Abstract 14395: A Common Genetic Variant Within SCN10A Modulates DNA Methylation of SCN5A Promoters
Risk stratification of Brugada syndrome (BrS) remains controversial and the majority of BrS patients have no genetic explanation. In a recent genome-wide association study (GWAS), SCN10A (rs10428132; T>G) single nucleotide polymorphisms (SNPs) were reported to be associated with BrS. We replicated the association of SCN10A (rs10428132) in our Japanese BrS patients and investigated the mechanism of pathogenesis. We genotyped the rs10428132 in 95 Japanese patients with BrS and 1,978 healthy controls. Subsequently, we examined whether the SCN10A SNP was related to SCN5A promoter methylation. Transverse sections of a septal site of the RV outflow tract were obtained by biopsy from 21 patients out of the BrS subjects and the 14 CpG dinucleotides in the SCN5A promoter by direct Sanger sequencing of the PCR amplicons of bisulfite treated DNA. The minor allele frequency of rs10428132 was significantly higher in BrS than the controls (P = 2.7x10-14, odds ratio (OR) 3.0). The PQ interval was longer in patients with the SCN10A risk allele than in those without as previously reported (CC: 157 ± 2.5 ms, CT: 172 ± 5.3 ms, TT: 172 ± 3.5 ms, P = 1.8x10-3). The rate of the methylation was higher in BrS patients with risk allele T than those without (GG: 6% vs. GT: 11.6% and TT 11.4%, respectively, P=0.03). The results suggested that the SCN10A SNP may modulate the SCN5A expression through SCN5A promoter methylation. The risk genotype of the SCN10A SNP may contribute to decrease SCN5A expression by promoting SCN5A promoter methylation and eventually be more likely develop BrS.
Author Disclosures: N. Hironobe: None. Y. Nakano: None. T. Tokuyama: None. A. Sairaku: None. H. Matsumura: None. S. Tomomori: None. M. Amioka: None. Y. Kihara: None.
- © 2016 by American Heart Association, Inc.