HLA-DRB1 and DQB1 alleles in Japanese type 1 autoimmune hepatitis: The predisposing role of the DR4/DR8 heterozygous genotype.

Abstract

OBJECTIVE:

Autoimmune 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.

METHODS:

HLA-DRB1 and DQB1 genotyping of 360 type 1 AIH patients and 1026 healthy controls was performed.

RESULTS:

The 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.

CONCLUSIONS:

The 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.

• Authors: Shomi Oka, Hiroshi Furukawa, Michio Yasunami, Aya Kawasaki, Hitomi Nakamura, Minoru Nakamura, Atsumasa Komori, Seigo Abiru, Shinya Nagaoka, Satoru Hashimoto, Atsushi Naganuma, Noriaki Naeshiro, Kaname Yoshizawa, Haruhiro Yamashita, Keisuke Ario, Hajime Ohta, Hironori Sakai, Iwao Yabuuchi, Atsushi Takahashi, Kazumichi Abe, Hiroshi Yatsuhashi, Shigeto Tohma, Hiromasa Ohira, Naoyuki Tsuchiya, Kiyoshi Migita
• Journal: PloS one (PLoS One) Vol. 12 Issue 10 Pg. e0187325 ( 2017) ISSN: 1932-6203 [Electronic] United States
• PMID: 29088299 (Publication Type: Journal Article)

Chemical References

• HLA-DQ beta-Chains
• HLA-DRB1 Chains

Topics

• Adult
• Alleles
• Female
• Genetic Predisposition to Disease
• Genotype
• HLA-DQ beta-Chains (genetics)
• HLA-DRB1 Chains (genetics)
• Haplotypes
• Hepatitis, Autoimmune (immunology)
• Heterozygote
• Humans
• Male
• Middle Aged