Polygenic risk score for drug-induced long QT syndrome: independent validation in a real-world patient cohort

Objective Drug-induced long QT syndrome (diLQTS) is an adverse reaction from over 150 FDA-approved medications, posing the risk of triggering torsades de pointes and sudden death. While common genetic variants may modestly impact QT interval individually, their collective effect can significantly amplify risk of diLQTS. Consequently, this study aimed to validate a polygenic risk score (PRS) for diLQTS previously proposed by Strauss et al. Methods A retrospective cohort study was conducted utilizing patients from the Michigan Genomics Initiative prescribed 27 high-risk QT-prolonging drugs and an ECG during the prescription. The primary outcome was marked prolongation of the QTc interval (either >60 ms change from baseline or >500 ms absolute value) during treatment with a high-risk QT-prolonging drug. Results The primary outcome occurred in 12.0% of n = 6070 self-reported White, 12.4% of 558 African American, and 8.2% of 110 Asian patients. The PRS significantly associated with diLQTS in White patients [adjusted odds ratio = 1.44 (95% CI: 1.09-1.89); P = 0.009]. However the study lacked sufficient statistical power to confirm the PRS as a risk factor in African Americans [adjusted odds ratio = 2.18 (95% CI: 0.98-5.49); P = 0.073] and Asians [adjusted odds ratio = 3.21 (95% CI: 0.69-16.87); P = 0.139] due to smaller sample sizes in these groups. Conclusion The previously published PRS for diLQTS was validated in a large, real-world cohort, demonstrating its potential as a tool for identifying high-risk patients. Incorporating this PRS into routine clinical practice could enable proactive measures to prevent life-threatening diLQTS.