PMID- 35184318
OWN - NLM
STAT- MEDLINE
DCOM- 20220811
LR  - 20221015
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Linking)
VI  - 76
IP  - 3
DP  - 2022 Sep
TI  - Genome-wide meta-analysis identifies susceptibility loci for autoimmune hepatitis 
      type 1.
PG  - 564-575
LID - 10.1002/hep.32417 [doi]
AB  - 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.
CI  - (c) 2022 American Association for the Study of Liver Diseases.
FAU - Li, You
AU  - Li Y
AD  - 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.
FAU - Sun, Ying
AU  - Sun Y
AUID- ORCID: 0000-0002-2570-9206
AD  - Department of Liver Disease, Senior Department of Hepatology, The Fifth Medical 
      Center of PLA General Hospital, Beijing, China.
FAU - Liu, Yanmin
AU  - Liu Y
AD  - Clinical Laboratory Center and Clinical Research Center for Autoimmune Liver 
      Disease, Beijing Youan Hospital, Capital Medical University, Beijing, China.
FAU - Wang, Bangmao
AU  - Wang B
AD  - Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical 
      University, Tianjin, China.
FAU - Li, Jia
AU  - Li J
AD  - Tianjin Second People's Hospital, Tianjin Institute of Hepatology, Tianjin, 
      China.
FAU - Wang, Hanxiao
AU  - Wang H
AD  - 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.
FAU - Zhang, Haiping
AU  - Zhang H
AD  - Clinical Laboratory Center and Clinical Research Center for Autoimmune Liver 
      Disease, Beijing Youan Hospital, Capital Medical University, Beijing, China.
FAU - Wang, Xiaoyi
AU  - Wang X
AD  - Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical 
      University, Tianjin, China.
FAU - Han, Xu
AU  - Han X
AD  - Tianjin Second People's Hospital, Tianjin Institute of Hepatology, Tianjin, 
      China.
FAU - Lin, Qiuxiang
AU  - Lin Q
AD  - Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical 
      University, Fuzhou, China.
FAU - Zhou, Yang
AU  - Zhou Y
AD  - Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical 
      University, Fuzhou, China.
FAU - Hu, Lilin
AU  - Hu L
AUID- ORCID: 0000-0002-5268-1130
AD  - Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong 
      University of Science and Technology, Wuhan, China.
FAU - Song, Yuhu
AU  - Song Y
AD  - Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong 
      University of Science and Technology, Wuhan, China.
FAU - Bao, Jie
AU  - Bao J
AD  - Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou 
      University, Zhengzhou, China.
FAU - Gong, Ling
AU  - Gong L
AD  - Department of Hepatology, The Affiliated Hospital of Hangzhou Normal University, 
      Hangzhou, China.
FAU - Sun, Mengying
AU  - Sun M
AD  - Department of Gastroenterology, The General Hospital of Western Theater Command, 
      Chengdu, China.
FAU - Yuan, Xiaoling
AU  - Yuan X
AD  - Department of Infectious Disease, Shanghai Ninth People's Hospital, Shanghai Jiao 
      Tong University School of Medicine, Shanghai, China.
FAU - Zhang, Xinhe
AU  - Zhang X
AD  - Department of Gastroenterology, First Affiliated Hospital of China Medical 
      University, ShenYang, China.
FAU - Lian, Min
AU  - Lian M
AD  - 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.
FAU - Xiao, Xiao
AU  - Xiao X
AD  - 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.
FAU - Miao, Qi
AU  - Miao Q
AD  - 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.
FAU - Wang, Qixia
AU  - Wang Q
AD  - 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.
FAU - Li, Ke-Ke
AU  - Li KK
AD  - Department of Dermatology, China-Japan Friendship Hospital, Beijing, China.
AD  - Graduate School, Peking Union Medical College and Chinese Academy of Medical 
      Sciences, Beijing, China.
FAU - Du, Shiyu
AU  - Du S
AD  - Department of Gastroenterology, China-Japan Friendship Hospital, Beijing, China.
FAU - Ma, Anlin
AU  - Ma A
AD  - Department of infection disease, China-Japan Friendship Hospital, Beijing, China.
FAU - Li, Yiling
AU  - Li Y
AD  - Department of Gastroenterology, First Affiliated Hospital of China Medical 
      University, ShenYang, China.
FAU - Xu, Jie
AU  - Xu J
AD  - Department of Infectious Disease, Shanghai Ninth People's Hospital, Shanghai Jiao 
      Tong University School of Medicine, Shanghai, China.
FAU - Tang, Shanhong
AU  - Tang S
AD  - Department of Gastroenterology, The General Hospital of Western Theater Command, 
      Chengdu, China.
FAU - Shi, Junping
AU  - Shi J
AD  - Department of Hepatology, The Affiliated Hospital of Hangzhou Normal University, 
      Hangzhou, China.
FAU - Xu, Yun
AU  - Xu Y
AD  - Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou 
      University, Zhengzhou, China.
FAU - Yang, Ling
AU  - Yang L
AUID- ORCID: 0000-0002-0751-5600
AD  - Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong 
      University of Science and Technology, Wuhan, China.
FAU - Zhang, Jiming
AU  - Zhang J
AD  - Department of Infectious Diseases, Huashan Hospital and Key Laboratory of Medical 
      Molecular Virology (MOH & MOE), Shanghai Medical College, Fudan University, 
      Shanghai, China.
FAU - Huang, Zuxiong
AU  - Huang Z
AD  - Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical 
      University, Fuzhou, China.
FAU - Zhou, Lu
AU  - Zhou L
AD  - Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical 
      University, Tianjin, China.
FAU - Cui, Yong
AU  - Cui Y
AD  - Department of Dermatology, China-Japan Friendship Hospital, Beijing, China.
AD  - Graduate School, Peking Union Medical College and Chinese Academy of Medical 
      Sciences, Beijing, China.
FAU - Seldin, Michael F
AU  - Seldin MF
AD  - Division of Rheumatology, Department of Medicine, Allergy and Clinical 
      Immunology, University of California at Davis, Davis, California, USA.
AD  - Department of Biochemistry and Molecular Medicine, University of California at 
      Davis, Davis, California, USA.
FAU - Gershwin, M Eric
AU  - Gershwin ME
AD  - Division of Rheumatology, Department of Medicine, Allergy and Clinical 
      Immunology, University of California at Davis, Davis, California, USA.
FAU - Yan, Huiping
AU  - Yan H
AD  - Clinical Laboratory Center and Clinical Research Center for Autoimmune Liver 
      Disease, Beijing Youan Hospital, Capital Medical University, Beijing, China.
FAU - Zou, Zhengsheng
AU  - Zou Z
AD  - Department of Liver Disease, Senior Department of Hepatology, The Fifth Medical 
      Center of PLA General Hospital, Beijing, China.
FAU - Zuo, Xianbo
AU  - Zuo X
AD  - Department of Dermatology, China-Japan Friendship Hospital, Beijing, China.
AD  - Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui 
      Medical University, Hefei, Anhui, China.
AD  - Department of Pharmacy, China-Japan Friendship Hospital, Beijing, China.
FAU - Tang, Ruqi
AU  - Tang R
AD  - 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.
FAU - Ma, Xiong
AU  - Ma X
AUID- ORCID: 0000-0001-9616-4672
AD  - 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.
CN  - Chinese AIH Consortium
LA  - eng
PT  - Journal Article
PT  - Meta-Analysis
PT  - Research Support, Non-U.S. Gov't
DEP - 20220603
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (CD28 Antigens)
RN  - 0 (CTLA-4 Antigen)
RN  - 0 (HLA Antigens)
SB  - IM
CIN - Hepatology. 2022 Sep;76(3):541-543. PMID: 35500149
MH  - CD28 Antigens/genetics
MH  - CTLA-4 Antigen/genetics
MH  - Genetic Predisposition to Disease
MH  - Genome-Wide Association Study
MH  - HLA Antigens
MH  - *Hepatitis, Autoimmune/genetics
MH  - Humans
MH  - Polymorphism, Single Nucleotide
EDAT- 2022/02/21 06:00
MHDA- 2022/08/12 06:00
CRDT- 2022/02/20 20:40
PHST- 2022/02/10 00:00 [revised]
PHST- 2021/11/19 00:00 [received]
PHST- 2022/02/16 00:00 [accepted]
PHST- 2022/02/21 06:00 [pubmed]
PHST- 2022/08/12 06:00 [medline]
PHST- 2022/02/20 20:40 [entrez]
AID - 10.1002/hep.32417 [doi]
PST - ppublish
SO  - Hepatology. 2022 Sep;76(3):564-575. doi: 10.1002/hep.32417. Epub 2022 Jun 3.