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：
8532969
负责人：
Nona Sotoodehnia
金额：
$ 63.61万
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/8532969
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 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，尤其是在心脏骤停风险高于一般人群的非裔美国人中，生存率较差。尽管环境因素显然有助于SCA风险，但家族聚集研究和遗传性心律不齐分子遗传学的进步表明，遗传因素赋予普通人群中SCA的易感性。确定这些遗传因素将提供有关SCA机制的洞察力，并有助于针对新型药物疗法的发展。迄今为止，很少有研究检查了非洲血统中的遗传危险因素。我们建议在非洲血统中系统地研究SCA风险的遗传基础，重点是使用靶向测序方法，从涉及节律发生的生物学上重要的分子途径中选择的候选基因群中稀有和常见的遗传变异。具体而言，我们将在1500个非裔美国人病例中序列约100个基因座和匹配的对照组，从以下候选基因中选择：与（1）SCA相关的基因中的欧洲血统中的基因；（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化（QRS和QT间隔）；（3）导致SCA的孟德尔心律失常综合征。除了建立统计关联外，我们还将在功能上剖析与SCA相关的基因和变体的作用。我们将通过整个RNA的原位分析以及胚胎和产后心脏的整个RNA在小鼠的一系列发育和产后阶段确定所鉴定的转录本的空间和时间分布。我们将使用斑马鱼来检验以下假设：发育过程中选定的基因候选物的滴定将损害心血管成分的起源或功能。对于已识别的编码变化，我们将比较含有识别的编码变化的人RNA的能力与其非变化的对应物来挽救MO诱导的效果，并将类似地测定过表达的效果。该应用程序代表了多中心的协作努力，旨在有效地将基因组学，统计遗传学和生物信息学的进步与新的和现有的生物学和临床材料联系起来，以识别非裔美国人中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不齐中所起的作用。