Positional Cloning and Candidate Gene Approach to Familial Atrial Fibrilation

家族性房颤的定位克隆和候选基因方法

• 批准号: 7655815
• 负责人: Dawood Darbar
• 金额: $ 37.3万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7655815
• 关键词: Action Potentials; Affect; Aging; Alleles; Anti-Arrhythmia Agents; Arrhythmia; Atrial Fibrillation; Biochemical; Biological Assay; Candidate Disease Gene; Cardiac; Chromosomes; Chromosomes, Human, Pair 5; Clinical; Complement; Correlation Studies; DNA Resequencing; Development; Dilated Cardiomyopathy; Disease; Disease Association; EKG P Wave; Epidemic; Family member; Functional disorder; Gap Junctions; Gene Mutation; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genotype; Heart; Heart Atrium; Human; In Vitro; Individual; Inherited; Investigation; Long QT Syndrome; Maintenance; Maps; Molecular; Molecular Target; Morbidity - disease rate; Mutation; Patients; Pharmacotherapy; Phenotype; Population; Potassium Channel; Predisposition; Recombinants; Registries; Reporting; Role; Secondary to; Signal Transduction; Sodium Channel; Sudden infant death syndrome; Syndrome; Techniques; Testing; Therapeutic; Validation; Variant; Ventricular Arrhythmia; clinical phenotype; clinical practice; cohort; common treatment; endophenotype; genetic pedigree; heart rhythm; improved; insight; kindred; mortality; mutation carrier; novel; patch clamp; positional cloning; proband; public health relevance; research study; segregation; success; trafficking; trait; transmission process

DESCRIPTION (provided by applicant): Atrial fibrillation (AF) is the most commonly encountered arrhythmia in clinical practice, reaching epidemic proportions in the aging U.S. population. Most AF is secondary to other conditions but up to 30% of patients have no obvious cause and are said to have "lone" or idiopathic AF. We and others have demonstrated that lone AF has a substantial heritable component and have shown that lone AF is phenotypically and genetically a heterogeneous disorder. It is therefore increasingly appreciated that there may be a familial predisposition to AF, and indeed a number of genetic loci have been described. In addition, mutations in genes encoding cardiac potassium channels and gap junctions have been reported in isolated cases and small kindreds. While inherited forms of AF exist, phenotypic complexity has limited efforts to ascertain mutation carriers and thus identify causal genes. In a large AF kindred, we have mapped a novel locus for AF on chromosome 5 using a prolonged signal-averaged P-wave duration as an intermediate or endophenotype for AF. In Specific Aim 1, we propose to identify the gene responsible for lone AF at the 5p15 locus and assess its contribution to AF in a large cohort of patients with familial, sporadic and typical AF. The human cardiac sodium channel is responsible for the fast depolarization upstroke of the cardiac action potential and is a molecular target for antiarrhythmic drugs some of which are effective in treating atrial arrhythmias. There is mounting evidence supporting the role of SCN5A, the gene encoding the human cardiac sodium channel, in AF. Mutations in SCN5A have been associated with inherited susceptibility to ventricular arrhythmias (congenital long QT syndrome and Brugada syndrome), impaired cardiac conduction or a combination of these phenotypes. Some of these syndromes include AF, and SCN5A mutations have also recently been associated with familial dilated cardiomyopathy and atrial arrhythmias. Therefore, we resequenced the gene in 375 AF patients including 118 with lone AF for variants in SCN5A and identified 19 rare missense variants including 8 novel alleles in 22 probands (5.9%). We hypothesize that some of these gene variants are responsible for AF susceptibility. In Specific Aim 2, we will test this hypothesis by ascertaining extended pedigrees for each variant carrier and correlating genotypes with the presence of AF. The clinical genetic studies will be complemented by experiments in Specific Aim 3 that will determine the electrophysiological consequences of SCN5A variants discovered in AF probands. These studies will use heterologously expressed recombinant human SCN5A sodium channels and patch-clamp recording techniques. Functional characterization of mutations and variants will not only enable validation of their disease-association but also provide insight into pathophysiological mechanisms of AF. The improved understanding of the diverse mechanisms leading to AF represents a first step in the development of subtype-specific therapeutic treatments for this common and morbid condition. PUBLIC HEALTH RELEVANCE: Atrial fibrillation (AF) is the most common abnormal heart rhythm (arrhythmia) seen in clinical practice. In this study, we are trying to identify genes that may predispose individuals to developing this arrhythmia. A better understanding of what causes of AF will provide us with new treatments for this common and morbid condition.

描述（由申请人提供）：心房颤动（AF）是临床实践中最常见的心律失常，在美国老龄化人口中达到流行病的比例。大多数房颤继发于其他疾病，但高达30%的患者没有明显的病因，被称为“单发”或特发性房颤。我们和其他人已经证明，单发房颤具有大量的遗传成分，并表明单发房颤在表型和遗传上是一种异质性疾病。因此，越来越多的人认识到，房颤可能存在家族性易感性，并且确实已经描述了许多遗传位点。此外，编码心脏钾通道和间隙连接的基因突变在个别病例和小种类中也有报道。虽然存在遗传形式的房颤，但表型复杂性限制了确定突变携带者从而确定致病基因的努力。在一个大型房颤家族中，我们利用延长的信号平均p波持续时间作为房颤的中间表型或内表型，在5号染色体上定位了一个新的房颤位点。在Specific Aim 1中，我们建议在5p15位点上确定负责单发房颤的基因，并评估其在一大批家族性房颤患者中对房颤的贡献。人心脏钠通道负责心脏动作电位的快速去极化上行程，是抗心律失常药物的分子靶点，其中一些药物对治疗心房心律失常有效。越来越多的证据支持编码人类心脏钠通道的基因SCN5A在房颤中的作用。SCN5A突变与室性心律失常（先天性长QT综合征和Brugada综合征）、心传导受损或这些表型的组合的遗传易感性相关。其中一些综合征包括房颤，SCN5A突变最近也与家族性扩张性心肌病和心房心律失常有关。因此，我们对375例房颤患者（其中118例为单发房颤）的SCN5A突变进行了基因重测序，鉴定出19个罕见错义突变，其中包括22个先证（5.9%）中的8个新等位基因。我们假设其中一些基因变异是导致AF易感性的原因。在特异性目标2中，我们将通过确定每个变异携带者的扩展谱系和将基因型与房颤的存在相关联来验证这一假设。特异性目标3中的实验将补充临床遗传学研究，以确定房颤先证者中发现的SCN5A变异的电生理后果。这些研究将使用异源表达的重组人SCN5A钠通道和膜片钳记录技术。突变和变异的功能特征不仅可以验证其与疾病的相关性，还可以深入了解房颤的病理生理机制。对导致房颤的多种机制的更好理解，代表了针对这种常见和病态疾病开发亚型特异性治疗方法的第一步。公共卫生相关性：心房颤动（AF）是临床实践中最常见的心律失常（心律失常）。在这项研究中，我们试图确定可能使个体易患这种心律失常的基因。更好地了解房颤的原因将为我们提供治疗这种常见和病态疾病的新方法。