H558R, a common SCN5A polymorphism, modifies the clinical phenotype of Brugada syndrome by modulating DNA methylation of SCN5A promoters

Abstract

BackgroundA common SCN5A polymorphism H558R (c.1673 A > G, rs1805124) improves sodium channel activity in mutated channels and known to be a genetic modifier of Brugada syndrome patients (BrS). We investigated clinical manifestations and underlying mechanisms of H558R in BrS.Methods and resultsWe genotyped H558R in 100 BrS (mean age 45 ± 14 years; 91 men) and 1875 controls (mean age 54 ± 18 years; 1546 men). We compared clinical parameters in BrS with and without H558R (H558R+ vs. H558R- group, N = 9 vs. 91). We also obtained right atrial sections from 30 patients during aortic aneurysm operations and compared SCN5A expression and methylation with or without H558R. H558R was less frequent in BrS than controls (9.0% vs. 19.2%, P = 0.028). The VF occurrence ratio was significantly lower (0% vs. 29.7%, P = 0.03) and spontaneous type 1 ECG was less observed in H558R+ than H558R- group (33.3% vs. 74.7%, P = 0.01). The SCN5A expression level was significantly higher and the methylation rate was significantly lower in sections with H558R (N = 10) than those without (0.98 ± 0.14 vs. 0.83 ± 0.19, P = 0.04; 0.7 ± 0.2% vs. 1.6 ± 0.1%, P = 0.004, respectively). In BrS with heterozygous H558R, the A allele mRNA expression was 1.38 fold higher than G allele expression.ConclusionThe SCN5A polymorphism H558R may be a modifier that protects against VF occurrence in BrS. The H558R decreased the SCN5A promoter methylation and increased the expression level in cardiac tissue. An allelic expression imbalance in BrS with a heterozygous H558R may also contribute to the protective effects in heterozygous mutations.Electronic supplementary materialThe online version of this article (doi: 10.1186/s12929-017-0397-x) contains supplementary material, which is available to authorized users.

A SNaPshot assay for detection of 45 mutations in the SCN5A gene in the Chinese Han Population

“…To our knowledge, the mutation of rs1805124 (H558R) has been reported to be associated with clinical disease (myocardial infarction, BrS, LQTS, etc. ), but no SCD‐related data have been reported in South China for this SNP mutation .…”

Persistent QT Prolongation in a Child with Gitelman Syndrome and <i>SCN5A</i> H558R Polymorphism

“…14) For example, H558R polymorphism reduced the occurrence of ventricular fibrillation in patients with Brugada syndrome. 15) On the contrary, it reportedly exhibited LQT3-like dysfunction when it coexisted with SCN5A A572D, another missense variant in healthy subjects. 13) The functional analysis of SCN5A-mutation-positive Brugada syndrome demonstrated that the polymorphism attenuates the slow inactivation of sodium channel, which is enhanced by the coexisting pathogenic mutation of SCN5A.…”

“…13) The functional analysis of SCN5A-mutation-positive Brugada syndrome demonstrated that the polymorphism attenuates the slow inactivation of sodium channel, which is enhanced by the coexisting pathogenic mutation of SCN5A. 10) Matsumura, et al 15) demonstrated that SCN5A H 558R polymorphism modulated the clinical manifestations of Brugada syndrome. In their report, patients with H558 R showed a lower methylation level of SCN5A promoter and expressed higher levels of SCN5A in right atrial sections compared with patients without H558R.…”

Associations between common ion channel single nucleotide polymorphisms and sudden cardiac death in adults

“…In addition, the mutation also prevents VF in patients with BrS. [ 38 ] However, the mutation has not been shown to be associated with cardiac repolarization abnormalities, such as T-wave alternans. [ 39 ] These results indicate that rs1805124 is substitutable or does not directly affect the incidence of SCD.…”