A Gilbert's syndrome UGT1A1 variant confers susceptibility to tranilast-induced hyperbilirubinemia

Pharmacogenomics J. 2004;4(1):49-53. doi: 10.1038/sj.tpj.6500221.


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.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase III
  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dinucleotide Repeats / genetics
  • Double-Blind Method
  • Genetic Predisposition to Disease*
  • Genetic Variation
  • Gilbert Disease / enzymology*
  • Gilbert Disease / genetics*
  • Glucuronosyltransferase / genetics*
  • Humans
  • Hyperbilirubinemia / chemically induced
  • Hyperbilirubinemia / genetics*
  • Isoenzymes / genetics
  • Polymorphism, Genetic
  • Prospective Studies
  • ortho-Aminobenzoates / adverse effects*


  • Isoenzymes
  • ortho-Aminobenzoates
  • UGT1A1 enzyme
  • Glucuronosyltransferase
  • tranilast