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

Abstract

AbstractBackgroundDrug-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 (ΔQTc). 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 (ΔQTc≥60 ms) and those with ΔQTc<60ms was assessed by Mann Whitney test. A multivariable regression model was used to assess the association between PRS and ΔQTc 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 ΔQTc 3 hours post-sotalol was 21 ms (IQR 12-30). Ten subjects (1%) had ΔQTc≥60 ms, and their PRS was significantly higher compared to those with ΔQTc<60 ms (P=0.0082). In the regression model, PRS was positively associated with ΔQTc (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.