title: KCNH2 polymorphism and methadone dosage interact to enhance QT duration.
abstract: BACKGROUND
  Many drugs increase the duration of the QT interval of patients, potentially leading to harmful effects such as polymorphic ventricular arrhythmias. Most of these drugs do so by inhibiting the rapid component IKr of the delayed rectifier potassium current IK. Methadone is the most prescribed heroin maintenance treatment and is known to inhibit the cardiac potassium channel hERG, which recapitulates IKr. In order to evaluate if any polymorphism of potassium channels' genes could explain some of the "idiosyncratic" QT prolongations observed in patients treated with methadone, we tested the association between KCNE1, KCNE2, and KCNH2 polymorphism and the QT interval prolongation in those patients, controlling for other variables associated with a decrease of the repolarizing reserve.
  
  
  METHODS
  A cohort of 82 patients treated with stable dosage of methadone (mean dosage 65 mg/d) for at least three months was genotyped for five polymorphisms in KCNE1, KCNE2 and KCNH2 genes and had their corrected QT (QTc) assessed.
  
  
  RESULTS
  The mean QTc interval was 415±34ms. In a linear regression model, longer QTc interval was associated with methadone dosage and with one genetic factor. Each copy of a Lys allele at codon 897 of KCNH2, the gene that encodes the cardiac potassium voltage-gated channel hERG, was associated with a 15.4ms longer QTc (95% CI [4.6-26.2]; p=0.001).
  
  
  CONCLUSIONS
  KCNH2 genotyping may be relevant in the analysis of cumulative risk factors for QT prolongation in patients on methadone maintenance treatment.
authors.affiliation: INSERM UMR-S 1144, Variabilité de la Réponse aux Psychotropes, Université Paris Descartes, Université Paris Diderot, PRES Sorbonne Paris Cité, Hôpital Fernand Widal, 200 rue du Fg St Denis, 75010 Paris, France; AP-HP, Hôpital Lariboisière, Service de Biochimie et Biologie moléculaire, 2 rue Ambroise Paré, 75010 Paris, France; Pharmacology Unit, Pharmacokinetics and Clinical Pharmacy, Faculty of Pharmacy, Saint Joseph University, Beirut, Lebanon.
authors.forename: Aline
authors.initials: A
authors.lastname: Hajj
authors.affiliation: INSERM UMR-S 1144, Variabilité de la Réponse aux Psychotropes, Université Paris Descartes, Université Paris Diderot, PRES Sorbonne Paris Cité, Hôpital Fernand Widal, 200 rue du Fg St Denis, 75010 Paris, France; AP-HP, Hôpital Fernand Widal, Service de Psychiatrie, 200 rue du Fg St Denis, 75010 Paris, France.
authors.forename: Kamilia
authors.initials: K
authors.lastname: Ksouda
authors.affiliation: INSERM UMR-S 1144, Variabilité de la Réponse aux Psychotropes, Université Paris Descartes, Université Paris Diderot, PRES Sorbonne Paris Cité, Hôpital Fernand Widal, 200 rue du Fg St Denis, 75010 Paris, France; AP-HP, Hôpital Lariboisière, Service de Biochimie et Biologie moléculaire, 2 rue Ambroise Paré, 75010 Paris, France.
authors.forename: Katell
authors.initials: K
authors.lastname: Peoc'h
authors.affiliation: INSERM UMR-S 1144, Variabilité de la Réponse aux Psychotropes, Université Paris Descartes, Université Paris Diderot, PRES Sorbonne Paris Cité, Hôpital Fernand Widal, 200 rue du Fg St Denis, 75010 Paris, France; Université Paris Descartes, Faculté de Pharmacie, Département de Biostatistiques, 4 avenue de l'Observatoire, 75006 Paris, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Curis
authors.affiliation: AP-HP, Hôpital Lariboisière, Service de Cardiologie, 2 rue Ambroise Paré, 75010 Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Messali
authors.affiliation: AP-HP, Hôtel Dieu Service de Pharmacie - Pharmacologie - Toxicologie, 1 place du Parvis Notre Dame, 75004 Paris, France.
authors.forename: Laurence Labat
authors.initials: LL
authors.lastname: Deveaux
authors.affiliation: INSERM UMR-S 1144, Variabilité de la Réponse aux Psychotropes, Université Paris Descartes, Université Paris Diderot, PRES Sorbonne Paris Cité, Hôpital Fernand Widal, 200 rue du Fg St Denis, 75010 Paris, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Bloch
authors.affiliation: INSERM UMR-S 1144, Variabilité de la Réponse aux Psychotropes, Université Paris Descartes, Université Paris Diderot, PRES Sorbonne Paris Cité, Hôpital Fernand Widal, 200 rue du Fg St Denis, 75010 Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Prince
authors.affiliation: INSERM UMR-S 1144, Variabilité de la Réponse aux Psychotropes, Université Paris Descartes, Université Paris Diderot, PRES Sorbonne Paris Cité, Hôpital Fernand Widal, 200 rue du Fg St Denis, 75010 Paris, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Mouly
authors.affiliation: INSERM UMR-S 1144, Variabilité de la Réponse aux Psychotropes, Université Paris Descartes, Université Paris Diderot, PRES Sorbonne Paris Cité, Hôpital Fernand Widal, 200 rue du Fg St Denis, 75010 Paris, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Scherrmann
authors.affiliation: INSERM UMR-S 1144, Variabilité de la Réponse aux Psychotropes, Université Paris Descartes, Université Paris Diderot, PRES Sorbonne Paris Cité, Hôpital Fernand Widal, 200 rue du Fg St Denis, 75010 Paris, France; AP-HP, Hôpital Fernand Widal, Service de Psychiatrie, 200 rue du Fg St Denis, 75010 Paris, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Lépine
authors.affiliation: INSERM UMR-S 1144, Variabilité de la Réponse aux Psychotropes, Université Paris Descartes, Université Paris Diderot, PRES Sorbonne Paris Cité, Hôpital Fernand Widal, 200 rue du Fg St Denis, 75010 Paris, France; AP-HP, Hôpital Lariboisière, Service de Biochimie et Biologie moléculaire, 2 rue Ambroise Paré, 75010 Paris, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Laplanche
authors.affiliation: Service de Pharmacologie, Hôpital Pasteur, 06000 Nice, France.
authors.forename: Milou-Daniel
authors.initials: MD
authors.lastname: Drici
authors.affiliation: INSERM UMR-S 1144, Variabilité de la Réponse aux Psychotropes, Université Paris Descartes, Université Paris Diderot, PRES Sorbonne Paris Cité, Hôpital Fernand Widal, 200 rue du Fg St Denis, 75010 Paris, France; AP-HP, Hôpital Fernand Widal, Service de Psychiatrie, 200 rue du Fg St Denis, 75010 Paris, France. Electronic address: florence.vorspan@lrb.aphp.fr.
authors.forename: Florence
authors.initials: F
authors.lastname: Vorspan
mesh_terms: D000328:Adult; D000368:Aged; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics*; D005260:Female; D059647:Gene-Environment Interaction; D005838:Genotype; D006321:Heart / Q000187:drug effects; D006329:Heart Conduction System / Q000187:drug effects*; D006556:Heroin Dependence / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced / Q000235:genetics; D008297:Male; D008691:Methadone / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D008875:Middle Aged; D009294:Narcotics / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D058850:Opiate Substitution Treatment; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D009294:Narcotics; D008691:Methadone
keywords: Channelopathies; Methadone; QT interval; Repolarization reserve