根据10月26日JAMA杂志上的一篇报告，除已知的临床和血管造影危险因素外，与氯吡格雷和血小板受体功能相关的3个基因(CYP2C19、ABCB1和ITGB3)的变异是早期支架内血栓形成的独立危险因素。
如图所示，支架内已形成血栓
法国巴黎心脏病学研究所、国家健康与医学研究院(INSERM)联合研究组、Salpetriere医院的Guillaume Cayla医生及其合作者，评估了已被报告与氯吡格雷药物遗传学和动脉血栓形成相关的所有23种基因变异，旨在确定何种基因变异对早期支架内血栓形成的影响最大。他们使用了法国全国注册数据库中在置入支架后30 d内有明确支架内血栓形成的123例患者的数据，然后以年龄和性别与之匹配的246例无支架内血栓形成的受试者作为对照。采集这369例受试者的外周血样，对可疑基因变异进行基因测定。
结果显示，仅发现3个基因的4种变异与早期支架内血栓形成显著相关。首先，CYP2C19丧失功能型等位基因在病例组中占49%，而在对照组中仅占26%。其次，CYP2C19获得功能型等位基因在病例组中占20%，而在对照组中占33%。这些结果为CYP2C19在氯吡格雷代谢中发挥重要作用的观点提供了更多证据。第三，病例中32%发生ABCB1变异，而对照组发生率仅为19%。“ABCB1基因编码药物流出转运蛋白P-糖蛋白可调控氯吡格雷的吸收，之前曾发现其与氯吡格雷反应降低相关，但临床后果并不一致”。第四，病例中16%发生ITGB3变异，而对照组的发生率为28%。ITGB3基因编码整合素b-3 “是血小板糖蛋白Ⅱb/Ⅲa受体的一种成分，可介导血小板聚集的最终通路”。
随着携带这些风险等位基因数量的增加，早期支架内血栓形成风险呈剂量依赖性稳步升高。将临床数据与遗传学数据联合的风险预测模型预测早期支架内血栓形成的效能显著高于单纯临床模型。联合模型对于早期支架内血栓形成的预测敏感性和特异性分别为67%和79%，而单纯使用临床数据模型的敏感性和特异性分别为60%和70%。“使用临床和遗传学数据联合模型预测风险位于最高三分位数的患者发生早期支架内血栓形成的风险是位于最低三分位数者的7倍” (JAMA 2011;306:1765-74)。
研究者还发现，两种非遗传因素[氯吡格雷负荷量和同时使用质子泵抑制剂(PPI)]与早期支架内血栓形成显著相关。置入支架时，病例较对照接受低负荷剂量氯吡格雷的机会增加，并且接受PPI的机会大幅增加，而PPI可能会干扰氯吡格雷的代谢。与遗传学危险因素不同，氯吡格雷剂量和PPI使用都是可以纠正的危险因素。
研究者总结认为，对于早期支架内血栓形成的预测，将遗传学与临床数据整合的风险预测模型较单纯临床模型具有更高的敏感性和特异性。
该研究由ACTION、法国心脏病学会、法国心脏病联合会(Fédération Francaise de Cardiologie)和INSERM出资赞助。早期支架内血栓形成患者的法国注册数据部分由礼来公司和SGAM基金会提供。Cayla医生及其合作者披露与多家医药企业存在利益关系。
相关英文论文摘要：
Clinical, Angiographic, and Genetic Factors Associated With Early Coronary Stent Thrombosis
Context Despite dual antiplatelet therapy, stent thrombosis remains a devastating and unpredictable complication of percutaneous coronary intervention (PCI).
Objective To perform a sequential analysis of clinical and genetic factors associated with definite early stent thrombosis.
Design, Setting, and Participants Case-control study conducted in 10 centers in France between January 2007 and May 2010 among 123 patients undergoing PCI who had definite early stent thrombosis and DNA samples available, matched on age and sex with 246 stent thrombosis–free controls.
Main Outcome Measure Accuracy of early stent thrombosis prediction by 23 genetic variants.
Results Among the 23 genetic variants investigated in 15 different genes, the significant determinants of early stent thrombosis were CYP2C19 metabolic status (adjusted odds ratio [OR], 1.99; 95% CI, 1.47-2.69), ABCB1 3435 TT genotype (adjusted OR, 2.16; 95% CI, 1.21-3.88), and ITGB3 PLA2 carriage (adjusted OR, 0.52; 95% CI, 0.28-0.95). Nongenetic independent correlates were acuteness of PCI (adjusted OR, 3.05; 95% CI, 1.54-6.07), complex lesions (American College of Cardiology/American Heart Association type C) (adjusted OR, 2.33; 95% CI, 1.40-3.89), left ventricular function less than 40% (adjusted OR, 2.25; 95% CI, 1.09-4.70), diabetes mellitus (adjusted OR, 1.82; 95% CI, 1.02-3.24), use of proton pump inhibitors (adjusted OR, 2.19; 95% CI, 1.29-3.75), and higher clopidogrel loading doses (adjusted OR, 0.73; 95% CI, 0.57-0.93). The discriminative accuracy of the clinical-only model was similar to that of a genetic-only model (area under the curve, 0.73 [95% CI, 0.67-0.78] vs 0.68 [95% CI, 0.62-0.74], respectively; P = .34). A combined clinical and genetic model led to a statistically significant increase in the discriminatory power of the model compared with the clinical-only model (area under the curve, 0.78 [95% CI, 0.73-0.83] vs 0.73 [95% CI, 0.67-0.78]; P = .004).
Conclusions This case-control study identified 3 genes (CYP2C19, ABCB1, and ITGB3) and 2 clopidogrel-related factors (loading dose and proton pump inhibitors) that were independently associated with early stent thrombosis. Future studies are needed to validate the prognostic accuracy of these risk factors in prospective cohorts.
英文论文链接：https://jama.ama-assn.org/content/306/16/1765.full?sid=8b9be1f3-cfc8-49c6-afdb-925eab5e7d61
