A polygenic predictor of baseline QTc is associated with sotalol-induced QT prolongation

Abstract

BackgroundDrug-induced QT interval prolongation raises the risk of fatal arrhythmia and is a central issue in safety pharmacology. Yet individual QT drug response is highly variable, and risk stratification remains a challenge. We hypothesized that genetic factors underlying the baseline QT influence this variation in QT drug response. MethodsA cohort of 990 healthy subjects was prospectively challenged with a single 80 mg oral sotalol dose. Exclusion criteria included abnormal ECG, cardiac disease, and QT-prolonging drug use. ECGs were obtained at baseline and 3 hours post-dose. QT response was defined as absolute change in Fridericia heart-rate corrected QT ({Delta}QTc). Plasma sotalol was measured 3 hours post-dose. Subjects were genotyped on the MEGA array. Principal component analysis of genotypes was used to define genetic ancestry. A polygenic risk score (PRS) for the baseline QTc comprised of 465,399 common variants was calculated from assayed and imputed genotypes. The difference in PRS between subjects with high QT response ({Delta}QTc[≥]60 ms) and those with {Delta}QTc<60ms was assessed by Mann Whitney test. A multivariable regression model was used to assess the association between PRS and {Delta}QTc after covariate adjustment. Results: Of the 990 subjects, 978 (99%) passed genomic quality control and were included in analysis. 62% were female (n=607), with median age 23 (interquartile range (IQR) 21-33). The median {Delta}QTc 3 hours post-sotalol was 21 ms (IQR 12-30). Ten subjects (1%) had {Delta}QTc[≥]60 ms, and their PRS was significantly higher compared to those with {Delta}QTc<60 ms (P=0.0082). In the regression model, PRS was positively associated with {Delta}QTc (P=0.0002). ConclusionCommon genetic variants associated with the baseline QT also capture part of the repolarization response to sotalol. This adds to the emerging concept that the genetic architecture of a trait can predict drug response.