Coronary artery disease(CAD) is a major cause of death and disability worldwide,and consumes a considerable amount of medical resources every year.Clopidogrel is a first-line antiplate.let therapy for CHD,butit is ass...Coronary artery disease(CAD) is a major cause of death and disability worldwide,and consumes a considerable amount of medical resources every year.Clopidogrel is a first-line antiplate.let therapy for CHD,butit is associated with substantial variability in PK and pharmacodynamics re.sponse.To date,gene variants explain only a smallproportion of the variability.The study aimed to identify new genetic loci-modifying antiplatelet response to clopidogrel in Chinese patients with CAD by a systematic analysis combining antiplatelet effects and PK,and further to investigate the PON1 gene promoter DNA methylation and genetic variations possibly influencing clinical outcomes in pa.tients undergoing PCI.We identified novel variants in two transporter genes(SLC14 A2 rs12456693,ATP-binding cassette [ABC]A1 rs2487032) and in N6 AMT1(rs2254638) associated with P2Y12 reaction unit(PRU) and plasma active metabolite(H4) concentration.These new variants dramatically im.proved the predictability of PRU variability to 37.7%.The associations between these loci and PK pa.rameters of clopidogrel and H4 were observed in additional patients,and its function on the activation of clopidogrel was validated in liver S9 fractions(P<0.05).Rs2254638 was further identified to exert a marginal risk effect formajor adverse cardiac events in an independent cohort.Multivariate logistic regression analysis indicated that PON1 methylation level at CpG site-161(OR=0.95;95% CI=0.92–0.98;P<0.01) and the use of angiotensin converting enzyme inhibitors(OR=0.48;95% CI=0.26–0.89;P<0.01) were associated with decreased risk of bleeding events.In conclusion,new genetic variants were systematically identified as risk factors for the reduced efficacy of clopidogrel treatment.The ab.normal expression of DNA methylation-regulating key genes in the pharmacokinetic and pharmacody.namics pathways of clopidogrel and aspirin may modify clinical outcomes in dual antiplatelet-treated patients undergoing PCI.展开更多
基金supported by National key R＆D program(2017YFC09093012016YFC0905003)+3 种基金 National Nature Science Foundation of China(8167351481373486) Science and Technology Development Projects of Guangdong Province,China(2016B090918114) Science and Technology Developme
文摘Coronary artery disease(CAD) is a major cause of death and disability worldwide,and consumes a considerable amount of medical resources every year.Clopidogrel is a first-line antiplate.let therapy for CHD,butit is associated with substantial variability in PK and pharmacodynamics re.sponse.To date,gene variants explain only a smallproportion of the variability.The study aimed to identify new genetic loci-modifying antiplatelet response to clopidogrel in Chinese patients with CAD by a systematic analysis combining antiplatelet effects and PK,and further to investigate the PON1 gene promoter DNA methylation and genetic variations possibly influencing clinical outcomes in pa.tients undergoing PCI.We identified novel variants in two transporter genes(SLC14 A2 rs12456693,ATP-binding cassette [ABC]A1 rs2487032) and in N6 AMT1(rs2254638) associated with P2Y12 reaction unit(PRU) and plasma active metabolite(H4) concentration.These new variants dramatically im.proved the predictability of PRU variability to 37.7%.The associations between these loci and PK pa.rameters of clopidogrel and H4 were observed in additional patients,and its function on the activation of clopidogrel was validated in liver S9 fractions(P<0.05).Rs2254638 was further identified to exert a marginal risk effect formajor adverse cardiac events in an independent cohort.Multivariate logistic regression analysis indicated that PON1 methylation level at CpG site-161(OR=0.95;95% CI=0.92–0.98;P<0.01) and the use of angiotensin converting enzyme inhibitors(OR=0.48;95% CI=0.26–0.89;P<0.01) were associated with decreased risk of bleeding events.In conclusion,new genetic variants were systematically identified as risk factors for the reduced efficacy of clopidogrel treatment.The ab.normal expression of DNA methylation-regulating key genes in the pharmacokinetic and pharmacody.namics pathways of clopidogrel and aspirin may modify clinical outcomes in dual antiplatelet-treated patients undergoing PCI.
