Pharmacogenet Genomics. 2026 Jun 16. doi: 10.1097/FPC.0000000000000610. Online ahead of print.
ABSTRACT
Drug-induced QT prolongation (diQTP) can lead to rare, but potentially fatal adverse effects of many medications, yet individual susceptibility varies due to both clinical and genetic factors. SDHAF3 p.F53L (rs62624461) is a genetic variant that plays a role in mitochondrial function and was previously associated with diQTP in one small prior study. Therefore, the objective of this retrospective pharmacogenetic study was to evaluate whether SDHAF3 p.F53L is associated with clinically significant diQTP. Data were obtained from the Michigan Genomics Initiative, which links genotype information with electronic health records at Michigan Medicine. Adult patients with available genotype and electrocardiogram data who received at least one high-risk QT-prolonging drug between 2001 and 2022 were included. The analysis was limited to 5848 patients of European ancestry, of whom 320 (5.5%) were carriers of the SDHAF3 p.F53L variant. QT prolongation was defined as a QTc greater than or equal to 500 ms or an increase greater than 60 ms from baseline during high-risk QT-prolonging drug prescription. Logistic regression under a dominant genetic model assessed associations between variant carrier status and diQTP, with and without propensity score adjustment. Baseline demographics and comorbidities were similar between carriers and noncarriers. No significant association was observed between SDHAF3 p.F53L and diQTP [unadjusted odds ratio (OR) = 1.06, 95% confidence interval (CI) = 0.76-1.48, P = 0.742; adjusted OR = 1.05, 95% CI = 0.74-1.51, P = 0.773]. These results suggest that SDHAF3 p.F53L does not meaningfully influence diQTP risk in a large, real-world clinical cohort. Future studies should examine this variant across diverse populations.
PMID:42296328 | DOI:10.1097/FPC.0000000000000610