P2RY12基因多态性及启动子区DNA甲基化对氯吡格雷抵抗的影响机制与定量研究

项目名称： P2RY12基因多态性及启动子区DNA甲基化对氯吡格雷抵抗的影响机制与定量研究

项目编号： No.81503157

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 李新刚

作者单位： 首都医科大学

项目金额： 17.9万元

中文摘要： 研究背景：氯吡格雷抵抗是导致缺血性脑血管病介入术后患者缺血事件再发的重要原因，遗传因素与药物抵抗直接相关。我们前期发现：出现与未出现缺血事件患者的活性代谢物浓度无统计学差异。科学问题：药物靶点基因P2RY12与药物抵抗的关系?科学假说：P2RY12基因多态性和启动子区DNA甲基化通过基因表达的调控机制，抵抗药物的抗血小板作用，导致了缺血事件再发。研究内容：选择基于中国人群的P2RY12基因Tag SNP和功能性SNP位点，考察位点变异与基因表达、血小板活性和缺血事件的相关性；考察P2RY12基因启动子区DNA甲基化水平对基因表达、血小板活性和缺血事件的影响；构建基于基因调控机制的氯吡格雷群体药动/药效模型，定量描述基因对血小板活性和缺血事件的影响。目标：阐明P2RY12基因多态性和启动子区DNA甲基化对药物抵抗的影响机制并建立定量关系。意义：实现对药物抵抗患者的准确筛查和个体化给药。

中文关键词： 氯吡格雷；P2RY12；遗传多态性；DNA甲基化；定量药理学

英文摘要： Introduction: Clopidogrel resistance (CR) is a major cause of recurrent ischemic events in ischemic cerebrovascular disease patients after intervention. Genetic factors are directly related to CR. We previously found that there was no statistical difference in the concentrations of clopidogrel active metabolite between ischemic event patients and non-ischemic event patients. Scientific question: what is the relationship between the drug target P2RY12 gene and CR? Scientific hypothesis: P2RY12 gene polymorphisms and the promoter DNA methylation through regulation of gene expressions prevent clopidogrel platelet inhibition leading to ischemic events. Research contents: 1) selection of P2RY12 Tag SNP genetic and functional SNP loci based on Chinese population; 2) study the correlations among site variations and gene expression, platelet activity and ischemic events; 3) study the correlations among P2RY12 gene promoter DNA methylation and gene expression, platelet activity and ischemic events; 4) build clopidogrel’s population pharmacokinetic/pharmacodynamic model based on gene regulatory mechanisms to quantify the impact of P2RY12 gene on platelet activity and ischemic events. Goal: to clarify the mechanisms of P2RY12 gene polymorphisms and promoter DNA methylation affecting CR and to establish a quantitative relationship. Significance: to achieve an accurate screening of CR in patients and individualized clopidogrel dosing.

英文关键词： clopidogrel;P2RY12;genetic polymorphism;DNA methylation;pharmacometrics