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 therefore sought to determine whether common and rare SCN10A variants are associated with early onset AF. Methods and Results SCN10A was sequenced in 225 AF patients in whom there was no evidence of other cardiovascular disease or dysfunction (lone AF). In an association study of the rs6795970 SNP variant, we included 515 AF patients, and two control cohorts of 730 individuals free of AF and 6,161 randomly sampled individuals. Functional characterization of SCN10A 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 higher G allele frequency of rs6795970 which encodes the alanine variant at position 1073 (described from here on as A1073, odds ratio = 1.35 [1.16–1.54]; p=2.3×10−05). Both of the common variants, A1073 andP1092, induced a gain-of-channel function, while the rare missense variants, V94G and R1588Q, resulted in a loss-of-channel function. Conclusions The common variant A1073 is associated with increased susceptibility to AF. Both rare and common variants have impact on the function of the channel, indicating that these variants influence susceptibility to AF. Hence, our study suggests that SCN10A variations are involved in the genesis of AF.

Channelopathy-related SCN10A gene variants predict cerebellar dysfunction in multiple sclerosis

“…14,15 These variants are located in a locus previously linked to Brugada syndrome 24 and variations in ECG 25 in various genome-wide association studies. While rs6801957 appears to alter Na V 1.8 expression by affecting a Tbox binding element in an SCN10A enhancer region, shown decelerated time-dependent recovery from inactivation, but larger peak current and accelerated time to peak with respect to rs6795970 A Na V 1.8 (1073 Val ).…”

“…While rs6801957 appears to alter Na V 1.8 expression by affecting a Tbox binding element in an SCN10A enhancer region, shown decelerated time-dependent recovery from inactivation, but larger peak current and accelerated time to peak with respect to rs6795970 A Na V 1.8 (1073 Val ). 15 Therefore, fine-mapping studies will be required to identify the actual causal variant, and functional studies in animal models of MS will be necessary to determine how these variants affect cerebellar dysfunction in MS. Purkinje neurons receive integrated inputs indirectly from a variety of regions in the brain and spinal cord. 26 They form the output layer of the cerebellar cortex and play a key role in cerebellar neural circuitry and function.…”

Association of SCN10A Polymorphisms with the Recurrence of Atrial Fibrillation after Catheter Ablation in a Chinese Han Population

“…showed that the G allele of rs6795970 was associated with a higher risk of AF. In addition, Jabbari et al 37. also reported that the G allele of rs6795970 increased the risk of AF.…”

A Novel Genetic Marker for Inherited Disorder of the Heart Conduction System

“…Гомозиготный генотип GG гена SCN10A играет протективную роль в отношении развития идиопатических атриовентрикулярных блокад и блокады правой ножки пучка Гиса. [3][4][5][6][7][8]. Однако имеющиеся результаты по гену SCN10A были получены при исследовании пациентов евро-пейской, азиатской и афроамериканской популяций, среди лиц сибирской популяции данный ген ранее не изучался.…”