Genetics of Atrial Fibrillation

心房颤动的遗传学

• 批准号: 8322122
• 负责人: John Barnard
• 金额: $ 38.32万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8322122
• 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 genomics; connexin 40; design; early onset; genetic association; genetic variant; genome wide association study; genome-wide; high risk; insertion/deletion mutation; insight; lifetime risk; meetings; mortality; novel; preempt; prevent; programs; promoter; protein expression; 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。房颤在老年人中最为普遍，其死亡率高出2倍。房颤是老年人中风最重要的危险因素，也是心脏栓塞性中风最常见的原因。尽管有深入的研究，房颤的治疗方案仍然不是最佳的。最近的数据支持房颤的遗传性，并提示常见房颤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适用性。我们的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。这将促进确定治疗干预和/或诊断测试的新靶点，以预测和潜在地预防房颤。DNA将来自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。我们的初始病例队列将由单纯性房颤（无冠状动脉、瓣膜或其他结构性心脏病的房颤）患者组成，与之前研究的混合病因房颤人群相比，这是一种定义严格且更均匀的表型，可能具有最直接的遗传关联。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名公开的基因型人群对照中评估550,000个特定的单核苷酸多态性（snp）。我们将进行多变量逻辑回归，以确定与AF相关的顶级snp，以进行后续验证。这些SNP将在600名早发性房颤（符合单发性房颤标准）和600名无疾病人群对照的独立人群中进行1536个SNP定制基因分型分析。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1536 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。我们将分别或联合分析各组，汇集所有研究的550K和1536 SNP分析数据，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，以确定与单发房颤和房颤合并心脏病显著相关的SNP。我们将对48例患者的前4个高度af相关snp附近的基因进行重测序，以确定新的变异，深入了解af相关的单倍型，并潜在地确定可能导致蛋白质功能或表达水平变化的致病变异。我们还将评估单发房颤中拷贝数变异的患病率，以及房颤患者心房组织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卒中相关风险。项目描述：房颤（AF）折磨着超过230万美国人，与2倍高的死亡率和5-7倍高的中风风险相关，使房颤成为老年人中风最有效的危险因素之一，也是心脏栓塞性中风最常见的原因。尽管在过去的十年中进行了深入的研究，房颤的治疗方案仍然不是最佳的。确定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卒中风险。

项目成果

Left ventricular hypertrophy and antiarrhythmic drugs in atrial fibrillation: impact on mortality.

• DOI: 10.1111/pace.12426
• 发表时间: 2014-10
• 期刊: Pacing and clinical electrophysiology : PACE
• 作者: Chung R;Houghtaling PL;Tchou M;Niebauer MJ;Lindsay BD;Tchou PJ;Chung MK
• 通讯作者: Chung MK

Implantable cardioverter-defibrillator FDA safety advisories: Impact on patient mortality and morbidity.

植入式心律转复除颤器 FDA 安全建议：对患者死亡率和发病率的影响。

• DOI: 10.1016/j.hrthm.2012.07.002
• 发表时间: 2012
• 期刊: Heart rhythm
• 影响因子: 5.5
• 作者: Sengupta,Jay;Kendig,ArthurC;Goormastic,Marlene;Hwang,Eui-Seock;Ching,ElizabethA;Chung,Roy;Lindsay,BruceD;Tchou,PatrickJ;Wilkoff,BruceL;Niebauer,MarkJ;Martin,DavidO;Varma,Niraj;Wazni,Oussama;Saliba,Walid;Kanj,Mohamed;Bh
• 通讯作者: Bh

Left atrial epicardial adiposity and atrial fibrillation.

• DOI: 10.1161/circep.110.957241
• 发表时间: 2010-06
• 期刊: Circulation. Arrhythmia and electrophysiology
• 作者: Batal O;Schoenhagen P;Shao M;Ayyad AE;Van Wagoner DR;Halliburton SS;Tchou PJ;Chung MK
• 通讯作者: Chung MK

Fish oil for atrial fibrillation prevention: can we intervene soon enough to make a difference?

鱼油预防心房颤动：我们能否尽快采取干预措施以发挥作用？

• DOI: 10.1016/j.hrthm.2012.03.005
• 发表时间: 2012
• 期刊: Heart rhythm
• 影响因子: 5.5
• 作者: VanWagoner,DavidR

Aggregate national experience with the wearable cardioverter-defibrillator: event rates, compliance, and survival.

• DOI: 10.1016/j.jacc.2010.04.016
• 发表时间: 2010-07-13
• 期刊: JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
• 影响因子: 24
• 作者: Chung, Mina K.;Szymkiewicz, Steven J.;Shao, Mingyuan;Zishiri, Edwin;Niebauer, Mark J.;Lindsay, Bruce D.;Tchou, Patrick J.
• 通讯作者: Tchou, Patrick J.