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

Fang Qiu,Xinli Bai,Jianfang Wu,Chan Wang,Yanmei Li,Hualiang Ji,Qing-An Huang ,Bing Ji,Yue Yang,Ping Zhu,Dekai Qiu,Sufang Chen,Mao‐Song Lin ,Min Xia,Xianbo Zuo,Xiaomin Zhang,Junming Li,Weifeng Zhao,Chongxu Han,Haiyan Zhang,Wenyan Tian,Qixia Wang,Yuhua Gong,Jing Xu,Lihua Huang,Yuan Mao,Xiaodong Zheng,Yi Zhao,M Eric Gershwin,Jianhui Nie ,Zhen Sun ,Xiang Zhu,Hong Qian ,Xiang Long ,Xiao Xiao,Wei Sun ,Ruqi Tang,Kui Zhang,Zhenzhong Li,Xiangdong Liu,Huijun Tang,Jidong Zhou ,Rohil Jawed,Xingjuan Shi,Qing Dong,Ye Tian,Zhe‐Xiong Lian ,Xiang Jiang,Jinxin Li,Yujue Wang,Jianjiang Yu,Michael F Seldin,Guochang Chen,Yaping Dai,Mi-Chun He ,Min Lian,Na Dai,Zhigang Hu,Zhuye Qing,Youlin Shao,Hao Pei,Yu Zhang,Yueqiu Gao,Ping Xu,Zhen Zhu,Yanqiu Zhang,Xudong Wang ,Weichang Chen,Peng Jiang,Po Jiang,Ping Li,Wei Xie,Mei Dong ,Jing‐Yuan Fang ,Jianqiong Zhang,Fan Yang,Junhai Han,Gengsheng He,Tianxue Wu,Ling Jiang,Jian Guo,Yiran Wei,Zhidong Zang,Yahui Jiang ,Li Li,Lei Liu,Lan Wang,Yan V Sun ,Jian Wu,Xiong Ma

doi:10.1038/ncomms14828

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.

Highlights

Primary biliary cholangitis (PBC) is an autoimmune liver disease with a strong hereditary component
The quantile–quantile plot of the case–control test showed a substantial excess of significant associations in the tail of the distribution even after removal of the major histocompatibility complex (MHC) region that includes human leukocyte antigen (HLA) genes (Supplementary Fig. 3)
We identified 179 single nucleotide polymorphisms (SNPs) in the MHC region and 39 SNPs in 8 non-MHC loci exceeding genome-wide significance in the discovery stage (Fig. 1; Supplementary Tables 4–7)

Summary

Introduction

Primary biliary cholangitis (PBC) is an autoimmune liver disease with a strong hereditary component. We performed a replication study of the 14 most significant single nucleotide polymorphisms (SNPs) identified in either or both of the European and Japanese cohorts, using 1,070 Han Chinese PBC cases and 1,198 healthy controls, and confirmed strong association of the TNFSF15, CD80 and 17q12 loci with the disease in Chinese patients, with P-value reaching GWA significance (Po5 Â 10 À 8) at TNFSF15 and CD80 loci[9] These early results ensured required samples for our subsequent GWAS design. These findings significantly expand our understanding of the disease susceptibility and suggest IL21 signalling pathway, in addition to CD4 T-cell activation and T-cell co-stimulation, are critical components in the development of PBC

Methods

Results

Conclusion