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: 7793517
• 负责人: Dawood Darbar
• 金额: $ 37.4万
• 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/7793517
• 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，在美国老年人群中达到流行病的比例。大多数房颤是继发于其他疾病的，但高达30%的患者没有明显的病因，据说患有“孤立性”或特发性房颤。我们和其他人已经证明，孤立性房颤具有很大的遗传性成分，并表明孤立性房颤是表型和遗传性的。一种异质性疾病。因此，越来越多的人认识到，可能存在AF的家族易感性，并且实际上已经描述了许多遗传基因座。此外，编码心脏钾通道和间隙连接的基因突变已在孤立病例和小心肌病中报告。虽然存在遗传形式的AF，但表型复杂性限制了确定突变携带者的努力，从而确定致病基因。在一个大的AF家族中，我们已经在5号染色体上绘制了一个新的AF基因座，使用延长的信号平均P波持续时间作为AF的中间或内在表型。在具体目标1中，我们建议在5p15基因座上鉴定负责孤立AF的基因，并在一个大的家族性AF患者队列中评估其对AF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，并且是抗心律失常药物的分子靶标，其中一些抗心律失常药物在治疗房性心律失常中是有效的。越来越多的证据支持SCN 5A（编码人类心脏钠通道的基因）在AF中的作用。SCN 5A中的突变与室性心律失常（先天性长QT综合征和Brugada综合征）、心脏传导受损或这些表型的组合的遗传易感性相关。这些综合征中的一些包括AF，并且SCN5A突变最近也与家族性扩张型心肌病和房性心律失常相关。因此，我们对375名房颤患者（包括118名孤立性房颤患者）的SCN 5A变异基因进行了重新测序，并在22名先证者（5.9%）中鉴定了19种罕见的错义变异，包括8种新等位基因。我们假设这些基因变异中的一些是房颤易感性的原因。在特定目标2中，我们将通过确定每个变异携带者的扩展谱系并将基因型与AF的存在相关联来测试这一假设。临床遗传学研究将通过特定目标3中的实验来补充，该实验将确定在AF先证者中发现的SCN 5A变异体的电生理学后果。这些研究将使用异源表达的重组人SCN 5A钠通道和膜片钳记录技术。突变和变体的功能表征不仅能够验证其疾病相关性，而且还可以深入了解AF的病理生理机制。对导致AF的各种机制的进一步了解代表了针对这种常见和病态疾病的亚型特异性治疗方法的发展的第一步。公共卫生相关性：房颤（AF）是临床实践中最常见的心律异常（心律失常）。在这项研究中，我们试图找出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针对这种常见和病态疾病的新治疗方法。