title: A Gilbert's syndrome UGT1A1 variant confers susceptibility to tranilast-induced hyperbilirubinemia.
abstract: Tranilast (N-(3'4'-demethoxycinnamoyl)-anthranilic acid (N-5)) is an investigational drug for the prevention of restenosis following percutaneous transluminal coronary revascularization. An increase in bilirubin levels was observed in 12% of patients upon administration of tranilast in a phase III clinical trial. To identify the potential genetic factors that may account for the drug-induced hyperbilirubinemia, we examined polymorphisms in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene in over a thousand patients. Our results suggested that the TA repeat polymorphism in UGT1A1, which predisposes some individuals to Gilbert's syndrome, predicted the susceptibility to tranilast-induced hyperbilirubinemia. The (TA)(7)/(TA)(7) genotype was present in 39% of the 127 hyperbilirubinemic patients vs 7% of the 909 controls (P=2 x 10(-22)). Rapid identification of genetic factors accounting for the observed adverse effect during the course of a double-blind clinical trial demonstrated the potential application of pharmacogenetics in the clinical development of safe and effective medicines.
authors.affiliation: Clinical Pharmacology and Discovery Medicine, GlaxoSmithKline, Philadelphia, PA, USA.
authors.forename: T M
authors.initials: TM
authors.lastname: Danoff
authors.forename: D A
authors.initials: DA
authors.lastname: Campbell
authors.forename: L C
authors.initials: LC
authors.lastname: McCarthy
authors.forename: K F
authors.initials: KF
authors.lastname: Lewis
authors.forename: M H
authors.initials: MH
authors.lastname: Repasch
authors.forename: A M
authors.initials: AM
authors.lastname: Saunders
authors.forename: N K
authors.initials: NK
authors.lastname: Spurr
authors.forename: I J
authors.initials: IJ
authors.lastname: Purvis
authors.forename: A D
authors.initials: AD
authors.lastname: Roses
authors.forename: C-F
authors.initials: CF
authors.lastname: Xu
mesh_terms: D018900:Dinucleotide Repeats / Q000235:genetics; D004311:Double-Blind Method; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005878:Gilbert Disease / Q000201:enzymology* / Q000235:genetics*; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D006932:Hyperbilirubinemia / Q000139:chemically induced / Q000235:genetics*; D007527:Isoenzymes / Q000235:genetics; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D062367:ortho-Aminobenzoates / Q000009:adverse effects*; D000099148:UGT1A1 Enzyme
chemical_list: D014453:Glucuronosyltransferase; D007527:Isoenzymes; D062367:ortho-Aminobenzoates; D000099148:UGT1A1 Enzyme; C012293:tranilast