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:

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

The Pharmacogenomics Journal volume 6, pages 52–62 (2006)Cite this article

Abstract

Common polymorphisms within the human UGT1A gene locus are associated with irinotecan and tranilast toxicity. To uncover additional functional variation across this gene cluster, cross-species sequence comparisons were performed. Evolutionarily conserved segments (a total of 47.1 kb) were re-sequenced in 24 African-American, 24 European-American, and 24 Asian individuals, and 381 segregating sites (including 123 singletons) were identified. Highly conserved coding sites were less likely to be polymorphic than diverged sites (P<0.0001) but this pattern was not observed at non-coding sites (P=0.1025). Among coding variants, the distribution of those computationally predicted to affect function was skewed toward low frequencies. Some alleles occurred at similar frequencies in each population; others had wide disparities. Although strong linkage disequilibrium was detected among the hepatically expressed genes, the degree of linkage disequilibrium varied among populations. These results suggest that rare functional gene variants and inter-population variability must be considered in the interpretation of association studies between UGT1A and drug metabolism/toxicity phenotypes.

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
Figure 3
Figure 4

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

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

    CAS  PubMed  Google Scholar 

  2. Mackenzie PI, Walter Bock K, Burchell B, Guillemette C, Ikushiro SI, Iyanagi T et al. Nomenclature update for the mammalian UDP glycosyltransferase (UGT) gene superfamily. Pharmacogenet Genomics 2005; 15: 677–685.

    CAS  PubMed  Google Scholar 

  3. Gong QH, Cho JW, Huang T, Potter C, Gholami N, Basu NK et al. Thirteen UDPglucuronosyltransferase genes are encoded at the human UGT1 gene complex locus. Pharmacogenetics 2001; 11: 357–368.

    Article  CAS  PubMed  Google Scholar 

  4. Zhang T, Haws P, Wu Q . Multiple variable first exons: a mechanism for cell- and tissue-specific gene regulation. Genome Res 2004; 14: 79–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Arias I . Chronic unconjugated hyperbilirubinemia without overt signs of hemolysis in adolescents and adults. J Clin Invest 1962; 41: 2233–2245.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Arias I, Gartner L, Cohen M, Ezzer J, Levi A . Chronic nonhemolytic unconjugated hyperbilirubinemia with glucuronosyl transferase deficiency: clinical, biochemical, pharmacologic, and genetic evidence for heterogeneity. Am J Med 1969; 47: 395–409.

    CAS  PubMed  Google Scholar 

  7. Crigler J, Najjar V . Congenital familial non-hemolytic jaundice with kernicterus. Pediatrics 1952; 10: 169–180.

    PubMed  Google Scholar 

  8. 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.

    CAS  PubMed  Google Scholar 

  9. 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.

    CAS  PubMed  Google Scholar 

  10. Ki CS, Lee KA, Lee SY, Kim HJ, Cho SS, Park JH et al. Haplotype structure of the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene and its relationship to serum total bilirubin concentration in a male Korean population. Clin Chem 2003; 49: 2078–2081.

    CAS  PubMed  Google Scholar 

  11. Sugatani J, Yamakawa K, Yoshinari K, Machida T, Takagi H, Mori M et al. Identification of a defect in the UGT1A1 gene promoter and its association with hyperbilirubinemia. Biochem Biophys Res Commun 2002; 292: 492–497.

    CAS  PubMed  Google Scholar 

  12. Lin JP, Cupples LA, Wilson PW, Heard-Costa N, O’Donnell CJ . Evidence for a gene influencing serum bilirubin on chromosome 2q telomere: a genomewide scan in the Framingham study. Am J Hum Genet 2003; 72: 1029–1034.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Kaplan M, Renbaum P, Levy-Lahad E, Hammerman C, Lahad A, Beutler E . Gilbert syndrome and glucose-6-phosphate dehydrogenase deficiency: a dose-dependent genetic interaction crucial to neonatal hyperbilirubinemia. Proc Natl Acad Sci USA 1997; 94: 12128–12132.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Haverfield EV, McKenzie CA, Forrester T, Bouzekri N, Harding R, Serjeant G et al. UGT1A1 variation and gallstone formation in sickle cell disease. Blood 2005; 105: 968–972.

    CAS  PubMed  Google Scholar 

  15. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Gupta E, Lestingi TM, Mick R, Ramirez J, Vokes EE, Ratain MJ . Metabolic fate of irinotecan in humans: correlation of glucuronidation with diarrhea. Cancer Res 1994; 54: 3723–3725.

    CAS  PubMed  Google Scholar 

  17. Gupta E, Mick R, Ramirez J, Wang X, Lestingi TM, Vokes EE et al. Pharmacokinetic and pharmacodynamic evaluation of the topoisomerase inhibitor irinotecan in cancer patients. J Clin Oncol 1997; 15: 1502–1510.

    CAS  PubMed  Google Scholar 

  18. Meyerhardt JA, Kwok A, Ratain MJ, McGovren JP, Fuchs CS . Relationship of baseline serum bilirubin to efficacy and toxicity of single-agent irinotecan in patients with metastatic colorectal cancer. J Clin Oncol 2004; 22: 1439–1446.

    CAS  PubMed  Google Scholar 

  19. Iyer L, King CD, Whitington PF, Green MD, Roy SK, Tephly TR et al. Genetic predisposition to the metabolism of irinotecan (CPT-11). Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes. J Clin Invest 1998; 101: 847–854.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Iyer L, Hall D, Das S, Mortell MA, Ramirez J, Kim S et al. Phenotype–genotype correlation of in vitro SN-38 (active metabolite of irinotecan) and bilirubin glucuronidation in human liver tissue with UGT1A1 promoter polymorphism. Clin Pharmacol Ther 1999; 65: 576–582.

    CAS  PubMed  Google Scholar 

  21. Gagne JF, Montminy V, Belanger P, Journault K, Gaucher G, Guillemette C . Common human UGT1A polymorphisms and the altered metabolism of irinotecan active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38). Mol Pharmacol 2002; 62: 608–617.

    CAS  PubMed  Google Scholar 

  22. 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.

    CAS  PubMed  Google Scholar 

  23. Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M et al. Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol 2004; 22: 1382–1388.

    CAS  PubMed  Google Scholar 

  24. 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 

  25. Sai K, Saeki M, Saito Y, Ozawa S, Katori N, Jinno H et al. UGT1A1 haplotypes associated with reduced glucuronidation and increased serum bilirubin in irinotecan-administered Japanese patients with cancer. Clin Pharmacol Ther 2004; 75: 501–515.

    CAS  PubMed  Google Scholar 

  26. Ratain MJ . Irinotecan dosing: does the CPT in CPT-11 stand for ‘Can’t Predict Toxicity’? J Clin Oncol 2002; 20: 7–8.

    PubMed  Google Scholar 

  27. Danoff TM, Campbell DA, McCarthy LC, Lewis KF, Repasch MH, Saunders AM et al. A Gilbert's syndrome UGT1A1 variant confers susceptibility to tranilast-induced hyperbilirubinemia. Pharmacogenomics J 2004; 4: 49–53.

    CAS  PubMed  Google Scholar 

  28. Xu CF, Lewis KF, Yeo AJ, McCarthy LC, Maguire MF, Anwar Z et al. Identification of a pharmacogenetic effect by linkage disequilibrium mapping. Pharmacogenomics J 2004; 4: 374–378.

    CAS  PubMed  Google Scholar 

  29. Shu Y, Leabman MK, Feng B, Mangravite LM, Huang CC, Stryke D et al. Evolutionary conservation predicts function of variants of the human organic cation transporter, OCT1. Proc Natl Acad Sci USA 2003; 100: 5902–5907.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Leabman MK, Huang CC, DeYoung J, Carlson EJ, Taylor TR, de la Cruz M et al. Natural variation in human membrane transporter genes reveals evolutionary and functional constraints. Proc Natl Acad Sci USA 2003; 100: 5896–5901.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Botstein D, Risch N . Discovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease. Nat Genet 2003; 33(Suppl): 228–237.

    CAS  PubMed  Google Scholar 

  32. 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.

    CAS  PubMed  Google Scholar 

  33. Springer MS, Murphy WJ, Eizirik E, O’Brien SJ . Placental mammal diversification and the Cretaceous–Tertiary boundary. Proc Natl Acad Sci USA 2003; 100: 1056–1061.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Goodman M, Porter CA, Czelusniak J, Page SL, Schneider H, Shoshani J et al. Toward a phylogenetic classification of Primates based on DNA evidence complemented by fossil evidence. Mol Phylogenet Evol 1998; 9: 585–598.

    CAS  PubMed  Google Scholar 

  35. Sugatani J, Kojima H, Ueda A, Kakizaki S, Yoshinari K, Gong QH et al. The phenobarbital response enhancer module in the human bilirubin UDP-glucuronosyltransferase UGT1A1 gene and regulation by the nuclear receptor CAR. Hepatology 2001; 33: 1232–1238.

    CAS  PubMed  Google Scholar 

  36. Tajima F . Statistical method for testing the neutral mutation hypothesis by DNA polymorphism. Genetics 1989; 123: 585–595.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Watterson GA . On the number of segregating sites in genetical models without recombination. Theor Popul Biol 1975; 7: 256–276.

    CAS  PubMed  Google Scholar 

  38. Miller MP, Kumar S . Understanding human disease mutations through the use of interspecific genetic variation. Hum Mol Genet 2001; 10: 2319–2328.

    CAS  PubMed  Google Scholar 

  39. Halushka MK, Fan JB, Bentley K, Hsie L, Shen N, Weder A et al. Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis. Nat Genet 1999; 22: 239–247.

    CAS  PubMed  Google Scholar 

  40. Fay JC, Wyckoff GJ, Wu CI . Positive and negative selection on the human genome. Genetics 2001; 158: 1227–1234.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Cargill M, Altshuler D, Ireland J, Sklar P, Ardlie K, Patil N et al. Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nat Genet 1999; 22: 231–238.

    CAS  PubMed  Google Scholar 

  42. Cohen JC, Kiss RS, Pertsemlidis A, Marcel YL, McPherson R, Hobbs HH . Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 2004; 305: 869–872.

    CAS  PubMed  Google Scholar 

  43. Wen G, Mahata SK, Cadman P, Mahata M, Ghosh S, Mahapatra NR et al. Both rare and common polymorphisms contribute functional variation at CHGA, a regulator of catecholamine physiology. Am J Hum Genet 2004; 74: 197–207.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Nebert DW, Vesell ES . Advances in pharmacogenomics and individualized drug therapy: exciting challenges that lie ahead. Eur J Pharmacol 2004; 500: 267.

    CAS  PubMed  Google Scholar 

  45. Iwai M, Maruo Y, Ito M, Yamamoto K, Sato H, Takeuchi Y . Six novel UDP-glucuronosyltransferase (UGT1A3) polymorphisms with varying activity. J Hum Genet 2004; 49: 123–128.

    CAS  PubMed  Google Scholar 

  46. Ng PC, Henikoff S . SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res 2003; 31: 3812–3814.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Ng PC, Henikoff S . Predicting deleterious amino acid substitutions. Genome Res 2001; 11: 863–874.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Ng PC, Henikoff S . Accounting for human polymorphisms predicted to affect protein function. Genome Res 2002; 12: 436–446.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Zhu Y, Spitz MR, Amos CI, Lin J, Schabath MB, Wu X . An evolutionary perspective on single-nucleotide polymorphism screening in molecular cancer epidemiology. Cancer Res 2004; 64: 2251–2257.

    CAS  PubMed  Google Scholar 

  50. Yamamoto K, Soeda Y, Kamisako T, Hosaka H, Fukano M, Sato H et al. Analysis of bilirubin uridine 5′-diphosphate (UDP)-glucuronosyltransferase gene mutations in seven patients with Crigler–Najjar syndrome type II. J Hum Genet 1998; 43: 111–114.

    CAS  PubMed  Google Scholar 

  51. Yamamoto K, Sato H, Fujiyama Y, Doida Y, Bamba T . Contribution of two missense mutations (G71R and Y486D) of the bilirubin UDP glycosyltransferase (UGT1A1) gene to phenotypes of Gilbert's syndrome and Crigler–Najjar syndrome type II. Biochim Biophys Acta 1998; 1406: 267–273.

    CAS  PubMed  Google Scholar 

  52. Saeki M, Saito Y, Jinno H, Tohkin M, Kurose K, Kaniwa N et al. Comprehensive UGT1A1 genotyping in a Japanese population by Pyrosequencing. Clin Chem 2003; 49: 1182–1185.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  54. 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.

    CAS  PubMed  Google Scholar 

  55. Kadakol A, Sappal BS, Ghosh SS, Lowenheim M, Chowdhury A, Chowdhury S et al. Interaction of coding region mutations and the Gilbert-type promoter abnormality of the UGT1A1 gene causes moderate degrees of unconjugated hyperbilirubinaemia and may lead to neonatal kernicterus. J Med Genet 2001; 38: 244–249.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 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.

    CAS  PubMed  Google Scholar 

  57. Akaba K, Kimura T, Sasaki A, Tanabe S, Wakabayashi T, Hiroi M et al. Neonatal hyperbilirubinemia and a common mutation of the bilirubin uridine diphosphate-glucuronosyltransferase gene in Japanese. J Hum Genet 1999; 44: 22–25.

    CAS  PubMed  Google Scholar 

  58. Strassburg CP, Oldhafer K, Manns MP, Tukey RH . Differential expression of the UGT1A locus in human liver, biliary, and gastric tissue: identification of UGT1A7 and UGT1A10 transcripts in extrahepatic tissue. Mol Pharmacol 1997; 52: 212–220.

    CAS  PubMed  Google Scholar 

  59. Frisse L, Hudson RR, Bartoszewicz A, Wall JD, Donfack J, Di Rienzo A . Gene conversion and different population histories may explain the contrast between polymorphism and linkage disequilibrium levels. Am J Hum Genet 2001; 69: 831–843.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Reich DE, Cargill M, Bolk S, Ireland J, Sabeti PC, Richter DJ et al. Linkage disequilibrium in the human genome. Nature 2001; 411: 199–204.

    CAS  PubMed  Google Scholar 

  61. Sawyer SL, Mukherjee N, Pakstis AJ, Feuk L, Kidd JR, Brookes AJ et al. Linkage disequilibrium patterns vary substantially among populations. Eur J Hum Genet 2005; 13: 677–686.

    CAS  PubMed  Google Scholar 

  62. Justice R . NDA 20-571/S-024/S-027/S-028. Department of Health and Human Services 2005.

  63. Holmes Jr DR, Savage M, LaBlanche J-M, 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.

    PubMed  Google Scholar 

  64. Roses AD . Pharmacogenetics and drug development: the path to safer and more effective drugs. Nat Rev Genet 2004; 5: 645–656.

    CAS  PubMed  Google Scholar 

  65. Hall D, Ybazeta G, Destro-Bisol G, Petzl-Erler ML, Di Rienzo A . Variability at the uridine diphosphate glucuronosyltransferase 1A1 promoter in human populations and primates. Pharmacogenetics 1999; 9: 591–599.

    CAS  PubMed  Google Scholar 

  66. Innocenti F, Grimsley C, Das S, Ramirez J, Cheng C, Kuttab-Boulos H et al. Haplotype structure of the UDP-glucuronosyltransferase 1A1 promoter in different ethnic groups. Pharmacogenetics 2002; 12: 725–733.

    CAS  PubMed  Google Scholar 

  67. Bigler J, Whitton J, Lampe JW, Fosdick L, Bostick RM, Potter JD . CYP2C9 and UGT1A6 genotypes modulate the protective effect of aspirin on colon adenoma risk. Cancer Res 2001; 61: 3566–3569.

    CAS  PubMed  Google Scholar 

  68. Chan AT, Tranah GJ, Giovannucci EL, Hunter DJ, Fuchs CS . Genetic variants in the UGT1A6 enzyme, aspirin use, and the risk of colorectal adenoma. J Natl Cancer Inst 2005; 97: 457–460.

    CAS  PubMed  Google Scholar 

  69. Ockenga J, Vogel A, Teich N, Keim V, Manns MP, Strassburg CP . UDP glucuronosyltransferase (UGT1A7) gene polymorphisms increase the risk of chronic pancreatitis and pancreatic cancer. Gastroenterology 2003; 124: 1802–1808.

    CAS  PubMed  Google Scholar 

  70. van der Logt EMJ, Bergevoet SM, Roelofs HMJ, van Hooijdonk Z, te Morsche RHM, Wobbes T et al. Genetic polymorphisms in UDP-glucuronosyltransferases and glutathione S-transferases and colorectal cancer risk. Carcinogenesis 2004; 25: 2407–2415.

    CAS  PubMed  Google Scholar 

  71. Verlaan M, te Morsche RH, Pap A, Laheij RJ, Jansen JB, Peters WH et al. Functional polymorphisms of UDP-glucuronosyltransferases 1A1, 1A6 and 1A8 are not involved in chronic pancreatitis. Pharmacogenetics 2004; 14: 351–357.

    CAS  PubMed  Google Scholar 

  72. Wang Y, Kato N, Hoshida Y, Otsuka M, Taniguchi H, Moriyama M et al. UDP-glucuronosyltransferase 1A7 genetic polymorphisms are associated with hepatocellular carcinoma in Japanese patients with hepatitis C virus infection. Clin Cancer Res 2004; 10: 2441–2446.

    CAS  PubMed  Google Scholar 

  73. Zheng Z, Park JY, Guillemette C, Schantz SP, Lazarus P . Tobacco carcinogen-detoxifying enzyme UGT1A7 and its association with orolaryngeal cancer risk. J Natl Cancer Inst 2001; 93: 1411–1418.

    CAS  PubMed  Google Scholar 

  74. Hinds DA, Stuve LL, Nilsen GB, Halperin E, Eskin E, Ballinger DG et al. Whole-genome patterns of common DNA variation in three human populations. Science 2005; 307: 1072–1079.

    CAS  PubMed  Google Scholar 

  75. Nebert DW . Polymorphisms in drug-metabolizing enzymes: what is their clinical relevance and why do they exist? Am J Hum Genet 1997; 60: 265–271.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Roe B . Shotgun library construction for DNA sequencing in Methods in Molecular Biology. In: Stodolski M, Stodolski M (eds). Library Construction, Physical Mapping, and Sequencing. Human Press Inc.: Totowa, NJ, 2004 pp 171–187.

    Google Scholar 

  77. Schwartz S, Elnitski L, Li M, Weirauch M, Riemer C, Smit A et al. MultiPipMaker and supporting tools: alignments and analysis of multiple genomic DNA sequences. Nucleic Acids Res 2003; 31: 3518–3524.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Nickerson DA, Tobe VO, Taylor SL . PolyPhred: automating the detection and genotyping of single nucleotide substitutions using fluorescence-based resequencing. Nucleic Acids Res 1997; 25: 2745–2751.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Brudno M, Do CB, Cooper GM, Kim MF, Davydov E, Green ED et al. LAGAN and Multi-LAGAN: efficient tools for large-scale multiple alignment of genomic DNA. Genome Res 2003; 13: 721–731.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Hill WG . Estimation of linkage disequilibrium in randomly mating populations. Heredity 1974; 33: 229–239.

    CAS  PubMed  Google Scholar 

  81. Strassburg CP, Vogel A, Kneip S, Tukey RH, Manns MP . Polymorphisms of the human UDP-glucuronosyltransferase (UGT) 1A7 gene in colorectal cancer. Gut 2002; 50: 851–856.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Vogel A, Kneip S, Barut A, Ehmer U, Tukey RH, Manns MP et al. Genetic link of hepatocellular carcinoma with polymorphisms of the UDP-glucuronosyltransferase UGT1A7 gene. Gastroenterology 2001; 121: 1136–1144.

    CAS  PubMed  Google Scholar 

  83. Aono S, Yamada Y, Keino H, Hanada N, Nakagawa T, Sasaoka Y et al. Identification of defect in the genes for bilirubin UDP-glucuronosyl-transferase in a patient with Crigler–Najjar syndrome type II. Biochem Biophys Res Commun 1993; 197: 1239–1244.

    CAS  PubMed  Google Scholar 

  84. Huang C-S, Chang P-F, Huang M-J, Chen E-S, Chen W-C . Glucose-6-phosphate dehydrogenase deficiency, the UDP-glucuronosyl transferase 1A1 gene, and neonatal hyperbilirubinemia. Gastroenterology 2002; 123: 127.

    CAS  PubMed  Google Scholar 

  85. 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.

    CAS  PubMed  Google Scholar 

  86. Maruo Y, Nishizawa K, Sato H, Doida Y, Shimada M . Association of neonatal hyperbilirubinemia with bilirubin UDP-glucuronosyltransferase polymorphism. Pediatrics 1999; 103: 1224–1227.

    CAS  PubMed  Google Scholar 

  87. Takeuchi K, Kobayashi Y, Tamaki S, Ishihara T, Maruo Y, Araki J et al. Genetic polymorphisms of bilirubin uridine diphosphate-glucuronosyltransferase gene in Japanese patients with Crigler–Najjar syndrome or Gilbert's syndrome as well as in healthy Japanese subjects. J Gastroenterol Hepatol 2004; 19: 1023–1028.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to our colleagues, Dr Mark Ratain, and Dr Eden Haverfield for critical reading of the manuscript and the members of the Pharmacogenetics of Anticancer Agents Research group for helpful discussions throughout the development of this project. This Pharmacogenetics of Anticancer Agents Research (PAAR) Group study was supported by NIH/NIGMS Grant U01GM61393, www.pharmacogenetics.org. Data will be deposited into the Pharmacogenetics Knowledge Base (PharmGKB), supported by NIH/NIGMS Pharmacogenetics Research Network and Database Grant U01GM61374, http://pharmgkb.org. This work was supported by NIH Grants GM61393 and HG02152.

Author information

Author notes

  1. C Grimsley

    Present address: Department of Natural Sciences, Parkland College, Champaign, IL, USA

  2. M L Maitland and C Grimsley: These two authors contributed equally to this work.

Authors and Affiliations

  1. Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, IL, USA

    M L Maitland & A Di Rienzo

  2. Department of Medicine, The University of Chicago, Chicago, IL, USA

    M L Maitland

  3. Department of Human Genetics, The University of Chicago, Chicago, IL, USA

    C Grimsley, H Kuttab-Boulos, D Witonsky & A Di Rienzo

  4. Department of Health Studies, The University of Chicago, Chicago, IL, USA

    K E Kasza

  5. Department of Chemistry and Biochemistry, Advanced Center for Genome Technology (ACGT), University of Oklahoma, Norman, OK, USA

    L Yang & B A Roe

Authors
  1. M L Maitland
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C Grimsley
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H Kuttab-Boulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D Witonsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K E Kasza
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. L Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. B A Roe
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A Di Rienzo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A Di Rienzo.

Additional information

Duality of Interest

Two of the authors, Carrie Grimsley and Anna Di Rienzo, receive royalties from Mayo Medical Laboratories related to UGT1A1 testing and would like to declare their potential conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Maitland, M., Grimsley, C., Kuttab-Boulos, H. et al. Comparative genomics analysis of human sequence variation in the UGT1A gene cluster. Pharmacogenomics J 6, 52–62 (2006). https://doi.org/10.1038/sj.tpj.6500351

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.tpj.6500351

Keywords

This article is cited by

Search

Advanced search

Quick links