Journal of Gastroenterology

, Volume 47, Issue 5, pp 596–605

Association of two polymorphisms of the IL28B gene with viral factors and treatment response in 1,518 patients infected with hepatitis C virus

  • Mariko Kobayashi
  • Fumitaka Suzuki
  • Norio Akuta
  • Hitomi Sezaki
  • Yoshiyuki Suzuki
  • Tetsuya Hosaka
  • Yusuke Kawamura
  • Masahiro Kobayashi
  • Satoshi Saitoh
  • Yasuji Arase
  • Kenji Ikeda
  • Kazuaki Chayama
  • Yuzo Miyakawa
  • Hiromitsu Kumada
Original Article—Liver, Pancreas, and Biliary Tract

Abstract

Background

Two nucleotide polymorphisms of the interleukin-28B (IL28B) gene, at rs8099917 and rs12979860, influence the response to interferon (IFN)-based therapies in patients infected with hepatitis C virus (HCV) of genotype 1. We aimed to investigate whether these polymorphisms showed complete linkage in Japanese patients.

Methods

A total of 1,518 Japanese patients infected with HCV were genotyped for the two IL28B loci, and the two sets of genotypes were compared.

Results

TT at rs8099917 and CC at rs12979860 were detected in 77.7 and 76.8%, respectively, of the 1,518 patients and TG/GG and CT/TT were detected in 22.3 and 23.2%. These two sets of IL28B genotype stood in strong linkage disequilibrium (r2 = 0.98). Discordance between the two IL28B polymorphisms occurred in 16 (1.1%) patients, and 13 (0.9%) of them possessed IFN-sensitive TT at rs8099917 and IFN-resistant CT at rs12979860. Three of these 13 patients had HCV of genotype 1b and had received pegylated-interferon and ribavirin, and none of them gained a sustained virological response. At rs8099917, IFN-resistant TG/GG were more frequent in patients infected with HCV of genotype 1 than in those infected with HCV of genotype 2 [258/1,046 (24.7%) vs. 75/441 (17.0%), p = 0.001]. The response to pegylated-interferon/ribavirin in 279 patients who were infected with HCV-1 and the response to IFN monotherapy in 361 patients who were infected with HCV-1 , was higher in those with TT than in those with TG/GG at rs8099917, as well as being higher in those with CC than in those with CT/TT at rs12979860 (p < 0.001).

Conclusions

Linkage disequilibrium between two IL28B polymorphisms at rs8099917 and rs12979860 is strong in Japanese HCV patients, but there are some discrepancies between the two sets of genotypes.

Keywords

Hepatitis C virus Chronic hepatitis C Interleukin-28B gene Interferon Single nucleotide polymorphism 

References

  1. 1.
    Cohen J. The scientific challenge of hepatitis C. Science. 1999;285:26–30.PubMedCrossRefGoogle Scholar
  2. 2.
    Alter HJ, Seeff LB. Recovery, persistence, and sequelae in hepatitis C virus infection: a perspective on long-term outcome. Semin Liver Dis. 2000;20:17–35.PubMedCrossRefGoogle Scholar
  3. 3.
    Seeff LB. Natural history of chronic hepatitis C. Hepatology. 2002;36:S35–46.PubMedCrossRefGoogle Scholar
  4. 4.
    Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL Jr, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975–82.PubMedCrossRefGoogle Scholar
  5. 5.
    Hadziyannis SJ, Sette H Jr, Morgan TR, Balan V, Diago M, Marcellin P, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med. 2004;140:346–55.PubMedGoogle Scholar
  6. 6.
    Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958–65.PubMedCrossRefGoogle Scholar
  7. 7.
    Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49:1335–74.PubMedCrossRefGoogle Scholar
  8. 8.
    Shiffman ML, Di Bisceglie AM, Lindsay KL, Morishima C, Wright EC, Everson GT, et al. Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment. Gastroenterology. 2004;126:1015–23.PubMedCrossRefGoogle Scholar
  9. 9.
    Kau A, Vermehren J, Sarrazin C. Treatment predictors of a sustained virologic response in hepatitis B and C. J Hepatol. 2008;49:634–51.PubMedCrossRefGoogle Scholar
  10. 10.
    Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature. 2009;461:399–401.PubMedCrossRefGoogle Scholar
  11. 11.
    Suppiah V, Moldovan M, Ahlenstiel G, Berg T, Weltman M, Abate ML, et al. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet. 2009;41:1100–4.PubMedCrossRefGoogle Scholar
  12. 12.
    Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N, et al. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet. 2009;41:1105–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Tadokoro K, Kobayashi M, Yamaguchi T, Suzuki F, Miyauchi S, Egashira T, et al. Classification of hepatitis B virus genotypes by the PCR-invader method with genotype-specific probes. J Virol Methods. 2006;138:30–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Kato N, Hijikata M, Ootsuyama Y, Nakagawa M, Ohkoshi S, Sugimura T, et al. Molecular cloning of the human hepatitis C virus genome from Japanese patients with non-A, non-B hepatitis. Proc Natl Acad Sci USA. 1990;87:9524–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Akuta N, Suzuki F, Sezaki H, Suzuki Y, Hosaka T, Someya T, et al. Association of amino acid substitution pattern in core protein of hepatitis C virus genotype 1b high viral load and non-virological response to interferon-ribavirin combination therapy. Intervirology. 2005;48:372–80.PubMedCrossRefGoogle Scholar
  16. 16.
    Ohnishi Y, Tanaka T, Ozaki K, Yamada R, Suzuki H, Nakamura Y. A high-throughput SNP typing system for genome-wide association studies. J Hum Genet. 2001;46:471–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Suzuki A, Yamada R, Chang X, Tokuhiro S, Sawada T, Suzuki M, et al. Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet. 2003;34:395–402.PubMedCrossRefGoogle Scholar
  18. 18.
    Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21:263–5.PubMedCrossRefGoogle Scholar
  19. 19.
    Akuta N, Suzuki F, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, et al. Predictive factors of early and sustained responses to peginterferon plus ribavirin combination therapy in Japanese patients infected with hepatitis C virus genotype 1b: amino acid substitutions in the core region and low-density lipoprotein cholesterol levels. J Hepatol. 2007;46:403–10.PubMedCrossRefGoogle Scholar
  20. 20.
    Thio CL, Thomas DL. Interleukin-28b: a key piece of the hepatitis C virus recovery puzzle. Gastroenterology. 2010;138:1240–3.PubMedCrossRefGoogle Scholar
  21. 21.
    Ito K, Higami K, Masaki N, Sugiyama M, Mukaide M, Saito H, et al. The rs8099917 polymorphism, when determined by a suitable genotyping method, is a better predictor for response to pegylated alpha interferon/ribavirin therapy in Japanese patients than other single nucleotide polymorphisms associated with interleukin-28B. J Clin Microbiol. 2011;49:1853–60.PubMedCrossRefGoogle Scholar
  22. 22.
    Akuta N, Suzuki F, Hirakawa M, Kawamura Y, Yatsuji H, Sezaki H, et al. Amino acid substitution in hepatitis C virus core region and genetic variation near the interleukin 28B gene predict viral response to telaprevir with peginterferon and ribavirin. Hepatology. 2010;52:421–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Rallon NI, Naggie S, Benito JM, Medrano J, Restrepo C, Goldstein D, et al. Association of a single nucleotide polymorphism near the interleukin-28B gene with response to hepatitis C therapy in HIV/hepatitis C virus-coinfected patients. AIDS. 2010;24:F23–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Rauch A, Kutalik Z, Descombes P, Cai T, Di Iulio J, Mueller T, et al. Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study. Gastroenterology. 2010;138:1338–45.PubMedCrossRefGoogle Scholar
  25. 25.
    Abe H, Ochi H, Maekawa T, Hayes N, Tsuge M, Miki D, et al. Common variation of IL28 affects gamma-GTP levels and inflammation of the liver in chronically infected hepatitis C virus patients. J Hepatol. 2010;53:439–43.PubMedCrossRefGoogle Scholar
  26. 26.
    Sezaki H, Suzuki F, Kawamura Y, Yatsuji H, Hosaka T, Akuta N, et al. Poor response to pegylated interferon and ribavirin in older women infected with hepatitis C virus of genotype 1b in high viral loads. Dig Dis Sci. 2009;54:1317–24.PubMedCrossRefGoogle Scholar
  27. 27.
    Carithers RL Jr, Emerson SS. Therapy of hepatitis C: meta-analysis of interferon alfa-2b trials. Hepatology. 1997;26:S83–8.CrossRefGoogle Scholar

Copyright information

© Springer 2012

Authors and Affiliations

  • Mariko Kobayashi
    • 1
    • 2
  • Fumitaka Suzuki
    • 2
  • Norio Akuta
    • 2
  • Hitomi Sezaki
    • 2
  • Yoshiyuki Suzuki
    • 2
  • Tetsuya Hosaka
    • 2
  • Yusuke Kawamura
    • 2
  • Masahiro Kobayashi
    • 2
  • Satoshi Saitoh
    • 2
  • Yasuji Arase
    • 2
  • Kenji Ikeda
    • 2
  • Kazuaki Chayama
    • 3
  • Yuzo Miyakawa
    • 4
  • Hiromitsu Kumada
    • 2
  1. 1.Research Institute for Hepatology, Toranomon HospitalKawasakiJapan
  2. 2.Department of HepatologyToranomon HospitalKawasakiJapan
  3. 3.Division of Frontier Medical Science, Department of Medical and Molecular Science, Programs for Biomedical Research, Graduate School of Biomedical ScienceHiroshima UniversityHiroshimaJapan
  4. 4.Miyakawa Memorial Research FoundationTokyoJapan

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