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

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

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.

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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.

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Authors and 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
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  2. Minoru Nakamura
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  3. Ayumi Kawauchi
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  15. Katsuhisa Omagari
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  18. Kazuhiro Tsukamoto
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the PBC Study Group in NHOSLJ

Corresponding author

Correspondence to Minoru Nakamura.

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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

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

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