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Published on: June 20, 2020
Genetic Investigation of Corrected QT Interval Sensitivity to Oral Bepridil Hydrochloride Hydrate in Patients With
Naoki Ishibashi1, Motoki Furutani1,2, Mika Nakashima1
1Department of Cardiovascular Medicine Hiroshima University Graduate School of Biomedical and Health Sciences Hiroshima Japan.
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.
Insights
A genetic variant in the follicle-stimulating hormone receptor (FSHR) gene, rs12622919, is linked to corrected QT interval (QTc) prolongation caused by the antiarrhythmic drug bepridil. This finding may help predict individual patient risk for this adverse drug reaction.
Area of Science:
- Pharmacogenetics
- Cardiology
- Genomics
Background:
- Bepridil is an antiarrhythmic drug for paroxysmal atrial fibrillation.
- Its use is limited by corrected QT interval (QTc) prolongation and ventricular arrhythmias.
- Identifying genetic factors for bepridil-associated QTc prolongation is crucial.
Purpose of the Study:
- To identify genetic variants associated with bepridil-induced QTc prolongation.
- To assess the predictive value of identified variants for patient risk stratification.
Main Methods:
- Genome-wide association study (GWAS) in 445 patients, with replication in 78 patients.
- QTc prolongation defined as ≥450 ms (men) and ≥460 ms (women).
- Logistic and linear regression analyses, followed by random-effects meta-analyses.
Main Results:
- The FSHR intronic variant rs12622919 showed genome-wide significance for bepridil-associated QTc prolongation.
- rs12622919 improved the discrimination of QTc prolongation prediction (AUC 0.77-0.78).
- Exploratory analyses suggested a potential association in women.
Conclusions:
- The FSHR variant rs12622919 is associated with bepridil-induced QTc prolongation.
- rs12622919 may serve as a genetic biomarker for risk assessment.
- Independent validation is required for clinical application.
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