Skip to main content

A polymorphism in the integrin αV subunit gene affects the progression of primary biliary cirrhosis in Japanese patients

Journal of Gastroenterology volume 46, pages 676–686 (2011)Cite this article

Abstract

Background

Accumulating evidence indicates that multiple genetic factors are involved in the pathogenesis of primary biliary cirrhosis (PBC). The aim of this study was to investigate whether polymorphisms of the integrin αV subunit gene (ITGAV), a component of integrin αVβ6, which plays an important role in the process of fibrosis, are associated with susceptibility to the onset and/or progression of PBC.

Methods

In the primary study, eight tag single nucleotide polymorphisms (SNPs) in ITGAV were analyzed by polymerase chain reaction (PCR)-restriction fragment length polymorphism, direct DNA sequencing, or high-resolution melting curve analysis in 309 Japanese patients with PBC who were registered in the National Hospital Organization Study Group for Liver Disease in Japan (PBC cohort I) and 293 gender-matched healthy Japanese volunteers (control subjects). For the replication study, 35 PBC patients who progressed to end-stage hepatic failure and underwent liver transplantation (PBC cohort II) were also analyzed.

Results

Three tag SNPs (rs3911238, rs10174098, and rs1448427) in ITGAV were significantly associated with the severe progression of PBC, but not with susceptibility to the onset of PBC, in the primary study (PBC cohort I). Among these SNPs, rs1448427 was also significantly associated with the severe progression to end-stage hepatic failure in the replication study of PBC patients who underwent liver transplantation (PBC cohort II).

Conclusions

ITGAV is a genetic determinant for the severe progression of PBC in Japanese patients. Genetic polymorphisms of ITGAV may be useful for identifying high-risk Japanese PBC patients, including those who will require liver transplantation, at the time of initial diagnosis.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1

References

  1. Kaplan MM, Gershwin ME. Primary biliary cirrhosis. N Engl J Med. 2005;353:1261–73.

    PubMed  Article  CAS  Google Scholar 

  2. Poupon R. Primary biliary cirrhosis: a 2010 update. J Hepatol. 2010;52:745–58.

    PubMed  Article  Google Scholar 

  3. Corpechot C, Carrat F, Bahr A, Chretien Y, Poupon RE, Poupon R. The effect of ursodeoxycholic acid therapy on the natural course of primary biliary cirrhosis. Gastroenterology. 2005;128:297–303.

    PubMed  Article  CAS  Google Scholar 

  4. Brind AM, Bray GP, Portmann BC, Williams R. Prevalence and pattern of familial disease in primary biliary cirrhosis. Gut. 1995;36:615–7.

    PubMed  Article  CAS  Google Scholar 

  5. Selmi C, Invernizzi P, Zuin M, Podda M, Seldin MF, Gershwin ME. Genes and (auto)immunity in primary biliary cirrhosis. Genes Immun. 2005;6:543–56.

    PubMed  Article  CAS  Google Scholar 

  6. Selmi C, Mayo MJ, Bach N, Ishibashi H, Invernizzi P, Gish RG, et al. Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment. Gastroenterology. 2004;127:485–92.

    PubMed  Article  Google Scholar 

  7. Hirschfield GM, Liu X, Xu C, Lu Y, Xie G, Lu Y, et al. Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants. N Engl J Med. 2009;360:2544–55.

    PubMed  Article  CAS  Google Scholar 

  8. Nakamura M, Yasunami M, Kondo H, Horie H, Aiba Y, Komori A, et al. Analysis of HLA-DRB1 polymorphisms in Japanese patients with primary biliary cirrhosis (PBC): the HLA-DRB1 polymorphism determines the relative risk of antinuclear antibodies for disease progression in PBC. Hepatol Res. 2010;40:494–504.

    PubMed  Article  Google Scholar 

  9. Agarwal K, Jones DEJ, Daly AK, James OFW, Vaidya B, Pearce S, et al. CTLA-4 gene polymorphism confers susceptibility to primary biliary cirrhosis. J Hepatol. 2000;32:538–41.

    PubMed  Article  CAS  Google Scholar 

  10. Juran BD, Atkinson EJ, Schlicht EM, Fridley BL, Lazaridis KN. Primary biliary cirrhosis is associated with a genetic variant in the 3′ flanking region of the CTLA4 gene. Gastroenterology. 2008;135:1200–6.

    PubMed  Article  CAS  Google Scholar 

  11. Joshita S, Umemura T, Yoshizawa K, Katsuyama Y, Tanaka E, Nakamura M, et al. Association analysis of cytotoxic T-lymphocyte antigen 4 gene polymorphisms with primary biliary cirrhosis in Japanese patients. J Hepatol. 2010;53:537–41.

    PubMed  Article  CAS  Google Scholar 

  12. Tanaka A, Nezu S, Uegaki S, Kikuchi K, Shibuya A, Miyakawa H, et al. Vitamin D receptor polymorphisms are associated with increased susceptibility to primary biliary cirrhosis in Japanese and Italian populations. J Hepatol. 2009;50:1202–9.

    PubMed  Article  CAS  Google Scholar 

  13. Donaldson P, Agarwal K, Craggs A, Craig W, James O, Jones D. HLA and interleukin 1 gene polymorphisms in primary biliary cirrhosis: associations with disease progression and disease susceptibility. Gut. 2001;48:397–402.

    PubMed  Article  CAS  Google Scholar 

  14. Hirschfield GM, Liu X, Han Y, Gorlov IP, Lu Y, Xu C, et al. Variants at IRF5-TNPO3, 17q12–21 and MMEL1 are associated with primary biliary cirrhosis. Nat Genet. 2010;42:655–7.

    PubMed  Article  CAS  Google Scholar 

  15. Liu X, Invernizzi P, Lu Y, Kosoy R, Lu Y, Bianchi I, et al. Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis. Nat Genet. 2010;42:658–60.

    PubMed  Article  CAS  Google Scholar 

  16. Poupon R, Ping C, Chrétien Y, Corpechot C, Chazouillères O, Simon T, et al. Genetic factors of susceptibility and of severity in primary biliary cirrhosis. J Hepatol. 2008;49:1038–45.

    PubMed  Article  CAS  Google Scholar 

  17. Ohishi Y, Nakamura M, Iio N, Higa S, Inayoshi M, Aiba Y, et al. Single-nucleotide polymorphism analysis of the multidrug resistance protein 3 gene for the detection of clinical progression in Japanese patients with primary biliary cirrhosis. Hepatology. 2008;48:853–62.

    PubMed  Article  CAS  Google Scholar 

  18. Bataller R, Brenner DA. Liver fibrosis. J Clin Invest. 2005;115:209–18.

    PubMed  CAS  Google Scholar 

  19. Huttenlocher A, Ginsberg MH, Horwitz AF. Modulation of cell migration by integrin-mediated cytoskeletal linkages and ligand-binding affinity. J Cell Biol. 1996;134:1551–62.

    PubMed  Article  CAS  Google Scholar 

  20. Luo B, Springer TA. Integrin structures and conformational signaling. Curr Opin Cell Biol. 2006;18:579–86.

    PubMed  Article  CAS  Google Scholar 

  21. Busk M, Pytela R, Sheppard D. Characterization of the integrin avb6 as a fibronectin-binding protein. J Biol Chem. 1992;267:5790–6.

    PubMed  CAS  Google Scholar 

  22. Prieto AL, Edelman GM, Crossin KL. Multiple integrins mediate cell attachment to cytotactin/tenascin. Proc Natl Acad Sci USA. 1993;90:10154–8.

    PubMed  Article  CAS  Google Scholar 

  23. Margadant C, Sonnenberg A. Integrin-TGF-beta crosstalk in fibrosis, cancer and wound healing. EMBO Rep. 2010;11:97–105.

    PubMed  Article  CAS  Google Scholar 

  24. Patsenker E, Popov Y, Stickel F, Jonczyk A, Goodman SL, Schuppan D. Inhibition of integrin alphavbeta6 on cholangiocytes blocks transforming growth factor-beta activation and retards biliary fibrosis progression. Gastroenterology. 2008;135:660–70.

    PubMed  Article  CAS  Google Scholar 

  25. Popov Y, Patsenker E, Stickel F, Zaks J, Bhaskar KR, Niedobitek G, et al. Integrin alphavbeta6 is a marker of the progression of biliary and portal liver fibrosis and a novel target for antifibrotic therapies. J Hepatol. 2008;48:453–64.

    PubMed  Article  CAS  Google Scholar 

  26. Lee SK, Kim M, Cheong JY, Cho SW, Yang S, Kwack KB. Integrin alpha V polymorphisms and haplotypes in a Korean population are associated with susceptibility to chronic hepatitis and hepatocellular carcinoma. Liver Int. 2009;29:187–95.

    PubMed  Article  CAS  Google Scholar 

  27. Scheuer P. Primary biliary cirrhosis. Proc R Soc Med. 1967;60:1257–60.

    PubMed  CAS  Google Scholar 

  28. Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21:263–5.

    PubMed  Article  CAS  Google Scholar 

  29. Wittwer CT, Reed GH, Gundry CN, Vandersteen JG, Pryor RJ. High-resolution genotyping by amplicon melting analysis using LCGreen. Clin Chem. 2003;49:853–60.

    PubMed  Article  CAS  Google Scholar 

  30. Wang B, Dolinski BM, Kikuchi N, Leone DR, Peters MG, Weinreb PH, et al. Role of alphavbeta6 integrin in acute biliary fibrosis. Hepatology. 2007;46:1404–12.

    PubMed  Article  CAS  Google Scholar 

  31. Hirai Y, Nelson CM, Yamazaki K, Takebe K, Przybylo J, Madden B, et al. Non-classical export of epimorphin and its adhesion to αV-integrin in regulation of epithelial morphogenesis. J Cell Sci. 2007;120:2032–43.

    PubMed  Article  CAS  Google Scholar 

  32. Segawa D, Miura K, Goto T, Ohshima S, Mikami K, Yoneyama K, et al. Distribution and isoforms of epimorphin in carbon tetrachloride-induced acute liver injury in mice. J Gastroenterol Hepatol. 2005;20:1769–80.

    PubMed  Article  CAS  Google Scholar 

  33. Yoshino R, Miura K, Segawa D, Hirai Y, Goto T, Ohshima S, et al. Epimorphin expression and stellate cell status in mouse liver injury. Hepatol Res. 2006;34:238–49.

    PubMed  Article  CAS  Google Scholar 

  34. Zhou J, Zhao L, Qin L, Wang J, Jia Y, Yao H, et al. Epimorphin regulates bile duct formation via effects on mitosis orientation in rat liver epithelial stem-like cells. PLoS One. 2010;5:e9732.

    PubMed  Article  Google Scholar 

  35. Vleggaar FP, Van Buuren HR, Zondervan PE, Ten Kate FJW, Hop WCJ, Adang R, et al. Jaundice in non-cirrhotic primary biliary cirrhosis: the premature ductopenic variant. Gut. 2001;49:276–81.

    PubMed  Article  CAS  Google Scholar 

  36. Hollis-Moffatt JE, Rowley KA, Phipps-Green AJ, Merriman ME, Dalbeth N, Gow P, Harrison AA, et al. The ITGAV rs3738919 variant and susceptibility to rheumatoid arthritis in four Caucasian sample sets. Arthritis Res Ther. 2009;11:R152.

    PubMed  Article  Google Scholar 

  37. Nakamura M, Kondo H, Mori T, Komori A, Matsuyama M, Ito M, et al. Anti-gp210 and anti-centromere antibodies are different risk factors for the progression of primary biliary cirrhosis. Hepatology. 2007;45:118–27.

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by Health and Labour Sciences Research Grants for Research on Measures for Intractable Diseases from the Ministry of Health, Labour and Welfare of Japan (M. Nakamura); a Grant-in-Aid for Scientific Research (C) (KAKENHI No. 20590545) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (K. Omagari); and the president’s discretionary fund of Nagasaki University, Japan (K. Tsukamoto). The authors thank the PBC patients and healthy volunteers for participating in this study, and also thank members of the PBC Study Group in NHSOLJ: Dr. Akira Saito (NHO Nishisaitama Chuo Hospital), Dr. Naohiko Masaki (Kokusai Medical Center), Dr. Michiyasu Yagura (NHO Tokyo Hospital), Drs. Yukio Watanabe and Yoko Nakamura (NHO Sagamihara Hospital), Drs. Koichi Honda and Toyokichi Muro (NHO Oita Medical Center), Dr. Yoshinobu Fukushima (NHO Kyushu Medical Center), Drs. Masaaki Shimada and Noboru Hirashima (NHO Nagoya Medical Center), Dr. Masakazu Kobayashi (NHO Matsumoto Medical Center), Dr. Yukio Ohara (NHO Hokkaido Medical Center), Dr. Tatsuji Komatsu (NHO Yokohama Medical Center), Dr. Hajime Ota (NHO Kanazawa Medical Center), Drs. Hiroshi Kohno and Hirotaka Kouno (NHO Kure Medical Center), Dr. Haruhiro Yamashita (NHO Okayama Medical Center), Dr. Takeaki Sato (NHO Kokura Medical Center), Dr. Toshiki Komeda (NHO Kyoto Medical Center), Dr. Michiaki Koga (NHO Ureshino Medical Center), Dr. Masahiko Takahashi (NHO Tokyo Medical Center), Dr. Tetsuo Yamamoto (NHO Yonago Medical Center), Dr. Kazuhiro Sugi (NHO Kumamoto Medical Center), Dr. Michio Kato (NHO Minami Wakayama Medical Center), Dr. Eiichi Takezaki (NHO Higashi Hiroshima Medical Center), Dr. Hiroshi Mano (NHO Sendai Medical Center), Dr. Hideo Nishimura (NHO Douhoku Hospital), Dr. Eiji Mita (NHO Osaka Medical Center), Dr. Hironori Sakai (NHO Beppu Medical Center), and Drs. Shinya Nagaoka, Seigo Abiru, and Koji Yano (NHO Nagasaki Medical Center), for providing blood samples and clinical information from PBC patients.

Conflict of interest

None.

Author information

Affiliations

  1. Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

    Tatsuo Inamine, Ayumi Kawauchi, Yayoi Shirakawa, Hisae Hashiguchi, Shinji Kondo & Kazuhiro Tsukamoto

  2. Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan

    Minoru Nakamura, Yoshihiro Aiba, Atsumasa Komori, Hiroshi Yatsuhashi & Hiromi Ishibashi

  3. Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

    Minoru Nakamura, Atsumasa Komori, Hiroshi Yatsuhashi & Hiromi Ishibashi

  4. Headquarters of PBC Research in the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ), Nagasaki, Japan

    Minoru Nakamura, Makoto Nakamuta, Shigeki Hayashi & Takeo Saoshiro

  5. Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Akinobu Taketomi, Ken Shirabe & Yoshihiko Maehara

  6. Department of Nutrition, Faculty of Nursing and Nutrition, Siebold University of Nagasaki, Nagasaki, Japan

    Katsuhisa Omagari

Authors
  1. Tatsuo Inamine
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Minoru Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ayumi Kawauchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yayoi Shirakawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hisae Hashiguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yoshihiro Aiba
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Akinobu Taketomi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ken Shirabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Makoto Nakamuta
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Shigeki Hayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Takeo Saoshiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Atsumasa Komori
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Hiroshi Yatsuhashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Shinji Kondo
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Katsuhisa Omagari
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Yoshihiko Maehara
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Hiromi Ishibashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Kazuhiro Tsukamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

the PBC Study Group in NHOSLJ

Corresponding author

Correspondence to Minoru Nakamura.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Inamine, T., Nakamura, M., Kawauchi, A. et al. A polymorphism in the integrin αV subunit gene affects the progression of primary biliary cirrhosis in Japanese patients. J Gastroenterol 46, 676–686 (2011). https://doi.org/10.1007/s00535-010-0351-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-010-0351-0

Keywords

  • PBC
  • Integrin αV
  • Hepatic fibrosis
  • Premature ductopenia
  • Progression