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1、LearningObjectivesWhatispharmacogenetics?Whatistheultimategoalofpharmacogenetics?Whatispharmacogenomics?Whatistheultimategoalofpharmacogenomics?PatientResponsetoMedicineVaries“Onesizefitsall?!”“Ihavehypertensionwhichisnotbeingcontrolled.Mydoctorprescribesadrugforhypertension,wewait3-4monthstofindits
2、notworkingandthentryanother one.In18months,Ivetried6newmedicationsandImfastlosingconfidenceinthishitormissapproachandinmyphysician”.PharmacogeneticsPharmacogeneticsisthestudyofinterindividualvariationsinDNAsequencerelatedtodrugresponse.Anultimategoalofpharmacogeneticsistounderstandhowsomeonesgenetic
3、make-updetermineshowwellamedicineworksinhisorherbody,aswellaswhatsideeffectsarelikelytooccur. In1902,BritishphysicianSirGarrodA.suggestedthatgeneticfactorsdirectchemicaltransformationsinhumansandunderlieindividualvariability.In1957,MotulskyA.demonstratedtherelationshipbetweenadversedrugreactionsandg
4、eneticallydeterminedvariation.GurwitzD,MotulskyAG.“Drugreactions,enzymes,andbiochemicalgenetics”:50yearslater.Pharmacogenomics.2007;8(11):1479-84. VogelF.coinedthetermpharmacogeneticsin1959 KalowW.(1962)showedthatanabnormalformofserumcholinesterase血清胆碱酯酶血清胆碱酯酶leadstocatastrophicadversereactionstosuc
5、cinylcholine琥珀胆碱琥珀胆碱(Anectine,Quelicin),andhe wrote the first systematic account of pharmacogenetics.PharmacogenomicsPharmacogenomicsisthestudyofthevariabilityoftheexpressionofindividualgenesrelevanttodiseasesusceptibilityaswellasdrugresponseatcellular,tissue,individualorpopulationlevel.Thetermisbro
6、adlyapplicabletodrugdesign,discovery,andclinicaldevelopment.TheultimategoalofpharmacogenomicsA.Better,SaferDrugstheFirstTime B.MoreAccurateMethodsofDeterminingAppropriateDrugDosages C.AdvancedScreeningforDiseasePharmacogenetic “Targets”Drug absorptionDrug distributionDrug-receptor interactionDrug me
7、tabolismDrug excretionConservationvs.Variation99.9%similarbetweenindividuals0.1%differenceshasfunctionalconsequencesSNP:AchangeinwhichasinglebaseintheDNAdiffersfromtheusualbaseatthatposition.MillionsofSNPshavebeencatalogedinthehumangenome.SomeSNPssuchthatwhichcausessicklecellareresponsiblefordisease
8、.OtherSNPsarenormalvariationsinthegenome.PharmacogeneticsGeneticPolymorphism:commonvariationinDNAsequence(i.e.in1%ofpopulation)MostareSNPsAlsodeletions,insertions,variablenumberoftandemrepeats(VNTRs)Deletion:glutathioneS-transferaseGSTM1PotentialTargetGenesarethosethatencode:Drug-metabolizingenzymes
9、TransportersDrugtargetsMalignanthyperthermia(MH。恶性。恶性高热高热)OMIM:145600.1q13.1 GeneticsofMHADIncidence:rare,1/500065000anesthetics,dependingondrugs,populations,anyages,anyracesMale2.4xfemaleThebasicdefectistheincreaseofintracellularCaofskeletalmuscleSpontaneous,animalmodelsforMHwerediscoveredinpigsand
10、dogsMHSGeneLociG-6-PDdeficiency-favism WorldwideXRXq28Succinylcholine琥珀胆碱琥珀胆碱OR suxamehoniumsensitivity：butyrylcholinesterase丁酰胆碱酯酶丁酰胆碱酯酶,BChE (OMIM:177400.3q26.1-q26.2)FamilyBlamesSoldiersSuicideonAnti-MalariaDrug.Washington Post, Oct. 12, 2008 CHICAGO-JuanTorresdidntbelievethathisson,ArmyReservist
11、JuanJohnM.Torres,hadkilledhimselfinAfghanistanjustweeksbeforehewastoreturnhomeinJuly2004Now,heisconvincedthathissondidindeedkillhimself.ButheblamesLariam(mefloquine),adrugtakenbytourists,PeaceCorpsvolunteersandtroopstopreventmalaria.AnArmypsychiatristsreportalsosuggeststhemedicationwasafactorinTorre
12、sssuicide. CytochromeP450（细胞色素（细胞色素P450）CYP2D6:debrisoquinehydroxylase异喹异喹胍羟化酶胍羟化酶Stronglyexpressedinliver22q13.1manydrugsaresubstratesforCYP2D6:amitriptyline,clozapine,haloperidol,propanolol,amiodarone,flecainidehighlypolymorphicwith50allelicvariantsidentifiedCYP2D6polymorphicvariantsRelativelycomm
13、ongeneinactivatingmutations:CYP2D6*4 splicesitevariants(GAtransitionatintron3/exon4)CYP2D6*3 bpdeletioninexon5CYP2D6*5genedeletionhomozygotesforthese(andotherrarer)mutantallelesarePM(poormetabolisers)andcompriseabout10%ofEuropeanpopulationsGuengerichF.AAPS J,2006;8:E101http:/drnelson.utmem.edu/P450l
14、ect.htmlWhataretheanticipatedbenefitsofpharmacogenomics?1.MorePowerfulMedicinesPharmaceuticalcompanieswillbeabletocreatedrugsbasedontheproteins,enzymes,andRNAmoleculesassociatedwithgenesanddiseases.2.Better,SaferDrugstheFirstTime Insteadofthestandardtrial-and-errormethodofmatchingpatientswiththerigh
15、tdrugs,doctorswillbeabletoanalyzeapatientsgeneticprofileandprescribethebestavailabledrugtherapyfromthebeginning. 3.MoreAccurateMethodsofDeterminingAppropriateDrugDosages Currentmethodsofbasingdosagesonweightandagewillbereplacedwithdosagesbasedonapersonsgenetics-howwellthebodyprocessesthemedicineandt
16、hetimeittakestometabolizeit.Thiswillmaximizethetherapysvalueanddecreasethelikelihoodofoverdose.4.AdvancedScreeningforDiseaseKnowingonesgeneticcodewillallowapersontomakeadequatelifestyleandenvironmentatearlyagesoastoavoidorlessentheseverityofageneticdisease. GeneChips:Genotyping基因分型基因分型 :curatesinfor
17、mationthatestablishesknowledgeabouttherelationshipsamongdrugs,diseasesandgenes,includingtheirvariationsandgeneproducts.Ourmissionistocatalyzepharmacogenomicsresearch.http:/www.pharmgkb.org/GenomicGenomicInformationInformationMolecular&Molecular&CellularCellularPhenotypePhenotypeClinicalClinicalPheno
18、typePhenotypeAllelesAllelesMoleculesMoleculesIndividualsIndividualsDrugDrugResponseResponseSystemsSystemsDrugsDrugsEnvironmentEnvironmentIsolatedIsolatedfunctionalfunctionalmeasuresmeasuresCodingCodingrelationshiprelationshipPharmacologicPharmacologicactivitiesactivitiesProteinProteinproductsproduct
19、sRoleinRoleinorganismorganismVariationsVariationsingenomeingenomeMolecularMolecularvariationsvariationsTreatmentTreatmentprotocolsprotocolsObservableObservablephenotypesphenotypesGeneticGeneticmakeupmakeupPhysiologyPhysiologyNon-geneticNon-geneticfactorsfactorsIntegratedIntegratedfunctionalfunctiona
20、lmeasuresmeasuresObservableObservablephenotypesphenotypesComplexityofRelationshipsinPharmacogeneticsComplexityofRelationshipsinPharmacogeneticsIndividualizedMedicineWhatisPharmacogenetics/Pharmacogenomics?v Pharmacogenetics studiesthegeneticsbasisoftherapeuticsandtheindividualreactionsresultedfromge
21、notypes;originally,itstudiestheeffectexertedondrugADMET(absorption,distribution,metabolism,excretion,&toxicity)processbythehumancytochromefamilyproteins.v Pharmacogenomics istheextensionandenhancementofthePharmacogeneticsstudiesinthemolecularsequencecontextoftheindividualgeneticstructuresofthewholegenome.DrugDevelopmentFuture:TargetedDiscovery,PredictiveMedicineThebestprescriptionisknowledge! CharlesEverettKoop(19162013)
