed iidrug iitrials ii
3. iTheiitime iiit iitakesiito iiget iiaiidrug iiapproved
4. The iilength iiof iitime iipatients iiare iioniimedication i ii
5. The iinumber iiof iimedications iipatients iimust iitake iito iifind iian iieffective i iitherapy. i
6. iThe iieffects iiofiiaiidisease iioniithe iibodyii(through iiearly iidetection) i.
PHARMACOGENOMICSIITODAY:
 The iicytochrome iiP450 ii(CYP) iifamily iiof iiliver iienzymes iiis i iresponsible iifor iibreaking iidown
iimore iithan ii30 iidifferent iiclasses iiof i idrugs. i I

5.  DNA i ivariations i iin i igenes i ithat i icode i ifor i ithese i ienzymesiicaniiinfluenceiitheiriiabilityiito
iimetabolize iicertain iidrugs. i iLess i iactive i ior i iinactive i iforms i iof i iCYP i ienzymes i ithat iiare
iiunable i ito i ibreak i idowni iand i iefficiently i ieliminate i idrugs i ifromi ithe i ibody i icani icause i idrug
iioverdose iiin iipatients.
 iiToday, iiclinical i iitriials iiresearchers i iuse i igenetic i itests i ifor i ivariations iiin iicytochrome i iP450
iigenesiitoiiscreeniiandiimonitoriipatients.iiIniiaddition,iimanyi ipharmaceuticali icompaniesi iscreen
iitheir iichemicaliicompounds i ito i isee i ihow i iwelli itheyiiare i ibrokeni idowni ibyiivariant i iforms iiof
iiCYP iienzymes i.
 Another iienzyme iicalled iiTPMTii(thiopurine iimethyltransferase) i iplays i iani iimportant i irole i iin
iithe iichemotherapy i itreatment i iof iia i icommon i ichildhood iileukemia iiby i ibreaking i idown
iithiopurines. i
 iA i ismall i ipercentage i iof i iCaucasians i ihave i igenetic i ivariants i ithat i iprevent i ithem i ifrom
iiproducingi iani iactivei iformi iofi ithisiiprotein.iiAsiiai iresult,i ithiopurinesiielevatei itoi itoxiciilevels
iiin iithe iipatient iibecause iithe iiinactive iiform iiof iiTMPT iiis iiunable iito iibreak iidown iithe iidrug.
 iiToday, iidoctors iican i iuse i ia iigenetic iitest iito i iscreen i ipatients i ifor i ithis i ideficiency, i iand i ithe
iiTMPT iiactivity iiis iimonitored iito iidetermine iiappropriate iithiopurine iidosage iilevels i.
PHARMACOGENOMICSIIINIIFUTURE:
 Newiidevelopments iiin iithis iifield iiwill iiimpact iion iidrug iidesign iiat iithree iimain iilevels.
 The iiinteraction iiof iithe iidrug iiwith iiits iireceptor iibinding iisite.
 The iiabsorption iiand iidistribution iiof iithe iidrug.
 The iielimination iiof iithe iidrug iifrom iithe iibody.

6. BENEFITSIIOFIIPHARMACOGENOMICS:
 Pharmacogenomics i icombines i itraditional iipharmaceutical i isciences i isuch i ias i ibiochemistry
iiwith iiannotated iiknowledge iiof i igenes, i iproteins, i iand i isingle i inucleotide i ipolymorphisms.
iiFollowingiiareiitheiibenefits.
MOREIIPOWERFULIIMEDICINES:
 Pharmaceuticali icompaniesi iwilli ibe i iablei ito i icreatei idrugsi ibasedi ioni ithe i iproteins,i ienzymes,
iiand iiRNA iimolecules iiassociated iiwith iigenes iiand iidiseases.
 iiThis iiwill i ifacilitate i idrugi idiscoveryi iand i iallow i idrugi imakers i ito i iproduce iia iitherapyi imore
iitargeted iito iispecific iidiseases.
 iiThis iiaccuracyi iwilli inoti ionlyi imaximize i itherapeutici ieffectsi ibuti ialsoi idecreasei idamagei ito
iinearby iihealthy iicells.
Better,iisaferiidrugsiitheiifirstiitime:
 Insteadiofistandarditrailiandierrori methodiofi matchi inipatientsiwithitheirightidrugs,idoctors
iwill iable i to ianalyze ithe ipatient’s i genetic iprofile iand iprescribe i the ibest iavalible idrug
itherapy ifrom ithe ibeginning.
 iNot ionly iwill ithis itake ithe iguesswork iout iof ifinding ithe iright idrug, iit iwill ispeed iup ithe
irecovery iandilikelihood iofiadverse ireaction iis ieliminated.
MOREIIACCURATEIIMETHODSIIOFIIDETERMININGIIAPPROPRIATE
IIDRUGIIDOSAGES:
 Current iimethods iiof iibasing iidosages iion iiweight iiand iiage iiwill iibe iireplaced iiwith
iidosages iibased iion iia iiperson’s iigenetics; iihow iiwell iithe iibody iiprocesses iithe iimedicine
iiand iithe iitime iitakes iito iimetabolize iiit. i
 iThis iiwill iimaximize iithe iitherapy’s iivalue iiand iidecrease iithe iilikelihood iiof iioverdose.

7. ADVANCEDIISCREENINGIIFORIIDISEASE:
 Knowing i ione’s i igenetic i icode i iwill i iallow i ia i iperson i ito i imake i iadequate i ilifestyle i iand
iienvironmentali ichanges i iat i iani iearlyi iage iiso iias iito i iavoid i ior i ilesseni ithe i iseverityiiofi ia
iigenetic iidisease. i
 iLikewise, i iadvance i iknowledge i iofi iparticular i idisease i isusceptibilityi iwilli iallow i icareful
iimonitoring, i iand i itreatments i ican i ibe i iintroduced i iat i ithe i imost i iappropriate i istage i ito
iimaximize iitheir iitherapy.
BETTERIIVACCINES:
 Vaccinesiimadeiiofiigeneticiimaterial, iieitheriiDNAiioriiRNA, iipromise i ialli ithe i ibenefits i iof
iiexisting iivaccines iiwithout iiall iithe iirisks.
 iiThey iiwill iiactivate iithe iiimmune iisystem iibut iiwill iibe iiunable iito iicause iiinfections.
 Theyi iwilli ibei iinexpensive,i istable,i ieasyi itoi istore,i iandi icapablei iofi ibeingi iengineeredi ito
iicarry iiseveral iistrains iiof iia iipathogen iiat iionce.
IMPROVEMENTSIIINIITHEIIDRUGIIDISCOVERYIIANDIIAPPROVAL
IIPROCESS:
 Pharmaceuticali icompaniesi iwilli ibei iablei itoi idiscoveri ipo- i itentiali itherapiesi imorei ieasily
iiusing iigenome iitargets.
 iiThe iidrugi iapprovali iprocess i ishould i ibe i ifacilitated i ias i itrials i iare i itargeted i ifor i ispecific
iigenetic iipopulation iigroups iiand iiproviding iigreater iidegrees iiof iisuccess.
 iiThei icostiiandi iriskiiofi iclinicali itrialsiiwilli ibei ireducedi ibyi itargetingi ionlyi ithosei ipersons
iicapable iiof iiresponding iito iia iidrug.
DECREASEIIINIITHEIIOVERALLIICOSTIIOFIIHEALTHIICARE:
 Decreases i iin i ithe i inumber i iof i iadverse i idrug i ireactions, i ithe i inumber i iof i ifailed i idrug
iitrials,i ithei itimei iiti itakesi itoi igetiiai idrugi iapproved,i ithei ilengthi iofi itimei ipatientsi iarei ion

8. iimedication, i ithe i inumber i iof i imedications i ipatients i imust i itake i ito i ifind i ian i ieffective
iitherapy, i ithe i ieffects iiof i ia i idisease i ion iithe iibody i i(through i iearly iidetection), iiand iian
iiincrease iiin iithe iirange iiof iipossible iidrug i itargets iiwill i ipromote i ia i inet i idecrease i iin i ithe
iicost iiof iihealth iicare i.
BARRIERSIITOIIPHARMACOGENOMICSIIPROGRESS:
 Pharmacogenomics iis iaideveloping iresearch ifield ithat iis istill iin iits iinfancy. iSeveral iofithe
ifollowing ibarriers iwill ihave itoiover icome ibefore imany ipharmacogenomics ibenefits ican
irealized. iThey iareithe ifollowing
COMPLEXITYIIOFIIFINDINGIIGENEIIVARIATIONSIITHATIIAFFECT
IIDRUGIRESPONSE:
 Singlei inucleotidei ipolymorphismsi i(SNPs)i iarei iDNAi ise- i iquencei ivariationsi ithati ioccur
iiwhen iia iisingle iinucleotide ii(A, iiiiT, iiC, iior iiG) iiin iithe iigenome iisequence iiis iialtered. iI
 SNPs iioccur iievery ii100 i ito i i300 i ibases i ialong i ithe i i3-billion-base iihuman i ige- iinome,
iitherefore i imillions i iof i iSNPs iimust i ibe i iidentified i iand iianalyzed i ito i idetermine i itheir
iiinvolvement ii(if iiany) iiin iidrug iiresponse. iI
 Further i icomplicatingi iofi ithe i iprocess i iis i iour i ilimited i iknowledge i iofi iwhichi igenes i iare
iiinvolved i iwith i ieach i idrug i iresponse. i iSince i imany i igenes i iare i ilikely i ito i iinfluence
iiresponses, i iobtaining i ithe i ibig i ipicture i ion i ithe i iimpact i iof i igene i ivariations i iis i ihighly
iitime-consuming iiand iicomplicated.
LIMITEDIIDRUGIIALTERNATIVES:
 Only i ione i ior i itwo i iapproved i idrugs iimay i ibe i iavailable i ifor i itreatment i iof i ia i iparticular
iicondition. i iIf i ipatients i ihave i igene i ivariations i ithat i iprevent i ithem i iusing i ithese i idrugs,
iithey i imay i ibe i ileft i iwithout i iany iifor i itreatment