学術雑誌論文 HLA-DRB1 and DQB1 alleles in Japanese type 1 autoimmune hepatitis: The predisposing role of the DR4/DR8 heterozygous genotype

Oka, Shomi  ,  Furukawa, Hiroshi  ,  Yasunami, Michio  ,  Kawasaki, Aya  ,  Nakamura, Hitomi  ,  Nakamura, Minoru  ,  Komori, Atsumasa  ,  Abiru, Seigo  ,  Nagaoka, Shinya  ,  Hashimoto, Satoru  ,  Naganuma, Atsushi  ,  Naeshiro, Noriaki  ,  Yoshizawa, Kaname  ,  Yamashita, Haruhiro  ,  Ario, Keisuke  ,  Ohta, Hajime  ,  Sakai, Hironori  ,  Yabuuchi, Iwao  ,  Takahashi, Atsushi  ,  Abe, Kazumichi  ,  Yatsuhashi, Hiroshi  ,  Tohma, Shigeto  ,  Ohira, Hiromasa  ,  Tsuchiya, Naoyuki  ,  Migita, Kiyoshi

12 ( 10 )  , p.e0187325 , 2017-10 , Public Library of Science
ISSN:1932-6203
内容記述
ObjectiveAutoimmune hepatitis (AIH) is a chronic progressive liver disease. AIH is composed predominantly of type 1 in Japanese populations. The genetic and environmental factors are associated with the pathogenesis of AIH. HLA-DRB1*03:01 and *04:01 are associated with type 1 AIH in European and *04:05 in Japanese populations. Here, we conducted an HLA association study in order to find HLA alleles or haplotypes predisposing or protective for Japanese AIH.MethodsHLA-DRB1 and DQB1 genotyping of 360 type 1 AIH patients and 1026 healthy controls was performed.ResultsThe predisposing association of DRB1*04:01 (P = 0.0006, corrected P [Pc] = 0.0193, odds ratio [OR] 2.97, 95% confidence interval [CI] 1.62–5.43), DRB1*04:05 (P = 1.89×10−21, Pc = 5.86×10−20, OR 3.41, 95% CI 2.65–4.38), and DQB1*04:01 (P = 4.66×10−18, Pc = 6.99×10−17, OR 3.89, 95% CI 2.84–5.33) and the protective association of DRB1*13:02 (P = 0.0003, Pc = 0.0080, OR 0.48, 95% CI 0.32–0.72) with Japanese type 1 AIH were observed. An association of the DR4/DR8 heterozygous genotype with Japanese AIH was identified for the first time (P = 3.12×10−9, OR 3.52, 95% CI 2.34–5.29). Susceptible diplotypes were DRB1*04:05-DQB1*04:01/DRB1*08:02-DQB1*03:02 (P = 0.0004, OR 24.77, 95% CI 1.45–424.31) and DRB1*04:05-DQB1*04:01/DRB1*08:03-DQB1*06:01 (P = 1.18×10−6, OR 10.64, 95% CI 3.19–35.46). Serum levels of Immunoglobulin G and Immunoglobulin M, International Autoimmune Hepatitis Group score, positive rate of anti-smooth muscle antibodies, and the rate of definite AIH were higher in AIH patients with DRB1*04:05 than without.ConclusionsThe important roles of specific combinations of DRB1 and DQB1 alleles or haplotypes in the pathogenesis of type 1 AIH were suggested. The association of DR4/DR8 heterozygous genotype suggested the pathologic importance of trans-complementing DQα-β heterodimer molecules encoded by DQA1 allele of one haplotype and the DQB1 allele of the other haplotype, as it was proposed in the HLA association studies of Type 1 diabetes.
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