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

Fang Qiu(Southeast University), Ruqi Tang(Shanghai Jiao Tong University), Xianbo Zuo(Anhui Medical University), Xingjuan Shi(Southeast University), Yiran Wei(Shanghai Jiao Tong University), Xiaodong Zheng(Anhui Medical University), Yaping Dai, Yuhua Gong, Lan Wang(81th Hospital of PLA), Ping Xu(Soochow University), Xiang Zhu(Soochow University), Jian Wu(Soochow University), Chongxu Han(Yangzhou University), Yueqiu Gao(Shanghai University of Traditional Chinese Medicine), Kui Zhang(Nanjing Drum Tower Hospital), Yuzhang Jiang(Huaian First People’s Hospital), Jianbo Zhou(Jiangyin People's Hospital), Youlin Shao(Changzhou Third People's Hospital), Zhigang Hu(Wuxi People's Hospital), Ye Tian(Soochow University), Haiyan Zhang(Shanghai Jiao Tong University), Na Dai(Jiangsu University), Lei Liu(Jiangsu University), Xudong Wu(Nantong University), Weifeng Zhao(Soochow University), Xiaomin Zhang(Southeast University), Zhidong Zang(Nanjing Second Hospital), Jinshan Nie(Soochow University), Wei‐Hao Sun(Jiangsu Province Hospital), Yi Zhao(Second Military Medical University), Yuan Mao(Kingmed Diagnostics), Po Jiang(Xian Yang Central Hospital), Hualiang Ji(Nantong University), Qing Dong(Suzhou Traditional Chinese Medicine Hospital), Junming Li(Nanchang University), Zhenzhong Li(Hebei Medical University), Xinli Bai(Zhongda Hospital Southeast University), Li Li(Nantong University), Maosong Lin(Shanghai University of Traditional Chinese Medicine), Ming Dong(Chinese Academy of Sciences), Jinxin Li(Nanchang University), Ping Zhu(Fudan University), Chan Wang(University of California, Davis), Yanqiu Zhang(University of Science and Technology of China), Peng Jiang(Xian Yang Central Hospital), Yujue Wang(Southeast University), Rohil Jawed(Southeast University), Jing Xu(Southeast University), Yu Zhang(University of Science and Technology of China), Qixia Wang(Shanghai Jiao Tong University), Yue Yang(Shanghai Jiao Tong University), Fan Yang(Shanghai Jiao Tong University), Min Lian(Shanghai Jiao Tong University), Xiang Jiang(Shanghai Jiao Tong University), Xiao Xiao(Shanghai Jiao Tong University), Yanmei Li(Shanghai Jiao Tong University), Jing‐Yuan Fang(Shanghai Jiao Tong University), Dekai Qiu(Shanghai Jiao Tong University), Zhen Zhu(Changzhou Third People's Hospital), Hong Qiu(81th Hospital of PLA), Jianqiong Zhang(Southeast University), Wenyan Tian(Soochow University), Sufang Chen(Soochow University), Ling Jiang(Soochow University), Bing Ji(81th Hospital of PLA), Ping Li(81th Hospital of PLA), Guochang Chen(Nanjing Drum Tower Hospital), Tianxue Wu(Yangzhou University), Yan V. Sun(Yangzhou University), Jianjiang Yu(Jiangyin People's Hospital), Huijun Tang(Jiangyin People's Hospital), Mi-chun He(Soochow University), Min Xia(Wuxi People's Hospital), Pei Hao, Lihua Huang, Zhuye Qing(Kingmed Diagnostics), Jianfang Wu(Soochow University), Qinghai Huang(Southeast University), Junhai Han(Southeast University), Wei Xie(Southeast University), Zhong Sheng Sun(Chinese Academy of Sciences), Jian Guo(Beijing Hospital), Gengsheng He(Fudan University), M. Eric Gershwin(University of California, Davis), Zhe‐Xiong Lian(University of Science and Technology of China), Xiang Liu(Southeast University), Michael F. Seldin(University of California, Davis), Xiangdong Liu(Southeast University), Weichang Chen(Soochow University), Xiong Ma(Shanghai Jiao Tong University)
Nature Communications
April 20, 2017
10.1038/ncomms14828
Cited by 149Open Access
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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.

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