Abstract 12219: Arrhythmia-associated Variants in the SCN5A Promoter and Regulatory Regions
Background: Mutations in the coding sequence of SCN5A, which encodes the predominant cardiac Na+ channel α-subunit, have been associated with inherited susceptibility to various arrhythmias. Variable expression of SCN5A is one possible mechanism responsible for this pleiotrophic effect. However, it is unknown if variants in the promoter and regulatory regions of SCN5A also modulate the risk of arrhythmias.
Methods and Results: We resequenced the core-promoter region of SCN5A (∼2.8 kb) in 961 patients with arrhythmia phenotype(s) (atrial fibrillation, n=423; sinus node dysfunction, n=46; conduction disease, n=123; Brugada syndrome, n=288; idiopathic ventricular fibrillation, n=75; early repolarization syndrome, n=6). We also resequenced the conserved noncoding sequences (CNSs) in intron 1 of SCN5A that have been implicated to regulate SCN5A transcription in previous in vitro and mouse studies. We identified 21 novel rare variants in the SCN5A promoter (atrial fibrillation, n=10; sinus node dysfunction, n=1; conduction disease, n=4; Brugada syndrome, n=3; idiopathic ventricular fibrillation, n=2; early repolarization syndrome, n=1). All variants were absent in >2,500 controls. Using luciferase reporter assay, 4 variants (idiopathic ventricular fibrillation, n=2; early repolarization syndrome, n=1; progressive conduction disease, n=1) were functionally characterized, and each displayed decreased promoter activity compared to wild-type sequences. Furthermore, one variant was significantly more common in patients with atrial fibrillation (17%) than ethnically matched controls (7%) and resulted in decreased promoter activity. In the intron 1 CNS sequences of SCN5A, we identified 3 rare variants in patients with atrial fibrillation, including one variant, which is predicted to disrupt a previously-validated TEF1 binding site and decreased regulation of SCN5A promoter compared to wild-type CNS sequence in luciferase assay.
Conclusions: Variants in the core-promoter and the transcriptional regulatory region of SCN5A were identified in multiple phenotypes, consistent with the idea that altered SCN5A transcription levels modulate susceptibility to arrhythmias.
- © 2012 by American Heart Association, Inc.