Common sodium channel promoter haplotype in Asian subjects underlies variability in cardiac conduction

Background - Reduced cardiac sodium current slows conduction and renders the heart susceptible to ventricular fibrillation. Loss of function mutations in SCN5A, encoding the cardiac sodium channel, are one cause of the Brugada syndrome, associated with slow conduction and a high incidence of ventricular fibrillation, especially in Asians. In this study, we tested the hypothesis that an SCN5A promoter polymorphism common in Asians modulates variability in cardiac conduction. Methods and Results - Resequencing 2.8 kb of SCN5A promoter identified a haplotype variant consisting of 6 polymorphisms in near-complete linkage disequilibrium that occurred at an allele frequency of 22% in Asian subjects and was absent in whites and blacks. Reporter activity of this variant haplotype, designated HapB, in cardiomyocytes was reduced 62% compared with wild-type haplotype (P = 0.006). The relationship between SCN5A promoter haplotype and PR and QRS durations, indexes of conduction velocity, was then analyzed in a cohort of 71 Japanese Brugada syndrome subjects without SCN5A mutations and in 102 Japanese control subjects. In both groups, PR and QRS durations were significantly longer in HapB individuals (P <= 0.002) with a gene-dose effect. In addition, up to 28% and 48% of variability in PR and QRS durations, respectively, were attributable to this haplotype. The extent of QRS widening during challenge with sodium channel blockers, known to be arrhythmogenic in Brugada syndrome and other settings, was also genotype dependent (P = 0.002). Conclusions - These data demonstrate that genetically determined variable sodium channel transcription occurs in the human heart and is associated with variable conduction velocity, an important contributor to arrhythmia susceptibility.