Significance of UGT1A1*28 Genotype in Patients with Advanced Liver Injury Caused by Chronic Hepatitis C

Open access

Summary

Background: Chronic hepatitis C (CHC) is a significant cause of liver related morbidity and mortality worldwide. The role of genetics in the host response to hepatitis C virus is not elucidated. Genetic variations in UGT1A1 gene are the most common cause of hereditary unconjugated hyperbilirubinemia-Gilbert syndrome. This is the first study investigating the association of UGT1A1 TA repeats promoter genotypes with the degree of liver injury, viremia and biochemical markers in CHC patients with advanced liver injury and late virological relapse.

Methods: Genetic testing of UGT1A1 TA repeats promoter genotypes was performed in 42 CHC patients with advanced fibrosis and cirrhosis who achieved sustained virological response and 42 healthy blood donors. CHC patients were evaluated for clinical findings, laboratory tests and imaging.

Results: UGT1A1*28 genotype (7/7 TA repeats) was observed in 23.8% CHC patients and 16.7% healthy controls with no significant difference in genotype frequencies (p=0.49). Pretreatment levels of ferritin and bilirubin were associated with the presence of UGT1A1*28 genotype, indicating its potential as a predictive marker. However, in our study, there was no correlation of UGT1A1*28 genotype with the degree of fibrosis or viremia. During antiviral treatment, dose reductions and treatment interruptions, as well as treatment success and occurrence of late virological relapse were not related to the presence of UGT1A1*28 genotype in CHC patients with severe liver injury.

Conclusions: Frequencies of UGT1A1*28 genotype are high in both Serbian CHC patients and healthy subjects. The presence of UGT1A1*28 genotype was not associated with ribavirin-related adverse effects and had no effect on long term outcome in CHC patients.

Summary

Background: Chronic hepatitis C (CHC) is a significant cause of liver related morbidity and mortality worldwide. The role of genetics in the host response to hepatitis C virus is not elucidated. Genetic variations in UGT1A1 gene are the most common cause of hereditary unconjugated hyperbilirubinemia-Gilbert syndrome. This is the first study investigating the association of UGT1A1 TA repeats promoter genotypes with the degree of liver injury, viremia and biochemical markers in CHC patients with advanced liver injury and late virological relapse.

Methods: Genetic testing of UGT1A1 TA repeats promoter genotypes was performed in 42 CHC patients with advanced fibrosis and cirrhosis who achieved sustained virological response and 42 healthy blood donors. CHC patients were evaluated for clinical findings, laboratory tests and imaging.

Results: UGT1A1*28 genotype (7/7 TA repeats) was observed in 23.8% CHC patients and 16.7% healthy controls with no significant difference in genotype frequencies (p=0.49). Pretreatment levels of ferritin and bilirubin were associated with the presence of UGT1A1*28 genotype, indicating its potential as a predictive marker. However, in our study, there was no correlation of UGT1A1*28 genotype with the degree of fibrosis or viremia. During antiviral treatment, dose reductions and treatment interruptions, as well as treatment success and occurrence of late virological relapse were not related to the presence of UGT1A1*28 genotype in CHC patients with severe liver injury.

Conclusions: Frequencies of UGT1A1*28 genotype are high in both Serbian CHC patients and healthy subjects. The presence of UGT1A1*28 genotype was not associated with ribavirin-related adverse effects and had no effect on long term outcome in CHC patients.

List of abbreviationsUGT1A1

, uridine diphosphate-glucuronosyl transferase 1A1

GS

, Gilbert syndrome

TA repeats

, thymine-adenine repeats

CHC

, chronic hepatitis C

SVR

, sustained virologic responce

HIV

, human immunodeficiency virus

PCR HCV RNA

, polymerase chain reaction hepatitis C virus ribonucleic acid

DNA

, deoxyribonucleic acid

ALT

, alanine aminotransferase

AST

, aspartate aminotransferase

GGT

, gamma-glutamyl transpeptidase

AFP

, alpha-fetoprotein

EOT

, end of treatment

HCC

, hepatocellular carcinoma

References

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  • 2. Lin JP, Vitek L, Schwertner HA. Serum bilirubin and genes controlling bilirubin concentrations as biomarkers for cardiovascular disease. Clin Chem 2010; 56(10): 1535–43.

  • 3. Franchini M, Targher G, Lippi G. Serum bilirubin levels and cardiovascular disease risk: a Janus Bifrons? Adv Clin Chem 2010; 50: 47–63.

  • 4. Radlović N. Hereditary hyperbilirubinemias. Srp Arh Celok Lek 2014; 142(3–4): 257–60.

  • 5. De Souza M, Vaisberg V, Abreu R, Ferreira A, da SilvaFerreira C, Nasser P, et al. UGT1A1*28 relationship with abnormal total bilirubin levels in chronic hepatitis C patients: Outcomes from a case-control study. Medicine (Baltimore) 2017; 96(11): e6306.

  • 6. Innocenti F, Undevia SD, Iyer L, et al. Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol 2004; 22: 1382–8.

  • 7. Shibata T, Minami Y, Mitsuma A, Morita S, Inada-Inoue M, Oguri T, et al. Association between severe toxicity of nilotinib and UGT1A1 polymorphisms in Japanese patients with chronic myelogenous leukemia. Int J Clin Oncol 2014; 19(2): 391–6.

  • 8. Wang LZ, Ramírez J, Yeo W, Chan MY, Thuya WL, Lau JY, et al. Glucuronidation by UGT1A1 is the dominant pathway of the metabolic disposition of belinostat in liver cancer patients. PLoS One 2013; 8(1): e54522.

  • 9. Culley CL, Kiang TK, Gilchrist SE, Ensom MH. Effect of the UGT1A1*28 allele on unconjugated hyperbilirubinemia in HIV-positive patients receiving Atazanavir: a systematic review. Ann Pharmacother 2013; 47(4): 561–72.

  • 10. Park WB, Choe PG, Song KH, Jeon JH, Park SW, Kim HB, et al. Genetic factors influencing severe atazanavir-associated hyperbilirubinemia in a population with low UDPglucuronosyltransferase 1A1*28 allele frequency. Clin Infect Dis 2010; 51(1): 101–6.

  • 11. Pavlović S, Zukić B, Stojiljković-Petrović M. Molecular genetic markers as a basis for personalized medicine. J Med Biochem 2014; 33: 8–21.

  • 12. Tseng CS, Tang KS, Lo HW, et al. UDP-glucuronosyltransferase 1A7 genetic polymorphisms are associated with hepatocellular carcinoma risk and onset age. Am J Gastroenterol 2005; 100: 1758–63.

  • 13. Premawardhena A, Fisher CA, Liu YT, Verma IC, de Silva S, Arambepola M, et al. The global distribution of length polymorphisms of the promoters of the glucuronosyltransferase 1 gene (UGT1A1): hematologic and evolutionary implications. Blood Cells Mol Dis 2003; 31(1): 98–101.

  • 14. Mitrović N, Delić D, Marković-Denić L, Jovičić M, Popović N, Bojović K, et al. Seroprevalence and risk factors for hepatitis C virus infection among blood donors in Serbia: A multicentre study. Dig Liver Dis 2015; 47(7): 572–6.

  • 15. Švirtlih N, Delić D, Simonović J, Jevtović D, Dokić L, Gvozdenović E, et al. Hepatitis C virus genotypes in Serbia and Montenegro: the prevalence and clinical significance. World J Gastroenterol 2007; 13(3): 355–60.

  • 16. Serfaty L. Follow-up of patients with chronic hepatitis C and a sustained viral response. Liver Int 2016; 36 Suppl 1: 67–71.

  • 17. Innes HA, Hutchinson SJ, Allen S, Bhattacharyya D, Bramley P, Delahooke TE, et al. Excess liver-related morbidity of chronic hepatitis C patients, who achieve a sustained viral response, and are discharged from care. Hepatology 2011; 54(5): 1547–58.

  • 18. Tachi Y, Hirai T, Miyata A, Ohara K, Iida T, Ishizu Y, et al. Progressive fibrosis significantly correlates with hepatocellular carcinoma in patients with a sustained virological response. Hepatol Res 2015; 45(2): 238–46.

  • 19. Lippi G, Chiozza L, Mattiuzzi C, Plebani M. Patient and sample identification. Out of the maze? J Med Biochem 2017; 36: 107–12.

  • 20. Radojković D, Kusić J. Silver staining of denaturing gradient gel electrophoresis gels. Clin Chem 2000; 46(6 Pt 1): 883–4.

  • 21. Owens D, Evans J. Population studies on Gilbert's syndrome. J Med Genet 1975; 12: 152–6.

  • 22. 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 U S A 1998; 95: 8170–4.

  • 23. Köhle C, Möhrle B, Münzel PA, Schwab M, Wernet D, Badary OA, et al. Frequent co-occurrence of the TATA box mutation associated with Gilbert's syndrome (UGT1A1*28) with other polymorphisms of the UDPglucuronosyltransferase- 1 locus (UGT1A6*2 and UGT1A7*3) in Caucasians and Egyptians. Biochem Pharmacol 2003; 65(9): 1521–7.

  • 24. Guy W. Neff, Christopher W, Eugene R. Schiff. The Current Economic Burden of Cirrhosis Gastroenterol Hepatol (N Y) 2011; 7(10): 661–71.

  • 25. Delić D. Hronična hepatitis C virusna infekcija. In: Hronični virusni hepatitis. 1st ed. Beograd: Zavod za udżbenike, 2012: 324–5.

  • 26. Delić D, Mitrović N, Popović N, et al. Kombinovana antivirusno-imunomodulatorna terapija – primena pegilovanog interferona alfa-2a i ribavirina kod bolesnika s hroničnim hepatitisom C. Srp Arh Celok Lek 2012; 140(9–10): 612–8.

  • 27. Fattovich G, Ribero ML, Pantalena M, Diodati G, Almasio P, Nevens F, et al. Hepatitis C virus genotypes: distribution and clinical significance in patients with cirrhosis type C seen at tertiary referral centres in Europe. J Viral Hepat 2001; 8: 206–16.

  • 28. Payan C, Roudot-Thoraval F, Marcellin P, Bled N, Duverlie G, Fouchard-Hubert I, et al. Changing of hepatitis C virus genotype patterns in France at the beginning of the third millenium: The GEMHEP GenoCII Study. J Viral Hepat 2005; 12: 405–13.

  • 29. Jurčić Z, Franulović O, Štefanović O. Nasljedne nekonjugirane hiperbilirubinemije.Paediatr Croat 2006; 50:112–21.

  • 30. Hirschfield GM, Alexander GJ. Gilbert's syndrome: an overview for clinical biochemists. Ann Clin Biochem 2006; 43(Pt 5): 340–3.

  • 31. Urbánek P, Leníček M, Muchová L, Subhanová I, Dušek L, Kasp íková N, et al. No association of promoter variations of HMOX1 and UGT1A1 genes with liver injury in chronic hepatitis C. Ann Hepatol 2011; 10(4): 445–51.

  • 32. Manolio TA, Burke GL, Savage PJ, Jacobs DR Jr, Sidney S, Wagenknecht LE, et al. Sex- and race-related differences in liver-associated serum chemistry tests in young adults in the CARDIA study. Clin Chem 1992; 38(9): 1853–9.

  • 33. Monaghan G, Ryan M, Seddon R, Hume R, Burchell B. Genetic variation in bilirubin UDP-glucuronosyltransferase gene promoter and Gilbert’s syndrome. Lancet 1996: 347: 578–81.

  • 34. Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. J Clin Endocrinol Metab 2001; 86: 724–31.

  • 35. Zucker SD, Horn PS, Sherman KE. Serum bilirubin levels in the U.S. population: gender effect and inverse correlation with colorectal cancer. Hepatology 2004; 40: 827–35.

  • 36. Mallat A, Hezode C, Lotersztajn S. Environmental factors as disease accelerators during chronic hepatitis C. Journal of Hepatology 2008; 48: 657–65.

  • 37. Piekuse L, Kreile M, Zarina A, et al. Association between inherited monogenic liver disorders and chronic hepatitis C. World Journal of Hepatology 2014; 6(2): 92–7.

  • 38. Bizya N, Sarantuya G, Namdag B. Yang S. Interferon and ribavirin combination therapy are linked to severe indirect hyperbilirubinemia in patients with nt-211G > A variant of UGT1A1 gene A. Journal of the Formosan Medical Association 2015; 114: 1147–8.

  • 39. Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer PJ. Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology 1994; 19: 1513–20.

  • 40. Kamath PS, et al. A model to predict survival in patients with end-stage liver disease. Hepatology 2001; 33: 464–70.

  • 41. Vagu C, Sultana C, Ruta S. Serum Iron Markers in Patients With Chronic Hepatitis C Infection. Hepat Mon 2013; 13(10): e13136.

  • 42. Barut S, Günal O, Erkorkmaz U. Serum ferritin levels in chronic hepatitis C patients during antiviral therapy and prediction of treatment response. Scand J Infect Dis 2012; 44(10): 761–5.

  • 43. Deterding K, Grüngreiff K, Lankisch TO, Potthoff A, Bahr MJ, et al. Gilbert's syndrome and antiviral therapy of hepatitis C. Ann Hepatol 2009; 8(3): 246–50.

  • 44. Simmons B, Saleem J, Hill A, Riley RD, Cooke GS. Risk of Late Relapse or Reinfection With Hepatitis C Virus After Achieving a Sustained Virological Response: A Systematic Review and Meta-analysis. Clinical Infectious Diseases 2016; 3: 683–94.

1. Strassburg CP. Pharmacogenetics of Gilbert's syndrome. Pharmacogenomics 2008; 9(6): 703–15.

2. Lin JP, Vitek L, Schwertner HA. Serum bilirubin and genes controlling bilirubin concentrations as biomarkers for cardiovascular disease. Clin Chem 2010; 56(10): 1535–43.

3. Franchini M, Targher G, Lippi G. Serum bilirubin levels and cardiovascular disease risk: a Janus Bifrons? Adv Clin Chem 2010; 50: 47–63.

4. Radlović N. Hereditary hyperbilirubinemias. Srp Arh Celok Lek 2014; 142(3–4): 257–60.

5. De Souza M, Vaisberg V, Abreu R, Ferreira A, da SilvaFerreira C, Nasser P, et al. UGT1A1*28 relationship with abnormal total bilirubin levels in chronic hepatitis C patients: Outcomes from a case-control study. Medicine (Baltimore) 2017; 96(11): e6306.

6. Innocenti F, Undevia SD, Iyer L, et al. Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol 2004; 22: 1382–8.

7. Shibata T, Minami Y, Mitsuma A, Morita S, Inada-Inoue M, Oguri T, et al. Association between severe toxicity of nilotinib and UGT1A1 polymorphisms in Japanese patients with chronic myelogenous leukemia. Int J Clin Oncol 2014; 19(2): 391–6.

8. Wang LZ, Ramírez J, Yeo W, Chan MY, Thuya WL, Lau JY, et al. Glucuronidation by UGT1A1 is the dominant pathway of the metabolic disposition of belinostat in liver cancer patients. PLoS One 2013; 8(1): e54522.

9. Culley CL, Kiang TK, Gilchrist SE, Ensom MH. Effect of the UGT1A1*28 allele on unconjugated hyperbilirubinemia in HIV-positive patients receiving Atazanavir: a systematic review. Ann Pharmacother 2013; 47(4): 561–72.

10. Park WB, Choe PG, Song KH, Jeon JH, Park SW, Kim HB, et al. Genetic factors influencing severe atazanavir-associated hyperbilirubinemia in a population with low UDPglucuronosyltransferase 1A1*28 allele frequency. Clin Infect Dis 2010; 51(1): 101–6.

11. Pavlović S, Zukić B, Stojiljković-Petrović M. Molecular genetic markers as a basis for personalized medicine. J Med Biochem 2014; 33: 8–21.

12. Tseng CS, Tang KS, Lo HW, et al. UDP-glucuronosyltransferase 1A7 genetic polymorphisms are associated with hepatocellular carcinoma risk and onset age. Am J Gastroenterol 2005; 100: 1758–63.

13. Premawardhena A, Fisher CA, Liu YT, Verma IC, de Silva S, Arambepola M, et al. The global distribution of length polymorphisms of the promoters of the glucuronosyltransferase 1 gene (UGT1A1): hematologic and evolutionary implications. Blood Cells Mol Dis 2003; 31(1): 98–101.

14. Mitrović N, Delić D, Marković-Denić L, Jovičić M, Popović N, Bojović K, et al. Seroprevalence and risk factors for hepatitis C virus infection among blood donors in Serbia: A multicentre study. Dig Liver Dis 2015; 47(7): 572–6.

15. Švirtlih N, Delić D, Simonović J, Jevtović D, Dokić L, Gvozdenović E, et al. Hepatitis C virus genotypes in Serbia and Montenegro: the prevalence and clinical significance. World J Gastroenterol 2007; 13(3): 355–60.

16. Serfaty L. Follow-up of patients with chronic hepatitis C and a sustained viral response. Liver Int 2016; 36 Suppl 1: 67–71.

17. Innes HA, Hutchinson SJ, Allen S, Bhattacharyya D, Bramley P, Delahooke TE, et al. Excess liver-related morbidity of chronic hepatitis C patients, who achieve a sustained viral response, and are discharged from care. Hepatology 2011; 54(5): 1547–58.

18. Tachi Y, Hirai T, Miyata A, Ohara K, Iida T, Ishizu Y, et al. Progressive fibrosis significantly correlates with hepatocellular carcinoma in patients with a sustained virological response. Hepatol Res 2015; 45(2): 238–46.

19. Lippi G, Chiozza L, Mattiuzzi C, Plebani M. Patient and sample identification. Out of the maze? J Med Biochem 2017; 36: 107–12.

20. Radojković D, Kusić J. Silver staining of denaturing gradient gel electrophoresis gels. Clin Chem 2000; 46(6 Pt 1): 883–4.

21. Owens D, Evans J. Population studies on Gilbert's syndrome. J Med Genet 1975; 12: 152–6.

22. 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 U S A 1998; 95: 8170–4.

23. Köhle C, Möhrle B, Münzel PA, Schwab M, Wernet D, Badary OA, et al. Frequent co-occurrence of the TATA box mutation associated with Gilbert's syndrome (UGT1A1*28) with other polymorphisms of the UDPglucuronosyltransferase- 1 locus (UGT1A6*2 and UGT1A7*3) in Caucasians and Egyptians. Biochem Pharmacol 2003; 65(9): 1521–7.

24. Guy W. Neff, Christopher W, Eugene R. Schiff. The Current Economic Burden of Cirrhosis Gastroenterol Hepatol (N Y) 2011; 7(10): 661–71.

25. Delić D. Hronična hepatitis C virusna infekcija. In: Hronični virusni hepatitis. 1st ed. Beograd: Zavod za udżbenike, 2012: 324–5.

26. Delić D, Mitrović N, Popović N, et al. Kombinovana antivirusno-imunomodulatorna terapija – primena pegilovanog interferona alfa-2a i ribavirina kod bolesnika s hroničnim hepatitisom C. Srp Arh Celok Lek 2012; 140(9–10): 612–8.

27. Fattovich G, Ribero ML, Pantalena M, Diodati G, Almasio P, Nevens F, et al. Hepatitis C virus genotypes: distribution and clinical significance in patients with cirrhosis type C seen at tertiary referral centres in Europe. J Viral Hepat 2001; 8: 206–16.

28. Payan C, Roudot-Thoraval F, Marcellin P, Bled N, Duverlie G, Fouchard-Hubert I, et al. Changing of hepatitis C virus genotype patterns in France at the beginning of the third millenium: The GEMHEP GenoCII Study. J Viral Hepat 2005; 12: 405–13.

29. Jurčić Z, Franulović O, Štefanović O. Nasljedne nekonjugirane hiperbilirubinemije.Paediatr Croat 2006; 50:112–21.

30. Hirschfield GM, Alexander GJ. Gilbert's syndrome: an overview for clinical biochemists. Ann Clin Biochem 2006; 43(Pt 5): 340–3.

31. Urbánek P, Leníček M, Muchová L, Subhanová I, Dušek L, Kasp íková N, et al. No association of promoter variations of HMOX1 and UGT1A1 genes with liver injury in chronic hepatitis C. Ann Hepatol 2011; 10(4): 445–51.

32. Manolio TA, Burke GL, Savage PJ, Jacobs DR Jr, Sidney S, Wagenknecht LE, et al. Sex- and race-related differences in liver-associated serum chemistry tests in young adults in the CARDIA study. Clin Chem 1992; 38(9): 1853–9.

33. Monaghan G, Ryan M, Seddon R, Hume R, Burchell B. Genetic variation in bilirubin UDP-glucuronosyltransferase gene promoter and Gilbert’s syndrome. Lancet 1996: 347: 578–81.

34. Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. J Clin Endocrinol Metab 2001; 86: 724–31.

35. Zucker SD, Horn PS, Sherman KE. Serum bilirubin levels in the U.S. population: gender effect and inverse correlation with colorectal cancer. Hepatology 2004; 40: 827–35.

36. Mallat A, Hezode C, Lotersztajn S. Environmental factors as disease accelerators during chronic hepatitis C. Journal of Hepatology 2008; 48: 657–65.

37. Piekuse L, Kreile M, Zarina A, et al. Association between inherited monogenic liver disorders and chronic hepatitis C. World Journal of Hepatology 2014; 6(2): 92–7.

38. Bizya N, Sarantuya G, Namdag B. Yang S. Interferon and ribavirin combination therapy are linked to severe indirect hyperbilirubinemia in patients with nt-211G > A variant of UGT1A1 gene A. Journal of the Formosan Medical Association 2015; 114: 1147–8.

39. Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer PJ. Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology 1994; 19: 1513–20.

40. Kamath PS, et al. A model to predict survival in patients with end-stage liver disease. Hepatology 2001; 33: 464–70.

41. Vagu C, Sultana C, Ruta S. Serum Iron Markers in Patients With Chronic Hepatitis C Infection. Hepat Mon 2013; 13(10): e13136.

42. Barut S, Günal O, Erkorkmaz U. Serum ferritin levels in chronic hepatitis C patients during antiviral therapy and prediction of treatment response. Scand J Infect Dis 2012; 44(10): 761–5.

43. Deterding K, Grüngreiff K, Lankisch TO, Potthoff A, Bahr MJ, et al. Gilbert's syndrome and antiviral therapy of hepatitis C. Ann Hepatol 2009; 8(3): 246–50.

44. Simmons B, Saleem J, Hill A, Riley RD, Cooke GS. Risk of Late Relapse or Reinfection With Hepatitis C Virus After Achieving a Sustained Virological Response: A Systematic Review and Meta-analysis. Clinical Infectious Diseases 2016; 3: 683–94.

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