Common and Rare Variants in SCN10A Modulate the Risk of Atrial Fibrillation

Abstract

BACKGROUND: -Genome-wide association studies (GWAS) have shown that the common single nucleotide polymorphism (SNP) rs6800541 located in SCN10A, encoding the voltage-gated Nav1.8 sodium channel, is associated with PR-interval prolongation and atrial fibrillation (AF). SNP rs6800541 is in high linkage disequilibrium with the non-synonymous variant in SCN10A, rs6795970 (V1073A, r2=0.933). We aim to determine whether common and rare SCN10A variants are associated with early onset lone AF. METHODS AND RESULTS: -The SCN10A gene was sequenced in 225 lone AF patients. In an association study of the common variant V1073A, we included 515 AF patients, and two control cohorts of 730 individuals free of AF and 6,161 individuals randomly sampled. Functional characterization of two common and two rare variants was performed by whole-cell patch-clamping. In the lone AF cohort, nine rare missense variants and one splice site donor variant were detected. Interestingly, AF patients were found to have lower minor allele frequency of the V1073A variant than controls (odds ratio = 0.74 [0.65-0.86]; p=2.3x10-05). Functional characterization revealed that both of the common variants, V1073A and L1092P, induced a gain-of-channel function, while the rare missense variants, V94G and R1588Q, resulted in a loss-of-channel function. CONCLUSIONS: -We report that the common variant V1073A is associated with decreased susceptibility to AF. In functional studies the two common variants gave rise to a gain-of-function. The rare variants found in lone AF patients showed loss-of-function, indicating that these variants increase susceptibility to AF. Hence, our study suggests that SCN10A variations are involved in the genesis of AF.