Genome-wide study of sudden cardiac arrest in the community

社区心脏骤停的全基因组研究

• 批准号: 7932176
• 负责人: DAVID Stuart SISCOVICK
• 金额: $ 174.34万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7932176
• 关键词: Accounting; African American; American; Architecture; Arrhythmia; Atherosclerosis; Basic Science; Blood; Blood Pressure; Candidate Disease Gene; Cardiac; Cardiology; Cardiovascular Diseases; Cardiovascular system; Clinical; Cohort Studies; Communities; Complement; County; DNA; Data; Data Set; Development; Diabetes Mellitus; European; Event; Family history of; Frequencies; Future; Gene Frequency; Genes; Genetic; Genetic Materials; Genetic Variation; Genome; Genomics; Genotype; Health; Heart Arrest; Heart failure; Human; Human Genome; Inherited; Intervention; Lipids; Maps; Molecular; Molecular Genetics; Myocardial Infarction; Nucleic Acid Regulatory Sequences; Pacific Northwest; Pathway interactions; Pattern; Pharmacotherapy; Phenotype; Population; Population Control; Predisposition; Research Design; Resources; Risk; Sample Size; Sampling; Scanning; Signal Transduction; Single Nucleotide Polymorphism; Site; Source; Stratification; Structure; Variant; Ventricular Fibrillation; Washington; Work; base; cardiovascular disorder epidemiology; cardiovascular risk factor; case control; cost; design; follow-up; genetic association; genome wide association study; genome-wide; insight; mortality; novel; population based; public health relevance; repository; sound

DESCRIPTION (provided by applicant): There is mounting evidence from studies of familial aggregation, candidate genes, and the molecular genetics of inherited arrhythmias that genetic variation influences susceptibility to sudden cardiac arrest (SCA), but the genetic architecture of SCA in the community remains unknown. This is a final submission of a revised application to identify novel associations (main effects) of common genetic variation across the genome with SCA, using a case-control, genome-wide association study (GWAS), design. We take advantage of available DNA from a large, population-based study of SCA from Seattle and King County (Washington); and, we use existing whole genome scan (WGS) data for controls. Among European Americans (EAs), we will conduct a GWAS of 2500 SCA cases and 7500 controls (step 1), followed by fine mapping of 100 genomic regions among 2500 SCA cases and 2500 controls (step 2); and replication in an independent sample of 1000 SCA cases and 1000 controls (step 3). We will obtain a WGS on 2500 SCA cases included in the Cardiac Arrest Blood Study - Repository (CABS-R) and 750 controls from the Cardiac Arrest Blood Study (CABS). We use existing WGS data from 600 controls (non-cases) from the Heart Attack Risk in Puget Sound (HARPS) Study and 6150 controls from the Atherosclerosis Risk in Communities (ARIC) study. Using WGS data from the Affymetrix 6.0 array, we will examine the associations of 700k single nucleotide polymorphisms (SNPs) with SCA to identify 100 genomic regions, based upon the "top hit" p-values, in EAs (step 1). Using an Illumina Bead Array, we will genotype 1536 SNPs, including approximately 15 SNPs from each of the 100 genomic regions from step 1, in 2500 EA cases and 2500 EA controls (step 2). Finally, we will replicate the findings from steps 1 and 2 (for those SNPs with a p-value < 0.0000014) using an independent sample of 1000 EA cases and 1000 EA controls (step 3). We will frequency match the selection of controls used in the GWAS (step 1) to the population (allelic) structure of the SCA cases; and, we will use genomic control in step 2 to minimize bias from population stratification. Given the large sample sizes and the three step design, we will have >80% statistical power to detect modest size genetic effects, while limiting the expected number of false positive associations. While underpowered, we include an exploratory WGS of 400 African-American (AA) SCA cases from the CABS-R and 900 AA controls (with available WGS data) from ARIC that also will provide a resource for future collaborative efforts. The identification of genetic variation across the genome associated with SCA using a large, case-control, GWAS followed by fine mapping and replication will minimize false negative and positive associations and provide insight into the mechanisms of SCA that will help to target interventions to reduce mortality from SCA. PUBLIC HEALTH RELEVANCE: There is mounting evidence that family history influences the risk of sudden cardiac arrest (SCA), a devastating cardiac event that accounts for 10% of total mortality in the US; however, the variation in the human genome associated with SCA remains unknown. We will investigate variation throughout the human genome to identify novel genes that influence SCA. The study results will provide insight into the molecular mechanisms of SCA and potentially help target the development of novel drug therapies to reduce mortality from SCA.

描述（由申请人提供）：从家族聚集，候选基因和遗传性心律不齐的分子遗传学的研究中有越来越多的证据，遗传变异会影响对心脏骤停（SCA）的易感性，但是社区中SCA的遗传结构仍然不明。这是修订应用程序的最终提交，以使用病例对照，全基因组范围的关联研究（GWAS），设计，确定整个基因组常见遗传变异的新型关联（主要影响）。我们利用来自西雅图和金县（华盛顿）的大型，基于人群的SCA研究的可用DNA；而且，我们使用现有的整个基因组扫描（WGS）数据进行控件。在欧美人（EAS）中，我们将进行2500例SCA病例和7500个对照的GWA（步骤1），然后在2500例SCA病例和2500个对照中对100个基因组区域进行精细映射（步骤2）；并在1000个SCA病例和1000个对照的独立样本中复制（步骤3）。我们将在心脏骤停研究中包括的2500例SCA病例（CABS -R）和心脏骤停血液研究（CABS）的750个对照中获得WGS。我们使用普吉特海湾（HARPS）研究中心脏病发作风险的600个控件（非CASE）的现有WGS数据以及社区（ARIC）研究中动脉粥样硬化风险的6150个控制。使用来自Affymetrix 6.0阵列的WGS数据，我们将研究700K单核苷酸多态性（SNP）与SCA的关联，以鉴定100个基因组区域，基于EAS中的“最高点击” P值（步骤1）。使用Illumina珠阵列，我们将在2500个EA病例和2500个EA对照中（步骤2）中的1536个基因型SNP，包括来自步骤1的100个基因组区域的大约15个SNP。最后，我们将使用1000个EA案例和1000个EA控件的独立样本（步骤3）复制步骤1和2（对于具有p值<0.0000014的SNP）的发现（步骤3）。我们将频率匹配GWAS中使用的控件（步骤1）与SCA病例的种群（等位基因）结构相匹配；而且，我们将在第2步中使用基因组控制来最大程度地减少人口分层的偏差。考虑到大型样本量和三个步骤设计，我们将具有> 80％的统计能力来检测适度的遗传效应，同时限制了误报阳性相关的预期数量。虽然能力不足，但我们包括CABS-R的400名非裔美国人（AA）SCA案件的探索性WGS和ARIC的900个AA控制（带有可用的WGS数据），还将为将来的协作工作提供资源。使用大型的病例对照，GWAS，然后进行精细的映射和复制，鉴定与SCA相关的基因组遗传变异将最小化假阴性和正相关，并提供对SCA机制的见解，这将有助于靶向靶向干预措施以降低SCA的死亡率。公共卫生相关性：持续的证据表明，家族史会影响心脏骤停的风险（SCA），这是一项毁灭性的心脏事件，占美国总死亡率的10％；但是，与SCA相关的人类基因组的变化仍然未知。我们将研究整个人类基因组的变异，以鉴定影响SCA的新基因。该研究结果将为SCA的分子机制提供洞察力，并有助于针对新型药物疗法的发展以降低SCA的死亡率。