常见的遗传变异风险得分与药物诱导的QT延长和Torsade de Pointes风险相关:试点研究
David G Strauss1, Jose Vicente2, Lars Johannesen2
1From 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.). david.strauss@fda.hhs.gov cnewtoncheh@mgh.harvard.edu.
基因QT得分,使用61种常见变异,预测药物诱导的QT延长和torsade de pointes风险. 这种基因洞察力有助于通过评估个体对QT延长药物的反应来个性化医疗.
科学领域:
- 药物基因组学
- 心脏病学
- 遗传学
背景情况:
- 药物诱导的QT间隔延长是危及生命的腹腔失常的危险因素.
- 常见的基因变异在药物诱导的QT延长中的作用尚不清楚.
研究的目的:
- 测试加权基因QT评分是否预测QT延长药物的个体反应.
- 评估基因QT分数与药物诱导的QTc延长之间的相关性.
主要方法:
- 一个随机,双盲,安慰剂控制的交叉试验的二次分析.
- 对22名接受多费提利德,素,拉诺拉和安慰剂的患者进行基因分析.
- 61个基因QT分数与QTc延长与药物度的相关性.
主要成果:
- 基因QT分数解释了白人药物诱导的QTc延长的23- 30%的变化.
- 在一个独立的病例对照样本中,基因QT得分显著预测了药物诱导的Torsade de pointes (P=1x10-7).
结论:
- 一个包含61种常见变异的基因QT得分显著预测药物诱导的QT延长和torsade de pointes.
- 基因发现有助于对药物的风险和益处进行个性化评估.
- 需要在更大的样本中进行进一步复制,以验证发现并确定特定的因果变异.
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