GENOMICS OF SUDDEN CARDIAC ARREST

描述(由申请人提供)：心脏骤停(SCA)是一个主要的公共卫生问题，在美国每年造成超过40万人死亡。虽然环境因素明显影响SCA的决定因素，但家族聚集性研究和遗传性心律失常的分子遗传学研究进展表明，遗传因素使普通人群对SCA易感性。识别这些遗传因素不仅有助于深入了解SCA的发病机制，还将对SCA的风险分层和预防具有重大的公共卫生意义。我们建议利用完整的序列信息和单倍型分析，系统地研究SCA和中间表型与参与心律失常发生的生物学上重要的分子通路的变异之间的关联。具体地说，我们将研究SCA风险与候选基因(目标1)的变异之间的关系，候选基因是电发生和传播的近端决定因素(例如心脏离子通道基因和连接蛋白)，以及影响这些近端决定因素的通路中的基因(例如神经体液调节剂)。我们将在遗传和环境环境的背景下探索这些关联，调查与药物(目标2a)、运动(目标2b)和其他遗传因素(目标2c)的相互作用。我们还将研究遗传变异对中间数量表型的主要影响，如心电图QT间期、心率和心率变异性(目标3)。这项申请代表了一项多中心的合作努力，旨在有效地将基因组学方面的进展与来自四项正在进行的研究的材料相结合，这些研究使严格鉴定SCA表型或相关的中间表型成为可能。具体地说，我们将使用基于人群的大型SCA病例储存库(心脏骤停血库)、两项病例对照研究(心脏骤停血液研究和团体健康合作研究)和一项队列研究(心血管健康研究)的材料：

DESCRIPTION (provided by applicant): Sudden cardiac arrest (SCA) is a major public health concern, accounting for over 400,000 deaths in the US each year. While environmental factors clearly contribute to the determinants of SCA, familial aggregation studies and advances in the molecular genetics of inherited arrhythmias suggest that genetic factors confer susceptibility to SCA in the general population. Identifying these genetic factors will not only provide insight into the mechanisms of SCA, it will also have significant public health implications for risk stratification and prevention of SCA. We propose to systematically investigate the association of SCA and intermediate phenotypes with variations in biologically important molecular pathways involved in arrhythmogenesis using complete sequence information and haplotype analyses. Specifically, we will study the association of SCA risk with variation in candidate genes (Aim 1) that are proximal determinants of electrogenesis and propagation (e.g. cardiac ion channel genes and connexins) and genes in pathways that influence these proximal determinants (e.g. neurohumoral modulators). We will explore these associations in the context of the genetic and environmental milieu, investigating interactions with medications (Aim 2a), exercise (Aim 2b), and other genetic factors (Aim 2c). We will also examine main effects of genetic variation on intermediate quantitative phenotypes, such as ECG QT interval, heart rate, and heart rate variability (Aim 3). This application represents a multi-center collaborative effort to efficiently combine advances in genomics with material from four on-going studies that enable rigorous identification of the SCA phenotype or relevant intermediate phenotypes. Specifically, we will use material from a large population-based repository of SCA cases (Cardiac Arrest Blood Repository), two case-control studies (Cardiac Arrest Blood Study and Group Health Cooperative study), and a cohort study (Cardiovascular Health Study):