Genetics of Atrial Fibrillation

描述（由申请人提供）：心房颤动 (AF) 是一种复杂的心律失常，困扰着超过 230 万美国人。房颤在老年人中最为常见，其死亡风险增加两倍。房颤是老年人中风最有力的危险因素，也是心源性中风的最常见原因。尽管进行了大量研究，房颤治疗方案仍然不够理想。最近的数据支持 AF 的遗传性，并表明常见 AF 具有复杂的遗传基础。鉴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公正的全基因组关联研究，以确定与 AF 相关的遗传变异，并深入了解 AF 的发病机制。这将促进治疗干预和/或诊断测试新靶点的识别，以预测和潜在预防 AF。 DNA 将来源于克利夫兰诊所和合作机构的 DNA/血液/组织库中收集的 AF 患者和对照样本。我们最初的病例队列将由患有孤立性房颤（没有冠状动脉、瓣膜或其他结构性心脏病的房颤）的受试者组成，这是一种比之前研究的混合病因学房颤人群严格定义且更加同质的表型，并且可能具有最直接的遗传关联。使用微阵列技术，将在 600 名孤独 AF 受试者、300 名匹配的无心脏病对照受试者和 1800 名公开基因型对照人群中每人评估 550,000 个特定单核苷酸多态性 (SNP)。我们将进行多变量逻辑回归来识别与 AF 相关的顶级 SNP，以便进行后续验证。这些 SNP 将在 1,536 个 SNP 定制基因分型测定中得到验证，该测定对 600 名早发 AF 受试者（符合孤立性 AF 的标准）和 600 名无病对照人群进行独立人群进行。由于大多数 AF 患者患有某种形式的结构性心脏病，因此我们将开始将 1,536 SNP 分析扩展到其他患有结构性心脏病（特别是明确定义的冠状动脉疾病）的 AF 受试者。我们将分别或联合分析各组，汇集所有研究中 550K 和 1536 个 SNP 测定的数据，并执行多元回归和新的测试策略，以最大限度地减少群体分层，从而识别与孤立性 AF 和 AF 合并心脏病显着相关的 SNP。我们将对 48 名患者中 4 个与 AF 高度相关的 SNP 附近的基因进行重新测序，以识别新的变异，深入了解 AF 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的拷贝数变异的患病率，以及一部分房颤患者的心房组织的体细胞突变和拷贝数变异。这些研究的未来好处包括加深对房颤发病机制的了解，以及开发个性化、基因特异性诊断测试和药物的潜在能力，以帮助预测、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，其死亡风险增加 2 倍，中风风险增加 5-7 倍，使 AF 成为老年人中风最有力的危险因素之一，也是心源性中风的最常见原因。尽管过去十年进行了深入研究，房颤治疗方案仍然不够理想。拟议的研究旨在确定增加房颤风险的遗传变异，其未来的好处包括增加对房颤发病机制的了解，以及开发个性化、基因特异性诊断测试和药物的潜在能力，以帮助预测、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.