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

描述(由申请人提供)： 研究团队和可用的数据。这一应用代表了一项多中心合作努力，使用正在进行的基于人群的研究的数据和样本来识别和复制影响心肌梗死(ML)、中风和心力衰竭(HF)发生率的遗传基因。背景是心血管健康研究(CHS)，这是一项由NHLBI资助的关于老年人心脏病和中风风险因素的队列研究。对急性髓细胞白血病和中风的复制工作使用了团体健康合作社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以获得大约1690次失误、1110次中风和870次高频事件。研究小组包括来自华盛顿大学、佛蒙特州大学、锡达斯-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。 背景和目的。连锁研究和候选基因方法在识别影响心血管事件风险的常见遗传变异模式方面取得的成功有限。技术的进步使在无关人群中进行全基因组(WG)关联研究成为可能。主要目标(目标1)是确定与三种主要心血管事件(ML、中风和心力衰竭)中的每一种的风险相关的10种潜在的遗传变异(总共30种变异)。第二个目标(目标2)是配置设计，以便在CHS参与者的大随机样本上进行WG扫描。这些工作组扫描然后可以用来为CHS中提供的大量其他高质量表型生成风险标记列表。然后，二级工作组分析可以用作未来CHS内或其他人群中的其他研究人员进行遗传学研究的基础。 方法：研究方法。这项拟议的研究有3个主要部分，一个针对CHS的两阶段设计，以及一个针对ML和卒中的外部复制研究。在5888名CHS参与者中，4056人在基线时没有所有临床心血管疾病。在第一阶段，将随机抽取2000名参与者进行Illumina Human Hap300珠片的WG扫描。队列分析将为三个主要结局中的每一个确定400个最感兴趣的区域，即ML、卒中和HF(总共1200个区域)。在第二阶段，将使用HapMap数据为1200个区域中的每个区域选择另外4个SNP，这些SNP加上最初确定的高信号SNP(在所有3个结果中有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到20个最值得复制的有趣区域。在第三部分中，确定的ML和卒中的最佳区域将在大规模的高血压病例对照研究中重复进行。拟议的三部分研究是有效的，具有出色的检测小到中等风险比率的能力，为AIM 2提供了大量的WG扫描样本，并包括外部复制。(摘要结束)

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)