Geneticandepigeneticpredispositionsunderlyingcardiovascularoutcomesamongpatientstreatedwithclopidogrelandaspirin

摘要： Coronaryarterydisease(CAD)isamajorcauseofdeathanddisabilityworldwide,andconsumesaconsiderableamountofmedicalresourceseveryyear.Clopidogrelisafirst-lineantiplate.lettherapyforCHD,butitisassociatedwithsubstantialvariabilityinPKandpharmacodynamicsre.sponse.Todate,genevariantsexplainonlyasmallproportionofthevariability.Thestudyaimedtoidentifynewgeneticloci-modifyingantiplateletresponsetoclopidogrelinChinesepatientswithCADbyasystematicanalysiscombiningantiplateleteffectsandPK,andfurthertoinvestigatethePON1genepromoterDNAmethylationandgeneticvariationspossiblyinfluencingclinicaloutcomesinpa.tientsundergoingPCI.Weidentifiednovelvariantsintwotransportergenes(SLC14A2rs12456693,ATP-bindingcassette[ABC]A1rs2487032)andinN6AMT1(rs2254638)associatedwithP2Y12reactionunit(PRU)andplasmaactivemetabolite(H4)concentration.Thesenewvariantsdramaticallyim.provedthepredictabilityofPRUvariabilityto37.7%.TheassociationsbetweentheselociandPKpa.rametersofclopidogrelandH4wereobservedinadditionalpatients,anditsfunctionontheactivationofclopidogrelwasvalidatedinliverS9fractions(P<0.05).Rs2254638wasfurtheridentifiedtoexertamarginalriskeffectformajoradversecardiaceventsinanindependentcohort.MultivariatelogisticregressionanalysisindicatedthatPON1methylationlevelatCpGsite-161(OR=0.95;95%CI=0.92–0.98;P<0.01)andtheuseofangiotensinconvertingenzymeinhibitors(OR=0.48;95%CI=0.26–0.89;P<0.01)wereassociatedwithdecreasedriskofbleedingevents.Inconclusion,newgeneticvariantsweresystematicallyidentifiedasriskfactorsforthereducedefficacyofclopidogreltreatment.Theab.normalexpressionofDNAmethylation-regulatingkeygenesinthepharmacokineticandpharmacody.namicspathwaysofclopidogrelandaspirinmaymodifyclinicaloutcomesindualantiplatelet-treatedpatientsundergoingPCI. ... （共2頁）