Identification of common genetic variants for atrial fibrillation and PR interval

房颤和 PR 间期常见遗传变异的识别

• 批准号: 7613151
• 负责人: Emelia J. Benjamin
• 金额: $ 86.18万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-15 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7613151
• 关键词: Age; Age related macular degeneration; Atrial Fibrillation; Biological Models; Body mass index; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Communities; Congestive Heart Failure; Coronary heart disease; Data; Data Sources; Dementia; Developmental Biology; Diabetes Mellitus; Disease; EKG P Wave; Electrophysiology (science); Environment; Europe; Family; Framingham Heart Study; Future; Gene Mutation; General Hospitals; General Population; Genes; Genetic; Genetic Epistasis; Genetic Screening; Genetic Variation; Genotype; Health; Heart; Heart failure; Human; Human Genome; Hypertension; Individual; Inherited; Ion Channel; Knowledge; Life; Massachusetts; Meta-Analysis; Morbidity - disease rate; Morphology; Mutation; Parents; Pathogenesis; Pathway interactions; Phenotype; Population; Prevalence; Public Health; Recording of previous events; Reporting; Research Personnel; Risk; Risk Factors; Role; Series; Single Nucleotide Polymorphism; Source; Stratification; Stroke; Testing; Time; Translations; Triglycerides; United States; Variant; Zebrafish; base; cohort; disorder risk; genetic epidemiology; genetic variant; genome wide association study; heart rhythm; human disease; indexing; insight; mortality; multidisciplinary; novel; offspring; public health relevance; sex; trait

DESCRIPTION (provided by applicant): Atrial fibrillation (AF) increases the risk of stroke, heart failure, dementia and death. The prevalence of AF doubles for each advancing decade of life and multiple data sources suggest that the prevalence of AF is increasing over time. It is estimated that the U.S. prevalence of AF will rise from 2.3 million in 2001 to about 6 to 12 million in 2050. The risk factors for AF are multi-factorial, and include well-known conditions such hypertension and heart failure as well as less familiar traits such as P wave morphology and PR interval. Traditionally, genetic contributions to AF have been considered rare, but in the past five years there have been increasing data demonstrating that all forms of AF, and particularly lone AF, are heritable. Although mutations have been identified in a series of ion channels in families and individuals with AF, these variants are rare causes of the disease. Thus, there remains a significant, but as yet, unexplained genetic basis for AF. The advent of the human genome and HapMap projects and high-throughput genotyping has fundamentally accelerated the ability to discover the genetic contribution to common variation in human disease. Genome-wide association studies (GWAS) have uncovered common single nucleotide polymorphisms (SNPs) underlying risk for diseases such as diabetes and coronary heart disease, and recently AF, as well as quantitative phenotypes such as QT interval. Hence, understanding the role of common genetic variation in AF is of paramount importance and recently achievable. We hypothesize that common variants contribute to variability in AF risk and PR interval in the general population. The specific aims are: Aim 1. To perform a meta-analysis of GWAS to identify common variants predisposing to AF using MGH, Framingham Heart Study (FHS), Rotterdam and Cardiovascular Health Study (CHS). Aim 2. To conduct a meta-analysis of GWAS with PR interval, a quantitative intermediate phenotype for AF, in the FHS, Rotterdam, CHS, MONICA/KORA and Gutenberg Heart (GHS) Studies. Aim 3. To replicate the top 250 AF SNPs and top 100 PR interval SNPs in six additional cohorts. Aim 4. To study mechanisms of SNPs replicated in Aim 3 in cellular and zebrafish model systems. Aim 5. To examine gene-environment (GEI) and gene-gene (epistasis) interactions. In summary, AF is a major source of morbidity and mortality in the population. We bring together a multi- institutional, multi-national team with expertise in AF, genetic epidemiology, statistical genetics, cellular electrophysiology and developmental biology. We propose leveraging existing cohorts and six ongoing GWAS to uncover the genetic contribution to AF and PR interval in the community. The multi-disciplinary breadth of the project will allow translation of the GWAS findings into basic insights of the cellular mechanisms underlying AF. Identification of genes and pathways involved in AF will provide opportunities to advance knowledge of the pathogenesis of AF, and provide novel targets for risk stratification and future therapies. PUBLIC HEALTH RELEVANCE Atrial fibrillation, a common, irregular heart rhythm, increases the risk of stroke and death. Although it is known that atrial fibrillation can be inherited, the specific genetic factors contributing to atrial fibrillation are largely unknown. Investigators from the Framingham Heart Study, Massachusetts General Hospital, Rotterdam, Cardiovascular Health Study and Vanderbilt propose to examine the results of large genetic screening studies, and test the most important findings in other studies in the United States and Europe in order to discover genetic factors contributing to risk of atrial fibrillation.

描述（由申请人提供）：心房颤动 (AF) 会增加中风、心力衰竭、痴呆和死亡的风险。每增长十年，房颤的患病率就会翻一番，并且多个数据源表明，房颤的患病率随着时间的推移而增加。据估计，美国房颤患病率将从 2001 年的 230 万上升到 2050 年的约 6 至 1200 万。房颤的危险因素是多因素的，包括高血压和心力衰竭等众所周知的疾病，以及 P 波形态和 PR 间期等不太熟悉的特征。传统上，遗传因素对房颤的影响很少见，但在过去五年中，越来越多的数据表明，所有形式的房颤，尤其是孤立性房颤，都是可遗传的。尽管已经在房颤家族和个体的一系列离子通道中发现了突变，但这些变异是导致该疾病的罕见原因。因此，房颤仍然存在重要但至今无法解释的遗传基础。人类基因组和单体型图项目以及高通量基因分型的出现从根本上加速了发现人类疾病常见变异的遗传因素的能力。全基因组关联研究 (GWAS) 发现了常见的单核苷酸多态性 (SNP)，这些单核苷酸多态性 (SNP) 是糖尿病、冠心病和最近的房颤等疾病的潜在风险，以及 QT 间期等定量表型。因此，了解 AF 中常见遗传变异的作用至关重要，并且最近已经实现。我们假设常见变异会导致一般人群中 AF 风险和 PR 间期的变异。具体目标是： 目标 1. 使用 MGH、弗雷明汉心脏研究 (FHS)、鹿特丹和心血管健康研究 (CHS) 进行 GWAS 荟萃分析，以识别易患 AF 的常见变异。目标 2. 在 FHS、鹿特丹、CHS、MONICA/KORA 和古腾堡心脏 (GHS) 研究中对 PR 间期（AF 的定量中间表型）进行 GWAS 荟萃分析。目标 3. 在另外 6 个队列中复制前 250 个 AF SNP 和前 100 个 PR 间期 SNP。目标 4. 研究目标 3 中的 SNP 在细胞和斑马鱼模型系统中复制的机制。目标 5. 检查基因-环境 (GEI) 和基因-基因（上位性）相互作用。总之，AF 是人群发病率和死亡率的主要来源。我们汇集了一支多机构、跨国团队，拥有房颤、遗传流行病学、统计遗传学、细胞电生理学和发育生物学方面的专业知识。我们建议利用现有队列和六个正在进行的 GWAS 来揭示遗传对社区 AF 和 PR 间期的影响。该项目的跨学科广度将使 GWAS 研究结果转化为 AF 细胞机制的基本见解。鉴定与 AF 相关的基因和通路将为增进对 AF 发病机制的了解提供机会，并为风险分层和未来治疗提供新的靶点。公共卫生相关性 心房颤动是一种常见的不规则心律，会增加中风和死亡的风险。尽管已知心房颤动可以遗传，但导致心房颤动的具体遗传因素在很大程度上尚不清楚。来自弗雷明汉心脏研究中心、鹿特丹马萨诸塞州总医院、心血管健康研究中心和范德比尔特大学的研究人员提议检查大型基因筛查研究的结果，并测试美国和欧洲其他研究中最重要的发现，以发现导致心房颤动风险的遗传因素。