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

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-?B) 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.

SUBMITTER: Qiu F

PROVIDER: S-EPMC5429142 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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

Qiu Fang F Tang Ruqi R Zuo Xianbo X Shi Xingjuan X Wei Yiran Y Zheng Xiaodong X Dai Yaping Y Gong Yuhua Y Wang Lan L Xu Ping P Zhu Xiang X Wu Jian J Han Chongxu C Gao Yueqiu Y Zhang Kui K Jiang Yuzhang Y Zhou Jianbo J Shao Youlin Y Hu Zhigang Z Tian Ye Y Zhang Haiyan H Dai Na N Liu Lei L Wu Xudong X Zhao Weifeng W Zhang Xiaomin X Zang Zhidong Z Nie Jinshan J Sun Weihao W Zhao Yi Y Mao Yuan Y Jiang Po P Ji Hualiang H Dong Qing Q Li Junming J Li Zhenzhong Z Bai Xinli X Li Li L Lin Maosong M Dong Ming M Li Jinxin J Zhu Ping P Wang Chan C Zhang Yanqiu Y Jiang Peng P Wang Yujue Y Jawed Rohil R Xu Jing J Zhang Yu Y Wang Qixia Q Yang Yue Y Yang Fan F Lian Min M Jiang Xiang X Xiao Xiao X Li Yanmei Y Fang Jingyuan J Qiu Dekai D Zhu Zhen Z Qiu Hong H Zhang Jianqiong J Tian Wenyan W Chen Sufang S Jiang Ling L Ji Bing B Li Ping P Chen Guochang G Wu Tianxue T Sun Yan Y Yu Jianjiang J Tang Huijun H He Michun M Xia Min M Pei Hao H Huang Lihua L Qing Zhuye Z Wu Jianfang J Huang Qinghai Q Han Junhai J Xie Wei W Sun Zhongsheng Z Guo Jian J He Gengsheng G Eric Gershwin M M Lian Zhexiong Z Liu Xiang X Seldin Michael F MF Liu Xiangdong X Chen Weichang W Ma Xiong X

Nature communications 20170420

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), 4q2 ...[more]

PMID: 28425483

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Project description:Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are forms of hepatic autoimmunity, and risk for both diseases has a strong genetic component. This study aimed to define the genetic architecture of PBC and PSC within the Polish population.Subjects were 443 women with PBC, 120 patients with PSC, and 934 healthy controls recruited from Gastroenterology Departments in various Polish hospitals. Allelotyping employed a pooled-DNA sample-based genome-wide association study (GWAS) approach, using Illumina Human Omni2.5-Exome BeadChips and the following novel selection criteria for risk loci: blocks of at least 10 single nucleotide polymorphisms (SNPs) in strong linkage disequilibrium, where the distance between each adjacent SNP pair in the block was less than 30 kb, and each SNP was associated with disease at a significance level of P < 0.005. A selected index SNP from each block was validated using TaqMan SNP genotyping assays.Nineteen and twenty-one SNPs were verified as associated with PBC and PSC, respectively, by individual genotyping; 19 (10/9, PBC/PSC) SNPs reached a stringent (corrected) significance threshold and a further 21 (9/12, PBC/PSC) reached a nominal level of significance (P < 0.05 with odds ratio (OR) > 1.2 or < 0.83), providing suggestive evidence of association. The SNPs mapped to seven (1p31.3, 3q13, 6p21, 7q32.1, 11q23.3, 17q12, 19q13.33) and one (6p21) chromosome region previously associated with PBC and PSC, respectively. The SNP, rs35730843, mapping to the POLR2G gene promoter (P = 1.2 × 10-5, OR = 0.39) demonstrated the highest effect size, and was protective for PBC, whereas for PSC respective SNPs were: rs13191240 in the intron of ADGRB3 gene (P = 0.0095, OR = 0.2) and rs3822659 (P = 0.0051, OR = 0.236) along with rs9686714 (P = 0.00077, OR = 0.2), both located in the WWC1 gene.Our cost-effective GWAS approach followed by individual genotyping confirmed several previously identified associations and discovered new susceptibility loci associated with PBC and/or PSC in Polish patients. However, further functional studies are warranted to understand the roles of these newly identified variants in the development of the two disorders.

Dataset Information

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

Publications

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

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