Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Aug 11;12(8):e0181875.
doi: 10.1371/journal.pone.0181875. eCollection 2017.

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

Joe-Elie Salem  1   2 , Marine Germain  2 , Jean-Sébastien Hulot  1   2 , Pascal Voiriot  3 , Bruno Lebourgeois  1 , Jean Waldura  3 , David-Alexandre Tregouet  1 , Beny Charbit  2 , Christian Funck-Brentano  1   2
Affiliations

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

Joe-Elie Salem et al. PLoS One. .

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.

PubMed Disclaimer

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Flow chart of the study.
Fig 2
Fig 2. Typical QT and T-wave changes (A) in a subject with a pronounced sotalol-induced IKr inhibition indicated by a notch and (B) in a subject with minimal sotalol-induced IKr inhibition.
The PC1 values and distribution of discovery cohort are shown. PC1 is issued from principal component analysis of ΔQTc, ΔTpTe and ΔTAmp. “Notcher” subjects are represented in red and “non notcher” in black.
Fig 3
Fig 3. Correlations between ΔQTcF (%), ΔTpTe (%) and ΔTAmp (%) in the discovery (Adisc-Cdisc, n = 489) and replication cohort (Arep-Crep, n = 495).
“Notcher” subjects are represented in red.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. 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
    1. 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
    1. 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
    1. 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
    1. 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

Associated data