Pharmacogenomics of Anti-platlet Intervention-2 (PAPI-2) Study

描述（由申请人提供）：氯吡格雷（Plavix）和阿司匹林的抗血小板治疗是心肌梗死二级预防的标准护理。尽管氯吡格雷被广泛使用，但仍有4 - 32%的个体对氯吡格雷无反应。这项续期申请将建立在我们完成抗血小板干预-1 （PAPI-1）阿米什药物基因组学研究的初始资助期间取得的重大进展的基础上。通过同类首个全基因组关联研究（GWAS），我们发现细胞色素P450 2C19*2 （CYP2C19*2）变异的功能缺失是氯吡格雷应答的主要决定因素，占应答变异的12%。在一项独立队列研究中，我们发现约30%携带CYP2C19*2基因的普通人群对氯吡格雷的血小板反应较差，发生缺血性心脏事件或死亡的风险高出2.4倍。本次更新申请的总体目标是继续推进抗血小板药物基因组学及其临床转化。我们假设(a) CYP2C19基因型定向抗血小板治疗将优于标准护理治疗；(b)氯吡格雷反应的遗传结构包括尚待鉴定基因中的常见和罕见变异。我们已经积累了一支多学科的研究人员和合作者团队，并将利用积极参与药物基因组学研究网络所产生的协同效应来解决以下具体问题：(1)开展PAPI-2研究，这是一项前瞻性多中心随机双盲临床试验，比较2000多名冠心病患者使用CYP2C19基因型导向与标准护理抗血小板治疗的心血管事件；(2)作为新的氯吡格雷药物基因组学GWAS联盟的一部分，通过进行大型GWAS来鉴定氯吡格雷反应的新基因和位点的常见变异；(3)通过对氯吡格雷反应分布的极端情况进行全基因组外显子（外显子组）测序，鉴定以前未知的影响血小板功能或氯吡格雷反应的基因中的罕见变异。

DESCRIPTION (provided by applicant): Anti-platelet therapy with clopidogrel (Plavix) and aspirin is the standard of care for secondary prevention of myocardial Infarction. Despite its widespread use, 4 - 32% of Individuals are not responsive to clopidogrel. This renewal application will build upon significant progress made during the initial funding period in which we completed the Amish Pharmacogenomics of Anti-platelet lnterventlon-1 (PAPI-1) Study. Through the first genome-wide association study (GWAS) of its kind, we found that the loss of function cytochrome P450 2C19*2 (CYP2C19*2) variant is a major determinant of clopidogrel response, accounting for 12% of the variation in response. In an Independent cohort, we found that ~30% of the general population harboring CYP2C19*2 have poorer platelet response to clopidogrel and are at a 2.4-fold higher risk of having an ischemic cardiac event or death. The overall goal of this renewal application is to continue to advance the science of anti-platelet pharmacogenomics and its clinical translation. We hypothesize (a) CYP2C19 genotype-directed anti-platelet therapy will be superior to standard of care therapy; and (b) the genetic architecture of clopidogrel response Includes common and rare variants in yet-to-be identified genes. We have amassed a team of multidisciplinary investigators and collaborators and will capitalize on synergies created by active participation in the Pharmacogenomics Research Network to address the following Specific Alms: (1) To conduct the PAPI-2 Study, a prospective multicenter randomized double-blind clinical trial comparing cardiovascular events using CYP2C19 genotype-directed versus standard of care anti-platelet therapy in over 2000 patients with coronary heart disease; (2) To identify common variants in novel genes and loci for clopidogrel response by performing a large GWAS as part of a new Clopidogrel Pharmacogenomics GWAS Consortium; and (3) To identify rare variants in genes previously not known to influence platelet function or clopidogrel response by performing genome-wide exon (exome) sequencing from the extremes of the distribution of clopidogrel response. RELEVANCE: The proposed randomized clinical trial will provide the evidence base for translation of genotype-directed anti-platelet therapy into clinical practice. The Identification of common and rare variants in novel genes for clopidogrel response will provide new insights into platelet biology and variation in anti-platelet therapy response, and potentially, new targets for more effective agents to prevent and treat CHD.