Strauss David G, Vicente Jose, Johannesen Lars, Blinova Ksenia, Mason Jay W, Weeke Peter, Behr Elijah R, Roden Dan M, Woosley Ray, Kosova Gulum, Rosenberg Michael A, Newton-Cheh Christopher
From Office of Clinical Pharmacology, Center for Drug Evaluation and Research (D.G.S., J.V., L.J.) and Office of Science and Engineering Laboratories, Center for Devices and Radiological Health (D.G.S., J.V., L.J., K.B.), US Food and Drug Administration, Silver Spring, MD; BSICoS Group, Aragón Institute for Engineering Research (I3A), IIS Aragón, University of Zaragoza, Spain (J.V.); Department of Clinical Physiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden (L.J.); Division of Cardiology, University of Utah, Salt Lake City (J.W.M.); Spaulding Clinical Research, West Bend, WI (J.W.M.); Departments of Medicine (P.W., D.R.), Pharmacology (D.R.), and Biomedical Informatics (D.R.), Vanderbilt University Medical Center, Nashville, TN; Department of Cardiology, Copenhagen University Hospital, Gentofte, Denmark (P.W.); Cardiology Clinical Academic Group, St. George's University of London, London, UK (E.R.B.); AZCERT, Inc, Oro Valley, AZ (R.W.); Center for Genomic Medicine and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA (G.K., M.A.R., C.N.-C.); Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge (G.K., M.A.R., C.N.-C.); and Division of Cardiac Electrophysiology, Veterans Administration Hospital System of Boston, Harvard Medical School, West Roxbury, MA (M.A.R.).
Circulation. 2017 Apr 4;135(14):1300-1310. doi: 10.1161/CIRCULATIONAHA.116.023980. Epub 2017 Feb 17.
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a risk factor for life-threatening ventricular arrhythmias, is a potential side effect of many marketed and withdrawn medications.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.
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, crossover 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) versus drug concentration.
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 (=0.55; 95% confidence interval, 0.09-0.81; =0.02), 23% in response to quinidine (=0.48; 95% confidence interval, -0.03 to 0.79; =0.06), and 27% in response to ranolazine (=0.52; 95% confidence interval, 0.05-0.80; =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 with 771 controls (=12%, =1×10).
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 pharmacological 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.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01873950.
药物诱导的QT间期延长是危及生命的室性心律失常的一个危险因素，是许多已上市和已撤市药物的潜在副作用。先前与基线QT间期相关的常见基因变异对药物诱导的QT延长和心律失常的影响尚不清楚。
我们检验了这样一个假设，即通过全基因组关联研究确定的、对基线QT间期有贡献的常见基因变异的加权组合，可以预测个体对多种QT延长药物的反应。在一项随机、双盲、安慰剂对照、交叉试验的二次分析中，对22名受试者进行了基因分析，该试验使用了3种QT延长药物，并进行了15次时间匹配的QT和血浆药物浓度测量。受试者接受了单剂量的多非利特、奎尼丁、雷诺嗪和安慰剂。结果是一个包含61个常见基因变异的基因QT评分与个体受试者药物诱导的心率校正QT（QTc）增加斜率与药物浓度之间的相关性。
基因QT评分与药物诱导的QTc延长相关。在白人受试者中，基因QT评分解释了对多非利特反应变异性的30%（r=0.55；95%置信区间，0.09-0.81；P=0.02），对奎尼丁反应变异性的23%（r=0.48；95%置信区间，-0.03至0.79；P=0.06），以及对雷诺嗪反应变异性的27%（r=0.52；95%置信区间，0.05-0.80；P=0.03）。此外，在一个由216例病例和771例对照组成的独立样本中，基因QT评分是药物诱导的尖端扭转型室速的显著预测因子（OR=1.12，P=1×10⁻⁴）。
我们证明，一个包含61个常见基因变异的基因QT评分解释了药物诱导的QT延长变异性的很大一部分，并且是药物诱导的尖端扭转型室速的显著预测因子。这些发现凸显了近期基因发现为改善药物治疗的个体化风险效益评估带来的机遇。需要在更大样本中重复这些发现，以更精确地估计解释的方差，并确定驱动这些效应的个体变异。
