HLA-DRB1 and DQB1 alleles in Japanese type 1 autoimmune hepatitis: The predisposing role of the DR4/DR8 heterozygous genotype.
HLA-DRB1 and DQB1 alleles in Japanese type 1 autoimmune hepatitis: The predisposing role of the DR4/DR8 heterozygous genotype.
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DOI：
10.1371/journal.pone.0187325
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Migita K
中科院分区：
文献类型：
--
作者：
Oka S;Furukawa H;Yasunami M;Kawasaki A;Nakamura H;Nakamura M;Komori A;Abiru S;Nagaoka S;Hashimoto S;Naganuma A;Naeshiro N;Yoshizawa K;Yamashita H;Ario K;Ohta H;Sakai H;Yabuuchi I;Takahashi A;Abe K;Yatsuhashi H;Tohma S;Ohira H;Tsuchiya N;Migita K
自身免疫性肝炎（AIH）是一种慢性进行性肝病。在日本人群中，AIH 主要为 1 型。 AIH的发病与遗传和环境因素有关。 HLA-DRB1*03:01 和 *04:01 与欧洲人群中的 1 型 AIH 相关，而 *04:05 在日本人群中与 1 型 AIH 相关。在这里，我们进行了一项 HLA 关联研究，以寻找易患或保护日本 AIH 的 HLA 等位基因或单倍型。对 360 名 1 型 AIH 患者和 1026 名健康对照者进行了 HLA-DRB1 和 DQB1 基因分型。 DRB1*04:01（P = 0.0006，校正 P [Pc] = 0.0193，优势比 [OR] 2.97，95% 置信区间 [CI] 1.62–5.43）、DRB1*04:05（P = 1.89×10−21，Pc = 5.86×10−20，OR）的易感关联3.41，95% CI 2.65–4.38）和 DQB1*04:01（P = 4.66×10−18，Pc = 6.99×10−17，OR 3.89，95% CI 2.84–5.33）以及 DRB1*13:02 的保护性关联（P = 0.0003，Pc =观察到日本 1 型 AIH 的风险为 0.0080，OR 0.48，95% CI 0.32–0.72。首次鉴定出 DR4/DR8 杂合基因型与日本 AIH 的关联（P = 3.12×10−9，OR 3.52，95% CI 2.34–5.29）。易感双倍型为 DRB1*04:05-DQB1*04:01/DRB1*08:02-DQB1*03:02（P = 0.0004，OR 24.77，95% CI 1.45–424.31）和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）。 DRB1*04:05的AIH患者的血清免疫球蛋白G、免疫球蛋白M水平、国际自身免疫性肝炎组评分、抗平滑肌抗体阳性率、确诊AIH率均高于无DRB1*04:05的AIH患者。提出了 DRB1 和 DQB1 等位基因或单倍型的特定组合在 1 型 AIH 发病机制中的重要作用。 DR4/DR8 杂合基因型的关联表明由一种单倍型的 DQA1 等位基因和另一种单倍型的 DQB1 等位基因编码的反式互补 DQα-β 异二聚体分子的病理学重要性，正如在 1 型糖尿病的 HLA 关联研究中所提出的那样。
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. HLA-DRB1 and DQB1 genotyping of 360 type 1 AIH patients and 1026 healthy controls was performed. 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. 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.
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