Pharmacogenomics of CVD risk Reduction

描述（由申请人提供）：本申请的总体目标是剖析个体对常规治疗和预防心血管疾病（CVD）药物反应的遗传决定因素。项目将由一个已建立的多学科小组执行，该小组有出版和生产力的记录，与外部小组（包括其他NIH资助的多中心网络）的学院互动，以及数据共享的历史。项目1：用于心血管疾病预防的抗血小板药物基因组学：该项目旨在确定预测氯吡格雷（Plavix） 1度和2度心血管事件预防反应的特定基因变异。我们将以正在进行的大型HAPI心脏研究为基础，在该研究中，1000名相关的Old Order Amish受试者已被广泛地描述为心血管疾病（包括对阿司匹林的反应），并已完成800个短串联重复序列标记基因组扫描。我们建议用氯吡格雷治疗这些患者，并测量血小板聚集和功能。我们将(1)确定氯吡格雷反应的频率和遗传性，以及氯吡格雷耐药与阿司匹林耐药的关系；(2)详尽定义100个候选基因的序列变异和单倍型结构，并对snp /单倍型与血小板功能表型进行连锁和关联分析；(3)进行全基因组连锁分析，以确定与氯吡格雷反应相关的染色体区域（以及最终的基因）。拟议的研究将提供氯吡格雷和TZD反应的重要见解，将对数百万美国人的心血管疾病预防和治疗具有重要意义。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to dissect the genetic determinants of individual variation in response to medications used routinely for the treatment and prevention of cardiovascular disease (CVD). Projects will be performed by an established multidisciplinary group that has a track record of publication and productivity, collegial interactions with outside groups, including other NIH funded multi-center networks, and a history of data sharing. Project 1: Pharmacogenomics of anti-platelet agents for CVD prevention: This project seeks to identify specific gene variants that predict response to clopidogrel (Plavix) for the 1 degree and 2 degree prevention of CV events. We will build upon our large ongoing HAPI Heart Study in which 1,000 related Old Order Amish subjects, all of whom have been extensively characterized with respect to CVD (including response to aspirin) and in whom an 800 short tandem repeat marker genome scan has been completed. We propose to treat these same subjects with clopidogrel and to obtain measures of platelet aggregation and function. We will (1) determine the frequency and heritability of clopidogrel response and the relationship between clopidogrel resistance and aspirin resistance; (2) exhaustively define sequence variation and haplotype structure of 100 candidate genes and perform linkage and association analysis of SNPs/haplotypes with platelet function phenotypes; and (3) perform genome-wide linkage analysis to identify chromosome regions (and ultimately genes) linked to clopidogrel response. The proposed studies will provide important insights into clopidogrel and TZD response, will have important implications for the prevention and treatment of CVD in millions of Americans.