Genetic Investigation of Corrected QT Interval Sensitivity to Oral Bepridil Hydrochloride Hydrate in Patients With Atrial Fibrillation

Background Bepridil is an antiarrhythmic drug used to treat paroxysmal atrial fibrillation; however, its use is limited by corrected QT interval (QTc) prolongation and the risk of ventricular arrhythmias. This study aimed to identify genetic variants associated with bepridil‐associated QTc prolongation after catheter ablation for paroxysmal atrial fibrillation. Methods A total of 523 patients who initiated bepridil therapy after catheter ablation at Hiroshima University between November 2013 and March 2023 were enrolled. Of these, 445 patients were included in a genome‐wide association study, and 78 were used as an independent replication cohort. QTc was measured 1 month after treatment initiation, with QTc prolongation defined as ≥450 ms in men and ≥460 ms in women. Logistic regression analyses were conducted using additive, dominant, and recessive genetic models. Variants showing suggestive associations in the genome‐wide association study ( P <1.00×10 −6 ) were evaluated in the replication cohort, followed by random‐effects meta‐analyses, with genome‐wide significance defined as P <5.00×10 −8 . Linear regression analyses were conducted for QTc prolongation. Results After quality control, 443 patients were analyzed in the genome‐wide association study. Of these, 122 (28%) exhibited QTc prolongation. Under the recessive model, rs12622919, an intronic variant in the FSHR (follicle‐stimulating hormone receptor) gene, showed a suggestive association. In the random‐effects meta‐analysis combining the discovery and replication cohorts, rs12622919 reached genome‐wide significance. Exploratory sex‐stratified analyses suggested a potential association in women ( P =0.026), although no statistically significant genotype‐by‐sex interaction was observed. Inclusion of rs12622919 improved discrimination for QTc prolongation (area under the curve, 0.77 [95% CI, 0.70–0.84]; Welch's t test, P <0.001), with the improvement remaining significant by DeLong's test (area under the curve, 0.78 [95% CI, 0.74–0.84]; P =0.0078). Conclusion The FSHR variant rs12622919 is associated with bepridil‐associated QTc prolongation and may serve as a genetic biomarker for individual risk assessment. Because the findings are based on meta‐analysis, independent validation is required.