Department of Neurology, 2nd Faculty of Medicine, Charles University, Prague and Motol University Hospital, Prague, Czech Republic.
Molecular Genetics Laboratory, Hospital Na Homolce, Prague, Czech Republic.
Am J Ther. 2018 Mar/Apr;25(2):e202-e212. doi: 10.1097/MJT.0000000000000416.
Variable response after clopidogrel is well documented and may affect major adverse clinical events after stroke. Impact of CYP2C19 genetic polymorphisms is an established marker linked to variable response after clopidogrel. However, the association of certain genetic polymorphisms with prediction of major adverse clinical events following stroke still remains controversial, especially in Caucasians.
The primary aim was to evaluate the impact of CYP2C19 allele *2 in heterozygote form on major adverse clinical events in Caucasian poststroke survivors treated with clopidogrel. The secondary aim was to analyze the potential link between CYP2C19 genetic polymorphism and variable response after clopidogrel.
One hundred thirty patients of Caucasian origin following documented ischemic stroke were included. Platelet reactivity was assessed by light transmittance aggregometry (LTA) and matched with various CYP2C19 loss-of-function genetic polymorphisms and major adverse clinical events (composite of vascular deaths, stroke/transient ischemic attack, and myocardial infarction).
Over the mean follow-up of 14.9 months, 19 patients experienced major adverse clinical events. The risk of major adverse clinical events was nearly 3-fold in loss-of-function allele carriers (hazard ratio = 2.904; 95% confidence interval, 1.083-7.786; P = 0.013), whereas the risk of ischemic stroke or transient ischemic attack alone was also higher (hazard ratio = 3.170; 95% confidence interval, 1.281-7.849; P = 0.034). Platelet activity was strongly associated with allele 2 status (rs = 0.21, P = 0.016) but not with other genetic polymorphisms. Carriers of allele2 exhibited lower platelet response to adenosine diphosphate-mean LTA (30.1% vs. 42.0%; P = 0.017). There were no significant differences in LTA results with other agonists. Strong association of increase in adenosine diphosphate-induced aggregation with diabetes mellitus (rs = 0.20, P = 0.023), increasing age (rs = 0.23, P = 0.008), and conversely diminishing over increased weight (rs = 0.23, P = 0.009) was also detected. The carriers of other gene allele variants lack uniformed impact on variable response after clopidogrel.
Even heterozygous CYP2C19*2 allele carriers among Caucasian patients after ischemic stroke had a higher risk of major adverse clinical events. The LTA, however, did not predict major adverse clinical events. The exact clinical utility of these findings is still uncertain and requires large outcome-driven randomized trial in Caucasians for proof of concept.
氯吡格雷的反应存在变异性，这在临床上已得到充分证实，可能会影响中风后的主要不良临床事件。细胞色素 P450 2C19（CYP2C19）基因多态性是影响氯吡格雷反应变异性的一个既定标志物。然而，某些基因多态性与中风后主要不良临床事件的预测之间的关联仍存在争议，尤其是在白种人群中。
本研究的主要目的是评估杂合子形式的 CYP2C19*2 等位基因对接受氯吡格雷治疗的白种人中风后幸存者的主要不良临床事件的影响。次要目的是分析 CYP2C19 遗传多态性与氯吡格雷反应变异性之间的潜在联系。
纳入了 130 名经证实的缺血性中风的白种人患者。通过光透射聚集度测定法（LTA）评估血小板反应，并与各种 CYP2C19 失活功能基因多态性和主要不良临床事件（血管死亡、中风/短暂性脑缺血发作和心肌梗死的复合事件）进行匹配。
在平均 14.9 个月的随访期间，19 名患者发生了主要不良临床事件。失活等位基因携带者发生主要不良临床事件的风险增加近 3 倍（风险比=2.904；95%置信区间，1.083-7.786；P=0.013），而单独发生缺血性中风或短暂性脑缺血发作的风险也更高（风险比=3.170；95%置信区间，1.281-7.849；P=0.034）。血小板活性与等位基因2 状态密切相关（rs=0.21，P=0.016），但与其他遗传多态性无关。携带等位基因2 的患者对二磷酸腺苷诱导的聚集反应较低（平均 LTA：30.1% vs. 42.0%；P=0.017）。用其他激动剂检测到的 LTA 结果无显著差异。还检测到二磷酸腺苷诱导的聚集增加与糖尿病（rs=0.20，P=0.023）、年龄增长（rs=0.23，P=0.008）之间存在强烈的相关性，而与体重增加之间存在相反的相关性（rs=0.23，P=0.009）。其他基因等位基因变异的携带者对氯吡格雷反应变异性没有一致的影响。
即使是白种人中风后杂合子形式的 CYP2C19*2 等位基因携带者，发生主要不良临床事件的风险也更高。然而，LTA 并不能预测主要不良临床事件。这些发现的确切临床应用仍不确定，需要在白种人群中进行大型以结果为导向的随机试验来证明其概念。
