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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

基本信息

批准号：
8242812
负责人：
Dawood Darbar
金额：
$ 37.35万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8242812
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 abstracting clinical phenotype clinical practice cohort common treatment endophenotype genetic pedigree heart rhythm improved insight kindred mortality mutation carrier novel patch clamp positional cloning proband research study segregation success trafficking trait transmission process

项目摘要

Abstract 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.

摘要