单位：[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, 145 Middle Shandong Road, Shanghai, 200001, China.[2]Department of liver disease, Senior Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, 100039, China.[3]Clinical Laboratory Center and Clinical Research Center for Autoimmune Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China.[4]Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, 300052, China.[5]Tianjin Second People's Hospital, Tianjin Institute of Hepatology, Nankai District, No. 75, Sudi Road, Tianjin, 300192, China.[6]Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, China.[7]Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China.华中科技大学同济医学院附属协和医院[8]Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China.[9]Department of Hepatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, 311121, China.[10]Department of Gastroenterology, The General Hospital of Western Theater Command, Chengdu, 610016, China.[11]Department of Infectious Disease, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.[12]Department of Gastroenterology, First Affiliated Hospital of China Medical University, ShenYang, 110001, China.[13]Department of Dermatology, China-Japan Friendship Hospital, Beijing, 100029, China.[14]Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China.[15]Department of Gastroenterology, China-Japan Friendship Hospital, Beijing, 100029, China.[16]Department of infection disease, China-Japan Friendship Hospital, Beijing, 100029, China.[17]Department of Infectious Diseases, Huashan Hospital and Key Laboratory of Medical Molecular Virology (MOH &[18]MOE), Shanghai Medical College, Fudan University, Shanghai, China.[18]Division of Rheumatology, Department of Medicine, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA.[19]Department of Biochemistry and Molecular Medicine, University of California at Davis, Davis, CA, USA.[20]Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, Anhui, 230022, China.[21]Department of Pharmacy, China-Japan Friendship Hospital, Beijing, 100029, China.
Background and Aims Autoimmune hepatitis (AIH) is a rare and chronic autoimmune liver disease. While genetic factors are believed to play a crucial role in the etiopathogenesis of AIH, our understanding of these genetic risk factors is still limited. In this study, we aimed to identify susceptibility loci to further understand the pathogenesis of this disease. Approach and Results We conducted a case-control association study of 1,622 Chinese patients with AIH type 1 and 10,466 population controls from two independent cohorts. A meta-analysis was performed to ascertain variants associated with AIH type 1. A single-nucleotide polymorphism within the human leukocyte antigen (HLA) region showed the strongest association with AIH (rs6932730: OR = 2.32; p = 9.21 x 10(-73)). The meta-analysis also identified two non-HLA loci significantly associated with AIH: CD28/CTLA4/ICOS on 2q33.3 (rs72929257: OR = 1.31; p = 2.92 x 10(-9)) and SYNPR on 3p14.2 (rs6809477: OR = 1.25; p = 5.48 x 10(-9)). In silico annotation, reporter gene assays, and CRISPR activation experiments identified a distal enhancer at 2q33.3 that regulated expression of CTLA4. In addition, variants near STAT1/STAT4 (rs11889341: OR = 1.24; p = 1.34 x 10(-7)), LINC00392 (rs9564997: OR = 0.81; p = 2.53 x 10(-7)), IRF8 (rs11117432: OR = 0.72; p = 6.10 x 10(-6)), and LILRA4/LILRA5 (rs11084330: OR = 0.65; p = 5.19 x 10(-6)) had suggestive association signals with AIH. Conclusions Our study identifies two novel loci (CD28/CTLA4/ICOS and SYNPR) exceeding genome-wide significance and suggests four loci as potential risk factors. These findings highlight the importance of costimulatory signaling and neuro-immune interaction in the pathogenesis of AIH.
基金：
National Natural Science Foundation of China [81830016, 81771732, 81620108002, 81922010, 81873561, 81570469, 82070581, 81790634, 82070583, 81770563, 81800504]; Shanghai Municipal Science and Technology Committee of the Shanghai outstanding academic leaders plan [20XD1422500]; Shanghai Education Development Foundation; Shanghai Municipal Education Commission [18SG17]; "Chen Guang" project by Shanghai Municipal Education Commission; Shanghai Education Development Foundation [19CG16]; National Key Research and Development Plan for Precision Medicine Research [2017YFC0910002]
第一作者单位：[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, 145 Middle Shandong Road, Shanghai, 200001, China.
共同第一作者：
通讯作者：
通讯机构：[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, 145 Middle Shandong Road, Shanghai, 200001, China.[2]Department of liver disease, Senior Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, 100039, China.[3]Clinical Laboratory Center and Clinical Research Center for Autoimmune Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China.[13]Department of Dermatology, China-Japan Friendship Hospital, Beijing, 100029, China.[20]Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, Anhui, 230022, China.[21]Department of Pharmacy, China-Japan Friendship Hospital, Beijing, 100029, China.[*1]Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai 200001, China.[*2]China-Japan Friendship Hospital, Beijing, 100029, China[*3]the Fifth Medical Center of PLA General Hospital, Beijing, 100039, China.[*4]Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China
推荐引用方式(GB/T 7714)：
Li You,Sun Ying,Liu Yanmin,et al.Genome-wide meta-analysis identifies susceptibility loci for autoimmune hepatitis type 1[J].HEPATOLOGY.2022,doi:10.1002/hep.32417.
APA：
Li You,Sun Ying,Liu Yanmin,Wang Bangmao,Li Jia...&Ma Xiong.(2022).Genome-wide meta-analysis identifies susceptibility loci for autoimmune hepatitis type 1.HEPATOLOGY,,
MLA：
Li You,et al."Genome-wide meta-analysis identifies susceptibility loci for autoimmune hepatitis type 1".HEPATOLOGY .(2022)
医学