Human leukocyte antigen class II molecules confer both susceptibility and progression in Japanese patients with primary biliary cirrhosis§

Authors

  • Takeji Umemura,

    Corresponding author
    1. Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
    • Department of Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan
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    • fax: +81-263-32-9412 Masao Ota, Ph.D., Department of Legal Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan. E-mail: otamasao@shinshu-u.ac.jp; fax: +81-263-37-3084

  • Satoru Joshita,

    1. Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
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  • Tetsuya Ichijo,

    1. Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
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  • Kaname Yoshizawa,

    1. Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
    2. Department of Gastroenterology, NHO Shinshu Ueda Medical Center, Ueda, Japan
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  • Yoshihiko Katsuyama,

    1. Department of Pharmacy, Shinshu University Hospital, Matsumoto, Japan
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  • Eiji Tanaka,

    1. Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
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  • Masao Ota,

    1. Department of Legal Medicine, Shinshu University School of Medicine, Matsumoto, Japan
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  • The Shinshu PBC Study Group


  • Potential conflict of interest: Nothing to report.

  • Thjs work was supported by The Ministry of Education, Culture, Sports, Science, and Technology of Japan (23590969) and The Ministry of Health, Labor, and Welfare of Japan.

  • §

    The Shinshu PBC Study Group includes the following members: Yuki Ichikawa-Yamada, Takefumi Kimura, Susumu Morita, Atsushi Kamijo, Michiharu Komatsu, Akihiro Matsumoto (Shinshu University School of Medicine), and Nobuyoshi Yamamura (Department of Gastroenterology, Suwa Red Cross Hospital).

Abstract

Along with twin and family studies, recent genome-wide association studies suggest that genetic factors contribute to the susceptibility and severity of primary biliary cirrhosis (PBC). Although several reports have demonstrated that the human leukocyte antigen (HLA) DRB1*08:03 allele is associated with disease susceptibility in Japan, the precise analysis of HLA haplotypes and the role of amino acid alignment have not been fully clarified. We investigated HLA class I A, B, and C and HLA class II DRB1 and DQB1 alleles and haplotypes in 229 Japanese patients with PBC and compared them with the published data of 523 healthy subjects. Significant associations were found with PBC susceptibility for the DRB1*08:03-DQB1*06:01 (13% versus 6%; P = 0.000025; odds ratio [OR] = 2.22) and DRB1*04:05-DQB1*04:01 haplotypes (17% versus 13%; P = 0.044; OR = 1.38). Conversely, there were significant protective associations with the DRB1*13:02-DQB1*06:04 (2% versus 5%; P = 0.00093; OR = 0.27) and DRB1*11:01-DQB1*03:01 haplotypes (1% versus 4%; P = 0.03; OR = 0.37). The frequency of the DRB1*09:01-DQB1*03:03 haplotype was significantly higher in patients who had received orthotopic liver transplantation (33% versus 11%; P = 0.0012; OR = 3.96). Furthermore, the frequency of serine at position 57 (P = 0.0000015; OR = 1.83) of the DRβchain differed the most in patients with PBC, compared with healthy subjects. Conclusion: This study established the role of HLA haplotypes in determining PBC susceptibility and progression in the Japanese population. Further resequencing of the HLA region is required to more precisely identify the genetic components of PBC. (HEPATOLOGY 2012)

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