CYP2C19基因多态性对氯吡格雷抑制血小板P2Y12受体信号通路作用的影响

More than 60% Chinese patients with coronary artery disease are CYP2C19 loss-of-function carriers. Thus, making a judgment about the relationship between CYP2C19 variants and clopidogrel response may be particularly important in Chinese.Our previous studies have demonstrated that CYP2C19 loss-of-function polymorphism was associated with the response of clopidogrel as measured by ADP-induced platelet aggregation and ischemic events. However, such study endpoints were not P2Y12-receptor specific.In this study, we would assess platelet response to clopidogrel through measurement of P2Y12 receptor-mediated Gαi and Gβγ pathways inhibition.Analysis of platelet VASP phosphorylation would be performed using a standardized flow cytometric assay. Moreover, platlet Akt phosphorylation in Ser-473 would be analyzed by Western blot.Then, we would investigate the impact of cytochrome 2C19 allelic variants on inhibition of the platelet P2Y12 receptor signalling pathway by clopidogrel.The conclusions of this study would provid theoretical basis for the variability of clopidogrel responsiveness.

60%以上的中国冠心病患者携带有CYP2C19功能缺失等位基因，明确它对氯吡格雷疗效的影响具有重要的意义。我们的前期研究结果发现CYP2C19基因多态性影响了氯吡格雷治疗后的血小板聚集率和临床结局；但是，这样的观察终点并不够特异。为了提高研究结论的说服力，我们选择血小板膜P2Y12受体介导的Gαi 和Gβγ信号通路水平来判断氯吡格雷的疗效，其中采用流式细胞学方法检测血小板VASP磷酸化水平、采用Western Blot方法检测血小板Akt Ser473磷酸化水平；观察不同CYP2C19基因型是否影响氯吡格雷对血小板膜P2Y12受体信号通路的抑制作用。期望通过我们的研究，为氯吡格雷反应差异的机制提供可靠的理论依据。