日本1型自身免疫性肝炎中的HLA - DRB1和DQB1等位基因：DR4/DR8杂合基因型的易感作用。
HLA-DRB1 and DQB1 alleles in Japanese type 1 autoimmune hepatitis: The predisposing role of the DR4/DR8 heterozygous genotype.
作者信息
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
机构信息
Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Japan.
Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital, 18-1 Sakuradai, Minami-ku, Sagamihara, Japan.
出版信息
PLoS One. 2017 Oct 31;12(10):e0187325. doi: 10.1371/journal.pone.0187325. eCollection 2017.
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 DRB104:01 (P = 0.0006, corrected P [Pc] = 0.0193, odds ratio [OR] 2.97, 95% confidence interval [CI] 1.62-5.43), DRB104:05 (P = 1.89×10-21, Pc = 5.86×10-20, OR 3.41, 95% CI 2.65-4.38), and DQB104:01 (P = 4.66×10-18, Pc = 6.99×10-17, OR 3.89, 95% CI 2.84-5.33) and the protective association of DRB113:02 (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 DRB104:05-DQB104:01/DRB108:02-DQB103:02 (P = 0.0004, OR 24.77, 95% CI 1.45-424.31) and DRB104:05-DQB104:01/DRB108:03-DQB106:01 (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.
目的
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主要由1型组成。遗传和环境因素与AIH的发病机制相关。HLA-DRB103:01和04:01与欧洲人的1型AIH相关，而在日本人群中与*04:05相关。在此，我们进行了一项HLA关联研究，以寻找与日本AIH易感性或保护性相关的HLA等位基因或单倍型。
方法
对360例1型AIH患者和1026名健康对照进行HLA-DRB1和DQB1基因分型。
结果
观察到DRB104:01（P = 0.0006，校正P值[Pc]= 0.0193，优势比[OR] 2.97，95%置信区间[CI] 1.62 - 5.43）、DRB104:05（P = 1.89×10-21，Pc = 5.86×10-20，OR 3.41，95% CI 2.65 - 4.38）和DQB104:01（P = 4.66×10-18，Pc = 6.99×10-17，OR 3.89，95% CI 2.84 - 5.33）与日本1型AIH的易感性关联，以及DRB113:02（P = 0.0003，Pc = 0.0080，OR 0.48，95% CI 0.32 - 0.72）与日本1型AIH的保护性关联。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）。易感单倍型为DRB104:05-DQB104:01/DRB108:02-DQB103:02（P = 0.0004，OR 24.77，95% CI 1.45 - 424.31）和DRB104:05-DQB104:01/DRB108:03-DQB106:01（P = 1.18×10-6，OR 10.64，95% CI 3.19 - 35.46）。携带DRB1*04:05的AIH患者的血清免疫球蛋白G和免疫球蛋白M水平、国际自身免疫性肝炎小组评分、抗平滑肌抗体阳性率以及确诊AIH的比例均高于未携带该基因的患者。
结论
提示DRB1和DQB1等位基因或单倍型的特定组合在1型AIH发病机制中起重要作用。DR4/DR8杂合基因型的关联提示了由一个单倍型的DQA1等位基因和另一个单倍型的DQB1等位基因编码的反式互补DQα-β异二聚体分子的病理重要性，这与1型糖尿病的HLA关联研究中所提出的情况相同。
Zotero 插件