Journal of Gastroenterology

, Volume 46, Issue 10, pp 1203–1212

Genetic polymorphisms in CTLA4 and SLC4A2 are differentially associated with the pathogenesis of primary biliary cirrhosis in Japanese patients

  • Yoshihiro Aiba
  • Minoru Nakamura
  • Satoru Joshita
  • Tatsuo Inamine
  • Atsumasa Komori
  • Kaname Yoshizawa
  • Takeji Umemura
  • Hitomi Horie
  • Kiyoshi Migita
  • Hiroshi Yatsuhashi
  • Makoto Nakamuta
  • Nobuyoshi Fukushima
  • Takeo Saoshiro
  • Shigeki Hayashi
  • Hiroshi Kouno
  • Hajime Ota
  • Toyokichi Muro
  • Yukio Watanabe
  • Yoko Nakamura
  • Toshiki Komeda
  • Masaaki Shimada
  • Naohiko Masaki
  • Tatsuji Komatsu
  • Michiyasu Yagura
  • Kazuhiro Sugi
  • Michiaki Koga
  • Kazuhiro Tsukamoto
  • Eiji Tanaka
  • Hiromi Ishibashi
  • The PBC Study Group in NHOSLJ
Original Article—Liver, Pancreas, and Biliary Tract

DOI: 10.1007/s00535-011-0417-7

Cite this article as:
Aiba, Y., Nakamura, M., Joshita, S. et al. J Gastroenterol (2011) 46: 1203. doi:10.1007/s00535-011-0417-7

Abstract

Background

Anti-gp210 and anti-centromere antibodies are different risk factors for the progression of primary biliary cirrhosis (PBC). In order to dissect the genetic basis for the production of these autoantibodies, as well as the development and progression of PBC in Japanese patients, we examined single nucleotide polymorphisms (SNPs) in cytotoxic T-lymphocyte antigen 4 (CTLA4) and solute carrier family 4 anion exchanger, member 2 (SLC4A2), which have been associated with the pathogenesis of PBC in Caucasian patients.

Methods

Four SNPs for both CTLA4 and SLC4A2 were genotyped, using the polymerase chain reaction–restriction fragment length polymorphism method and TaqMan assay, in 450 Japanese PBC patients and 371 sex-matched healthy controls.

Results

The CTLA4 rs231775, rs3087243, and rs231725 SNPs were significantly associated with PBC susceptibility. The CTLA4 rs231725 SNP was significantly associated with progression to late-stage disease. The CTLA-4 haplotype 1 (rs231775 G, rs231777 C, rs3087243 G, rs231725 A; GCGA) was a risk factor for PBC susceptibility but a protective factor for PBC progression. Conversely, the CTLA-4 haplotype 2 (ACAG) was a protective and risk factor, respectively, for PBC susceptibility and progression. In addition, the CTLA4 rs231777 SNP and haplotype 3 (ATGG) was significantly associated with anti-gp210 antibody production, while SLC4A2 haplotype 4 (rs2069443 A, rs2303933 G, rs2303937 A, rs2303941 T; AGAT) and haplotype 3 (AAGC) were significantly associated with PBC susceptibility and anti-centromere antibody production, respectively.

Conclusions

CTLA4 and SLC4A2 genetic polymorphisms are differentially associated with PBC development and progression, as well as anti-gp210 or anti-centromere antibody production, in Japanese PBC patients.

Keywords

PBCSNPsCTLA4SLC4A2Autoantibody

Supplementary material

535_2011_417_MOESM1_ESM.doc (170 kb)
Supplementary Tables (DOC 170 kb)

Copyright information

© Springer 2011

Authors and Affiliations

  • Yoshihiro Aiba
    • 1
  • Minoru Nakamura
    • 1
    • 2
    • 3
  • Satoru Joshita
    • 4
  • Tatsuo Inamine
    • 5
  • Atsumasa Komori
    • 1
    • 2
  • Kaname Yoshizawa
    • 4
  • Takeji Umemura
    • 4
  • Hitomi Horie
    • 1
  • Kiyoshi Migita
    • 1
    • 2
  • Hiroshi Yatsuhashi
    • 1
    • 2
  • Makoto Nakamuta
    • 3
  • Nobuyoshi Fukushima
    • 3
  • Takeo Saoshiro
    • 3
  • Shigeki Hayashi
    • 3
  • Hiroshi Kouno
    • 3
  • Hajime Ota
    • 3
  • Toyokichi Muro
    • 3
  • Yukio Watanabe
    • 3
  • Yoko Nakamura
    • 3
  • Toshiki Komeda
    • 3
  • Masaaki Shimada
    • 3
  • Naohiko Masaki
    • 3
  • Tatsuji Komatsu
    • 3
  • Michiyasu Yagura
    • 3
  • Kazuhiro Sugi
    • 3
  • Michiaki Koga
    • 3
  • Kazuhiro Tsukamoto
    • 5
  • Eiji Tanaka
    • 4
  • Hiromi Ishibashi
    • 1
    • 2
  • The PBC Study Group in NHOSLJ
  1. 1.Clinical Research CenterNational Hospital Organization Nagasaki Medical CenterOmuraJapan
  2. 2.Department of HepatologyNagasaki University Graduate School of Biomedical SciencesOmuraJapan
  3. 3.Headquarters of PBC Study Group in National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ)OmuraJapan
  4. 4.Division of Gastroenterology and Hepatology, Department of MedicineShinshu University School of MedicineMatsumotoJapan
  5. 5.Department of PharmacotherapeuticsNagasaki University Graduate School of Biomedical SciencesNagasakiJapan