Abstract 1965: Common Variants in KCNN3 Are Associated With Early-Onset Atrial Fibrillation
Background Atrial fibrillation (AF) occurring in the absence of structural heart disease and with an early-onset is heritable. We sought to determine common genetic factors underlying early-onset AF (EOAF) by performing a meta-analysis of five genome-wide association studies.
Methods Subjects of European descent with EOAF were defined as having AF before 66 years of age and no structural heart disease. Cases and controls were derived from the Competence Network on atrial fibrillation (AFNET) / KORA S4, Massachusetts General Hospital / Framingham Heart Study, Cleveland Clinic, ARIC, and the Group Health /Cardiovascular Health Studies. Subjects were genotyped, HapMap SNPs were imputed, and analyses were performed adjusting for age, sex, and hypertension; a meta-analysis of the study-specific results was conducted. Significant results were replicated in two independent studies with EOAF (AFNET, Vanderbilt) and two community based studies (AGES and the Rotterdam Study).
Results 1,335 cases of EOAF and 12,844 referent subjects were available. We identified a novel locus for AF on chromosome 1q21. The most significant SNP, rs13376333, is intronic to the potassium channel KCNN3, and has an adjusted odds ratio of 1.56 (p = 6.3×10 –12). This association was replicated in two additional cohorts with EOAF and two studies with community based AF. In a meta-analysis of the primary and replication cohorts with EOAF, rs13376333 had an odds ratio of 1.52 (p = 1.83×10 –21).
Conclusion We have identified a novel locus on chromosome 1q21 for early-onset AF in the voltage-independent, calcium activated potassium channel KCNN3 that is potentially involved in cardiac repolarization. This finding may have important implications for the pathophysiology, detection and therapy of early-onset AF.