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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL092217-02
Application #
7793517
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Wang, Lan-Hsiang
Project Start
2009-04-01
Project End
2013-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
2
Fiscal Year
2010
Total Cost
$374,034
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Patel, Neel J; Wells, Quinn S; Huang, Shi et al. (2017) Relation of Obstructive Sleep Apnea and a Common Variant at Chromosome 4q25 to Atrial Fibrillation. Am J Cardiol 119:1387-1391
Hockman, Dorit; Burns, Alan J; Schlosser, Gerhard et al. (2017) Evolution of the hypoxia-sensitive cells involved in amniote respiratory reflexes. Elife 6:
Mosley, Jonathan D; Shoemaker, M Benjamin; Wells, Quinn S et al. (2017) Investigating the Genetic Architecture of the PR Interval Using Clinical Phenotypes. Circ Cardiovasc Genet 10:
Lubitz, Steven A; Yin, Xiaoyan; Lin, Henry J et al. (2017) Genetic Risk Prediction of Atrial Fibrillation. Circulation 135:1311-1320
Darbar, Dawood; McCauley, Mark (2017) The Pharmacogenomics of a Mutation 'Hotspot' for the Short QT Syndrome. JACC Clin Electrophysiol 3:744-746
Huang, Henry D; Darbar, Dawood (2017) Genetic Risk Scores for Atrial Fibrillation: Do They Improve Risk Estimation? Can J Cardiol 33:422-424
Huang, Henry; Darbar, Dawood (2017) Genetic heterogeneity of atrial fibrillation susceptibility loci across racial or ethnic groups. Eur Heart J 38:2595-2598
Christophersen, Ingrid E; Rienstra, Michiel; Roselli, Carolina et al. (2017) Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation. Nat Genet 49:946-952
Thorolfsdottir, Rosa B; Sveinbjornsson, Gardar; Sulem, Patrick et al. (2017) A Missense Variant in PLEC Increases RiskĀ of Atrial Fibrillation. J Am Coll Cardiol 70:2157-2168
McCauley, Mark; Darbar, Dawood (2017) Germline versus somatic mutations in genetic atrial fibrillation. Heart Rhythm 14:1539-1540

Showing the most recent 10 out of 74 publications