Rare, Common Genetic Variation Is Associated With Atrial Fibrillation Risk

Both rare and common genetic variation is associated with an increased risk of atrial fibrillation (AF), according to a recent study published in JAMA Cardiology.

“[AF] has a substantial genetic component. The importance of polygenic risk is well established, while the contribution of rare variants to disease risk warrants characterization in large cohorts,” the researchers noted.

In this genetic association and nested case-control study, researchers analyzed 403,990 individuals (median age, 58 years). Cardiomyopathy (CM) and heart failure (HF) were assessed using cause-specific Cox regressions. The key end point of interest was defined as the risk of AF and incident CM or HF prior to and subsequent to AF diagnosis. Analysis took place between January and October 2023.

Researchers evaluated the impact of rare pLOF variants on the risk of incident AF. Their findings identified pLOF variants in 6 genes (TTN, RPL3L, PKP2, CTNNA3, KDM5B, and C10orf71) that were associated with AF. Of these, TTN, RPL3L, PKP2, CTNNA3, and KDM5B replicated in an external cohort. According to the results, carriers with a high polygenic risk score (PRS) incurred a substantial 10-year risk of AF (16% in female individuals, 24% in male individuals older than 60 years of age). Moreover, the results showed that rare pLOF variants were associated with increased risk of CM both prior to AF (hazard ratio [HR], 3.13; 95% CI, 2.24-4.36) and following AF (HR, 2.98; 95% CI, 1.89-4.69).

“We showed an interplay between rare and common genetic variation and demonstrated a substantial absolute risk of AF in individuals with a high PRS carrying a rare pLOF variant,” the researchers concluded. “These findings may contribute to possible future genetic risk stratification and improved clinical practice.”