title: Pharmacogenetics of Drug-Induced QT Interval Prolongation: An Update.
abstract: A prolonged QT interval is an important risk factor for ventricular arrhythmias and sudden cardiac death. QT prolongation can be caused by drugs. There are multiple risk factors for drug-induced QT prolongation, including genetic variation. QT prolongation is one of the most common reasons for withdrawal of drugs from the market, despite the fact that these drugs may be beneficial for certain patients and not harmful in every patient. Identifying genetic variants associated with drug-induced QT prolongation might add to tailored pharmacotherapy and prevent beneficial drugs from being withdrawn unnecessarily. In this review, our objective was to provide an overview of the genetic background of drug-induced QT prolongation, distinguishing pharmacokinetic and pharmacodynamic pathways. Pharmacokinetic-mediated genetic susceptibility is mainly characterized by variation in genes encoding drug-metabolizing cytochrome P450 enzymes or drug transporters. For instance, the P-glycoprotein drug transporter plays a role in the pharmacokinetic susceptibility of drug-induced QT prolongation. The pharmacodynamic component of genetic susceptibility is mainly characterized by genes known to be associated with QT interval duration in the general population and genes in which the causal mutations of congenital long QT syndromes are located. Ethnicity influences susceptibility to drug-induced QT interval prolongation, with Caucasians being more sensitive than other ethnicities. Research on the association between pharmacogenetic interactions and clinical endpoints such as sudden cardiac death is still limited. Future studies in this area could enable us to determine the risk of arrhythmias more adequately in clinical practice.
authors.affiliation: Department of Epidemiology, Erasmus MC-University Medical Center Rotterdam, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.
authors.forename: Maartje N
authors.initials: MN
authors.lastname: Niemeijer
authors.affiliation: Department of Medical Informatics, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Marten E
authors.initials: ME
authors.lastname: van den Berg
authors.affiliation: Department of Epidemiology, Erasmus MC-University Medical Center Rotterdam, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.
authors.forename: Mark
authors.initials: M
authors.lastname: Eijgelsheim
authors.affiliation: Department of Medical Informatics, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Rijnbeek
authors.affiliation: Department of Epidemiology, Erasmus MC-University Medical Center Rotterdam, PO Box 2040, 3000 CA, Rotterdam, The Netherlands. b.stricker@erasmusmc.nl.|Department of Internal Medicine, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands. b.stricker@erasmusmc.nl.|Inspectorate of Health Care, Utrecht, The Netherlands. b.stricker@erasmusmc.nl.
authors.forename: Bruno H
authors.initials: BH
authors.lastname: Stricker
mesh_terms: D000818:Animals; D053840:Brugada Syndrome / Q000139:chemically induced / Q000235:genetics; D000075224:Cardiac Conduction System Disease; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000235:genetics*; D010597:Pharmacogenetics / Q000379:methods