CYP2C19*2和CYP2C19*17基因多态性与冠状动脉介入治疗后病人氯吡格雷反应性的关联分析
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摘要
目的探究CYP2C19*2和CYP2C19*17基因多态性与冠状动脉介入治疗后病人氯吡格雷反应性的关系。方法青海省心脑血管病专科医院于2014年3月至2017年3月期间招募了347例经皮冠状动脉介入的支架植入病人。采集经氯吡格雷(75 mg/d)治疗至少7 d的病人血液样品,用VerifyNow P2Y_(12)测定法测量血小板活性(PRU)和(%)抑制性。应用聚合酶链式反应检测CYP2C19*2(rs4244285)和CYP2C19*17(rs12248560)基因多态性,比较氯吡格雷应答组和无应答组病人CYP2C19*2(rs4244285)和CYP2C19*17(rs12248560)基因型的分布频率差异以及等位基因频率差异。结果分组时,PRU>208的病人对氯吡格雷治疗无反应;104例(30%)病人为无应答者,243例(70%)病人为应答者。243例氯吡格雷应答组和104例无应答组CYP2C19*2(rs4244285)基因型分布频率野生型GG为80.7%/54.8%,杂合型GA为17.3%/38.5%,突变型AA为2.1%/6.7%,两组比较χ~2=7.04,P<0.001;等位基因频率野生型G为89.3%/74.0%,突变型A为10.7%/26.0%,两组比较χ~2=5.25,P<0.001。CYP2C19*17(rs12248560)基因型分布频率野生型CC为67.9%/75.0%,杂合型CT为30.5%/23.1%,突变型TT为1.6%/1.9%,两组比较χ~2=0.81,P=0.388;等位基因频率野生型C为83.1%/84.1%,突变型T为16.9%/13.1%,两组比较χ~2=0.68,P=0.416。结论 CYP2C19*2多态性与氯吡格雷治疗无反应相关,CYP2C19*17多态性增强了氯吡格雷的抗血小板活性。根据这两种多态性的单倍型,氯吡格雷治疗的病人可以被保护或不受支架血栓形成和缺血事件的威胁。
Objective To investigate the correlation of the CYP2 C19*2 and CYP2 C19*17 polymorphisms with patients clopidogrel responsiveness after percutaneous coronary intervention.Methods A total of 347 Turkish patients who underwent percutaneous coronary interventions with stent implantation in the Qinghai Cardiovascular Hospital from March 2014 to March 2017 were included in our study.Platelet reactivity(PRU) and inhibition(%) were measured with VerifyNow P2 Y_(12) assay in blood samples collected from patients who took a standard dose of clopidogrel(75 mg/d) for at least 7 days.CYP2 C19*2 and CYP2 C19*17 polymorphism were detected by means of polymerase chain reaction.The distribution and allele frequency difference of CYP2 C19*2(rs4244285) and CYP2 C19*17(rs12248560) genotype in responder group and in non-responder group were compared.Results 104(30%) patients were non-responders and 243(70%) patients were responders,according to the patients with PRU values >208 as non-responsiveness to clopidogrel therapy.CYP2 C19*2(rs4244285) wild GG genotype frequencies in 243 clopidogrel response groups and 104 non-response groups was 80.7%,and 54.8%;heterozygous GA was17.3%,and 38.5%;mutant AA was 2.1%,and 6.7%(χ~2=7.04,P<0.001).Wild-type G allele frequency was 89.3%,and 74.0%;mutant A was 10.7%,and 26.0%(χ~2=5.25,P<0.001).CYP2 C19*17(rs12248560) wild CC genotype frequencies was 67.9%,and 75.0%,heterozygous CT was 30.5%,and 23.1%,mutant TT was 1.6%,and 1.9%(χ~2=0.81,P=0.388).Wild type C allele frequency was 83.1%,and 84.1%,mutant T allele frequency was 16.9%,and 13.1%(χ~2=0.68,P=0.416).Conclusions Our findings suggest that the CYP2 C19*2 polymorphism is associated with non-responsiveness to clopidogrel therapy and the CYP2 C19*17 polymorphism enhances antiplatelet activity of clopidogrel.Depending on haplotypes of these two polymorphisms,clopidogrel-treated patients can be protected or not from stent thrombosis and ischaemic events.
Objective To investigate the correlation of the CYP2 C19*2 and CYP2 C19*17 polymorphisms with patients clopidogrel responsiveness after percutaneous coronary intervention.Methods A total of 347 Turkish patients who underwent percutaneous coronary interventions with stent implantation in the Qinghai Cardiovascular Hospital from March 2014 to March 2017 were included in our study.Platelet reactivity(PRU) and inhibition(%) were measured with VerifyNow P2 Y_(12) assay in blood samples collected from patients who took a standard dose of clopidogrel(75 mg/d) for at least 7 days.CYP2 C19*2 and CYP2 C19*17 polymorphism were detected by means of polymerase chain reaction.The distribution and allele frequency difference of CYP2 C19*2(rs4244285) and CYP2 C19*17(rs12248560) genotype in responder group and in non-responder group were compared.Results 104(30%) patients were non-responders and 243(70%) patients were responders,according to the patients with PRU values >208 as non-responsiveness to clopidogrel therapy.CYP2 C19*2(rs4244285) wild GG genotype frequencies in 243 clopidogrel response groups and 104 non-response groups was 80.7%,and 54.8%;heterozygous GA was17.3%,and 38.5%;mutant AA was 2.1%,and 6.7%(χ~2=7.04,P<0.001).Wild-type G allele frequency was 89.3%,and 74.0%;mutant A was 10.7%,and 26.0%(χ~2=5.25,P<0.001).CYP2 C19*17(rs12248560) wild CC genotype frequencies was 67.9%,and 75.0%,heterozygous CT was 30.5%,and 23.1%,mutant TT was 1.6%,and 1.9%(χ~2=0.81,P=0.388).Wild type C allele frequency was 83.1%,and 84.1%,mutant T allele frequency was 16.9%,and 13.1%(χ~2=0.68,P=0.416).Conclusions Our findings suggest that the CYP2 C19*2 polymorphism is associated with non-responsiveness to clopidogrel therapy and the CYP2 C19*17 polymorphism enhances antiplatelet activity of clopidogrel.Depending on haplotypes of these two polymorphisms,clopidogrel-treated patients can be protected or not from stent thrombosis and ischaemic events.
引文
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[15] SILLER-MATULA JM,TRENK D,SCHR?R K,et al.Response variability to P2Y12 receptor inhibitors:expectations and reality[J].JACC Cardiovasc Interv,2013,6(11):1111-1128.
[16] SERRA R,DE FRANCISCIS S.The need to identify new P2Y12 receptor inhibitors in the management and prevention of arterial thrombosis[J].Thromb Res,2014,134(3):533-534.
[2] GEROSA M,MERONI PL,ERKAN D.Recognition and management of antiphospholipid syndrome[J].Curr Opin Rheumatol,2016,28(1):51-59.
[3] TANTRY US,NAVARESE EP,MYAT A,et al.Combination oral antithrombotic therapy for the treatment of myocardial infarction:recent developments[J].Expert Opin Pharmacother,2018,19(7):653-665.
[4] GURBEL PA,BLIDEN KP,HIATT BL,et al.Clopidogrel for coronary stenting:response variability,drug resistance,and the effect of pretreatment platelet reactivity[J].Circulation,2003,107(23):2908-2913.
[5] QURESHI Z,HOBSON AR.Clopidogrel "resistance":where are we now?[J].Cardiovasc Ther,2013,31(1):3-11.
[6] CHANG HW,KIM HJ,YOO JS,et al.Clopidogrel versus ticagrelor for secondary prevention after coronary artery bypass grafting[J].J Clin Med,2019,8(1):104.
[7] SAIZ-RODRíGUEZ M,BELMONTE C,ABAD-SANTOS F.CYP2C19 ultrarapid phenotype as a risk predictor of subsequent events during clopidogrel treatment in patients undergoing a percutaneous neurointervention[J].Clinical Pharmacology & Therapeutics,2019.DOI:10.1002/cpt.1300.
[8] AYESH BM,AL-ASTAL IR,YASSIN MM.The clinical effects of CYP2C19 *2 allele frequency on Palestinian patients receiving clopidogrel after percutaneous coronary intervention[J].Int J Clin Pharm,2019,41(2):96-103.
[9] SHULDINER AR,O'CONNELL JR,BLIDEN KP,et al.Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy[J].JAMA,2009,302(8):849-857.
[10] JIANG XL,SAMANT S,LESKO LJ,et al.Clinical pharmacokinetics and pharmacodynamics of clopidogrel[J].Clin Pharmacokinet,2015,54(2):147-166.
[11] ZEYMER U.Oral antiplatelet therapy in acute coronary syndromes:recent developments[J].Cardiol Ther,2013,2(1):47-56.
[12] TCT-458:protective effect of the cyp polymorphism with increased activation of clopidogrel on cardiovascular events[J].The American Journal of Cardiology,2009,104(6):169D.
[13] NORGARD NB,MONTE SV.Obesity and Inflammation and altered clopidogrel pharmacokinetics and pharmacodynamics[J].Drug Metab Lett,2017,11(1):3-13.
[14] HOLMES MV,PEREL P,SHAH T,et al.CYP2C19 genotype,clopidogrel metabolism,platelet function,and cardiovascular events:a systematic review and meta-analysis[J].JAMA,2011,306(24):2704-2714.
[15] SILLER-MATULA JM,TRENK D,SCHR?R K,et al.Response variability to P2Y12 receptor inhibitors:expectations and reality[J].JACC Cardiovasc Interv,2013,6(11):1111-1128.
[16] SERRA R,DE FRANCISCIS S.The need to identify new P2Y12 receptor inhibitors in the management and prevention of arterial thrombosis[J].Thromb Res,2014,134(3):533-534.