A genome-wide association study identifies six novel risk loci for primary biliary cholangitis

Fang Qiu, Ruqi Tang, Xianbo Zuo, Xingjuan Shi, Yiran Wei, Xiaodong Zheng, Yaping Dai, Yuhua Gong, Lan Wang, Ping Xu, Xiang Zhu, Jian Wu, Chongxu Han, Yueqiu Gao, Kui Zhang, Yuzhang Jiang, Jianbo Zhou, Youlin Shao, Zhigang Hu, Ye Tian, Haiyan Zhang, Na Dai, Lei Liu, Xudong Wu, Weifeng Zhao, Xiaomin Zhang, Zhidong Zang, Jinshan Nie, Weihao Sun, Yi Zhao, Yuan Mao, Po Jiang, Hualiang Ji, Qing Dong, Junming Li, Zhenzhong Li, Xinli Bai, Li Li, Maosong Lin, Ming Dong, Jinxin Li, Ping Zhu, Chan Wang, Yanqiu Zhang, Peng Jiang, Yujue Wang, Rohil Jawed, Jing Xu, Yu Zhang, Qixia Wang, Yue Yang, Fan Yang, Min Lian, Xiang Jiang, Xiao Xiao, Yanmei Li, Jingyuan Fang, Dekai Qiu, Zhen Zhu, Hong Qiu, Jianqiong Zhang, Wenyan Tian, Sufang Chen, Ling Jiang, Bing Ji, Ping Li, Guochang Chen, Tianxue Wu, Yan Sun, Jianjiang Yu, Huijun Tang, Michun He, Min Xia, Hao Pei, Lihua Huang, Zhuye Qing, Jianfang Wu, Qinghai Huang, Junhai Han, Wei Xie, Zhongsheng Sun, Jian Guo, Gengsheng He, M. Eric Gershwin, Zhexiong Lian, Xiang Liu, Michael F. Seldin, Xiangdong Liu (), Weichang Chen () and Xiong Ma ()
Additional contact information
Fang Qiu: Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University
Ruqi Tang: Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease
Xianbo Zuo: Institute of Dermatology, Anhui Medical University
Xingjuan Shi: Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University
Yiran Wei: Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease
Xiaodong Zheng: Institute of Dermatology, Anhui Medical University
Yaping Dai: The Fifth People’s Hospital of Wuxi
Yuhua Gong: The Third People’s Hospital of Zhenjiang
Lan Wang: The 81th Hospital of PLA
Ping Xu: The Fifth People’s Hospital of Suzhou, Soochow University
Xiang Zhu: The Fifth People’s Hospital of Suzhou, Soochow University
Jian Wu: The First Affiliated Hospital of Soochow University
Chongxu Han: Subei People’s Hospital, Clinical Medical College, Yangzhou University
Yueqiu Gao: Shuguang Hospital, Shanghai University of Traditional Chinese Medicine
Kui Zhang: Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School
Yuzhang Jiang: Huai’an First People’s Hospital, Nanjing Medical University
Jianbo Zhou: Jiangyin People’s Hospital, Southeast University
Youlin Shao: The Third People’s Hospital of Changzhou
Zhigang Hu: Affiliated Wuxi People’s Hospital of Nanjing Medical University
Ye Tian: The Second Affiliated Hospital of Soochow University
Haiyan Zhang: Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease
Na Dai: Jiangsu University affiliated Kunshan Hospital
Lei Liu: Yixing People’s Hospital
Xudong Wu: Yancheng First People’s Hospital
Weifeng Zhao: The First Affiliated Hospital of Soochow University
Xiaomin Zhang: The University Hospital, Southeast University
Zhidong Zang: The Second Hospital of Nanjing, Southeast University
Jinshan Nie: Taicang First People’s Hospital, Soochow University
Weihao Sun: The First Affiliated Hospital of Nanjing Medical University
Yi Zhao: Eastern Hepatobiliary Surgery Hospital
Yuan Mao: Nanjing Kingmed Clinical Laboratory Co. Ltd.
Po Jiang: The Second People’s Hospital of Jingjiang
Hualiang Ji: Hai’an People’s Hospital, Nantong University Medical School
Qing Dong: Suzhou Hospital of Traditional Chinese Medicine
Junming Li: The First Affiliated Hospital of Nanchang University
Zhenzhong Li: The Second Hospital of Hebei Medical University
Xinli Bai: Zhongda Hospital, School of Medicine, Southeast University
Li Li: Taizhou People’s Hospital
Maosong Lin: Traditional Chinese Medicine Hospital of Kunshan
Ming Dong: Beijing Institutes of Life Science, Chinese Academy of Sciences
Jinxin Li: Beijing Hospital
Ping Zhu: School of Public Health, Fudan University
Chan Wang: Allergy, and Clinical Immunology, Rowe Program in Genetics, University of California-Davis
Yanqiu Zhang: School of Life Sciences, University of Science and Technology of China
Peng Jiang: The First Affiliated Hospital, Hainan Medical University
Yujue Wang: Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University
Rohil Jawed: Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University
Jing Xu: Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University
Yu Zhang: Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University
Qixia Wang: Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease
Yue Yang: Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease
Fan Yang: Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease
Min Lian: Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease
Xiang Jiang: Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease
Xiao Xiao: Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease
Yanmei Li: Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease
Jingyuan Fang: Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease
Dekai Qiu: Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease
Zhen Zhu: The Third People’s Hospital of Changzhou
Hong Qiu: The 81th Hospital of PLA
Jianqiong Zhang: Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University
Wenyan Tian: The First Affiliated Hospital of Soochow University
Sufang Chen: The Fifth People’s Hospital of Suzhou, Soochow University
Ling Jiang: The First Affiliated Hospital of Soochow University
Bing Ji: The 81th Hospital of PLA
Ping Li: The 81th Hospital of PLA
Guochang Chen: Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School
Tianxue Wu: Subei People’s Hospital, Clinical Medical College, Yangzhou University
Yan Sun: Subei People’s Hospital, Clinical Medical College, Yangzhou University
Jianjiang Yu: Jiangyin People’s Hospital, Southeast University
Huijun Tang: Jiangyin People’s Hospital, Southeast University
Michun He: The First Affiliated Hospital of Soochow University
Min Xia: Affiliated Wuxi People’s Hospital of Nanjing Medical University
Hao Pei: The Fifth People’s Hospital of Wuxi
Lihua Huang: The Fifth People’s Hospital of Wuxi
Zhuye Qing: Nanjing Kingmed Clinical Laboratory Co. Ltd.
Jianfang Wu: Traditional Chinese Medicine Hospital of Kunshan
Qinghai Huang: Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University
Junhai Han: Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University
Wei Xie: Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University
Zhongsheng Sun: Beijing Institutes of Life Science, Chinese Academy of Sciences
Jian Guo: Beijing Hospital
Gengsheng He: School of Public Health, Fudan University
M. Eric Gershwin: Allergy, and Clinical Immunology, Rowe Program in Genetics, University of California-Davis
Zhexiong Lian: School of Life Sciences, University of Science and Technology of China
Xiang Liu: The First Affiliated Hospital, Hainan Medical University
Michael F. Seldin: Allergy, and Clinical Immunology, Rowe Program in Genetics, University of California-Davis
Xiangdong Liu: Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University
Weichang Chen: The First Affiliated Hospital of Soochow University
Xiong Ma: Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease

Nature Communications, 2017, vol. 8, issue 1, 1-8

Abstract: Abstract Primary biliary cholangitis (PBC) is an autoimmune liver disease with a strong hereditary component. Here, we report a genome-wide association study that included 1,122 PBC cases and 4,036 controls of Han Chinese descent, with subsequent replication in a separate cohort of 907 PBC cases and 2,127 controls. Our results show genome-wide association of 14 PBC risk loci including previously identified 6p21 (HLA-DRA and DPB1), 17q12 (ORMDL3), 3q13.33 (CD80), 2q32.3 (STAT1/STAT4), 3q25.33 (IL12A), 4q24 (NF-κB) and 22q13.1 (RPL3/SYNGR1). We also identified variants in IL21, IL21R, CD28/CTLA4/ICOS, CD58, ARID3A and IL16 as novel PBC risk loci. These new findings and histochemical studies showing enhanced expression of IL21 and IL21R in PBC livers (particularly in the hepatic portal tracks) support a disease mechanism in which the deregulation of the IL21 signalling pathway, in addition to CD4 T-cell activation and T-cell co-stimulation are critical components in the development of PBC.

Date: 2017
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DOI: 10.1038/ncomms14828

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