精细定位确定了1型自身免疫性肝炎中独立的HLA关联。
Fine mapping identifies independent HLA associations in autoimmune hepatitis type 1.
作者信息
Li You, Zhou Lu, Huang Zuxiong, Yang Yue, Zhang Jiming, Yang Ling, Xu Yun, Shi Junping, Tang Shanhong, Yuan Xiaoling, Xu Jie, Li Yiling, Han Xu, Li Jia, Liu Yanmin, Sun Ying, Jin Xiaozhi, Xiao Xiao, Wang Bangmao, Lin Qiuxiang, Zhou Yang, Song Xuejiao, Cui Yong, Hu Lilin, Song Yuhu, Bao Jie, Gong Ling, Gershwin M Eric, Zuo Xianbo, Yan Huiping, Zou Zhengsheng, Tang Ruqi, Ma Xiong
机构信息
Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China.
Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China.
出版信息
JHEP Rep. 2023 Oct 5;6(1):100926. doi: 10.1016/j.jhepr.2023.100926. eCollection 2024 Jan.
BACKGROUND & AIMS: Association studies have greatly refined the important role of the major histocompatibility complex (MHC) region in autoimmune hepatitis (AIH). However, the effects of human leucocyte antigen (HLA) polymorphisms on AIH are not well established. The aim of this study is to systematically characterise the association of MHC variants with AIH in our well-defined cohort of patients.
METHODS
We performed an imputation-based analysis on the extensive association observed within the MHC region using the Han-MHC reference panel, and tested the comprehensive associations of HLA polymorphisms with AIH in 1622 Chinese AIH type 1 patients and 10,466 population controls.
RESULTS
A total of 588 HLA variants were significantly associated with AIH, with HLA-B∗35:01 ( = 8.17 × 10; odds ratio [OR] = 7.32) contributing the strongest signal. Stepwise conditional analysis revealed additional independent signals at HLA-B∗08:01 ( = 1.35 × 10; OR = 4.26) and rs7765379 ( = 5.08 × 10; OR = 1.66). A strong link between the lead HLA variant and clinical phenotypes of AIH was observed: patients with HLA-B∗35:01 were less frequently positive for ANA and tended to have higher serum AST and ALT levels at diagnosis, but lower serum IgG levels.
CONCLUSIONS
Our study reveals three novel and independent variants at HLA-B∗35:01, HLA-B∗08:01, and rs7765379 associated with AIH across the whole MHC region in the Han Chinese population. The findings illustrate the value of the MHC region in AIH and provide a new perspective for the immunogenetics of AIH.
IMPACT AND IMPLICATIONS
This study revealed three novel and independent variants associated with autoimmune hepatitis across the whole major histocompatibility complex region in the Han Chinese population. These findings are significant in identifying autoantigens, providing insights into the activation of the autoimmune processes, and further advancing our understanding of the immunogenetic basis underlying autoimmune hepatitis.
背景与目的
关联研究极大地明确了主要组织相容性复合体（MHC）区域在自身免疫性肝炎（AIH）中的重要作用。然而，人类白细胞抗原（HLA）多态性对AIH的影响尚未完全明确。本研究的目的是在我们明确界定的患者队列中系统地表征MHC变异与AIH的关联。
方法
我们使用汉族MHC参考面板对在MHC区域内观察到的广泛关联进行了基于归因的分析，并在1622例中国1型AIH患者和10466例人群对照中测试了HLA多态性与AIH的全面关联。
结果
共有588个HLA变异与AIH显著相关，其中HLA-B∗35:01（P = 8.17×10⁻⁹；优势比[OR]=7.32）贡献了最强信号。逐步条件分析在HLA-B∗08:01（P = 1.35×10⁻⁶；OR = 4.26）和rs7765379（P = 5.08×10⁻⁵；OR = 1.66）处揭示了额外的独立信号。观察到主要HLA变异与AIH临床表型之间存在密切联系：携带HLA-B∗35:01的患者ANA阳性频率较低，诊断时血清AST和ALT水平往往较高，但血清IgG水平较低。
结论
我们的研究揭示了汉族人群整个MHC区域中与AIH相关的三个新的独立变异，分别为HLA-B∗35:01、HLA-B∗08:01和rs7765379。这些发现阐明了MHC区域在AIH中的价值，并为AIH的免疫遗传学提供了新的视角。
影响与意义
本研究揭示了汉族人群整个主要组织相容性复合体区域中与自身免疫性肝炎相关的三个新的独立变异。这些发现对于识别自身抗原、深入了解自身免疫过程的激活以及进一步推进我们对自身免疫性肝炎免疫遗传基础的理解具有重要意义。
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