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GregoryTaylor DougBrutlag GenomicsandMedicine December10,2015 ThePracticalReachofPharmacogenomics:areCustomDrugsaPossibility? Inrecentyears’researchershavebandedtogetherinaconcertedefforttotryand understandthegenome.TheHumanGenomeProjecttosequencetheentiregenomewasfirst conceivedin1986andinitiatedin1990,after13yearsthegenomewasfullydecodedbutthat’s nottheendoftheprocess.Thefirstgenomecostmillionstosequencebutafternumerous scientificdiscoveriesandtechnologicaladvancementsthecostofsequencingdowntoaslittle as$1000.Withthepricereducingsodrasticallycouldwebereachingapointintimewhere pharmaceuticalscantapintothewealthofknowledgehiddenwithineveryperson’sgenome? ThereachofpharmacogenomicsiseverexpandingwithnewtechniquessuchasSNPsearches andGWAstudiestoanalyzedrugsbuthowreliablearethesestudiesandhowpracticalare they?Andbeyondthatwhataretheethicsinvolvedinanalyzingthegenomeandwhoshould gettoknowwhatthegenomesays?Thispaperaimstoanswersomeofthesequestionsandget abetterpictureofjustwhatstandsinbetweenmedicaladvancementandachievingcustom madedrugstocuredevastatingdiseases. Direct-to-consumergenetictestshasbeenspeculatedsincethedawnofTheHuman GenomeProject.Pharmaceuticstooknoticeofthepotentialwhenawaveofdiscoveriesof commonDNAsequencesthatareassociatedwithrisksfordiseasessuchasheartcomplications (includingheartattackandangina),morbidity,andothercommonillnessthataccountformost ofthehealthcarecostsinvariousnations.ResearchersHelgasonA,andStefanssonKexplored thisintheirpaper“ThePast,thePresent,andFutureofDirect-to-ConsumerGeneticTests.” Theyclaimthatthepredictivepowerofthegenomicsequence,giventhesheeramountof associationsalreadydiscoveredwithdiseaseswithhighincidencewouldmakeDTCgenetic testsamaingoalofpharmaceuticsinthefuture.Indeedthepairpostulatesthattheimportance ofDTCgenetictestsliesinthevariationsbetweenindividualsandhowthesevariationscan causedifferencesinchanceandseverityofdisease,i.e.sex,age,weight,andotherbiological markers.Betheypreventativetestsorgenomictestsafteradiseasehassprungupconsumer testshavethepotentialtocurecertaindisease. Buthowhasgenomicscausedsuchamiraculousturnfordiseasestudy?DTCtestscan playatransitionalroleinunderstandingofdiseaseandbytestingindividualswhohavealready contractedadiseaseresearchescanfindoutmoreandmoreaboutwhatchangesinthebody leadtotheillness.BelowisafigurefromthestudyconductedbHelgasonandStefansson: JusttwoyearsafterstudiesofthegenometheGenomeWideAssociationstudieslaunched whichaccountsfortheskyrocketingresults.Overtimewithbetterandbettertechnologymore diseaseswillbediscoveredandthestrengthofDTCwillonlyincrease.Therearethreemain reasonstheGWAstudiesworkedsowellandwillonlycontinuetoworksowell.Thefirstishow muchinformationtheHumanGenomeProjectmadeavailablebyprovidinganexamplehuman genomeandtheensuingHapMapprojectthatfolloweduptheHumanGenomeProject.The secondarenewgenotypingtechnologiesthathaveallowedscientiststheabilitytoanalyze thousandsofSNPs.AndthethirdisjustthesheeramountofDNAsamplesthatcanbegathered fromindividualsinflictedwithdiseasesofinterestandcontrolsamplesofDNAfromthesame population.Theseunprecedentedresultsshowthattheirtrulyisvalueincontinuedresearchof thegenomeandthatmaybeonedayDTCgenometestscanbeusedbypharmaceuticalsto eitherprovidespecificpatientswithdrugstocuretheirdiseasesortoprovidethevast communitywithdrugsdesignedtocurecomplexdiseases.Whilethisideaisfantasticintheory, therearelimitationstogenomestudies. IntruthstudyingdiseasesisnotassimpleasrunningaGWAstudyandanalyzingthe SNPs,theactualpathtofindingcuresfordiseasesisstillwelloff.InGamazonER,SkolAD,and PereraMA’spaper“TheLimitsofGenome-WideMethodsforPharmacogenomicTesting”the researchersgointotheproblemswithGWAanalysis.Theultimategoalofpharmacogenomicsis thetransitionfromDNAsequenceandgenomicdiscoverytoindividualizedpatientcare,butthe problemwiththisgoalisthatGWAstudiesandgenomicdiscoveryingeneralareafarwayoff fromactuallyprovidingcurestodisease.IntheirwordsGWA’s“Systematicallyevaluatehighthroughputgenotypingtechnologiesfortheirabilitytoassayvariationinpharmacogenetically importantgenes(pharmacogenes).”Theresearchersproceededtoanalyze253oftheir “pharmacogenes”foundthroughGWAstudiesandfoundthatnotasinglegeneshowedmore than85%ownershipofit’srespectivedisease.Indeed,pharmacogenomicsisforcedtorely moreheavilyonSNPgenotypingtofindassociationssinceGWAdonotprovidecoverageofall chromosomalregions.Thegraphsbelowaccountforthecoveragesshownusingdifferent interfaces: ThemaingoalofpharmacogenicswouldbetostudytheHapMapandotherhigh-throughput genotypingplatformsforsufficientgenotypicinformationtosuccessfullycaptureallthe variationfoundinre-sequencingsothatresearchersandmedicalpractitionersknowexactly howtotreatadisease.Theproblemisthatiftheplatformscannotsufficientlycaptureallofthe variationsthoseverysameresearchersandmedicalpractitionerswouldfailtoidentifysomeof thecausativevariantsthatleadtophenotypeexpression.Thefiguresaboveshowjusthowfew diseasesarecoveredmorethan50%,andwithsuchlittleinformationonthesediseasescures foundthroughDTCgenomictestsaren’tyetverypractical. Sofaritsbeenshownthatthepotentialforgenomicsonapracticallevelisimmensebut therealityofitsusewithtoday’stechnologyisbleak.Whileresearchersareveryhopefulforthe outcomeoffutureprocessingitsstillveryclearthatwithtoday’sknowledgeondiseaseitsjust notenoughtofindcures.Therearemonogenic,oligogenic,andcomplexdiseasescodedinthe humangenome.ResearchersNerbertD,ZhangG,andVesellEdoveintojusthowcomplexitis tofindandtreatdiseasesastheygettobemoreandmorecomplex.Intheirpaper“From HumanGeneticsandGenomicstoPharmacogeneticsandPharmacogenomics:PastLessons, FutureDirections”Theysetofftheirpaperhighlightingthedifferencesinfullyunderstanding thesethreedifferentformsofdisease: Thisgraphrevealsthatthemainissuewithfindingacureforcomplexdiseasesisthefactthat thenumberofgenesthatdirectlycausephenotypicexpressionarewideandtheirisn’tone majorcause.Itcouldbethatthesegenesarepleiotropicorunderepistasisforothergenes. Whilemonogenicdiseasearerathereasytofindacureforsincethereisonegenethathasan outlandishcontributiontothephenotype,otherformsofdiseasearehardertosiftthrough. Thatbeingsaidtherearestillwaysoffindingthosemanygenesthatcontributeto complexdiseases.Withcurrenttechnologiesitsstillpossibletoafewofthegenesthathavea highP-valueofsignificanceforcertaincomplexdisorders: Resultslikethesearewhatgiveresearchersthedrivetocontinueparsingthroughcomplex diseases.Eventhoughthesearejustoneortwooftheseveralgenesthatdirectlycontributeto phenotypicexpressionitshopethatmorestillcanbefound. Inconclusion,DTCgenetictestsarenotarealityquiteyetbutwithincreasingresults witheachstudythatpassestherealitymaycomesoon.GWAstudiesandSNPreviewsreveal thegenesthateffectdiseasesandcanultimatelyleadtopharmaceuticaladvancementto developdrugstocombatillness. WorksCited: Nebert, Daniel W., Ge Zhang, and Elliot S. Vesell. "From Human Genetics and Genomics to Pharmacogenetics and Pharmacogenomics: Past Lessons, Future Directions." Drug Metabolism Reviews. U.S. National Library of Medicine, n.d. Web. 11 Dec. 2015. "Result Filters." National Center for Biotechnology Information. U.S. National Library of Medicine, n.d. Web. 11 Dec. 2015. "The Past, Present, and Future of Direct-to-consumer Genetic Tests." Www.ncbi.nlm.nih.gov. N.p., n.d. Web.