Agenome-wideassociationstudyidentifiesnovelgeneticlocithatmodifypharmacokinetic-pharmacodynamicresponsestoclopidogrel

摘要： OBJECTIVEGeneticvariantsinthepharmacokinetic(PK)mechanismarethemainunderlyingfactorsthatmodifytheantiplateletefficacyofclopidogrel.Hence,jointanalysisofgeneticvariantsthatmodifypharmacodynamic(PD)andPKresponsestoclopidogrelshouldbeeffectiveforidentifyingthegeneticvariantsaffectingtheantiplateletresponsetothedrug.METHODSAgenome-wideassociationstudywasconductedtoidentifynewgeneticlocithatmodifyPDresponsestoclopidogrelanditsactivemetaboliteH4in115Chinesepatientswithcoronaryheartdisease(CHD).RESULTSWeidentifiednovelvariantsintwotransportergenes(rs12456693inSLC14A2andrs2487032inABCA1)andinN6AMT1(rs2254638)associatedwithclopidogrel-treatedP2Y12reactionunit(PRU)andplasmaH4concentration.Theassociationsbetweenthesesinglenucleotidepolymorphisms(SNPs)andPKparametersofclopidogrelandH4wereobservedin31additionalCHDpatients(P<0.05).Thenewvariants,togetherwithCYP2C19*2andclinicalfactors,dramaticallyimprovedthepredictabilityofPRUvariabilityto37.7%comparedwiththepublishedvalueofapproximately20%.ThefunctionoftheseSNPsontheactivationofclopidogrelwasvalidatedin32liverS9fractions,andtheN6AMT1rs2254638TvariantwasfoundtobeassociatedwithdecreasedformationofH4(P=0.0386).Meanwhile,N6AMT1rs2254638wasfurtheridentifiedtoexertamarginalriskeffectforMACEinanindependentCHDpatientcohort(OR:1.428,95%CI:0.978-2.086,P=0.0653,FDR=0.4726).Inconclusion,wesystematicallyidentifiednewgeneticvariantsasriskfactorsforthereducedefficacyofclopidogrel.CONCLUSIONOurstudyfindingsenhancedtheunderstandingoftheabsorptionandmetabolicmechanismsthatinfluencePDresponsestoclopidogreltreatment. ... （共2頁(yè)）