Genome-wide Association Studies of Specific Antinuclear Autoantibody Subphenotypes in Primary Biliary Cholangitis

Chan Wang, Xiaodong Zheng, Peng Jiang, Ruqi Tang, Yuhua Gong, Yaping Dai, Lan Wang, Ping Xu, Wenjuan Sun, Lu Wang, Chongxu Han, Yuzhang Jiang, Yiran Wei, Kui Zhang, Jian Wu, Youlin Shao, Yueqiu Gao, Jianjiang Yu, Zhigang Hu, Zhidong ZangYi Zhao, Xudong Wu, Na Dai, Lei Liu, Jinshan Nie, Bo Jiang, Maosong Lin, Li Li, You Li, Sufang Chen, Lixin Shu, Fang Qiu, Qiuyuan Wu, Mingming Zhang, Ru Chen, Rohil Jawed, Yu Zhang, Xingjuan Shi, Zhen Zhu, Hao Pei, Lihua Huang, Weifeng Zhao, Ye Tian, Xiang Zhu, Hong Qiu, M. Eric Gershwin, Weichang Chen, Michael F Seldin, Xiangdong Liu, Liangdan Sun, Xiong Ma

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


Anti-nuclear antibodies to speckled 100 kDa (sp100) and glycoprotein 210 (gp210) are specific serologic markers of primary biliary cholangitis (PBC) of uncertain/controversial clinical or prognostic significance. To study the genetic determinants associated with sp100 and gp210 autoantibody subphenotypes, we performed a genome-wide association analysis of 930 PBC cases based on their autoantibody status, followed by a replication study in 1,252 PBC cases. We confirmed single-nucleotide polymorphisms rs492899 (P = 3.27 × 10−22; odds ratio [OR], 2.90; 95% confidence interval [CI], 2.34-3.66) and rs1794280 (P = 5.78 × 10−28; OR, 3.89; 95% CI, 3.05-4.96) in the human major histocompatibility complex (MHC) region associated with the sp100 autoantibody. However, no genetic variant was identified as being associated with the gp210 autoantibody. To further define specific classical human leukocyte antigen (HLA) alleles or amino acids associated with the sp100 autoantibody, we imputed 922 PBC cases (211 anti-sp100-positive versus 711 negative cases) using a Han Chinese MHC reference database. Conditional analysis identified that HLA-DRβ1-Asn77/Arg74, DRβ1-Ser37, and DPβ1-Lys65 were major determinants for sp100 production. For the classical HLA alleles, the strongest association was with DRB1*03:01 (P = 1.51 × 10−9; OR, 2.97; 95% CI, 2.06-4.29). Regression analysis with classical HLA alleles identified DRB1*03:01, DRB1*15:01, DRB1*01, and DPB1*03:01 alleles can explain most of the HLA association with sp100 autoantibody. Conclusion: This study indicated significant genetic predisposition to the sp100 autoantibody, but not the gp210 autoantibody, subphenotype in PBC patients. Additional studies will be necessary to determine if these findings have clinical significance to PBC pathogenesis and/or therapeutics.

Original languageEnglish (US)
Pages (from-to)294-307
Number of pages14
Issue number1
StatePublished - Jul 1 2019

ASJC Scopus subject areas

  • Hepatology


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