Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

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

The Pharmacogenomics Journal volume 4, pages 49–53 (2004)Cite this article

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 × 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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

Abbreviations

PRESTO:

Prevention of REStenosis with Tranilast and its Outcomes

PTCR:

percutaneous transluminal coronary revascularization

SNP:

single-nucleotide polymorphism

UGT1A1:

uridine diphosphate glucuronosyltransferase 1A1

References

  1. Nobuyoshi M, Kimura T, Nosaka H, Mioka S, Ueno K, Yokoi H et al. Restenosis after successful percutaneous transluminal coronary angioplasty: serial angiographic follow-up of 229 patients. J Am Coll Cardiol 1988; 12: 616–623.

    Article  CAS  PubMed  Google Scholar 

  2. Tamai H, Katoh O, Suzuki S, Fujii K, Aizawa T, Takase S et al. Impact of tranilast on restenosis after coronary angioplasty: tranilast restenosis following angioplasty trial (TREAT). Am Heart J 1999; 138: 968–975.

    Article  CAS  PubMed  Google Scholar 

  3. Holmes D, Fitzgerald P, Goldberg S, LaBlanche J, Lincoff AM, Savage M et al. The PRESTO (Prevention of restenosis with tranilast and its outcomes) protocol: a double-blind, placebo-controlled trial. Am Heart J 2000; 139: 23–31.

    Article  CAS  PubMed  Google Scholar 

  4. Bosma PJ, Seppen J, Goldhoorn B, Bakker C, Oude Elferink RP, Chowdhury JR et al. Bilirubin UDP-glucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man. J Biol Chem 1994; 269: 17960–17964.

    CAS  PubMed  Google Scholar 

  5. Crigler JF, Najjar VA . Congenital familial non-hemolytic jaundice with kernicterus. Pediatrics 1952; 10: 169–180.

    PubMed  Google Scholar 

  6. Seppen J, Bosma PJ, Goldhoorn BG, Bakker CT, Chowdhury JR, Chowdhury NR et al. Discrimination between Crigler–Najjar type I and II by expression of mutant bilirubin uridine diphosphate-glucuronosyltransferase. J Clin Invest 1994; 94: 2385–2391.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Tukey RH, Strassburg CP . Human UDP-glucuronosyltransferases: metabolism, expression, and disease. Ann Rev Pharmacol Toxicol 2000; 40: 581–616.

    Article  CAS  Google Scholar 

  8. Kadakol A, Ghosh SS, Sappal BS, Sharma G, Chowdhury JR, Chowdhury NR . Genetic lesions of bilirubin uridine-diphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler–Najjar and Gilbert syndromes: correlation of genotype to phenotype. Hum Mutat 2000; 16: 297–306.

    Article  CAS  PubMed  Google Scholar 

  9. Gilbert NA, Lereboullet P . La cholémie simple familiale. Sein Méd 1901; 21: 241–243.

    Google Scholar 

  10. Owens D, Evans J . Population studies on Gilbert's syndrome. J Med Genet 1975; 12: 152–156.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bailey A, Robinson D, Dawson AM . Does Gilbert's disease exist? Lancet 1977; 1: 931–933.

    Article  CAS  PubMed  Google Scholar 

  12. Black M, Billing BH . Hepatic bilirubin UDP-glucuronyl transferase activity in liver disease and Gilbert's syndrome. N Engl J Med 1969; 280: 1266–1271.

    Article  CAS  PubMed  Google Scholar 

  13. Bosma PJ, Chowdhury JR, Bakker C, Gantla S, de Boer A, Oostra BA et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. N Engl J Med 1995; 333: 1171–1175.

    Article  CAS  PubMed  Google Scholar 

  14. Aono S, Adachi Y, Uyama E, Yamada Y, Keino H, Nanno T et al. Analysis of genes for bilirubin UDP-glucuronosyltransferase in Gilbert's syndrome. Lancet 1995; 345: 958–959.

    Article  CAS  PubMed  Google Scholar 

  15. Monaghan G, Ryan M, Seddon R, Hume R, Burchell B . Genetic variation in bilirubin UPD-glucuronosyltransferase gene promoter and Gilbert's syndrome. Lancet 1996; 347: 578–581.

    Article  CAS  PubMed  Google Scholar 

  16. Borlak J, Thum T, Landt O, Erb K, Hermann R . Molecular diagnosis of a familial nonhemolytic hyperbilirubinemia (Gilbert's syndrome) in healthy subjects. Hepatology 2000; 32: 792–795.

    Article  CAS  PubMed  Google Scholar 

  17. Rauchschwalbe SK, Zuhlsdorf MT, Schuhly U, Kuhlmann J . Predicting the risk of sporadic elevated bilirubin levels and diagnosing Gilbert's syndrome by genotyping UGT1A1*28 promoter polymorphism. Int J Clin Pharmacol Ther 2002; 40: 233–240.

    Article  CAS  PubMed  Google Scholar 

  18. Raijmakers MT, Jansen PL, Steegers EA, Peters WH . Association of human liver bilirubin UDP-glucuronyltransferase activity with a polymorphism in the promoter region of the UGT1A1 gene. J Hepatology 2000; 33: 348–351.

    Article  CAS  Google Scholar 

  19. Beutler E, Gelbart T, Demina A . Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism? Proc Natl Acad Sci USA 1998; 95: 8170–8174.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ando Y, Chida M, Nakayama K, Saka H, Kamataki T . The UGT1A1*28 allele is relatively rare in a Japanese population. Pharmacogenetics 1998; 8: 357–360.

    Article  CAS  PubMed  Google Scholar 

  21. Soeda Y, Yamamoto K, Adachi Y, Hori T, Aono S, Koiwai O et al. Predicted homozygous mis-sense mutation in Gilbert's syndrome. Lancet 1995; 346: 1494.

    Article  CAS  PubMed  Google Scholar 

  22. Sato H, Adachi Y, Koiwai O . The genetic basis of Gilbert's syndrome. Lancet 1996; 347: 557–558.

    Article  CAS  PubMed  Google Scholar 

  23. Koiwai O, Nishizawa M, Hasada K, Aono S, Adachi Y, Mamiya N et al. Gilbert's syndrome is caused by a heterozygous missense mutation in the gene for bilirubin UDP-glucuronosyltransferase. Hum Mol Genet 1995; 4: 1183–1186.

    Article  CAS  PubMed  Google Scholar 

  24. Schork NJ . Power calculations for genetic association studies using estimated probability distributions. Am J Hum Genet 2002; 70: 1480–1489.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zucker SD, Qin X, Rouster SD, Yu F, Green RM, Keshavan P et al. Mechanism of indinavir-induced hyperbilirubinemia. Proc Natl Acad Sci USA 2001; 98: 12671–12676.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ando Y, Saka H, Ando M, Sawa T, Muro K, Ueoka H et al. Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic analysis. Cancer Res 2000; 60: 6921–6926.

    CAS  PubMed  Google Scholar 

  27. Iyer L, Das S, Janisch L, Wen M, Ramirez J, Karrison T et al. UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity. Pharmacogenomics J 2002; 2: 43–47.

    Article  CAS  PubMed  Google Scholar 

  28. Holmes Jr DR, Savage M, LaBlanche JM, Grip L, Serruys PW, Fitzgerald P et al. Results of Prevention of REStenosis with Tranilast and its Outcomes (PRESTO) trial. Circulation 2002; 106: 1243–1250.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the significant contribution of our colleagues in Genetics Research, Clinical Pharmacology and Discovery Medicine. Thanks are also due to the tranilast clinical team, the principal investigators and patients who participated in this study. This study was wholly funded by GSK Research and Development.

Author information

Authors and Affiliations

  1. Clinical Pharmacology and Discovery Medicine, GlaxoSmithKline, Philadelphia, PA, USA

    T M Danoff & M H Repasch

  2. Etiologics Ltd., Medical Research Council, Harwell, Oxfordshire, UK

    D A Campbell

  3. Discovery Genetics, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, UK

    L C McCarthy, K F Lewis, I J Purvis & C-F Xu

  4. Genetics Research, GlaxoSmithKline, Research Triangle Park, NC, USA

    A M Saunders, N K Spurr & A D Roses

Authors
  1. T M Danoff
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D A Campbell
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L C McCarthy
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K F Lewis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M H Repasch
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A M Saunders
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. N K Spurr
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. I J Purvis
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A D Roses
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. C-F Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C-F Xu.

Additional information

DUALITY OF INTEREST

None declared

Rights and permissions

Reprints and permissions

About this article

Cite this article

Danoff, T., Campbell, D., McCarthy, L. et al. A Gilbert's syndrome UGT1A1 variant confers susceptibility to tranilast-induced hyperbilirubinemia. Pharmacogenomics J 4, 49–53 (2004). https://doi.org/10.1038/sj.tpj.6500221

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.tpj.6500221

Keywords

This article is cited by

Search

Advanced search

Quick links