细胞色素P2C19基因多态性与氯吡格雷治疗反应研究

Dual antiplatelet with clopidogrel and aspirin is the standard therapy of acute coronary syndromes and percutaneous coronary interventions with stenting. The pharmacodynamics response to clopidogrel has substantial individual variability, patients with poor response to clopidogrel appear to be at increased risk for recurrent ischemia events，including cardiac death, myocardial infarction and stroke.The genetic basis of various efficacy with clopidogrel treatment are polymorphisms of CYP2C19. CYP2C19 phenotype was various according to different race, CYP2C19*2, *3, *17 were frequent variant allele (95%) among the variant-function group in Caucasians, and several studies reported low frequency variant-function allele including CYP2C19*6-*14 in different races. But the genes encoding CYP2C19 in Asians was not clear so far. Moreover, whether CYP2C19*2, *3, *17 have a prominent effect on the conversion to active metabolite with clopidogrel and hence on cardiovascular disease composite are still controversial. No studies focused on the influence of low frequency variant-function allele on efficacy and safety with clopidogrel treatment.In order to provide experimental basis and theoretical directions for gene-guiding individual treatment, the current study plans to investigate the phenotype frequency with CYP2C19 in Asians and the effects of CYP2C19 polymorphisms on active metabolism and treatment response with clopidogrel.

氯吡格雷与阿司匹林双联抗血小板是急性冠脉综合征及冠脉介入治疗的标准治疗。个体对氯吡格雷治疗反应存在较大差异，药物治疗低反应者再发缺血事件（心血管死亡、心梗、卒中）明显增加。CYP2C19基因多态性是氯吡格雷治疗反应多样性的遗传学基础。CYP2C19基因多态性存在显著种族差异，CYP2C19*2,*3,*17是白种人群常见的功能变异等位基因，其他低频功能变异等位基因CYP2C19*6-*14在不同种族也有少量报道，亚洲人群CYP2C19基因表达谱尚缺乏系统研究。CYP2C19主要功能变异等位基因*2，*3，*17对氯吡格雷活性代谢及心血管复合终点影响尚无定论,低频功能变异等位基因对氯吡格雷疗效和安全性影响的研究没有报道。我们拟研究亚洲人群CYP2C19基因表达谱及基因多态性对氯吡格雷活性代谢和治疗反应的影响，为基因导向的个体化药物治疗提供实验依据和理论指导。

急性冠脉综合征（ACS）是威胁生命的心血管疾病，已经明确ACS的不同临床表现形式（不稳定型心绞痛、非ST段抬高心梗、ST段抬高心梗）均具有共同的病理生理基础即动脉粥样硬化斑块破裂或侵蚀诱发血栓形成导致血管的急性闭塞。冠脉介入治疗（PCI）联合氯吡格雷和阿司匹林双联抗血小板治疗极大改善了ACS患者的生存预后，但是仍有患者在标准治疗下再发缺血事件。PCI后再发缺血事件致死致残率高，尤其支架血栓导致的死亡高达20-40%、非致命性心梗达50-70%。先前研究显示CYP2C19基因多态性导致氯吡格雷代谢活性下降、血小板抑制减弱，可能导致PCI后再发缺血事件增加。我们在NSTEMI-ACS接受PCI的人群中进行了CYP2C19基因多态性研究，按照CYP2C19基因型分为野生型、杂合子和纯合子三组，分别接受氯吡格雷负荷剂量600mg和维持剂量75mg，随访12个月的临床终点事件和影像终点事件。研究发现：1、CYP2C19功能缺失等位基因携带者占全部基因型54.7%（杂合子44.1%，纯合子10.6%）；2、亚洲人群近一半（44.7%）的氯吡格雷治疗患者存在血小板治疗高反应性（PRU>235）；3、功能缺失等位基因携带患者VerifyNow检测血小板治疗反应性显著升高（纯合子310.4±36.6PRU vs杂合子225.2±28.2PRU vs 野生型192.6±30.4PRU，p<0.01 ）；4、12个月光学干涉断层成像随访功能缺失等位基因携带者腔内支架血栓发生率显著升高（纯合子11.5% vs 杂合子6.27% vs 野生型2.09%，p<0.01）；5、12个月临床随访功能缺失等位基因携带者主要终点事件显著升高。我们的研究证实CYP2C19基因变异在亚洲人群显著高于白种人，功能缺失等位基因携带导致PCI后氯吡格雷治疗患者的血小板高反应性和心血管复合终点以及腔内影像支架血栓的显著增加。