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

Abstract

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.

KIR/HLA genotypes confer susceptibility and progression in patients with autoimmune hepatitis

“…This study revealed KIR3DL1/HLA-B Bw4-80Ile to be significantly increased in AIH in addition to the HLA-DRB1*04:05-DQB1*04:01 haplotype, a confirmed susceptibility factor in Japan. 3,29 This haplotype has also been associated with primary biliary cholangitis in the Japanese. 24 Although both genetic factors correlated positively with AIH, we did not observe any synergistic properties.…”

“…The frequency of the HLA-DRB1*04:05-DQB1:04:01 haplotype was significantly higher in patients with AIH (69%) than in healthy individuals (28%) (OR 5.62; 95% CI 3.52-8.97; p <0.001) as in previous studies (Table S2). 29 Next, we evaluated this haplotype and the KIR3DL1/HLA-B Bw4-80Ile found in association with AIH for independence by logistic regression analysis. Both the HLA-DRB1*04:05-DQB1:04:01 haplotype (OR 5.67; 95% CI 3.53-9.11; p <0.001) and KIR3DL1/HLA-B Bw4-80Ile (OR 1.86; 95% CI 1.17-2.98; p = 0.009) were independent susceptibility genes related to AIH.…”

Independent association of HLA-DPB1*02:01 with rheumatoid arthritis in Japanese populations

“…RA patients fulfilled the 1987 American College of Rheumatology criteria for RA [ 24 ] or the 2010 Rheumatoid Arthritis Classification Criteria [ 25 ]. Four hundred thirteen Japanese healthy controls (mean age ± SD, 39.3 ± 11.0 years, vs. ACPA(+)RA: P = 6.50X10 -130 , vs. ACPA(-)RA, P = 5.51X10 -71 , 61 male [14.8%], vs. ACPA(+)RA: P = 0.0792, vs. ACPA(-)RA, P = 0.2195) were recruited at Kanazawa University, Sagamihara National Hospital, and Teikyo University [ 26 ] or by the Pharma SNP Consortium (Tokyo, Japan) [ 27 , 28 ]. Rheumatoid factor and ACPA were measured by N-latex RF kit (Siemens Healthcare Diagnostics, München, Germany) or Mesacup-2 test CCP (Medical & Biological Laboratories, Nagoya, Japan), respectively.…”

“…SE alleles contain DRB1*01 : 01 , DRB1*04 : 01 , DRB1*04 : 05 , DRB1*04 : 10 , DRB1*10 : 01 , and DRB1*14 : 06 [ 5 ]. Genotyping results for some of the RA patients and the healthy controls were previously reported [ 7 , 26 , 29 , 30 , 31 , 32 ].…”

Generation of a novel mouse model for the study of autoimmune liver disease overlap syndrome

“…ADs effects 5-9% of the general population but the etiology for most ADs is still unclear [37]. [39] whereas HLA-DRB1 is also connected to RA [40]. Moreover, HLA- DRB3 is associated with Graves̓ disease [41] and HLA-DR3 is a genetic predisposition for SLE [42].…”