Identification of common genetic variants for atrial fibrillation and PR interval

说明(申请人提供)：房颤(房颤)增加中风、心力衰竭、痴呆症和死亡的风险。房颤的患病率随着年龄的增长每十年翻一番，多个数据来源表明房颤的患病率正在随着时间的推移而增加。据估计，美国房颤的患病率将从2001年的230万上升到2050年的约600万到1200万。房颤的危险因素是多因素的，包括众所周知的疾病，如高血压和心力衰竭，以及不太熟悉的特征，如P波形态和PR间期。传统上，对房颤的遗传贡献被认为是罕见的，但在过去的五年里，越来越多的数据表明，所有形式的房颤，特别是单纯性房颤，都是可遗传的。虽然已经在房颤患者的家庭和个人的一系列离子通道中发现了突变，但这些变异是导致这种疾病的罕见原因。因此，房颤仍有一个重要的、但尚未解释的遗传基础。人类基因组和HapMap项目以及高通量基因分型的出现从根本上加快了发现人类疾病常见变异的基因贡献的能力。全基因组关联研究已经发现了常见的单核苷酸多态(SNPs)，以及QT间期等定量表型，这些SNPs是糖尿病和冠心病等疾病的潜在风险，最近还发现了房颤。因此，了解常见的基因变异在房颤中的作用是非常重要的，而且是最近可以实现的。我们假设普通人群中常见的变异导致房颤风险和PR间期的变异性。具体目标是：目的1.利用MGH、Framingham心脏研究(FHS)、鹿特丹和心血管健康研究(CHS)对GWAs进行荟萃分析，以确定诱发房颤的常见变异。目的2.在FHS、鹿特丹、CHS、MONICA/KORA和古登堡心脏(GHS)研究中，对伴有PR间期的房颤患者进行Meta分析。目的3.在另外6个队列中复制房颤前250个SNP和PR间期前100个SNP。目的4.研究AIM 3在细胞和斑马鱼模型系统中复制SNPs的机制。目的5.研究基因-环境(GEI)和基因-基因(上位性)的相互作用。总而言之，房颤是人群发病率和死亡率的主要来源。我们汇集了一支拥有房颤、遗传流行病学、统计遗传学、细胞电生理学和发育生物学专业知识的多机构、多国团队。我们建议利用现有的队列和六个正在进行的GWA来揭示社区中对房颤和PR间期的遗传贡献。该项目的跨学科广度将允许将Gwas的调查结果转化为对房颤基础细胞机制的基本见解。识别与房颤相关的基因和途径将为进一步了解房颤的发病机制提供机会，并为危险分层和未来的治疗提供新的靶点。公共卫生相关性房颤是一种常见的不规则心律，会增加中风和死亡的风险。虽然已经知道房颤是可以遗传的，但导致房颤的特定遗传因素在很大程度上还不清楚。来自鹿特丹马萨诸塞州总医院弗雷明翰心脏研究、心血管健康研究和Vanderbilt的研究人员建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，以发现导致房颤风险的遗传因素。

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.