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A Common Genetic Variant Risk Score is Associated with Drug-Induced QT Prolongation and Torsade de Pointes Risk: A Pilot Study.

Strauss, DG; Vicente, J; Johannesen, L; Blinova, K; Mason, JW; Weeke, P; Behr, ER; Roden, DM; Woosley, R; Kosova, G; et al. Strauss, DG; Vicente, J; Johannesen, L; Blinova, K; Mason, JW; Weeke, P; Behr, ER; Roden, DM; Woosley, R; Kosova, G; Rosenberg, MA; Newton-Cheh, C (2017) A Common Genetic Variant Risk Score is Associated with Drug-Induced QT Prolongation and Torsade de Pointes Risk: A Pilot Study. Circulation, 135 (14). pp. 1300-1310. ISSN 1524-4539 https://doi.org/10.1161/CIRCULATIONAHA.116.023980
SGUL Authors: Behr, Elijah Raphael

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Abstract

Background -Drug-induced QT interval prolongation, a risk factor for life-threatening ventricular arrhythmias, is a potential side effect of many marketed and withdrawn medications. The contribution of common genetic variants previously associated with baseline QT interval to drug-induced QT prolongation and arrhythmias is not known. Methods -We tested the hypothesis that a weighted combination of common genetic variants contributing to QT interval at baseline, identified through genome-wide association studies, can predict individual response to multiple QT-prolonging drugs. Genetic analysis of 22 subjects was performed in a secondary analysis of a randomized, double-blind, placebo-controlled, cross-over trial of 3 QT-prolonging drugs with 15 time-matched QT and plasma drug concentration measurements. Subjects received single doses of dofetilide, quinidine, ranolazine and placebo. The outcome was the correlation between a genetic QT score comprising 61 common genetic variants and the slope of an individual subject's drug-induced increase in heart rate corrected QT (QTc) vs. drug concentration. Results -The genetic QT score was correlated with drug-induced QTc prolongation. Among white subjects, genetic QT score explained 30% of the variability in response to dofetilide (r = 0.55 [95% CI, 0.09-0.81], P = 0.02), 23% in response to quinidine (r = 0.48 [95% CI, -0.03 to 0.79], P = 0.06) and 27% in response to ranolazine (r = 0.52 [95% CI, 0.05 to 0.80], P = 0.03). Furthermore, the genetic QT score was a significant predictor of drug-induced torsade de pointes in an independent sample of 216 cases compared to 771 controls (r(2) = 12%, P = 1x10(-7)). Conclusions -We demonstrate that a genetic QT score comprising 61 common genetic variants explains a significant proportion of the variability in drug-induced QT prolongation and is a significant predictor of drug-induced torsade de pointes. These findings highlight an opportunity for recent genetic discoveries to improve individualized risk-benefit assessment for pharmacologic therapies. Replication of these findings in larger samples is needed to more precisely estimate variance explained and to establish the individual variants that drive these effects. Clinical Trial Registration - http://clinicaltrials.gov Unique identifier: NCT01873950.

Item Type: Article
Additional Information: This is a non-final version of an article published in final form in Strauss, DG; Vicente, J; Johannesen, L; Blinova, K; Mason, JW; Weeke, P; Behr, ER; Roden, DM; Woosley, R; Kosova, G; et al. (2017) A Common Genetic Variant Risk Score is Associated with Drug-Induced QT Prolongation and Torsade de Pointes Risk: A Pilot Study. Circulation, 135 (14). pp. 1300-1310.
Keywords: antiarrhythmia agent, drug therapy, genetic testing, genetics, diagnostics, genomics, pharmacogenomics, Cardiovascular System & Hematology, 1103 Clinical Sciences, 1102 Cardiovascular Medicine And Haematology, 1117 Public Health And Health Services
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cardiac (INCCCA)
Journal or Publication Title: Circulation
ISSN: 1524-4539
Language: eng
Dates:
DateEvent
4 April 2017Published
17 February 2017Published Online
26 January 2017Accepted
Publisher License: Publisher's own licence
Projects:
Project IDFunderFunder ID
HL124262National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
U19HL65962Fondation Leducqhttp://dx.doi.org/10.13039/501100001674
P50GM115305Fondation Leducqhttp://dx.doi.org/10.13039/501100001674
SP/02/001British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
PubMed ID: 28213480
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/108622
Publisher's version: https://doi.org/10.1161/CIRCULATIONAHA.116.023980

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