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Polymorphisms of the uridine-diphosphoglucuronosyltransferase 1A1 gene and coronary artery disease


Bilirubin, an antioxidant in the blood, plays a role in protection from atherosclerosis. The level of bilirubin is highly correlated to the incidence of coronary artery disease (CAD). Unconjugated bilirubin is conjugated with glucuronic acid through the reaction of uridine 5′-diphosphate-glucuronosyl transferase 1A1 (UGT1A1). The interactions of CAD and the variations in the coding regions of the UGT1A1 gene have never been evaluated. The purpose of this study was to analyze the influence of the UGT1A1 variant on the incidence of CAD. There were 135 participants in this study: 61 in the experimental group, who had CAD, and 74 in the control group, who did not have CAD. The blood samples from all 135 participants were collected and assayed to clarify the relationship between bilirubin and CAD. The assay of the polymerase chain reaction and the sequence of the UGT1A1 gene were examined to find the gene’s polymorphisms. The bilirubin levels for the participants in the control group were significantly higher than for the patients in the CAD group. Although the concentration of bilirubin in the UGT1A1 variant was higher than the wild type for the patients in the CAD group, there was no significant difference in the polymorphism of UGT1A1 between the patients in the CAD group and the participants in the control group.



coronary artery disease


polymerase chain reaction


uridine 5′-diphosphate-glucuronosyl transferase 1A1


  1. 1.

    Dudnik, L.B. and Khrapova, N.G. Characterization of bilirubin inhibitory properties in free radical oxidation reactions. Membr. Cell Biol. 12 (1998) 233–240.

    PubMed  CAS  Google Scholar 

  2. 2.

    Neuzil, J. and Stocker, R. Free and albumin-bound bilirubin are efficient coantioxidants for alpha-tocopherol, inhibiting plasma and low density lipoprotein lipid peroxidation. J. Biol. Chem. 269 (1994) 16712–16719.

    PubMed  CAS  Google Scholar 

  3. 3.

    Nakagami, T., Toyomura, K., Kinoshita, T. and Morisawa, S. A beneficial role of bile pigments as an endogenous tissue protector: anti-complement effects of biliverdin and conjugated bilirubin. Biochim. Biophys. Acta 1158 (1993) 189–193.

    PubMed  CAS  Google Scholar 

  4. 4.

    Mayer, M. Association of serum bilirubin concentration with risk of coronary artery disease. Clin. Chem. 4611 (2000) 1723–1727.

    Google Scholar 

  5. 5.

    Schwertner, H.A., Jackson, W.G. and Tolan, G. Association of low serum concentration of bilirubin with increased risk of coronary artery disease. Clin. Chem. 40 (1994) 18–23.

    PubMed  CAS  Google Scholar 

  6. 6.

    Wu, T.W. Is serum bilirubin a risk factor for coronary artery disease? Clin. Chem. 40 (1994) 9–10.

    PubMed  CAS  Google Scholar 

  7. 7.

    Schwertner, H.A and Joseph, R.F. Jr. Comparison of various lipid, lipoprotein, and bilirubin combinations as risk factors for predicting coronary artery disease. Atherosclerosis 150 (2000) 381–387.

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    Hunt, S.C., Kronenberg, F., Eckfeldt, J.H., Hopkins, P.N., Myers, R.H. and Heiss G. Association of plasma bilirubin with coronary heart disease and segregation of bilirubin as a major gene trait: the NHLBI family heart study. Atherosclerosis 154 (2001) 747–754.

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Hopkins, P.N., Wu, L.L., Hunt, S.C., James, B.C., Vincent, G.M. and Williams, R.R. Higher serum bilirubin associated with decreased risk for early familial coronary artery disease. Arterioscler. Thromb. Vasc. Biol. 16 (1996) 250–255.

    PubMed  CAS  Google Scholar 

  10. 10.

    Breimer, L.H., Wannamethee, G., Ebrahim, S. and Shaper, A.G. Serum bilirubin and risk of ischemic heart disease in middle-aged British men. Clin. Chem. 41 (1995) 1504–1508.

    PubMed  CAS  Google Scholar 

  11. 11.

    Endler, G., Hamwi, A., Sunder-Plassmann, R., Exner, M., Vukovich, T., Mannhaleter, C., Wojta, J., Huber, K. and Wagner, O. Is low serum bilirubin an independent risk factor for coronary artery disease in men but not in women? Clin. Chem. 49 (2003) 1201–1204.

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Bosma, P.J. Inherited disorders of bilirubin metabolism. J. Hepatol. 38 (2003) 107–117.

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    Ritter, J.K., Crawfoed, J.M. and Owens, I.S. Cloning of two human liver bilirubin UDP-glucuronosyltransferase cDNAs with expression in COS-1 cells. J. Biol. Chem. 266 (1991) 1043–1047.

    PubMed  CAS  Google Scholar 

  14. 14.

    Bosma, P.J., Seppen, J., Goldhoorn, B., Bakker, C., Oude Elferink RPJ., Chowdhury, J.R., Chowdhury, N.R. and Jansen, P.L. Bilirubin UDPglucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man. J. Biol. Chem. 269 (1994) 17960–17964.

    PubMed  CAS  Google Scholar 

  15. 15.

    Huang, C.S., Luo, G.A., Huang, M.J, Yu, S.C. and Yang, S.S. Variations of the bilirubin uridine-diphosphoglucuronosyl transferase 1 A1 gene in healthy Taiwanese. Pharmacogenetics 10 (2000) 539–544.

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Raijalers, M.T.M., Jamsem, P.L.M., Steegers, E.A.P. and Peters, W.H.M. Association of human liver bilirubin UDP-glucuronyltransferase activity with a polymorphism in the promoter region of the UGT1A1 gene. J. Hepatol. 33 (2000) 348–351.

    Article  Google Scholar 

  17. 17.

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

    PubMed  Article  CAS  Google Scholar 

  18. 18.

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

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Maruo, Y., Poon, K.K.H., Oto, M., Iwai, M., Takahashi, H., Mori, A., Sato, H. and Takeuchi, Y. Co-occurrence of three different mutations in the bilirubin UDP-glucuronosyltransferase gene in a Chinese family with Crigler-Najjar syndrome type I and Gilbert’s syndrome. Clin. Genet. 64 (2003) 420–423.

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    Maruo, Y., Nishizawa, K., Sato, H., Sawa, H. and Shimada, M. Prolonged unconjugated hyperbilirubinemia associated with breast milk and mutations of the bilirubin uridine diphosphate-glucuronosyltransferase gene. Pediatrics 106 (2000) 59–62.

    Article  Google Scholar 

  21. 21.

    Kadakol, A., Ghosh, S.S., Sappal, B.S., Sharma, G., Chowdhury, J.R. and Chowdhury, N.R. Genetic lesions of bilirubin uridine-diphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes: correlation of genotype to phenotype. Human Mutation 16 (2000) 297–306.

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    Miners, J.O., McKinnon, R.A. and Mackenzie, P.I. Genetic polymorphisms of UDP-glucuronosyltransferases and their functional significance. Toxicology 181–182 (2002) 453–456.

    PubMed  Article  Google Scholar 

  23. 23.

    Ciotti, M., Chen, F., Rubaltelli, F.F. and Owens, I.S. Coding defect and a TATA box mutation at the bilirubin UDP-glucuronosyltransferase gene cause Crigler-Najjar type I disease. Biochim. Biophys. Acta 1407 (1998) 40–50.

    PubMed  CAS  Google Scholar 

  24. 24.

    Galbraith, R. Heme oxygenase: who needs it? Exp. Biol. Med. 222 (1999) 299–305.

    Article  CAS  Google Scholar 

  25. 25.

    Tenhunen, R., Marver, H.S. and Shcmid, R. The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. P.N.A.S. 61 (1968) 748–755.

    PubMed  Article  CAS  Google Scholar 

  26. 26.

    Maines, M.D. The heme osygenase system: a regulator of second messenger gases. Annu. Rev. Pharmacol. Toxicol. 37 (1997) 517–554.

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    Watanabe, Y., Nakajima, M., Ohashi, N., Kume, T. and Yokoi, T. Glucuronidation of etoposide in human liver microsomes is specifically catalyzed by UDP-glucuronosyltransferase 1A1. Drug Metab. Dispos. 31 (2003) 589–595.

    PubMed  Article  CAS  Google Scholar 

  28. 28.

    Shimizu, M., Tsuyuki, A., Yamamoto, C., Ohta, K., Matsushita, R., Suzuki, K., Matsumoto, Y. and Masamichi, F. Effects of Aspirin and/or salicylate on hydrolysis and glucuronidation of indomethacin in rat erythrocytes and hepatocytes. Biol. Pharm. Bull. 26 (2003) 675–682.

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    Pruesaritanont, T., Subramanian, R., Xiaojun, Fang, Ma, B., Qiu, Y., Lin, J.H., Pearson, P.G. and Baillie, T.A. Glucuronidation of statins in animals and humans: A novel mechanism of statin lactonization. Drug Metab. Dispos. 30 (2002) 505–512.

    Article  Google Scholar 

  30. 30.

    Wierzbicki, A.S. and Crook, M.A. Cholestatic liver dysfunction. Lancet 354 (1999) 954.

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Buchwald, H., Williams, S.E., Matts, J.P. and Boen, J.R. Lipid modulation and liver function tests. A report of the Program on the surgical control of hyperlipidemia (POSCH). J. Cardiovasc. Risk. 9 (2002) 83–87.

    PubMed  Article  Google Scholar 

  32. 32.

    Grosser, N., Abate, A., Oberle, S., Verman, H.J., Dennery, P.A., Becker, J.C., Pohle, T., Seidman, D.S. and Schroder, H. Heme oxygenase-1 induction may explain the antioxidant profile of aspirin. Biochim. Biophys. Res. Commun. 308 (2003) 956–960.

    Article  CAS  Google Scholar 

  33. 33.

    Grosser, N., Hemmerle, A., Berndt, G., Erdamm, L., Jomlelmann, U., Schurger, S., Wijayanti, N., Immenschuh, S. and Shroder, H. The antioxidant defense protein heme oxygenase 1 is a novel target for statins in endothelial cells. Free Rad. Biol. Med. 37 (2004) 2064–2071.

    PubMed  Article  CAS  Google Scholar 

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Correspondence to Meng-Jung Chen.

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Hsieh, C., Chen, M., Liao, Y. et al. Polymorphisms of the uridine-diphosphoglucuronosyltransferase 1A1 gene and coronary artery disease. Cell Mol Biol Lett 13, 1–10 (2008).

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Key words

  • Atherosclerosis
  • Coronary artery disease
  • UGT1A1
  • Bilirubin
  • Antioxidant