Genetic risk factors for Sudden Cardiac Death

描述(申请人提供)：该奖项的目的是使首席研究员Nona Sotoodehnia博士成为心血管疾病分子流行病学领域的独立临床科学家，特别关注心脏性猝死(SCD)。培训计划包括两个配套活动：攻读S遗传流行病学硕士学位的授课课程，以及一个为期5年的综合研究计划，调查SCD与肾素-血管紧张素系统(RAS)和交感神经系统(SNs)候选基因的关系。本研究的科学目标如下：1)确定与SCD相关的RAS和SNs中的遗传标记，2)确定这些遗传因素与SCD易感的中间表型(如左心室重量和心率)的相关性，以及3)调查特定的环境、药物和其他遗传因素对上述遗传关联的影响。据我们所知，这将是第一次系统地调查普通人群中SCD的遗传风险因素的研究。与NHLBI资助的UW基因组应用计划的研究人员合作，我们将首先使用完整的序列信息确定五个候选基因的共同单倍型结构。然后，我们将在每个基因中确定几个信息丰富的单核苷酸多态，以捕获常见的单倍型，以便进一步对研究参与者进行基因分型。然后，使用单倍型分析的遗传学调查将在两项研究中进行，这两项研究可以严格鉴定SCD的表型：心血管健康研究(CHS)，一个由5888名65岁以上的男性和女性组成的混杂队列；以及西雅图心脏骤停血液研究(CABS)，这是社区中SCD的病例对照研究。利用CHS的临床特征、亚临床疾病和药物使用的信息，我们还将调查基因与中间表型的关联，并探索基因-环境和药物-基因的相互作用。通过这一奖项的结束，首席研究员将在传统流行病学方法方面取得坚实的基础，并获得尖端的人类基因组流行病学分析技能，这将使她能够作为一名独立的研究员在心血管和遗传流行病学领域做出贡献。

DESCRIPTION (provided by applicant): The purpose of this award is to enable the Principle Investigator, Dr. Nona Sotoodehnia, to develop into an independent clinical scientist in the field of molecular epidemiology of cardiovascular diseases with a special focus on sudden cardiac death (SCD). The training plan includes two concomitant activities: didactic coursework with a pursuit of a master s degree in genetic epidemiology, and a comprehensive 5-year program of research investigating the association of SCD with candidate genes in the renin-angiotensin (RAS) and sympathetic nervous systems (SNS). The scientific goals of this research proposal are as follows: 1) to identify genetic markers in the RAS and SNS associated with SCD, 2) to determine the association of these genetic factors with intermediate phenotypes that predispose to SCD (e.g. left ventricular mass and heart rate), and 3) to investigate the influence of specific environmental, pharmacologic, and other genetic factors on the above genetic associations. To the best of our knowledge, this will be the first study to systematically investigate genetic risk factors for SCD in the general population. In collaboration with investigators from the NHLBI-funded UW Program for Genomic Applications, we will first determine common haplotype structure for the five candidate genes using complete sequence information. We will then identify a few informative single nucleotide polymorphisms in each gene that capture the common haplotypes for further genotyping of the study participants. The genetic investigations using haplotype analysis will then be performed in two studies that allow rigorous identification of the SCD phenotype: the Cardiovascular Health Study (CHS), a biracial cohort of 5,888 men and women over age 65, and the Seattle Cardiac Arrest Blood Study (CABS), a case-control study of SCD in the community. Using CHS information on clinical characteristics, subclinical disease, and medications use, we will also investigate association of genotype with intermediate phenotypes and explore gene-environment and drug-gene interactions. By the conclusion of this award, the Principle Investigator will have achieved a solid foundation in traditional epidemiologic methods as well as attained cutting-edge human genome epidemiology analytic skills, which will enable her to contribute as an independent investigator to the fields of cardiovascular and genetic epidemiology.