Atrial fibrillation (AF), the most common sustained cardiac arrhythmia in adults, is associated with significant morbidity and increased mortality. While risk factors for AF are multifactorial, ~30% of patients have AF that is unassociated with underlying heart or systemic disease ('lone' AF). Over the last decade, we and others have shown that lone AF has a substantial genetic basis. The human cardiac sodium channel is responsible for the rapid upstroke of the cardiac action potential (AP) and blockers of Nav1.5, the canonical sodium channel encoded by SCN5A, are antiarrhythmic. We and others have shown that mutations in SCN5A cause a range of cardiac channelopathies including AF characterized by enhanced late sodium current (INa-L), prolonged AP duration and early afterdepolarizations. Genome wide association studies (GWAS) have implicated a second sodium channel Nav1.8, encoded by SCN10A, in AF susceptibility. We have identified multiple rare SCN10A variants in patients with lone AF. This raises the hypothesis, to be tested here, that rare variation in SCN10A is associated with AF.
In Specific Aim 1, we will conduct a case-control genetic association study to determine whether a priori rare potentially pathogenic SCN10A variants are enriched in lone AF probands than in controls. In addition, we will ascertain extended pedigrees for each rare SCN10A variant carrier to determine familial aggregation with AF and determine genotype-phenotype correlations. Rare SCN10A variants that are highly conserved, predicted to be deleterious and aggregate with AF will be functionally characterized by expressing them in a dorsal root ganglia cell-line to determine the peak and INa-L. In vitro functional characterization of rare SCN10A variants will enable their AF-association and may provide novel insights into underlying genetic mechanisms of the arrhythmia. Furthermore, these studies also have the potential of uncovering Nav1.8 as a novel therapeutic target for antiarrhythmic intervention. In the previous cycle of this award, we used positional cloning and candidate gene approaches to identify genes encoding cardiac ion channels and signaling proteins which impart a large risk for the arrhythmia. In contrast, GWAS have identified common AF susceptibility loci with modest effects. While these approaches have provided important insights into the genetic architecture of AF, collectively they explain only a small fraction of the heritability of AF. This raises the hypothesis that rare variants with modest or large effects may be identified by whole exome sequencing (WES).
In Specific Aim 2, we will screen a large cohort of patients with AF for rare variants in genes implicated by WES and GWAS as candidates for mediating AF susceptibility. We have identified four high priority novel candidate genes that cosegregated with AF using WES. Furthermore, in collaboration with other AF investigators, we have uncovered six additional AF susceptibility loci and five novel candidate genes when a meta-analysis of AF GWAS was performed. We will functionally characterize each gene variant using in vitro electrophysiology and in vivo zebrafish expression in order to determine their pathogenicity.
Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, affects ~2% of the US adult population and increases the risk of stroke, heart failure, dementia and death. Although there is growing recognition that AF is a heritable disorder, the genetic basis for the disorder remains poorly understood. These studies will identify new AF genes and uncover underlying mechanisms that will allow us to develop new treatments for this common and morbid condition.
| Choi, Seung Hoan; Weng, Lu-Chen; Roselli, Carolina et al. (2018) Association Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation. JAMA 320:2354-2364 |
| Thorolfsdottir, Rosa B; Sveinbjornsson, Gardar; Sulem, Patrick et al. (2018) Coding variants in RPL3L and MYZAP increase risk of atrial fibrillation. Commun Biol 1:68 |
| McCauley, Mark D; Darbar, Dawood (2018) Race and Socioeconomic Status Regulate Lifetime Risk of Atrial Fibrillation. Circ Arrhythm Electrophysiol 11:e006584 |
| Argenziano, Mariana; Lambers, Erin; Hong, Liang et al. (2018) Electrophysiologic Characterization of Calcium Handling in Human Induced Pluripotent Stem Cell-Derived Atrial Cardiomyocytes. Stem Cell Reports 10:1867-1878 |
| Chalazan, Brandon; Dickerman, Deanna; Sridhar, Arvind et al. (2018) Relation of Body Mass Index to Symptom Burden in Patients withAtrial Fibrillation. Am J Cardiol 122:235-241 |
| Cox, Nathan J; Unlu, Gokhan; Bisnett, Brittany J et al. (2018) Dynamic Glycosylation Governs the Vertebrate COPII Protein Trafficking Pathway. Biochemistry 57:91-107 |
| 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 |
| 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 |
Showing the most recent 10 out of 80 publications
