Abstract 20513: A Common SCN10A Variant May Promote DNA Methylation of SCN5A Promoter and Decrease SCN5A Expression in Brugada Syndrome Patients Without SCN5A Exonic Mutation

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The SCN5A is a major causative gene of Brugada syndrome (BrS), but it accounts for only 11-28% of cases and the majority of BrS patients have no genetic explanation. We resequenced SCN5A coding regions in 95 BrS patients. We also genotyped the GWAS reported SCN10A SNP rs10428132 in 95 Japanese patients with BrS and 1,978 healthy controls. The minor allele frequency of rs10428132 was significantly higher in BrS than the controls (P = 2.7x10-14, odds ratio (OR) 3.0). We investigated the expression and methylation of SCN5A using right ventricular (RV) cardiomyocyte in BrS patients without SCN5A exonic mutation. We obtained RV sections from 20 BrS patients and 16 control patients role out cardiomyopathy. We examined SCN5A mRNA expression using digital PCR. The epigenetics of SCN5A promoter was analyzed in 16 CpG dinucleotides by bisulfite PCR. The SCN5A mRNA expression was significantly lower in BrS patients than controls. The methylation of SCN5A CpG island was similar in the two groups. 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). Even in BrS cases without SCN5A exonic mutation, the SCN5A mRNA expression was reduced. The minor genotype of the SCN10A SNP may contribute to decrease SCN5A expression by promoting SCN5A promoter methylation and eventually be more likely develop BrS.

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