Fine mapping of the MHC region identifies major independent variants associated with Han Chinese primary biliary cholangitis

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

Research output: Contribution to journalArticle

Abstract

The genetic association of primary biliary cholangitis with major histocompatibility complex (MHC) has been widely confirmed among different ethnicities. To map specific MHC region variants associated with PBC in a Han Chinese cohort, we imputed HLA antigens and amino acids (AA) in 1126 PBC cases and 1770 healthy control subjects using a Han-MHC reference database. We demonstrate that HLA-DRB1 and/or HLA-DQB1 contributed the strongest signals, and that HLA-DPB1 was a separate independent locus. Regression analyses with classical HLA alleles indicate that HLA-DQB1*03:01 or HLA-DQβ1-Pro55, HLA-DPB1*17:01 or HLA-DPβ1-Asp84 and HLA-DRB1*08:03 could largely explain MHC association with PBC. Forward stepwise regression analyses with HLA amino acid variants localize the major signals to HLA-DRβ1-Ala74, HLA-DQβ1-Pro55 and HLA-DPβ1-Asp84. Electrostatic potential calculations implicated AA variations at HLA-DQβ1 position 55 and HLA-DPβ1 position 84 as critical to peptide binding properties. Furthermore, although several critical Han Chinese AA variants differed from those shown in European populations, the predicted effects on antigen binding are likely to be very similar or identical and underlie the major component of MHC association with PBC.

Original languageEnglish (US)
Article number102372
JournalJournal of autoimmunity
Volume107
DOIs
StatePublished - Feb 2020

Keywords

  • Imputation
  • MHC
  • Primary biliary cholangitis
  • Single nucleotide polymorphism
  • Stepwise regression analysis

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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  • Cite this

    Wang, C., Zheng, X., Tang, R., Han, C., Jiang, Y., Wu, J., Shao, Y., Gao, Y., Yu, J., Hu, Z., Zang, Z., Zhao, Y., Dai, N., Liu, L., Wu, X., Nie, J., Jiang, B., Lin, M., Li, L., ... Sun, L. (2020). Fine mapping of the MHC region identifies major independent variants associated with Han Chinese primary biliary cholangitis. Journal of autoimmunity, 107, [102372]. https://doi.org/10.1016/j.jaut.2019.102372