GENomE wide analysis of sotalol-induced IKr inhibition during ventricular REPOLarization, “GENEREPOL study”: Lack of common variants with large effect sizes

Many drugs used for non-cardiovascular and cardiovascular purposes, such as sotalol, have the side effect of prolonging cardiac repolarization, which can trigger life-threatening cardiac arrhythmias by inhibiting the potassium-channel IKr (KCNH2). On the electrocardiogram (ECG), IKr inhibition induces an increase in QTc and Tpeak-Tend (TpTe) interval and a decrease of T wave maximal amplitude (TAmp). These changes vary markedly between subjects, suggesting the existence of predisposing genetic factors. 990 healthy individuals, prospectively challenged with an oral 80mg sotalol dose, were monitored for changes in ventricular repolarization on ECG between baseline and 3 hours post dosing. QTc and TpTe increased by 5.5±3.5% and 15±19.6%, respectively, and TAmp decreased by 13.2±15.5%. A principal-component analysis derived from the latter ECG changes was performed. A random subsample of 489 individuals were subjected to a genome-wide-association analysis where 8,306,856 imputed single nucleotide polymorphisms (SNPs) were tested for association with QTc, TpTe and TAmp modulations, as well their derived principal-components, to search for common genetic variants associated with sotalol-induced IKr inhibition. None of the studied SNPs reached the statistical threshold for genome-wide significance. This study supports the lack of common variants with larger effect sizes than one would expect based on previous ECG genome-wide-association studies. Clinical trial registration: ClinicalTrials.gov NCT00773201