Genetics of Atrial Fibrillation

心房颤动的遗传学

• 批准号: 7820906
• 负责人: John Barnard
• 金额: $ 3.72万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2011-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7820906
• 关键词: 4q25; Age; American; Arrhythmia; Atrial Fibrillation; Biological Assay; Blood; Candidate Disease Gene; Case-Control Studies; Chromosomes; Chromosomes, Human, Pair 1; Clinic; Complex; Control Groups; Copy Number Polymorphism; Coronary; Coronary Arteriosclerosis; Custom; DNA; DNA Resequencing; DNA Sequence Rearrangement; Data; Diagnostic tests; Disease; Elderly; Environment; Etiology; Exons; Family; Future; Gender; Gene Bank; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genetic Variation; Genome; Genomics; Genotype; Germany; Goals; Haplotypes; Heart Atrium; Heart Diseases; Iceland; Individual; Institution; Introns; Linkage Disequilibrium; Literature; Logistic Regressions; Meta-Analysis; Methods; Microarray Analysis; Mutation; Myocardial Infarction; Odds Ratio; Pathogenesis; Patients; Pharmaceutical Preparations; Phenotype; Polymorphism Analysis; Population; Population Control; Predisposition; Prevalence; Probability; Reporting; Research; Risk; Risk Factors; Sample Size; Sampling; Single Nucleotide Polymorphism; Slide; Somatic Mutation; Specific qualifier value; Stratification; Stroke; Testing; Therapeutic Intervention; Tissue Banking; Tissue Banks; Tissues; Validation; Variant; Weight; base; case control; clinical application; cohort; comparative; connexin 40; design; early onset; genetic association; genetic variant; genome wide association study; genome-wide; genome-wide analysis; high risk; insertion/deletion mutation; insight; lifetime risk; meetings; mortality; novel; preempt; prevent; programs; promoter; protein function; trait

DESCRIPTION (provided by applicant): Atrial fibrillation (AF) is a complex arrhythmia that afflicts more than 2.3 million Americans. Most prevalent in the elderly, AF is associated with a 2-fold higher risk for mortality. AF is the most potent risk factor for stroke in the elderly and the most common cause of cardioembolic stroke. Despite intensive study, AF treatment options remain suboptimal. Recent data support the hereditability of AF and suggest a complex genetic basis for common AF. Identification of genes that increase risk for AF may have important clinical applicability. The overall goal of our research program is to perform an unbiased whole genome association study to identify genetic variants associated with AF and to gain insight into the pathogenesis of AF. This will promote the identification of new targets for therapeutic intervention and/or diagnostic tests to predict and potentially prevent AF. DNA will be derived from AF patient and control samples collected in DNA/blood/tissue banks at the Cleveland Clinic and collaborating institutions. Our initial case cohort will be comprised of subjects with Lone AF (AF without coronary, valvular, or other structural heart disease), a tightly defined and much more homogeneous phenotype than previously studied mixed etiology AF populations, and likely to have the most direct genetic associations. Using microarray technology, 550,000 specific single nucleotide polymorphisms (SNPs) will be assessed in each of 600 lone AF subjects, 300 matched heart disease-free control subjects, and 1800 publicly accessible genotyped population controls. We will perform multivariate logistic regression to identify the top SNPs associated with AF for subsequent validation. These SNPs will be validated in a 1,536 SNP custom genotyping assay performed with an independent population of 600 subjects with early onset AF (meeting criteria for lone AF) and 600 disease-free population controls. Because most patients with AF have some form of structural heart disease, we will begin to extend the 1,536 SNP analysis to other AF subjects with structural heart disease, specifically well-defined coronary artery disease. We will analyze groups separately, as well as jointly, pooling data from the 550K and 1536 SNP assays from all studies, and perform multiple regression and novel testing strategies to minimize population stratification in order to identify SNPs significantly associated with lone AF and AF with heart disease. We will resequence the genes in the vicinity of the top 4 highly AF-associated SNPs in 48 patients to identify new variations, gain insight into AF-associated haplotypes, and potentially identify causative variations that could cause changes in protein function or expression levels. We will also evaluate the prevalence of copy number variations in lone AF, as well as somatic mutations and copy number variations in atrial tissue from a subset of patients with AF. Future benefits of these studies include increased understanding of the mechanisms of AF pathogenesis and the potential ability to develop personalized, gene-specific diagnostic tests and drugs that will aid in predicting, preventing and treating AF and its associated risks for stroke. Project Narrative: Atrial fibrillation (AF) afflicts more than 2.3 million Americans and is associated with a 2-fold higher risk for mortality and a 5-7 fold increased risk of stroke, making AF one of the most potent risk factors for stroke in the elderly and the most common cause of cardioembolic stroke. Despite intensive study for the past decade, AF treatment options remain suboptimal. Future benefits of the proposed studies to identify genetic variants that increase risk for AF include increased understanding of the mechanisms of AF pathogenesis and the potential ability to develop personalized, gene-specific diagnostic tests and drugs that will aid in predicting, preventing and treating AF and its associated risk for stroke.

描述（由申请人提供）：房颤（AF）是一种复杂的心律失常，困扰着230多万美国人。AF在老年人中最常见，死亡风险高2倍。AF是老年人卒中的最强风险因素，也是心源性卒中的最常见原因。尽管进行了深入研究，但房颤治疗方案仍不理想。最近的数据支持遗传性房颤，并提出了一个复杂的遗传基础，常见的AF。识别基因，增加房颤的风险可能有重要的临床应用。我们研究计划的总体目标是进行无偏倚的全基因组关联研究，以识别与AF相关的遗传变异，并深入了解AF的发病机制。这将促进识别用于治疗干预和/或诊断测试的新靶点，以预测和潜在预防AF。DNA将来自AF患者和对照样本，收集DNA/血液/克利夫兰诊所和合作机构的组织库。我们的初始病例队列将由孤立性AF（无冠状动脉、瓣膜或其他结构性心脏病的AF）受试者组成，这是一种严格定义的表型，比先前研究的混合病因AF人群更同质，可能具有最直接的遗传相关性。使用微阵列技术，将在600名单独的AF受试者、300名匹配的无心脏病对照受试者和1800名公开获得的基因分型人群对照中评估550，000个特异性单核苷酸多态性（SNP）。我们将进行多变量逻辑回归，以确定与AF相关的最佳SNP，用于后续验证。这些SNP将在1，536 SNP定制基因分型试验中进行验证，该试验使用600例早发性AF受试者（符合孤立性AF标准）和600例无疾病人群对照的独立人群。由于大多数房颤患者患有某种形式的结构性心脏病，我们将开始将1,536个SNP分析扩展到其他患有结构性心脏病的房颤受试者，特别是明确定义的冠状动脉疾病。我们将分别和联合分析各组，汇总所有研究的550 K和1536 SNP检测数据，并进行多元回归和新的测试策略，以最大限度地减少人群分层，以识别与孤立性AF和AF伴心脏病显著相关的SNP。我们将对48例患者中前4个高度AF相关SNP附近的基因进行重新测序，以确定新的变异，深入了解AF相关单倍型，并可能确定可能导致蛋白质功能或表达水平变化的致病变异。我们还将评估孤立性房颤中拷贝数变异的患病率，以及房颤患者亚组心房组织中的体细胞突变和拷贝数变异。这些研究的未来益处包括增加对房颤发病机制的理解，以及开发个性化、基因特异性诊断测试和药物的潜在能力，这些测试和药物将有助于预测，预防和治疗房颤及其相关的中风风险。项目叙述：心房颤动（AF）困扰着超过230万美国人，并且与死亡风险增加2倍和中风风险增加5-7倍相关，使AF成为老年人中风的最有效风险因素之一，也是心源性栓塞性中风的最常见原因。尽管在过去十年中进行了深入研究，但AF治疗选择仍然不理想。这些旨在识别增加房颤风险的遗传变异的拟议研究的未来益处包括增加对房颤发病机制的理解，以及开发个性化、基因特异性诊断测试和药物的潜在能力，这些测试和药物将有助于预测、预防和治疗房颤及其相关的中风风险。