Genomics of Sudden Cardiac Arrest Among African Americans

非裔美国人心脏骤停的基因组学

基本信息

批准号：
8713423
负责人：
Nona Sotoodehnia
金额：
$ 64.52万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-17 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8713423
关键词：
Address Affect African African American Animal Model Architecture Arrhythmia Autonomic nervous system Bioinformatics Biological Assay Biology Candidate Disease Gene Cardiac Cardiology Cardiovascular Physiology Cardiovascular system Clinical Code Complex Consensus Data Analyses Development Discipline Disease Electrocardiogram Electrophysiology (science)Embryo Environmental Risk Factor European Functional RNA Functional disorder Gene Transfer Techniques General Population Genes Genetic Genetic Determinism Genetic Models Genetic Predisposition to Disease Genetic Variation Genomics Heart Heart Arrest Human In Situ Inherited Injection of therapeutic agent Investigation Lead Light Link Measures Methods Modeling Molecular Molecular Genetics Mus National Heart, Lung, and Blood Institute Pathway interactions Pharmacotherapy Play Population Positioning Attribute Predisposition Prevention Public Health RNA Research Risk Role Specimen Staging Stratification Structure Sudden Death Surface Syndrome Technology Testing Titrations Transcript Transgenic Organisms Translating Variant Zebrafish base clinical material cost drug development genetic association genetic risk factor genetic variant genome wide association study insight novel novel strategies postnatal rare variant trait

项目摘要

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.

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，他们的心脏骤停风险高于一般人群，而且生存率很差。虽然环境因素显然会导致 SCA 风险，但家族聚集性研究和遗传性心律失常分子遗传学的进展表明，遗传因素导致普通人群对 SCA 易感性。识别这些遗传因素将有助于深入了解 SCA 的机制，并可能有助于开发新的药物疗法。迄今为止，很少有研究检查非洲人后裔的遗传风险因素。我们建议系统地研究非洲人后裔 SCA 风险的遗传基础，重点关注候选位点的罕见和常见遗传变异，这些候选位点选自参与节律发生的生物学重要分子途径，并采用靶向测序方法。具体来说，我们将对 1500 个非洲裔美国人病例和匹配对照中的大约 100 个基因座进行测序，这些基因座选自以下候选基因组： (1) 欧洲血统中与 SCA 相关的基因； (2) SCA 的中间决定因素，例如通过表面 EKG 测量的心脏传导和复极（QRS 和 QT 间期）； (3) 导致 SCA 的孟德尔心律失常综合征。除了建立统计关联之外，我们还将从功能上剖析与 SCA 相关的基因和变异的作用。我们将通过全RNA原位分析以及胚胎和出生后心脏切片来确定已识别转录本在小鼠一系列发育和出生后阶段的空间和时间分布。我们将使用斑马鱼来检验这样的假设：在发育过程中对选定的候选基因进行滴定会损害心血管成分的起源或功能。对于已识别的编码变异，我们将比较含有已识别编码变异的人类RNA与其非变异对应物拯救MO诱导效应的能力，并将类似地测定过度表达的影响。该应用代表了一项多中心合作努力，旨在有效地将基因组学、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，我们将使用模型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发挥的作用。