The cardiac sodium channel (SCN5A) is a target for the treatment of arrhythmias. We hypothesized that vulnerability to atrial fibrillation (AF) could be caused by genetic variation in SCN5A. We recruited 157 patients with early‐onset AF who lacked traditional risk factors, and 314 matched controls. SCN5A was subject to targeted genotyping of a common loss‐of‐function H558R polymorphism and comprehensive mutation scanning. Genotype frequencies in the AF cohort vs controls were as follows: HH, 50 vs 63% HR, 40 vs 33% and RR, 10 vs 4% (P=0.008). Additional coding sequence mutations were ruled out. The R558 allele was more common in patients than in controls (30 vs 21%, P=0.002), conferring an odds ratios for AF of 1.6 (95% confidence interval 1.2–2.2). The SCN5A R558 allele, present in one‐third of the population, thus constitutes a risk factor for lone AF and may increase susceptibility to sodium channel blocker‐induced proarrhythmia.

Clinical Pharmacology & Therapeutics (2007) 81, 35–41. doi:10.1038/sj.clpt.6100016