中国汉族老年急性冠脉综合征患者氯吡格雷抗血小板治疗反应性的药物基因组学相关分析

摘要

Objective To study the pharmacogenomic-associated factors of clopidogrel antiplatelet reactivity in Han Chinese elderly patients with acute coronary syndrome(ACS). Methods During September 1st, 2011 to September 1st, 2012, ACS patients over 60 years were continuously enrolled from hospitalized patients in Institute of Geriatric Cardiology, Chinese PLA General Hospital, following strict inclusion criteria. All of the enrolled patients were prescribed with normal dose of aspirin and clopidogrel. The adenosine diphosphate (ADP)-induced platelet aggregation rate on the 5th day was determined by light transmission aggregation (LTA). SnapShot method was applied to detect candidate gene variants, which related with clopidogrel metabolism and activity (including PON1 Q129R, CYP2C19*2, CYP2C19*3, CYP2C19*17 and ABCB1 C3435T). Results In the total 246 enrolled ACS patients, univariate analysis showed that only CYP2C19*2 variant was significantly related with ADP-induced platelet aggregation rate after stable clopidogrel treatment (P= 0.001). The CYP2C19*2 carriers showed an obviously higher platelet aggregation rate compared with the non-carriers [(46.1 ±21.25)% vs (39.38 ± 19.44)%, P＜0.001]. After adjusting the impact of age, gender, body mass index, comorbidities, concomitant medications and so on, stepwise multiple regression showed that CYP2C19*2 was still significantly related with ADP-induced platelet aggregation rate after stable clopidogrel treatment, which could explain 22.2% variance of clopidogrel antiplatelet reactivity variance (P = 0.001). Conclusion CYP2C19*2 is the major pharmacogenomic determinant which affects clopidogrel antiplatelet reactivity in Chinese Han elderly patients with acute coronary syndrome.%目的 探讨影响中国汉族老年急性冠脉综合征患者氯吡格雷抗血小板反应性的药物基因组学关联因素.方法 严格按照病例纳入和排除标准,连续募集201 1年9月1日至2012年9月1日期间,在解放军总医院住院诊断为急性冠脉综合征的60岁以上患者,并给予常规氯吡格雷和阿司匹林双联抗血小板治疗.采用光密度比浊法检测患者服用稳定剂量氯吡格雷后第5日的腺苷二磷酸(ADP)诱导的血小板聚集率.采用SnapShot基因分型法检测氯吡格雷的代谢和作用通路上的候选相关基因变异型(包括PON1Q192R,CYP2C19*2,CYP2C19*3,CYP2C19*17以及ABCB1 C3435T).结果 在246例符合入选标准的老年急性冠脉综合征患者中,单因素相关分析显示,在候选的氯吡格雷代谢和作用相关基因变异型中,仅有CYP2C 19*2基因型与氯吡格雷稳定治疗后的血小板反应性显著相关(P=0.001),其中CYP2C19*2携带者口服稳定剂量氯吡格雷第5日时ADP诱导的血小板聚集率(46.1％±21.25％)显著高于非携带者(39.38％±19.44％,P＜ 0.001).利用多元逐步回归分析,经校正年龄、性别、体质量指数、合并疾病和合并用药等临床环境相关因素后,CYP2C19*2仍与患者稳定剂量治疗下的血小板聚集率密切相关,它能够解释22.2％的氯吡格雷抗血小板反应性个体间变异(P=0.001).结论 CYP2C19*2是影响中国汉族老年急性冠脉综合征患者氯吡格雷抗血小板反应性的主要药物基因组学相关因素.