Association of the NOS1AP rs10494366 Genetic Variant With Drug‐Induced QT Prolongation

Drug-induced QTc prolongation (diQTP) is a major risk factor for torsades de pointes and sudden cardiac death. This study evaluated whether carriers of the G allele of the NOS1AP rs10494366 T > G variant have greater risk for diQTP when prescribed high-risk QT-prolonging medications. A retrospective case-control analysis was conducted using the Michigan Genomics Initiative (MGI) biobank, linking genotype and electronic health records for 5848 patients of European ancestry prescribed ≥ 1 CredibleMeds high-risk drug for torsades de pointes between 2001 and 2022. QTc was Bazett-corrected, and diQTP was defined as change of > 60 ms from the baseline QTc and/or QTc ≥ 500 ms. Associations between rs10494366 and diQTP were tested using unadjusted and propensity-score-adjusted logistic regression. The minor-allele frequency (G) was 0.36, and genotype frequencies were in Hardy-Weinberg equilibrium (p = 0.07). diQTP occurred in 12.2% of participants. The G allele was not significantly associated with risk of diQTP in either the unadjusted analysis (OR 0.94 [95% CI 0.84-1.05] p = 0.27) or the adjusted analysis (OR 0.94 [95% CI 0.83-1.06] p = 0.30). In this large, real-world cohort of patients with European ancestry, the NOS1AP rs10494366 variant was not significantly associated with the risk of diQTP. These findings suggest that previously observed associations between this variant and baseline QTc may not extend to all drug-induced settings.