Fine mapping identifies independent HLA associations in autoimmune hepatitis type 1

You Li; Lu Zhou; Zuxiong Huang; Yue Yang; Jiming Zhang; Ling Yang; Yun Xu; Junping Shi; Shanhong Tang; Xiaoling Yuan; Jie Xu; Yiling Li; Xu Han; Jia Li; Yanmin Liu; Ying Sun; Xiaozhi Jin; Xiao Xiao; Bangmao Wang; Qiuxiang Lin; Yang Zhou; Xuejiao Song; Yong Cui; Lilin Hu; Yuhu Song; Jie Bao; Ling Gong; M Eric Gershwin; Xianbo Zuo; Huiping Yan; Zhengsheng Zou; Ruqi Tang; Xiong Ma; Chinese AIH Consortium

doi:10.1016/j.jhepr.2023.100926

Fine mapping identifies independent HLA associations in autoimmune hepatitis type 1

JHEP Rep. 2023 Oct 5;6(1):100926. doi: 10.1016/j.jhepr.2023.100926. eCollection 2024 Jan.

Authors

You Li¹, Lu Zhou², Zuxiong Huang³, Yue Yang^{4

5}, Jiming Zhang⁶, Ling Yang⁷, Yun Xu⁸, Junping Shi⁹, Shanhong Tang¹⁰, Xiaoling Yuan¹¹, Jie Xu¹¹, Yiling Li¹², Xu Han¹³, Jia Li¹³, Yanmin Liu¹⁴, Ying Sun¹⁵, Xiaozhi Jin¹⁶, Xiao Xiao¹, Bangmao Wang², Qiuxiang Lin³, Yang Zhou³, Xuejiao Song⁴, Yong Cui⁴, Lilin Hu⁷, Yuhu Song⁷, Jie Bao⁸, Ling Gong⁹, M Eric Gershwin¹⁷, Xianbo Zuo^{4

5}, Huiping Yan¹⁴, Zhengsheng Zou¹⁵, Ruqi Tang¹, Xiong Ma^{1

18}; Chinese AIH Consortium

Affiliations

¹ 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.
² Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China.
³ Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China.
⁴ Department of Dermatology, China-Japan Friendship Hospital, Beijing, China.
⁵ Department of Pharmacy, China-Japan Friendship Hospital, Beijing, China.
⁶ Department of Infectious Diseases, Huashan Hospital and Key Laboratory of Medical Molecular Virology (MOH & MOE), Shanghai Medical College, Fudan University, Shanghai, China.
⁷ Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁸ Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
⁹ Department of Infectious disease and Hepatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China.
¹⁰ Department of Gastroenterology, The General Hospital of Western Theater Command, Chengdu, China.
¹¹ Department of Infectious Disease, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
¹² Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang, China.
¹³ Tianjin Second People's Hospital, Tianjin Institute of Hepatology, Tianjin, China.
¹⁴ Clinical Laboratory Center and Clinical Research Center for Autoimmune Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing, China.
¹⁵ Senior Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China.
¹⁶ Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Hepatology Institute of Wenzhou Medical University, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, Wenzhou, China.
¹⁷ Division of Rheumatology, Department of Medicine, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA.
¹⁸ Institute of Aging & Tissue Regeneration, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Abstract

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 (p = 8.17 × 10^-304; odds ratio [OR] = 7.32) contributing the strongest signal. Stepwise conditional analysis revealed additional independent signals at HLA-B∗08:01 (p = 1.35 × 10^-33; OR = 4.26) and rs7765379 (p = 5.08 × 10^-18; 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.

Keywords: Autoimmune hepatitis; HLA-B∗35:01; Human leucocyte antigen.