Pharmacogenomics of CVD risk Reduction

降低 CVD 风险的药物基因组学

• 批准号: 7125152
• 负责人: ALAN R. SHULDINER
• 金额: $ 145.03万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-23 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7125152
• 关键词: cardiovascular disorder prevention; chemoprevention; clinical research; pharmacogenetics

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.

描述(由申请人提供)：这项提案的总体目标是剖析个体变异的遗传决定因素，以回应常规用于治疗和预防心血管疾病(CVD)的药物。项目将由一个成熟的多学科小组执行，该小组有出版和生产力的记录，与外部小组的合作互动，包括NIH资助的其他多中心网络，以及数据共享的历史。项目1：用于预防心血管疾病的抗血小板药物的药物基因组学：该项目旨在确定预测氯吡格雷(Plavix)对预防心血管事件的1度和2度的反应的特定基因变异。我们将在我们正在进行的大型Hapi心脏研究的基础上再接再厉，在该研究中，1,000名相关的旧秩序阿米什受试者，所有这些人都被广泛描述了心血管疾病(包括对阿司匹林的反应)，并且已经完成了800个短串联重复标记的基因组扫描。我们建议用氯吡格雷治疗同样的受试者，并获得血小板聚集和功能的测量。我们将(1)确定氯吡格雷反应的频率和遗传度，以及氯吡格雷抵抗和阿司匹林抵抗之间的关系；(2)详尽地定义100个候选基因的序列变异和单倍型结构，并进行SNPs/单倍型与血小板功能表型的连锁和关联分析；(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(并最终确定基因)。这项拟议的研究将为氯吡格雷和TZD的反应提供重要的见解，将对数百万美国人预防和治疗心血管疾病具有重要意义。