Biochemical Genetics

, Volume 50, Issue 11–12, pp 967–977 | Cite as

Comprehensive Analysis of UGT1A1 Genetic Polymorphisms in Chinese Tibetan and Han Populations

  • Xiaoqing Zhang
  • Xiaohong Meng
  • Yuewen Wang
  • Wei Yan
  • Jin Yang
Article

Abstract

The study of polymorphism of the UGT1A1 gene has not been reported in the Chinese Tibetan population, and there are no comparisons of genetic polymorphism in the gene between Chinese Han and Tibetan populations. In this study, we directly sequenced the functional regions of the UGT1A1 gene in 200 unrelated healthy Chinese volunteers, detecting 20 variations (including five novel ones). The distributions of allele and genotype frequencies differ between the two groups. UGT1A1*6 is the major reduced functional variant in the populations, and the *27 allele was detected only in the Han group. Differences in the frequencies of the UGT1A1*6/*63 genotype between the Tibetan and Han populations were statistically significant (P = 0.009). Our genetic data might provide fundamental information for the advance of personalized medicine and will facilitate genotype-phenotype studies in larger populations.

Keywords

Chinese Genetic polymorphisms Haplotype UGT1A1 gene 

References

  1. Akaba K, Kimura T, Sasaki A, Tanabe S, Ikegami T, Hashimoto M, Umeda H, Yoshida H, Umetsu K, Chiba H, Yuasa I, Hayasaka K (1998) Neonatal hyperbilirubinemia and mutation of the bilirubin uridine diphosphate-glucuronosyltransferase gene: a common missense mutation among Japanese, Koreans and Chinese. IUBMB Life 46:21–26CrossRefGoogle Scholar
  2. Borucki K, Weikert C, Fisher E, Jakubiczka S, Luley C, Westphal S, Dierkes J (2009) Haplotypes in the UGT1A1 gene and their role as genetic determinants of bilirubin concentration in healthy German volunteers. Clin Biochem 42:1635–1641PubMedCrossRefGoogle Scholar
  3. Bosma PJ, Chowdhury JR, Bakker C, Gantla S, Boer A, Oostra BA, Lindhout D, Tytgat GN, Jansen PL, Oude Elferink RP (1995) The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert’s syndrome. N Engl J Med 333:1171–1175PubMedCrossRefGoogle Scholar
  4. Fertrin K, Goncalves M, Saad S, Costa F (2002) Frequencies of UDP-glucuronosyltransferase 1 (UGT1A1) gene promoter polymorphisms among distinct ethnic groups from Brazil. Am J Med Gen 108:117–119CrossRefGoogle Scholar
  5. Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altshuler D (2002) The structure of haplotype blocks in the human genome. Science 296:2225–2229PubMedCrossRefGoogle Scholar
  6. Guillemette C, Millikan RC, Newman B, Housman DE (2000) Genetic polymorphisms in uridine diphospho-glucuronosyltransferase 1A1 and association with breast cancer among African Americans. Cancer Res 60:950–956PubMedGoogle Scholar
  7. Innocenti F, Grimsley C, Das S, Ramírez J, Cheng C, Kuttab-Boulos H, Ratain MJ, Di Rienzo A (2002) Haplotype structure of the UDP-glucuronosyltransferase 1A1 promoter in different ethnic groups. Pharmacogenetics 12:725–733PubMedCrossRefGoogle Scholar
  8. Iyer L, Das S, Janisch L, Wen M, Ramírez J, Karrison T, Fleming GF, Vokes EE, Schilsky RL, Ratain MJ (2002) UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity. Pharmacogenomics J 2:43–47PubMedCrossRefGoogle Scholar
  9. Jada SR, Lim R, Wong CI, Shu X, Lee SC, Zhou Q, Goh BC, Chowbay B (2007) Role of UGT1A1*6, UGT1A1*28 and ABCG2 c.421C → A polymorphisms in irinotecan-induced neutropenia in Asian cancer patients. Cancer Sci 98:1461–1467PubMedCrossRefGoogle Scholar
  10. Kaniwa N, Kurose K, Jinno H, Tanaka-Kagawa T, Saito Y, Saeki M, Sawada J, Tohkin M, Hasegawa R (2005) Racial variability in haplotype frequencies of UGT1A1 and glucuronidation activity of a novel single nucleotide polymorphism 686C → T (P229L) found in an African–American. Drug Metab Dispos 33:458–465PubMedCrossRefGoogle Scholar
  11. Ki CS, Lee KA, Lee SY, Kim HJ, Cho SS, Park JH, Cho S, Sohn KM, Kim JW (2003) Haplotype structure of the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene and its relationship to serum total bilirubin concentration in a male Korean population. Clin Chem 49:2078–2081PubMedCrossRefGoogle Scholar
  12. Lin R, Wang X, Wang Y, Zhang F, Wang Y, Fu W, Yu T, Li S, Xiong M, Huang W, Jin L (2009) Association of polymorphisms in four bilirubin metabolism genes with serum bilirubin in three Asian populations. Hum Mutat 30:609–615PubMedCrossRefGoogle Scholar
  13. Mackenzie PI, Bock KW, Burchell B, Guillemette C, Ikushiro S, Iyanagi T, Miners JO, Owens IS, Nebert DW (2005) Nomenclature update for the mammalian UDP glycosyltransferase (UGT) gene superfamily. Pharmacogenet Genomics 15:677–685PubMedCrossRefGoogle Scholar
  14. Maruo Y, Mori A, Iwai M, Addario C, Takahashi H, Sato H (2004) Two linked polymorphic mutations (A(TA)7TAA and T-3279G) of UGT1A1 as the principal cause of Gilbert syndrome. Hum Genet 115:525–526PubMedCrossRefGoogle Scholar
  15. Mimura Y, Maruo Y, Ohta Y, Sato H, Takeuchi Y (2011) Effect of common exon variant (p.P364L) on drug glucuronidation by the human UDP-glucuronosyltransferase 1 family. Basic Clin Pharmacol Toxicol 109:486–493PubMedCrossRefGoogle Scholar
  16. Minami H, Sai K, Saeki M, Saito Y, Ozawa S, Suzuki K, Kaniwa N, Sawada J, Hamaguchi T, Yamamoto N, Shirao K, Yamada Y, Ohmatsu H, Kubota K, Yoshida T, Ohtsu A, Saijo N (2007) Irinotecan pharmacokinetics/pharmacodynamics and UGT1A genetic polymorphisms in Japanese: roles of UGT1A1*6 and *28. Pharmacogenet Genomics 17:497–504PubMedCrossRefGoogle Scholar
  17. Miners JO, McKinnon RA, Mackenzie PI (2002) Genetic polymorphisms of UDP-glucuronosyl- transferases and their functional significance. Toxicology 182:453–456CrossRefGoogle Scholar
  18. Okuda T, Fujioka Y, Kamide Y, Kawano Y, Goto Y, Yoshimasa Y, Tomoike H, Iwai N, Hanai S, Miyata T (2002) Verification of 525 coding SNPs in 179 hypertension candidate genes in the Japanese population: identification of 159 SNPs in 93 genes. J Hum Genet 47:387–394PubMedCrossRefGoogle Scholar
  19. Saeki M, Saito Y, Jinno H, Sai K, Ozawa S, Kurose K, Kaniwa N, Komamura K, Kotake T, Morishita H, Kamakura S, Kitakaze M, Tomoike H, Shirao K, Tamura T, Yamamoto N, Kunitoh H, Hamaguchi T, Yoshida T, Kubota K, Ohtsu A, Muto M, Minami H, Saijo N, Kamatani N, Sawada JI (2006) Haplotype structures of the UGT1A gene complex in a Japanese population. Pharmacogenomics J 6:63–75PubMedCrossRefGoogle Scholar
  20. Sai K, Saeki M, Saito Y, Ozawa S, Katori N, Jinno H, Hasegawa R, Kaniwa N, Sawada J, Komamura K, Ueno K, Kamakura S, Kitakaze M, Kitamura Y, Kamatani N, Minami H, Ohtsu A, Shirao K, Yoshida T, Saijo N (2004) UGT1A1 haplotypes associated with reduced glucuronidation and increased serum bilirubin in irinotecan-administered Japanese patients with cancer. Clin Pharmacol Ther 75:501–515PubMedCrossRefGoogle Scholar
  21. Sava M, Kraemer DM (2005) Heterozygous G71R-mutation causing Gilbert’s syndrome in one of 103 random persons of German descent. J Hepatol 42:778–779PubMedCrossRefGoogle Scholar
  22. Shi Y, Zhao X, Yu L, Tao R, Tang J, La Y, Duan Y, Gao B, Gu N, Xu Y, Feng G, Zhu S, Liu H, Salter H, He L (2004) Genetic structure adds power to detect schizophrenia susceptibility at SLIT3 in the Chinese Han population. Genome Res 14:1345–1349PubMedCrossRefGoogle Scholar
  23. Sutomo R, Laosombat V, Sadewa AH, Yokoyama N, Nakamura H, Matsuo M, Nishio H (2002) Novel missense mutation of the UGT1A1 gene in Thai siblings with Gilbert’s syndrome. Pediatr Int 44:427–432PubMedGoogle Scholar
  24. Tukey RH, Strassburg CP (2000) Human UDP-glucuronosyltransferases: metabolism, expression, and disease. Annu Rev Pharmacol Toxicol 40:581–616PubMedCrossRefGoogle Scholar
  25. Wada K, Takeuchi A, Saiki K, Sutomo R, Rostenberghe H, Yusoff NM, Laosombat V, Sadewa AH, Talib NA, Yusoff S, Lee MJ, Ayaki H, Nakamura H, Matsuo M, Nishio H (2006) Evaluation of mutation effects on UGT1A1 activity toward 17beta-estradiol using liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 838:9–14PubMedCrossRefGoogle Scholar
  26. Yusoff S, Rostenberghe H, Yusoff NM, Talib NA, Ramli N, Ismail NZ, Ismail WP, Matsuo M, Nishio H (2006) Frequencies of A(TA)7TAA, G71R, and G493R mutations of the UGT1A1 gene in the Malaysian population. Biol Neonate 89:171–176PubMedCrossRefGoogle Scholar
  27. Zhou YY, Lee LY, Ng SY, Hia CP, Low KT, Chong YS, Goh DL (2009) UGT1A1 haplotype mutation among Asians in Singapore. Neonatology 96:150–155PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Xiaoqing Zhang
    • 1
  • Xiaohong Meng
    • 2
  • Yuewen Wang
    • 1
  • Wei Yan
    • 1
  • Jin Yang
    • 1
  1. 1.National Engineering Research Center for Miniaturized Detection System, College of Life Sciences, Northwest UniversityXi’anChina
  2. 2.504 Section of Xi’an High-tech InstituteXi’anChina

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