CAV1 —A Susceptibility Gene for Atrial Fibrillation: The Impact of Coding and Noncoding Variants

Background Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia with a strong genetic predisposition. Genome‐wide association studies have highlighted CAV1 (caveolin 1), a caveolar protein involved in various signaling pathways, as a candidate for cardiac conduction disorders. Methods We explored the role of CAV1 in AF in various models to dissect possible disease mechanisms. First, CAV1 expression was examined together with the AF risk gene SHOX2 in a porcine model of induced AF. Then we screened a cohort of 282 patients with early‐onset AF to identify genetic variants within CAV1 and found 1 coding and 5 noncoding variants. The coding variant was functionally investigated in zebrafish, and a comprehensive analysis panel was applied to investigate the noncoding variants. Results In the porcine AF model, CAV1 and SHOX2 were significantly downregulated in the right atrium and atrioventricular node. Cardiac‐specific overexpression of the coding variant in zebrafish increased heart rate and caused fibrillatory waves and loss of the PR interval, supporting a pathogenic effect. Four of the 5 novel identified noncoding variants showed an association with AF and PR interval in published data sets, including 1 with genome‐wide significance. The noncoding variants localized to binding sites of transcription factors EOMES, RFX5, TEAD4 and MAX. Luciferase reporter gene assays demonstrated that 3 variants significantly altered the ability of those transcription factors to activate reporter gene expression. Conclusions This work underscores CAV1 as an AF susceptibility gene and highlights the critical role of coding and noncoding variants in AF disease mechanisms.