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

Abstract

Tranilast (N-(3 0 4 0 -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 ¼ 2 Â 10 À22 ). 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.

Comparative genomics analysis of human sequence variation in the UGT1A gene cluster

“…62 For the agent tranilast, a phase III clinical trial failed to demonstrate significant reduction of restenosis after coronary artery stenting, 63 but with an appropriately powered, retrospective, genome-wide analysis, UGT1A1*28 was identified as a predictor of a common toxicity of tranilast -hyperbilirubinemia. 27,28,64 As early studies suggested this specific dinucleotide repeat to be important to clinical phenotypes, its variability among primates and human populations has been extensively characterized. 65,66 However, other sites within the UGT1A locus may modify UGT1A1*28-associated phenotypes.…”

“…27 A staged, genome-wide analysis has associated three single nucleotide polymorphisms (SNPs) of the UGT1A locus with this toxicity. 28 Although it is reasonable to assume that the association between hyperbilirubinemia and these pharmacologic agents is based on genetic variation at UGT1A1, for other metabolic/ toxicologic phenotypes of UGT1A, the overlapping tissue distributions and substrate affinities of enzymes encoded by this locus may complicate interpretation of single genotype or single exon-haplotype association studies.…”

Pazopanib-induced hyperbilirubinemia is associated with Gilbert's syndrome UGT1A1 polymorphism

“…The UGT1A1 genetic variant TA7 is known to cause reduced expression of UGT1A1 (Bosma et al, 1995), and the TA7/TA7 (*28/*28) genotype predisposes individuals to Gilbert's syndrome, a benign form of episodic jaundice (Bosma et al, 1995;Raijmakers et al, 2000). This UGT1A1 TA-repeat polymorphism has also been reported to be associated with hyperbilirubinemia induced by several drugs, such as tranilast, nilotinib, and indinavir (Zucker et al, 2001;Danoff et al, 2004;Singer et al, 2007). Pazopanib is a potent inhibitor of UGT1A1 activity in vitro, with an IC 50 of 1.2 mM.…”

UGT1A1 promoter polymorphism increases risk of nilotinib-induced hyperbilirubinemia

“…6 The (TA) 7 allele, whether homozygous or heterozygous, confers a increased risk of leukopenia and diarrhea during irinotecan treatment. 7,8 The homozygous (TA) 7 /(TA) 7 genotype (henceforth referred to as '7/7') has also been associated with increased risk of hyperbilirubinemia during treatment with the anti-restenosis drug tranilast 9 and the anti-HIV treatment indinavir. 10 Nilotinib is a novel inhibitor of the BCR-ABL chimeric kinase that causes chronic myeloid leukemia (CML).…”