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

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Arrhythmology

Background:

• Atrial fibrillation (AF) is a common arrhythmia with genetic links.
• Genome-wide association studies suggest CAV1 (caveolin 1) as a potential AF susceptibility gene.
• CAV1 plays roles in cellular signaling pathways relevant to cardiac function.

Purpose of the Study:

• To investigate the role of CAV1 in atrial fibrillation (AF) pathogenesis.
• To identify and functionally characterize genetic variants in CAV1 associated with AF.
• To elucidate the molecular mechanisms underlying CAV1's contribution to AF.

Main Methods:

• Examined CAV1 and SHOX2 expression in a porcine model of induced AF.
• Screened 282 early-onset AF patients for CAV1 genetic variants.
• Functionally assessed a coding CAV1 variant in zebrafish and analyzed noncoding variants using luciferase assays and public datasets.

Main Results:

• CAV1 and SHOX2 were downregulated in the atria and atrioventricular node in the porcine AF model.
• A coding CAV1 variant in zebrafish led to increased heart rate and AF-like changes.
• Four novel noncoding CAV1 variants were associated with AF and PR interval, one with genome-wide significance.
• Noncoding variants affected transcription factor binding and reporter gene activation.

Conclusions:

• CAV1 is confirmed as a susceptibility gene for atrial fibrillation.
• Both coding and noncoding variants within CAV1 contribute to AF pathogenesis.
• This research deepens the understanding of genetic factors in cardiac conduction disorders.