老年冠状动脉支架植入术后患者CYP2C19基因681G〉A单核苷酸多态性与氯吡格雷抵抗的相关性

Relation of cytochrome P450 2C19 gene 681G〉A single nucleotide polymorphism to clopidogrel resistance after PCI in Chinese elderly patients

目的拟通过该项研究，探讨在中国汉族老年冠心病患者植入药物洗脱支架后，CYP2C19基因681G〉A位点单核苷酸多态性与氯吡格雷抵抗（CR）之间的关系。方法2010年6月至2011年4月，连续入选在沈阳军区总医院心血管内科住院治疗并成功接受经皮冠状动脉药物洗脱支架植入术的老年（年龄≥60岁）冠心病患者614例。所有人选患者全部接受双联抗血小板治疗（氯吡格雷＋阿司匹林），均给予负荷剂量氯吡格雷600mg及阿司匹林300mg，并于服药24h后采静脉血测定20μmol／L的ADP诱导的残余血小板聚集率（RPA）。定义RPA≥70％为CR，RPA〈70％为氯吡格雷非抵抗（NCR）。使用酚．氯仿法提取全血中白细胞基因组DNA标本，并通过聚合酶链反应．限制性片段长度多态性（PCR-RFLP）方法测定CYP2C19基因681G〉A位点单核苷酸多态类型。结果在所有入选的614例老年冠心病患者中，CR的发生率为20．5％（126例），NCR为79．5％（488例）。CYP2C19基因681G〉A多态位点的三种基因型（GGGA，AA）的频率，在CR组中分别为32．6％、47．6％和19．8％，在NCR组中分别为47．9％，45．1％和7．0％。其中，AA型纯合子在CR组中的频率显著高于NCR组（OR=3．03，95％CI：1．889-5．784，P=0．003）。A等位基因的携带者较G等位基因携带者更易发生CR（OR=1．85，95％CI：1．392-2．459，P：0．002）。结论在中国汉族老年冠心病患者中，CYP2C19基因681G〉A位点单核苷酸多态性与氯吡格雷抵抗的发生存在相关性，其A等位基因可能是氯吡格雷抵抗的遗传易感因素之一。

Objective We sought to determine the association between the single nucleotide polymorphism of cytochrome P450 2C19（CYP2C19） 681G〉A and the occurrence of clopidogrel resistance （CR） in Chinese elderly patients. Methods Totally 614 hospitalized patients （aged over 60 years） in Shenyang General Hospital between June 2010 and April 2011 were enrolled. These patients underwent successful percutaneous coronary intervention with drug-eluting stents and received treatment with dual antiplatelet regimen （aspirin plus clopidogrel）. All enrolled patients were given a loading dose of 600mg clopidogrel and 300mg aspirin. Twenty-four hours later, blood samples were collected ant 20 μmol/L ADP-induced platelet aggregation ratio （PAR） was assessed. The maximum residual platelet aggregation （RPA） ≥70% was defined as CR, and the RPA〈70% as non-CR （NCR）. Genomic DNA was extracted from whole blood samples according to standard protocols, the single nucleotide polymorphism of the CYP2C 19 681G〉A was genotyped by polymerase chain reaction-restriction fragment length polymorphism （PCR-RFLP） in all cases. Results CR was found in 126 cases （20.5%）. CYP2C19 681G〉A polymorphism was observed in this population group. The frequencies of the three kinds of genotypes （GG, GA, AA） in CR group and NCR group were 32.6%, 47.6%, 19.8% and 47.9%, 45.0% 7.0%, respectively. The frequency of AA genotype was significantly higher in NCR group than in CR group （OR=3.03, 95% CI： 1.889-5.784, P=0.003）. The A allele carriers were more likely to develop CR compared with that of G allele carriers （OR=1.85, 95%CI： 1.392-2.459, P=0.002）. Conclusion CYP2C19 681G/A polymorphism is associated with the risk of CR, and the A allele carriers may be a possible genetic susceptibility factor for elderly patients with CR.