Genetics of Atrial Fibrillation

描述(申请人提供)：房颤(房颤)是一种复杂的心律失常，困扰着超过230万美国人。房颤在老年人中最常见，与死亡率高2倍的风险有关。房颤是老年人卒中最重要的危险因素，也是心源性卒中最常见的原因。尽管进行了密集的研究，但房颤的治疗方案仍然不太理想。最近的数据支持房颤的遗传性，并提示常见的房颤存在复杂的遗传基础。确定增加房颤风险的基因可能具有重要的临床应用价值。我们研究计划的总体目标是进行一项无偏见的全基因组关联研究，以确定与房颤相关的遗传变异，并深入了解房颤的发病机制。这将促进为治疗干预和/或诊断测试确定新的靶点，以预测和潜在地预防房颤。DNA将来自在克利夫兰诊所和合作机构的DNA/血液/组织库中收集的房颤患者和对照样本。我们最初的病例队列将包括患有孤立性房颤(没有冠状动脉、瓣膜或其他结构性心脏病的房颤)的受试者，这是一种定义严格且比之前研究的混合病因房颤人群更同质的表型，可能具有最直接的遗传联系。利用微阵列技术，将在600名孤独的房颤受试者、300名匹配的无心脏病对照受试者和1800名可公开获得的基因分型对照人群中的每一人中评估550,000个特定的单核苷酸多态(SNPs)。我们将进行多变量Logistic回归，以确定与房颤相关的最高SNP，以供后续验证。这些SNP将在1,536个SNP定制基因分型分析中得到验证，该分析针对600名早发性房颤(符合孤立性房颤标准)的独立人群和600名无病人群对照进行。由于大多数房颤患者都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患者，特别是明确定义的冠状动脉疾病。我们将单独以及联合分析来自所有研究的550K和1536个SNP分析的数据，并执行多元回归和新的测试策略以最大限度地减少人群分层，以确定与孤立性房颤和伴有心脏病的房颤显著相关的SNP。我们将对48名患者前4个与房颤高度相关的SNPs附近的基因进行重新测序，以确定新的变异，深入了解与房颤相关的单倍型，并潜在地识别可能导致蛋白质功能或表达水平变化的致病变异。我们还将评估孤立性房颤患者中拷贝数变异的流行率，以及部分房颤患者心房组织中的体细胞突变和拷贝数变异。这些研究的未来好处包括增加对房颤发病机制的了解，以及开发个性化的、基因特异性的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。项目简介：房颤(AF)困扰着230多万美国人，并与死亡率增加2倍和中风风险增加5-7倍有关，使房颤成为老年人中风最有效的危险因素之一，也是心源性中风的最常见原因。尽管在过去的十年中进行了大量的研究，但房颤的治疗方案仍然不够理想。为识别增加房颤风险的基因变异而进行的拟议研究的未来好处包括增加对房颤发病机制的了解，以及开发个性化的、基因特异性的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。

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.