Infection

, Volume 41, Issue 2, pp 371–378 | Cite as

Polymorphism of estrogen receptor alpha (ESR1) is associated with virological response to entecavir (ETV) in nucleoside-naïve adult patients with chronic hepatitis B

  • T.-T. Zhang
  • J. Ye
  • S.-L. Xia
  • Y.-F. Zhang
  • Q. Su
  • Z.-H. Zhang
  • X. Li
Clinical and Epidemiological Study

Abstract

Introduction

Polymorphisms in estrogen receptor alpha (ESR1) are reported to be associated with the susceptibility to persistent HBV infection, HBV liver cirrhosis and HBV-related hepatocellular carcinoma (HCC).

Materials and methods

To test the hypothesis that polymorphisms in estrogen receptor alpha (ESR1) might influence the virological response to entecavir (ETV) therapy, we examined two polymorphisms (PvuII and XbaI) in 76 nucleoside-naïve chronic hepatitis B (CHB) patients. All of the patients (52 HBeAg-positive and 24 HBeAg-negative) were treated with ETV 0.5 mg daily and followed up for a median time of 96 weeks (range 48–96). Polymorphisms were determined using the polymerase chain reaction–restriction fragment-length polymorphism (PCR–RFLP) method.

Results

Under an additive model, the univariate analysis showed that patients carrying the PvuII T/C genotype might have higher virological responders than those carrying the T/T and C/C genotypes at week 48 (87.7 vs. 57.1 vs. 58.3 %; P = 0.012) and week 96 (96.7 vs. 64.3 vs. 24 87.5 %; P = 0.018), although this difference disappeared with the multiple analysis at week 48 [95 % confidence interval (CI) 0.687–3.841; P = 0.269] and week 96 (95 % CI 0.861–18.016; P = 0.077). Conversely, the univariate analysis suggests statistical significance between the recessive model of PvuII (TT vs. TC/CC) and virological response at week 48 (57.1 vs. 81.1 %; P = 0.033) and week 96 (64.3 vs. 94.7 %; P = 0.017). Multiple regression analysis affirmed the significant and independent association between the recessive model of PvuII and virological response. In other words, patients carrying at least one PvuII C allele (TC/CC) had a better likelihood of achieving virological response compared with those carrying the T/T genotype at week 48 (95 % CI 1.026–14.785, P = 0.046) and week 96 (95 % CI 1.456–57.509; P = 0.018). XbaI polymorphisms were not significantly associated with virological response.

Conclusion

Our results suggest that the PvuII polymorphism may play an important role in determining ETV efficacy after 48 and 96 weeks of treatment, at least in this study population.

Keywords

Polymorphism ESR1 Response Chronic hepatitis B 

Notes

Acknowledgements

We thank all the physicians and staff members at the Department of Infection who were involved in the care and collection of patients. This study was supported by a grant from the National Natural Science Foundation of China (30771907) and Foundation of Pre-973 Program Projects (2009CB526411) to Dr. Li.

Conflict of interest

None.

Supplementary material

15010_2012_320_MOESM1_ESM.doc (24 kb)
Supplementary material 1 (DOC 23 kb)

References

  1. 1.
    Dienstag JL. Hepatitis B virus infection. N Engl J Med. 2008;359:1486–500.PubMedCrossRefGoogle Scholar
  2. 2.
    Mommeja-Marin H, Mondou E, Blum MR, Rousseau F. Serum HBV DNA as a marker of efficacy during therapy for chronic HBV infection: analysis and review of the literature. Hepatology. 2003;37:1309–19.PubMedCrossRefGoogle Scholar
  3. 3.
    Liaw YF, Leung N, Kao JH, Piratvisuth T, Gane E, Han KH, et al. Asian–Pacific consensus statement on the management of chronic hepatitis B: a 2008 update. Hepatol Int. 2008;2:263–83.PubMedCrossRefGoogle Scholar
  4. 4.
    Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007;45:507–39.PubMedCrossRefGoogle Scholar
  5. 5.
    European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol. 2009;51:237–67.CrossRefGoogle Scholar
  6. 6.
    Cornberg M, Protzer U, Petersen J, Wedemeyer H, Berg T, Jilg W, et al. Prophylaxis, diagnosis and therapy of hepatitis B virus infection—the German guideline. Z Gastroenterol. 2011;49:871–930.PubMedCrossRefGoogle Scholar
  7. 7.
    Muneer B, Testa G, Millis JM, Mohanty SR. Entecavir therapy in a hepatitis B-related decompensated cirrhotic patient. South Med J. 2008;101:1173–6.PubMedCrossRefGoogle Scholar
  8. 8.
    Yoo BC, Kim JH, Chung YH, Lee KS, Paik SW, Ryu SH, et al. Twenty-four-week clevudine therapy showed potent and sustained antiviral activity in HBeAg-positive chronic hepatitis B. Hepatology. 2007;45:1172–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Lee JS, Park ET, Kang SS, Gu ES, Kim JS, Jang DS, et al. Clevudine demonstrates potent antiviral activity in naïve chronic hepatitis B patients. Intervirology. 2010;53:83–6.PubMedCrossRefGoogle Scholar
  10. 10.
    Karatayli E, Karatayli SC, Cinar K, Gokahmetoglu S, Güven K, Idilman R, et al. Molecular characterization of a novel entecavir mutation pattern isolated from a multi-drug refractory patient with chronic hepatitis B infection. J Clin Virol. 2012;53:130–4.PubMedCrossRefGoogle Scholar
  11. 11.
    Arrese E, Basaras M, Blanco S, Ruiz P, Cisterna R. Evolution of hepatitis B virus during long-term therapy in patients with chronic hepatitis B. Ann Hepatol. 2011;10:434–40.PubMedGoogle Scholar
  12. 12.
    Myung HJ, Jeong SH, Kim JW, Kim HS, Jang JH, Lee DH, et al. Efficacy and predictors of the virologic response to entecavir therapy in nucleoside-naive patients with chronic hepatitis B. Korean J Hepatol. 2010;16:57–65.PubMedCrossRefGoogle Scholar
  13. 13.
    Song JC, Min BY, Kim JW, Kim JY, Kim YM, Shin CM, et al. Pretreatment serum HBsAg-to-HBV DNA ratio predicts a virologic response to entecavir in chronic hepatitis B. Korean J Hepatol. 2011;17:268–73.PubMedCrossRefGoogle Scholar
  14. 14.
    Deng G, Zhou G, Zhai Y, Li S, Li X, Li Y, et al. Association of estrogen receptor alpha polymorphisms with susceptibility to chronic hepatitis B virus infection. Hepatology. 2004;40:318–26.PubMedCrossRefGoogle Scholar
  15. 15.
    Zhai Y, Zhou G, Deng G, Xie W, Dong X, Zhang X, et al. Estrogen receptor alpha polymorphisms associated with susceptibility to hepatocellular carcinoma in hepatitis B virus carriers. Gastroenterology. 2006;130:2001–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Zhang TT, Zhang ZH, Gao YF, Zhang YF, Yang DL, Li X. T29C genotype polymorphism of estrogen receptor alpha is associated with initial response to interferon-alpha therapy in chronic hepatitis B patients. Hepatobiliary Pancreat Dis Int. 2010;9:275–9.PubMedGoogle Scholar
  17. 17.
    Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005;353:487–97.PubMedCrossRefGoogle Scholar
  18. 18.
    Walsh JC, Mandalia S, Gazzard BG. Responses to a 1 month self-report on adherence to antiretroviral therapy are consistent with electronic data and virological treatment outcome. AIDS. 2002;16:269–77.PubMedCrossRefGoogle Scholar
  19. 19.
    Lu M, Safren SA, Skolnik PR, Rogers WH, Coady W, Hardy H, et al. Optimal recall period and response task for self-reported HIV medication adherence. AIDS Behav. 2008;12:86–94.PubMedCrossRefGoogle Scholar
  20. 20.
    Hongthanakorn C, Chotiyaputta W, Oberhelman K, Fontana RJ, Marrero JA, Licari T, et al. Virological breakthrough and resistance in patients with chronic hepatitis B receiving nucleos(t)ide analogues in clinical practice. Hepatology. 2011;53:1854–63.PubMedCrossRefGoogle Scholar
  21. 21.
    Kamezaki H, Kanda T, Wu S, Nakamoto S, Arai M, Maruyama H, et al. Emergence of entecavir-resistant mutations in nucleos(t)ide-naive Japanese patients infected with hepatitis B virus: virological breakthrough is also dependent on adherence to medication. Scand J Gastroenterol. 2011;46:1111–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Yan Z, Tan W, Xu B, Dan Y, Zhao W, Deng C, et al. A cis-acting regulatory variation of the estrogen receptor alpha (ESR1) gene is associated with hepatitis B virus-related liver cirrhosis. Hum Mutat. 2011;32:1128–36.PubMedCrossRefGoogle Scholar
  23. 23.
    Cohn CS, Sullivan JA, Kiefer T, Hill SM. Identification of an enhancer element in the estrogen receptor upstream region: implications for regulation of ER transcription in breast cancer. Mol Cell Endocrinol. 1999;158:25–36.PubMedCrossRefGoogle Scholar
  24. 24.
    Iwashita S, Koyama K, Nakamura Y. VNTR sequence on human chromosome 11p15 that affects transcriptional activity. J Hum Genet. 2001;46:717–21.PubMedCrossRefGoogle Scholar
  25. 25.
    Nilsson S, Gustafsson JA. Estrogen receptor transcription and transactivation: basic aspects of estrogen action. Breast Cancer Res. 2000;2:360–6.PubMedCrossRefGoogle Scholar
  26. 26.
    Klinge CM. Estrogen receptor interaction with co-activators and co-repressors. Steroids. 2000;65:227–51.PubMedCrossRefGoogle Scholar
  27. 27.
    Shimizu I, Ito S. Protection of estrogens against the progression of chronic liver disease. Hepatol Res. 2007;37:239–47.PubMedCrossRefGoogle Scholar
  28. 28.
    Wang SH, Yeh SH, Lin WH, Yeh KH, Yuan Q, Xia NS, et al. Estrogen receptor alpha represses transcription of HBV genes via interaction with hepatocyte nuclear factor 4alpha. Gastroenterology. 2012;142:989–998.e4.PubMedCrossRefGoogle Scholar
  29. 29.
    Tong S. Hepatitis B virus, a sex hormone-responsive virus. Gastroenterology. 2012;142:696–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Marcellin P, Liang J. A personalized approach to optimize hepatitis B treatment in treatment-naive patients. Antivir Ther. 2010;15:53–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Bihl F, Loggi E, Chisholm JV 3rd, Biselli M, Morelli MC, Cursaro C, et al. Sustained and focused hepatitis B virus nucleocapsid-specific T-cell immunity in liver transplant recipients compared to individuals with chronic and self-limited hepatitis B virus infection. Liver Transpl. 2008;14:478–85.PubMedCrossRefGoogle Scholar
  32. 32.
    Huang CF, Lin SS, Ho YC, Chen FL, Yang CC. The immune response induced by hepatitis B virus principal antigens. Cell Mol Immunol. 2006;3:97–106.PubMedGoogle Scholar
  33. 33.
    Stoop JN, van der Molen RG, Kuipers EJ, Kusters JG, Janssen HL. Inhibition of viral replication reduces regulatory T cells and enhances the antiviral immune response in chronic hepatitis B. Virology. 2007;361:141–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Bertoletti A, Gehring AJ. The immune response during hepatitis B virus infection. J Gen Virol. 2006;87:1439–49.PubMedCrossRefGoogle Scholar
  35. 35.
    Milich DR, Schödel F, Hughes JL, Jones JE, Peterson DL. The hepatitis B virus core and e antigens elicit different Th cell subsets: antigen structure can affect Th cell phenotype. J Virol. 1997;71:2192–201.PubMedGoogle Scholar
  36. 36.
    Okasha SA, Ryu S, Do Y, McKallip RJ, Nagarkatti M, Nagarkatti PS. Evidence for estradiol-induced apoptosis and dysregulated T cell maturation in the thymus. Toxicology. 2001;163:49–62.PubMedCrossRefGoogle Scholar
  37. 37.
    Polanczyk MJ, Carson BD, Subramanian S, Afentoulis M, Vandenbark AA, Ziegler SF, et al. Cutting edge: estrogen drives expansion of the CD4+CD25+ regulatory T cell compartment. J Immunol. 2004;173:2227–30.PubMedGoogle Scholar
  38. 38.
    Jiang Y, Li W, Yu L, Liu J, Xin G, Yan H, et al. Enhancing the antihepatitis B virus immune response by adefovir dipivoxil and entecavir therapies. Cell Mol Immunol. 2011;8:75–82.PubMedCrossRefGoogle Scholar
  39. 39.
    Wu X, Xin Z, Zhu X, Pan L, Li Z, Li H, et al. Evaluation of susceptibility locus for response to interferon-α based therapy in chronic hepatitis B patients in Chinese. Antiviral Res. 2012;93:297–300.PubMedCrossRefGoogle Scholar
  40. 40.
    Zhu X, Du T, Wu X, Guo X, Niu N, Pan L, et al. Human leukocyte antigen class I and class II genes polymorphisms might be associated with interferon α therapy efficiency of chronic hepatitis B. Antiviral Res. 2011;89:189–92.PubMedCrossRefGoogle Scholar
  41. 41.
    Ren S, Yu H, Zhang H, Liu Y, Huang Y, Ma L, et al. Polymorphisms of interferon-inducible genes OAS associated with interferon-α treatment response in chronic HBV infection. Antiviral Res. 2011;89:232–7.PubMedCrossRefGoogle Scholar
  42. 42.
    Wang S, Huang D, Sun S, Ma W, Zhen Q. Interleukin-10 promoter polymorphism predicts initial response of chronic hepatitis B to interferon alfa. Virol J. 2011;8:28.PubMedCrossRefGoogle Scholar
  43. 43.
    Wu X, Zhu X, Zhu S, Li J, Ma J, Li Z, et al. A pharmacogenetic study of polymorphisms in interferon pathway genes and response to interferon-alpha treatment in chronic hepatitis B patients. Antiviral Res. 2009;83:252–6.PubMedCrossRefGoogle Scholar
  44. 44.
    Jin YJ, Shim JH, Chung YH, Kim JA, Choi JG, Park WH, et al. HLA-DRB1*010101 allele is closely associated with poor virological response to lamivudine therapy in patients with chronic hepatitis B. Digestion. 2011;84:35–42.PubMedCrossRefGoogle Scholar
  45. 45.
    Park YK, Lee JM, do Kim Y, Chang HY, Kim JK, Lee CK, et al. Association between polymorphism of tumor necrosis factor-alpha promoter and response to lamivudine treatment in patients with chronic hepatitis B. Dig Dis Sci. 2010;55:2043–8.PubMedCrossRefGoogle Scholar
  46. 46.
    Thursz M, Yee L, Khakoo S. Understanding the host genetics of chronic hepatitis B and C. Semin Liver Dis. 2011;31:115–27.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • T.-T. Zhang
    • 1
  • J. Ye
    • 2
  • S.-L. Xia
    • 1
  • Y.-F. Zhang
    • 1
  • Q. Su
    • 1
  • Z.-H. Zhang
    • 1
  • X. Li
    • 1
  1. 1.Department of Infectious DiseasesFirst Affiliated Hospital, Anhui Medical CollegeHefeiChina
  2. 2.Department of Infectious DiseasesSecond Affiliated Hospital, Anhui Medical CollegeHefeiChina

Personalised recommendations