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  3. Common Genetic Variant Risk Score Is Associated With Drug-induced Qt Prolongation And Torsade De Pointes Risk: A Pilot Study.
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  3. Common Genetic Variant Risk Score Is Associated With Drug-induced Qt Prolongation And Torsade De Pointes Risk: A Pilot Study.

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Common Genetic Variant Risk Score Is Associated With Drug-Induced QT Prolongation and Torsade de Pointes Risk: A

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.

Circulation
|February 19, 2017

View abstract on PubMed

Summary
This summary is machine-generated.

A genetic QT score, using 61 common variants, predicts drug-induced QT prolongation and torsade de pointes risk. This genetic insight aids personalized medicine by assessing individual responses to QT-prolonging drugs.

Keywords:
anti-arrhythmia agentsdrug therapygenetic testinggeneticsgenomicspharmacogeneticstorsade de pointes

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Area of Science:

  • Pharmacogenomics
  • Cardiology
  • Genetics

Background:

  • Drug-induced QT interval prolongation is a risk factor for life-threatening ventricular arrhythmias.
  • The role of common genetic variants in drug-induced QT prolongation is not well understood.

Purpose of the Study:

  • To test if a weighted genetic QT score predicts individual responses to QT-prolonging drugs.
  • To assess the correlation between a genetic QT score and drug-induced QTc prolongation.

Main Methods:

  • Secondary analysis of a randomized, double-blind, placebo-controlled, crossover trial.
  • Genetic analysis of 22 subjects receiving dofetilide, quinidine, ranolazine, and placebo.
  • Correlation of a 61-variant genetic QT score with QTc prolongation versus drug concentration.

Main Results:

  • The genetic QT score explained 23-30% of variability in drug-induced QTc prolongation in white subjects.
  • The genetic QT score significantly predicted drug-induced torsade de pointes in an independent case-control sample (P=1x10^-7).

Conclusions:

  • A genetic QT score comprising 61 common variants significantly predicts drug-induced QT prolongation and torsade de pointes.
  • Genetic discoveries offer potential for improved individualized risk-benefit assessment of medications.
  • Further replication in larger samples is needed to validate findings and identify specific causal variants.