Abstract 14591: A Common SCN5A Polymorphism H558R Modifies Clinical Phenotype of Brugada Syndrome by Modulating DNA Methylation of SCN5A Promoters
Objectives: The common SCN5A polymorphism, rs1805124 (c.1673A>G, H558R), has been reported to improve the sodium channel activity in mutated channels and as a genetic modifier of Brugada syndrome (BrS). We investigated the effects of H558R on the clinical manifestations of BrS and rationale of the H558R behavior.
Method: We genotyped the rs1805124 in 95 BrS patients (91 males, mean age 42 ± 14 years) and 1,875 normal controls (1546 male, mean age 54±18 years) by Taq man assay and compared the frequency of the H558R in the BrS patients and controls. The SCN5A gene mutation was screened by resequencing in the BrS patients. We compared the parameters of 12-lead electrocardiogram (ECG), signal-averaged ECG and electrophysiological in BrS patients with and without H558R. We obtained the right atrial sections from 30 patients during aortic aneurysm operations, in whom we also genotyped rs1805124. We examined the expression level of SCN5A by real time RT-PCR using cDNA and the 14 CpG dinucleotides in the SCN5A promoter by direct Sanger sequencing of the PCR amplicons of bisulfite treated DNA.
Result: H558R was less frequent in patients with BrS than in normal controls (4.7% vs. 10.3%, P = 0.01). H558R (minor allele A) was not observed in patients with BrS with ventricular fibrillation (VF; n = 20), whereas 9(12%) of patients without VF (n = 75) had H558R (P=0.02). Nonsynonymous mutation of SCN5A was not detected in patients with H558R. The H558R carriers showed lower ST elevation in lead V1 than noncarriers (1.7±0.4 vs. 2.8±0.1 mV, P =0.02). The expression level of SCN5A was significant higher in the patients with H558R (N=10) than those without H558R (N=20) (1.2±0.2 .vs 0.55±0.18 P=0.025). In addition, rate of the methylation was lower in BrS patients with H558R than those without (0.7±0.2% .vs 1.6±0.1% P=0.004) .
Conclusions: We demonstrated that H558R was a protective genetic modulator even in BrS patients without SCN5A mutation. To the best of our knowledge, this was the first report showing that H558R modulated the DNA methylation of SCN5A promoters. These results suggested that H558R may contribute to increase the SCN5A expression by inhibiting SCN5A promoter methylation and eventually work protective in clinical phenotype of BrS.
Author Disclosures: H. Matsumura: None. Y. Nakano: None. A. Sairaku: None. T. Tokuyama: None. S. Tomomori: None. M. Amioka: None. N. Hironobe: None. Y. Kihara: None.
- © 2016 by American Heart Association, Inc.