Genetic risk factors for Sudden Cardiac Death

该奖项的目的是使主要研究者Nona Sotoodehnia博士能够发展成为心血管疾病分子流行病学领域的独立临床科学家，特别关注心源性猝死（SCD）。该培训计划包括两个伴随活动：追求遗传流行病学硕士学位的教学课程，以及调查SCD与肾素-血管紧张素（RAS）和交感神经系统（SNS）中候选基因相关性的全面5年研究计划。本研究提案的科学目标如下：1）确定与SCD相关的RAS和SNS中的遗传标记物，2）确定这些遗传因素与易患SCD的中间表型（例如左心室质量和心率）的相关性，3）研究特定环境、药理学和其他遗传因素对上述遗传相关性的影响。据我们所知，这将是第一个系统研究一般人群中SCD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一些信息性的单核苷酸多态性，这些多态性捕获了研究参与者进一步基因分型的常见单倍型。然后在两项研究中使用单倍型分析进行遗传调查，以严格鉴定SCD表型：心血管健康研究（CHS），一项由5，888名65岁以上男性和女性组成的birthday队列，以及西雅图心脏骤停血液研究（CABS），一项社区SCD病例对照研究。利用CHS关于临床特征、亚临床疾病和药物使用的信息，我们还将研究基因型与中间表型的关联，并探索基因-环境和药物-基因相互作用。通过这个奖项的结论，首席研究员将在传统的流行病学方法，以及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个独立的研究人员贡献心血管和遗传流行病学领域的坚实基础。

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.