title: Pharmacogenetic analysis of adverse drug effect reveals genetic variant for susceptibility to liver toxicity.
abstract: A retrospective pharmacogenetic study was conducted to identify possible genetic susceptibility factors in patients in whom the administration of the anti-Parkinson drug, tolcapone (TASMAR), was associated with hepatic toxicity. We studied 135 cases of patients with elevated liver transaminase levels (ELT) of >/=1.5 times above the upper limit of normal, in comparison with matched controls that had also received the drug but had not experienced ELT. DNA samples were genotyped for 30 previously described or newly characterized bi-allelic single nucleotide polymorphisms (SNPs), representing 12 candidate genes selected based on the known metabolic pathways involved in the tolcapone elimination. SNPs located within the UDP-glucuronosyl transferase 1A gene complex, which codes for the enzymes involved in the main elimination pathway of the drug, were found to be significantly associated with the occurrence of tolcapone-associated ELTs.
authors.affiliation: F Hoffmann-La Roche Ltd, Basel, Switzerland. gonzalo.acuna@roche.com
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Acuña
authors.forename: Dorothee
authors.initials: D
authors.lastname: Foernzler
authors.forename: Diane
authors.initials: D
authors.lastname: Leong
authors.forename: Michael
authors.initials: M
authors.lastname: Rabbia
authors.forename: Ralf
authors.initials: R
authors.lastname: Smit
authors.forename: Ernest
authors.initials: E
authors.lastname: Dorflinger
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Gasser
authors.forename: Josephine
authors.initials: J
authors.lastname: Hoh
authors.forename: Jürg
authors.initials: J
authors.lastname: Ott
authors.forename: Edilio
authors.initials: E
authors.lastname: Borroni
authors.forename: Zung
authors.initials: Z
authors.lastname: To
authors.forename: Annick
authors.initials: A
authors.lastname: Thompson
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.forename: Lara
authors.initials: L
authors.lastname: Hashimoto
authors.forename: Klaus
authors.initials: K
authors.lastname: Lindpaintner
mesh_terms: D001577:Benzophenones / Q000009:adverse effects* / Q000627:therapeutic use; D016001:Confidence Intervals; D005260:Female; D005820:Genetic Testing / Q000379:methods; D014644:Genetic Variation / Q000235:genetics; D014453:Glucuronosyltransferase / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D009596:Nitrophenols; D016017:Odds Ratio; D010597:Pharmacogenetics / Q000379:methods* / Q000706:statistics & numerical data; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012189:Retrospective Studies; D000077867:Tolcapone
chemical_list: D001577:Benzophenones; D009596:Nitrophenols; D000077867:Tolcapone; C110655:UDP-glucuronosyltransferase, UGT1A6; D014453:Glucuronosyltransferase