Genetics of Atrial Fibrillation

心房颤动的遗传学

• 批准号: 7841097
• 负责人: John Barnard
• 金额: $ 25.08万
• 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: 2009-07-15 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7841097
• 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）：心房颤动（AF）是一种复杂的心律不齐，折磨了超过230万美国人。 AF在老年人中最普遍，与死亡率的风险高2倍。 AF是老年人中风的最有效危险因素，也是心脏符号中风的最常见原因。尽管进行了深入的研究，但AF治疗方案仍然是最佳选择。最近的数据支持AF的遗传性，并为共同AF提出了复杂的遗传基础。鉴定增加AF风险的基因可能具有重要的临床适用性。我们的研究计划的总体目标是进行无偏见的整个基因组关联研究，以识别与AF相关的遗传变异，并深入了解AF的发病机理。这将促进对治疗干预和/或诊断测试的新目标的鉴定，以预测和预防AF。 DNA将来自AF患者，并在克利夫兰诊所和协作机构的DNA/血液/组织库中收集的对照样品。我们的最初病例队列将由具有唯一AF的受试者（无冠状动脉，瓣膜或其他结构性心脏病）组成，比以前研究的混合病因AF种群紧密定义，更均匀的表型，并且可能具有最直接的遗传相关性。使用微阵列技术，将评估550,000个特定的单核苷酸多态性（SNP）（SNP），在600名单独的AF受试者中，300名匹配的无心脏病对照受试者和1800个公开可访问的基因型人群控制中评估。我们将执行多元逻辑回归，以识别与AF关联的顶级SNP，以进行后续验证。这些SNP将在1,536个SNP自定义基因分型测定中进行验证，该测定法具有600名患者的独立人群，具有早期发作AF（满足孤独AF的符合标准）和600个无疾病的人群控制。由于大多数AF患者具有某种形式的结构性心脏病，因此我们将开始将1,536个SNP分析扩展到患有结构性心脏病的其他AF受试者，特别是定义明确的冠状动脉疾病。我们将分别分析组以及共同分析来自所有研究的550K和1536 SNP分析的数据，并执行多重回归和新型测试策略，以最大程度地减少人口分层，以识别与心脏病与孤独AF和AF显着相关的SNP。我们将在48名患者的前4个高度AF相关SNP附近的基因重新陈述，以鉴定新的变异，深入了解与AF相关的单倍型，并有可能识别可能导致蛋白质功能或表达水平变化的致病变异。我们还将评估孤独AF中拷贝数变化的患病率，以及来自AF患者子集的房屋中房组织中的体细胞突变和拷贝数变化。这些研究的未来好处包括对AF发病机理机制的了解以及开发个性化的，基因特异性诊断测试的潜在能力以及将有助于预测，预防和治疗其中风的风险的药物。项目叙述：心房颤动（AF）折磨了超过230万美国人，与死亡率的风险高2倍，5-7倍增加中风的风险，使AF成为老年人中风最有效的风险因素之一，也是最常见的心脏人物中风原因。尽管在过去十年中进行了深入的研究，但AF治疗方案仍然是最佳选择。拟议研究的未来益处是确定增加AF风险的遗传变异，包括增加对AF发病机理机制的了解以及开发个性化的，基因特异性诊断测试的潜在能力，并有助于预测，预测和治疗其中风的风险。