Abstract 13007: Common and Rare Variants in SCN10A Associated with Atrial Fibrillation
Introduction: Genetic studies have identified ion channel gene variants that segregate in families with atrial fibrillation (AF). SCN10A encodes Nav1.8 sodium channel, is expressed in the atria and ventricles and has been associated with variable cardiac conduction. Here we tested the hypothesis that vulnerability to AF is associated with mutations in SCN10A.
Methods: The entire SCN10A coding region was resequenced in 289 lone AF probands. Mutations identified in the AF probands were then genotyped in controls (n=736) from the same population. We also examined the affect of the common SCN10A variants, rs795970 (V1073A) and rs12632942 (L1092P) on the PR interval measured from the electrocardiogram in the absence of AV nodal blocking agents among lone AF probands (n=246) and a reference population drawn from the Vanderbilt Genome-Electronic Records (VGER) dataset (n=2021).
Results: In 29 (10%) probands, 19 novel variants not found in the control population (0%, P<0.005) were identified. All novel variants were found to affect highly conserved residues of the Nav1.8 channel. In 2 families with >1 affected member, novel variants (A1886V, Y158D, 814H) co-segregated with AF. Twenty-one (11%) lone AF probands carrying SCN10A variants (V1073A, L1092P, I206M, A1886V, V1697I, 417delK, V1548F) presented with the first episode of AF associated with slow ventricular rates (HR <100), in the absence of atrio-ventricular (AV) nodal blocking drugs. In lone AF probands and individuals from the VGER dataset, both V1073A and L1092P were found to affect the pr-interval in a gene dose effect (Table).
Conclusions: The findings of the present study support the idea that SCN10A variants are causative for the variable PR interval identified by GWAS. The data also suggest that SCN10A variants exert relatively large effects on AV conduction in patients with lone AF, both during sinus rhythm and during AF.
- © 2011 by American Heart Association, Inc.