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 TianHaiyan 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, Xiong Ma

Research output: Contribution to journalArticle

24 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)14828
Number of pages1
JournalNature Communications
DOIs
StateAccepted/In press - 2017

Fingerprint

Cholangitis
Interleukin-21 Receptors
genome
Genome-Wide Association Study
loci
liver
T-cells
Genes
Association reactions
Liver
HLA-DR alpha-Chains
descent
Interleukin-16
stimulation
Deregulation
activation
Chemical activation
T-Lymphocytes
interleukin-21
Autoimmune Diseases

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Qiu, F., Tang, R., Zuo, X., Shi, X., Wei, Y., Zheng, X., ... Ma, X. (Accepted/In press). A genome-wide association study identifies six novel risk loci for primary biliary cholangitis. Nature Communications, 14828. https://doi.org/10.1038/ncomms14828

A genome-wide association study identifies six novel risk loci for primary biliary cholangitis. / Qiu, Fang; Tang, Ruqi; Zuo, Xianbo; Shi, Xingjuan; Wei, Yiran; Zheng, Xiaodong; Dai, Yaping; Gong, Yuhua; Wang, Lan; Xu, Ping; Zhu, Xiang; Wu, Jian; Han, Chongxu; Gao, Yueqiu; Zhang, Kui; Jiang, Yuzhang; Zhou, Jianbo; Shao, Youlin; Hu, Zhigang; Tian, Ye; Zhang, Haiyan; Dai, Na; Liu, Lei; Wu, Xudong; Zhao, Weifeng; Zhang, Xiaomin; Zang, Zhidong; Nie, Jinshan; Sun, Weihao; Zhao, Yi; Mao, Yuan; Jiang, Po; Ji, Hualiang; Dong, Qing; Li, Junming; Li, Zhenzhong; Bai, Xinli; Li, Li; Lin, Maosong; Dong, Ming; Li, Jinxin; Zhu, Ping; Wang, Chan; Zhang, Yanqiu; Jiang, Peng; Wang, Yujue; Jawed, Rohil; Xu, Jing; Zhang, Yu; Wang, Qixia; Yang, Yue; Yang, Fan; Lian, Min; Jiang, Xiang; Xiao, Xiao; Li, Yanmei; Fang, Jingyuan; Qiu, Dekai; Zhu, Zhen; Qiu, Hong; Zhang, Jianqiong; Tian, Wenyan; Chen, Sufang; Jiang, Ling; Ji, Bing; Li, Ping; Chen, Guochang; Wu, Tianxue; Sun, Yan; Yu, Jianjiang; Tang, Huijun; He, Michun; Xia, Min; Pei, Hao; Huang, Lihua; Qing, Zhuye; Wu, Jianfang; Huang, Qinghai; Han, Junhai; Xie, Wei; Sun, Zhongsheng; Guo, Jian; He, Gengsheng; Eric Gershwin, M.; Lian, Zhexiong; Liu, Xiang; Seldin, Michael F.; Liu, Xiangdong; Chen, Weichang; Ma, Xiong.

In: Nature Communications, 2017, p. 14828.

Research output: Contribution to journalArticle

Qiu, F, Tang, R, Zuo, X, Shi, X, Wei, Y, Zheng, X, Dai, Y, Gong, Y, Wang, L, Xu, P, Zhu, X, Wu, J, Han, C, Gao, Y, Zhang, K, Jiang, Y, Zhou, J, Shao, Y, Hu, Z, Tian, Y, Zhang, H, Dai, N, Liu, L, Wu, X, Zhao, W, Zhang, X, Zang, Z, Nie, J, Sun, W, Zhao, Y, Mao, Y, Jiang, P, Ji, H, Dong, Q, Li, J, Li, Z, Bai, X, Li, L, Lin, M, Dong, M, Li, J, Zhu, P, Wang, C, Zhang, Y, Jiang, P, Wang, Y, Jawed, R, Xu, J, Zhang, Y, Wang, Q, Yang, Y, Yang, F, Lian, M, Jiang, X, Xiao, X, Li, Y, Fang, J, Qiu, D, Zhu, Z, Qiu, H, Zhang, J, Tian, W, Chen, S, Jiang, L, Ji, B, Li, P, Chen, G, Wu, T, Sun, Y, Yu, J, Tang, H, He, M, Xia, M, Pei, H, Huang, L, Qing, Z, Wu, J, Huang, Q, Han, J, Xie, W, Sun, Z, Guo, J, He, G, Eric Gershwin, M, Lian, Z, Liu, X, Seldin, MF, Liu, X, Chen, W & Ma, X 2017, 'A genome-wide association study identifies six novel risk loci for primary biliary cholangitis', Nature Communications, pp. 14828. https://doi.org/10.1038/ncomms14828
Qiu, Fang ; Tang, Ruqi ; Zuo, Xianbo ; Shi, Xingjuan ; Wei, Yiran ; Zheng, Xiaodong ; Dai, Yaping ; Gong, Yuhua ; Wang, Lan ; Xu, Ping ; Zhu, Xiang ; Wu, Jian ; Han, Chongxu ; Gao, Yueqiu ; Zhang, Kui ; Jiang, Yuzhang ; Zhou, Jianbo ; Shao, Youlin ; Hu, Zhigang ; Tian, Ye ; Zhang, Haiyan ; Dai, Na ; Liu, Lei ; Wu, Xudong ; Zhao, Weifeng ; Zhang, Xiaomin ; Zang, Zhidong ; Nie, Jinshan ; Sun, Weihao ; Zhao, Yi ; Mao, Yuan ; Jiang, Po ; Ji, Hualiang ; Dong, Qing ; Li, Junming ; Li, Zhenzhong ; Bai, Xinli ; Li, Li ; Lin, Maosong ; Dong, Ming ; Li, Jinxin ; Zhu, Ping ; Wang, Chan ; Zhang, Yanqiu ; Jiang, Peng ; Wang, Yujue ; Jawed, Rohil ; Xu, Jing ; Zhang, Yu ; Wang, Qixia ; Yang, Yue ; Yang, Fan ; Lian, Min ; Jiang, Xiang ; Xiao, Xiao ; Li, Yanmei ; Fang, Jingyuan ; Qiu, Dekai ; Zhu, Zhen ; Qiu, Hong ; Zhang, Jianqiong ; Tian, Wenyan ; Chen, Sufang ; Jiang, Ling ; Ji, Bing ; Li, Ping ; Chen, Guochang ; Wu, Tianxue ; Sun, Yan ; Yu, Jianjiang ; Tang, Huijun ; He, Michun ; Xia, Min ; Pei, Hao ; Huang, Lihua ; Qing, Zhuye ; Wu, Jianfang ; Huang, Qinghai ; Han, Junhai ; Xie, Wei ; Sun, Zhongsheng ; Guo, Jian ; He, Gengsheng ; Eric Gershwin, M. ; Lian, Zhexiong ; Liu, Xiang ; Seldin, Michael F. ; Liu, Xiangdong ; Chen, Weichang ; Ma, Xiong. / A genome-wide association study identifies six novel risk loci for primary biliary cholangitis. In: Nature Communications. 2017 ; pp. 14828.
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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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AU - Tang, Ruqi

AU - Zuo, Xianbo

AU - Shi, Xingjuan

AU - Wei, Yiran

AU - Zheng, Xiaodong

AU - Dai, Yaping

AU - Gong, Yuhua

AU - Wang, Lan

AU - Xu, Ping

AU - Zhu, Xiang

AU - Wu, Jian

AU - Han, Chongxu

AU - Gao, Yueqiu

AU - Zhang, Kui

AU - Jiang, Yuzhang

AU - Zhou, Jianbo

AU - Shao, Youlin

AU - Hu, Zhigang

AU - Tian, Ye

AU - Zhang, Haiyan

AU - Dai, Na

AU - Liu, Lei

AU - Wu, Xudong

AU - Zhao, Weifeng

AU - Zhang, Xiaomin

AU - Zang, Zhidong

AU - Nie, Jinshan

AU - Sun, Weihao

AU - Zhao, Yi

AU - Mao, Yuan

AU - Jiang, Po

AU - Ji, Hualiang

AU - Dong, Qing

AU - Li, Junming

AU - Li, Zhenzhong

AU - Bai, Xinli

AU - Li, Li

AU - Lin, Maosong

AU - Dong, Ming

AU - Li, Jinxin

AU - Zhu, Ping

AU - Wang, Chan

AU - Zhang, Yanqiu

AU - Jiang, Peng

AU - Wang, Yujue

AU - Jawed, Rohil

AU - Xu, Jing

AU - Zhang, Yu

AU - Wang, Qixia

AU - Yang, Yue

AU - Yang, Fan

AU - Lian, Min

AU - Jiang, Xiang

AU - Xiao, Xiao

AU - Li, Yanmei

AU - Fang, Jingyuan

AU - Qiu, Dekai

AU - Zhu, Zhen

AU - Qiu, Hong

AU - Zhang, Jianqiong

AU - Tian, Wenyan

AU - Chen, Sufang

AU - Jiang, Ling

AU - Ji, Bing

AU - Li, Ping

AU - Chen, Guochang

AU - Wu, Tianxue

AU - Sun, Yan

AU - Yu, Jianjiang

AU - Tang, Huijun

AU - He, Michun

AU - Xia, Min

AU - Pei, Hao

AU - Huang, Lihua

AU - Qing, Zhuye

AU - Wu, Jianfang

AU - Huang, Qinghai

AU - Han, Junhai

AU - Xie, Wei

AU - Sun, Zhongsheng

AU - Guo, Jian

AU - He, Gengsheng

AU - Eric Gershwin, M.

AU - Lian, Zhexiong

AU - Liu, Xiang

AU - Seldin, Michael F.

AU - Liu, Xiangdong

AU - Chen, Weichang

AU - Ma, Xiong

PY - 2017

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AB - 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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