血小板P2Y12受体基因多态性与氯吡格雷临床安全关联性的系统评价和Meta分析

Systematic review and meta analysis for correlation between genetic polymorphism of platelet P2Y12 receptor and clinical safety of clopidogrel

目的系统评价服用氯吡格雷患者的临床疗效受P2Y12基因(T744C、G52T、C34T)多态性的影响程度,以期为其安全使用提供有效证据。方法计算机检索Web of Science、Elsevier SD、Pubmed、The Cochrane Library、Clinical Trial、CBM、CNKI,万方全文数据库及维普全文数据库,查找有关服用氯吡格雷患者P2Y12基因多态与氯吡格雷疗效相关的观察性临床试验,检索时限均从建库截至2014年8月20日。对符合条件的研究,由两位研究者按照纳入和排除标准,独立筛选文献、提取资料、评价质量,并交叉核对后,采用Rev Man 5.3软件和Stata12.0软件进行Meta分析。结果共纳入13篇文献,包含13个观察性临床研究(n=2 787)。Meta分析结果显示:P2Y12基因突变有增加亚洲人群氯吡格雷抵抗发生率[相对危险度(RR)=1.44,95%CI(1.11,1.88),P=0.007],其中P2Y12基因位点G52T和C34T增加氯吡格雷抵抗[分别为RR=1.28,95%CI(1.06,1.56),P=0.01和RR=2.70,95%CI(1.37,5.29),P=0.004],同时增加心血管不良事件[分别是RR=1.99,95%CI(1.63,2.44),P<0.000 01和RR=1.31,95%CI(1.07,1.62),P=0.01],而T744C对发生氯吡格雷抵抗和不良心血管事件均无影响[分别为RR=1.02,95%CI(0.64,1.61),P=0.94和RR=0.74,95%CI(0.36,1.50),P=0.40]。结论血小板P2Y12受体基因突变可能增加氯吡格雷抵抗发生率,其中G52T和C34T在增加氯吡格雷抵抗和心血管不良事件起着重要作用,而T744C对其均无影响。由于本次研究存在一些不足,血小板P2Y12受体基因多态性对服用氯吡格雷患者的临床疗效影响还待进一步研究证实。

AIM To systematically evaluate the clinical efficacy of clopidogrel influenced by P2Y12 polymorphism in patients with taking clopidogrel,in order to provide references for its safe medication.METHODS Papers which were related to correlation between the genetic polymorphism of P2Y12 and the clinical efficacy of clopidogrel were retrieved in electronic databases covering Web of Science,Elsevier SD,Pubmed,The Cochrane Library,Clinical Trial,CBM,CNKI,Wan Fang and VIP from establishment dates to October 20,2014.Observational clinical trials were included,cross-checked,assessed and pooled for meta-analysis.Meta-analysis was performed by the software Rev Man 5.3 and Stata12.0.RESULTS A total of 13 articles including 13 observational clinical trials（n = 2 787） were included.The results of meta-analysis showed that P2Y12 gene mutations have increased the incidence of clopidogrel resistance in Asian subgroup（risk ratio（RR） = 1.44,95%CI（1.11,1.88）,P = 0.007）.The risk of clopidogrel resistance was higher in G52 T and C34 T patients（RR = 1.28,95%CI（1.06,1.56）,P = 0.01 and RR = 2.70,95%CI（1.37,5.29）,P =0.004,respectively）.Meanwhile,G52 T and C34 T also increased the risk of cardiovascular adverse events（RR = 1.99,95% CI（1.63,2.44）,P〈 0.000 01 and RR = 1.31,95% CI（1.07,1.62）,P = 0.01,respectively].However,T744 C had no effect on clopidogrel resistance（RR = 1.02,95%CI（0.64,1.61）,P = 0.94） and cardiovascular adverse events（RR = 0.74,95%CI（0.36,1.50）,P = 0.40）.CONCLUSION P2Y12 gene mutations may increase the incidence of clopidogrel resistance,G52 T and C34 T but not T744 C play important roles in increasing the incidence of clopidogrel resistance and cardiovascular adverse events.The clinical efficacy of clopidogrel influenced by genetic polymorphism of platelet P2Y12 receptor still need more clinical studies to be confirmed.