WGA Study to Identify Genetic Variants Associated with CV Events in CHS

描述（由申请人提供）： 研究团队和现有数据。本申请代表了多中心协作努力，其使用来自正在进行的基于人群的研究的数据和样本来鉴定和复制影响心肌梗死（MI）、中风和心力衰竭（HF）的发生率的遗传基因座。这项研究的背景是心血管健康研究（CHS），这是一项由NHLBI资助的老年人心脏病和中风风险因素的队列研究。MI和中风的复制工作使用了Group Health Cooperative成员中的心脏和血管健康（HVH）病例对照研究。来自CHS和HVH的数据和生物标本可用于约1690例MI、1110例卒中和870例HF事件。研究小组包括来自华盛顿大学、佛蒙特大学、雪松西奈医学遗传学研究所和CHS指导委员会的流行病学、心血管疾病、遗传学和生物统计学专家。 背景和目标。连锁研究和候选基因方法在确定影响心血管事件风险的遗传变异的常见模式方面取得了有限的成功。技术的进步使得在无关人群中进行全基因组（WG）关联研究成为可能。主要目的（目的1）是鉴定与三种主要心血管事件MI、中风和HF中的每一种的风险相关的10种潜在遗传变异（总共30种变异）。次要目的（目的2）是配置设计，以便在CHS参与者的大随机样本中进行WG扫描。然后，这些WG扫描可用于生成CHS中大量其他高质量表型的风险标志物列表。第二次工作组分析，然后可以作为未来的遗传研究的基础，无论是在CHS或其他研究人员在其他人群。 方法.拟议的研究有3个主要部分，CHS中的两阶段设计加上MI和卒中的外部复制研究。在5888例CHS参与者中，4056例在基线时没有任何临床心血管疾病。在第一阶段，将随机选择2000名参与者，使用Illumina HumanHap300 BeadChip进行WG扫描。队列分析将确定MI、卒中和HF三个主要结局中每一个的400个最感兴趣的区域（总共1200个区域）。在第二阶段，HapMap数据将用于为1200个区域中的每个区域选择额外的4个SNP，这些SNP加上最初确定的高信号SNP（所有3个结果中的6000个）将在其他2000名CHS参与者中进行基因分型。队列分析将确定12至20个最值得复制的区域。在第三部分中，将在大型HVH病例对照研究中重复确定MI和卒中的最佳区域。拟议的三部分研究是有效的，具有良好的能力，以检测小到中等大小的风险比，提供了一个大样本的WG扫描的目的2，并包括外部复制。 (End摘要）

DESCRIPTION (provided by applicant): Research team and available data. This application represents a multi-center collaborative effort using data and specimens from on-going population-based studies to identify and replicate genetic loci that affect the incidence of myocardial infarction (Ml), stroke, and heart failure (HF). The setting is the Cardiovascular Health Study (CHS), an NHLBI-funded cohort study of risk factors for heart disease and stroke among older adults. Replication efforts for Ml and stroke use the Heart and Vascular Health (HVH) case-control study among members of Group Health Cooperative. Data and biologic specimens, from both CHS and HVH, are available on about 1690 MIs, 1110 strokes, and 870 HF events. The research team includes experts in epidemiology, cardiovascular disease, genetics and biostatistics from the University of Washington, the University of Vermont, Cedars-Sinai Institute of Medical Genetics, and the CHS Steering Committee. Context and aim. Linkage studies and candidate-gene approaches have had limited success in identifying common patterns of genetic variation that influence the risk of cardiovascular events. Advances in technology have made it possible to conduct whole-genome (WG) association studies in unrelated populations. The primary aim (aim 1) is to identify 10 underlying genetic variants associated with the risk of each of three major cardiovascular events, Ml, stroke and HF (total of 30 variants). The secondary aim (aim 2) is to configure the design so that the WG scans are conducted on a large random sample of CHS participants. These WG scans can then be used to generate lists of risk markers for the large number of other high-quality phenotypes available in CHS. The secondary WG analyses can then be used as the basis for future genetic studies either within CHS or by other investigators in other populations. Methods. The proposed study has 3 major parts, a two-stage design in CHS plus an external replication study for Ml and stroke. Among the 5888 CHS participants, 4056 were free of all clinical cardiovascular disease at baseline. In the first stage, a random sample of 2000 participants will be selected for WG scans with the Illumina HumanHap300 BeadChip. Cohort analyses will identify the 400 most interesting regions for each of the three major outcomes, Ml, stroke and HF (total of 1200 regions). In the second stage, HapMap data will be used to select an additional 4 SNPs for each of the 1200 regions, and these SNPs plus the originally identified high-signal SNP (6000 across all 3 outcomes) will be genotyped in the other 2000 CHS participants. Cohort analyses will identify the 12 to 20 most interesting regions for replication. In the third part, the best regions identified for Ml and stroke will be replicated in the large HVH case-control study. The proposed three-part study is efficient, has excellent power to detect small to modest-sized hazard ratios, provides a large sample of WG scans for aim 2, and includes an external replication. (End of Abstract)