Genomics of Sudden Cardiac Arrest Among African Americans

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，特别是在非裔美国人中，心脏骤停的风险高于一般人群，生存率很低。虽然环境因素显然有助于SCA的风险，家族聚集性研究和遗传性心律失常的分子遗传学的进展表明，遗传因素赋予SCA在一般人群中的易感性。识别这些遗传因素将提供对SCA机制的深入了解，并可能有助于靶向开发新的药物疗法。迄今为止，很少有研究审查非洲裔人的遗传风险因素。 我们建议系统地调查SCA风险的遗传基础，非洲裔，集中在罕见和常见的遗传变异的候选基因座，从生物学上重要的分子途径参与节律，使用有针对性的测序方法。具体地说，我们将对1500例非裔美国人病例和匹配对照中的大约100个位点进行测序，这些基因选自以下候选基因组：（1）与欧洲血统中的SCA相关的基因;（2）SCA的中间决定因素，如通过体表心电图测量的心脏传导和复极（QRS和QT间期）;（3）导致SCA的孟德尔遗传综合征。 除了建立统计学关联，我们还将从功能上剖析与SCA相关的基因和变体的作用。我们将确定的转录物的空间和时间分布在一系列的发展和出生后的阶段，在小鼠通过整个安装RNA原位分析和切片的胚胎和出生后的心脏。我们将使用斑马鱼来检验这一假设，即在发育过程中，所选候选基因的滴定将损害心血管成分的发生或功能。对于鉴定的编码变异，我们将比较含有鉴定的编码变异的人RNA与其非变异对应物拯救MO诱导效应的能力，并将类似地测定过表达的效应。 该申请代表了多中心的合作努力，以有效地将基因组学，统计遗传学和生物信息学的进展与新的和现有的生物和临床材料联系起来，以确定非裔美国人中SCD的遗传决定因素。重要的是，我们将使用模式生物将遗传关联转化为功能研究，以阐明这些基因在心脏电生理学和心律失常中所起的作用。

DESCRIPTION (provided by applicant): Sudden cardiac arrest (SCA) is a major public health concern, particularly among African Americans where risk of cardiac arrest is higher than that of the general population, and survival is poor. While environmental factors clearly contribute to SCA risk, 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 provide insight into the mechanisms of SCA and potentially help target the development of novel drug therapies. Few studies to date have examined genetic risk factors among those of African descent. We propose to systematically investigate the genetic basis of SCA risk among those of African descent, focusing on both rare and common genetic variation in candidate loci selected from biologically important molecular pathways involved in rhythmogenesis, using a targeted sequencing approach. Specifically, we will sequence approximately 100 loci among 1500 African American cases and matched controls, selected from the following sets of candidate genes: genes associated with (1) SCA among those of European descent; (2) intermediate determinants of SCA, such as cardiac conduction and repolarization as measured by the surface EKG (QRS and QT intervals); and (3) Mendelian arrhythmic syndromes that lead to SCA. Beyond establishing statistical associations, we will functionally dissect the role of the genes and variants associated with SCA. We will determine the spatial and temporal distribution of the identified transcripts across a range of developmental and post-natal stages in mice through both whole mount RNA in situ analyses and sectioning of embryonic and postnatal heart. We will use zebrafish to test the hypothesis that titration of selected gene candidates during development will compromise the genesis or function of cardiovascular components. For the identified coding variation, we will compare the capacities of human RNAs containing identified coding variation with their non-variant counterparts to rescue MO-induced effects, and will similarly assay the effects of over-expression. This application represents a multi-center collaborative effort to efficiently link advances in genomics, statistical genetics, and bioinformatics, with new and existing biologic and clinical material to identify genetic determinants of SCD among African Americans. Importantly, we will use model organisms to translate genetic associations into functional studies, to elucidate the roles played by these genes in cardiac electrophysiology and arrhythmias.