GENomE wide analysis of sotalol-induced IKr inhibition during ventricular REPOLarization, "GENEREPOL study": Lack of common variants with large effect sizes
- PMID: 28800628
- PMCID: PMC5553738
- DOI: 10.1371/journal.pone.0181875
GENomE wide analysis of sotalol-induced IKr inhibition during ventricular REPOLarization, "GENEREPOL study": Lack of common variants with large effect sizes
Abstract
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.
Conflict of interest statement
Figures



Similar articles
-
Identify drug-induced T wave morphology changes by a cell-to-electrocardiogram model and validation with clinical trial data.J Electrocardiol. 2009 Nov-Dec;42(6):534-42. doi: 10.1016/j.jelectrocard.2009.07.010. Epub 2009 Aug 22. J Electrocardiol. 2009. PMID: 19700171
-
The time course of new T-wave ECG descriptors following single- and double-dose administration of sotalol in healthy subjects.Ann Noninvasive Electrocardiol. 2010 Jan;15(1):26-35. doi: 10.1111/j.1542-474X.2009.00336.x. Ann Noninvasive Electrocardiol. 2010. PMID: 20146779 Free PMC article.
-
Electrocardiographic markers of repolarization heterogeneity during dofetilide or sotalol initiation for paroxysmal atrial fibrillation.Am J Cardiol. 2014 Jun 15;113(12):2030-5. doi: 10.1016/j.amjcard.2014.03.047. Epub 2014 Apr 1. Am J Cardiol. 2014. PMID: 24793679
-
[Ventricular arrhythmias. A potential risk associated with the use of non-cardiovascular drugs prolonging the QT interval].Minerva Med. 2002 Jun;93(3):181-97. Minerva Med. 2002. PMID: 12094149 Review. Italian.
-
Electrophysiologic properties of sotalol and d-sotalol. A current view.Eur Heart J. 1993 Nov;14 Suppl H:24-9. doi: 10.1093/eurheartj/14.suppl_h.24. Eur Heart J. 1993. PMID: 7904935 Review.
Cited by
-
Pharmacogenomic markers associated with drug-induced QT prolongation: a systematic review.Pharmacogenomics. 2025 Jan-Feb;26(1-2):53-72. doi: 10.1080/14622416.2025.2481025. Epub 2025 Mar 21. Pharmacogenomics. 2025. PMID: 40116580
-
Association of Thyroid Function Genetic Predictors With Atrial Fibrillation: A Phenome-Wide Association Study and Inverse-Variance Weighted Average Meta-analysis.JAMA Cardiol. 2019 Feb 1;4(2):136-143. doi: 10.1001/jamacardio.2018.4615. JAMA Cardiol. 2019. PMID: 30673079 Free PMC article.
-
Androgenic Effects on Ventricular Repolarization: A Translational Study From the International Pharmacovigilance Database to iPSC-Cardiomyocytes.Circulation. 2019 Sep 24;140(13):1070-1080. doi: 10.1161/CIRCULATIONAHA.119.040162. Epub 2019 Aug 5. Circulation. 2019. PMID: 31378084 Free PMC article.
-
Association of Oral Contraceptives With Drug-Induced QT Interval Prolongation in Healthy Nonmenopausal Women.JAMA Cardiol. 2018 Sep 1;3(9):877-882. doi: 10.1001/jamacardio.2018.2251. JAMA Cardiol. 2018. PMID: 30073300 Free PMC article.
-
A Polygenic Predictor of Baseline QTc is Associated With Sotalol-Induced QT Prolongation.Circulation. 2024 Dec 10;150(24):1984-1986. doi: 10.1161/CIRCULATIONAHA.124.070337. Epub 2024 Dec 9. Circulation. 2024. PMID: 39652646 No abstract available.
References
-
- Kannankeril P, Roden DM, Darbar D. Drug-induced long QT syndrome. Pharmacol Rev. 2010; 62(4):760–81. doi: 10.1124/pr.110.003723 - DOI - PMC - PubMed
-
- Roden DM. Cellular basis of drug-induced torsades de pointes. Br J Pharmacol. 2008;154(7):1502–7. doi: 10.1038/bjp.2008.238 - DOI - PMC - PubMed
-
- Lupoglazoff JM, Denjoy I, Berthet M, Neyroud N, Demay L, Richard P, et al. Notched T waves on Holter recordings enhance detection of patients with LQt2 (HERG) mutations. Circulation. 2001;103(8):1095–101. - PubMed
-
- Graff C, Andersen MP, Xue JQ, Hardahl TB, Kanters JK, Toft E, et al. Identifying drug-induced repolarization abnormalities from distinct ECG patterns in congenital long QT syndrome: a study of sotalol effects on T-wave morphology. Drug Saf. 2009;32(7):599–611. doi: 10.2165/00002018-200932070-00006 - DOI - PubMed
-
- Malfatto G, Beria G, Sala S, Bonazzi O, Schwartz PJ. Quantitative analysis of T wave abnormalities and their prognostic implications in the idiopathic long QT syndrome. J Am Coll Cardiol. 1994;23(2):296–301. - PubMed
MeSH terms
Substances
Associated data
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical