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

Background Drug-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. Methods A 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). Conclusion Common 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. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT00773201 ### Funding Statement The clinical study was supported by a grant from INSERM/DHOS (Clinical and Translational Research award 2007, RCT07002) and by the French Ministry of Health (PHRC2008-AOR08004). Dr. Lancaster was supported by the National Institutes of Health T32 HG008962. Dr. Davogustto was supported by the American Heart Association SFRN grant. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study protocol and all methods applied were approved by the Committee for the Protection of Human Subjects of Paris Ile de France V (Paris, France) and prior written informed consent was obtained from all subjects after being fully informed regarding the nature and risks of the study. We did the study in accordance with the principles of the international conference on harmonization guidelines on good clinical practice and the world medical association declaration of Helsinki. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Summary level data produced in the present study are available upon reasonable request to the authors. To avoid subject reidentification, subject-level data will not be available.