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Genome‐wide Association Studies of Specific Antinuclear Autoantibody Subphenotypes in Primary Biliary Cholangitis
Author(s) -
Wang Chan,
Zheng Xiaodong,
Jiang Peng,
Tang Ruqi,
Gong Yuhua,
Dai Yaping,
Wang Lan,
Xu Ping,
Sun Wenjuan,
Wang Lu,
Han Chongxu,
Jiang Yuzhang,
Wei Yiran,
Zhang Kui,
Wu Jian,
Shao Youlin,
Gao Yueqiu,
Yu Jianjiang,
Hu Zhigang,
Zang Zhidong,
Zhao Yi,
Wu Xudong,
Dai Na,
Liu Lei,
Nie Jinshan,
Jiang Bo,
Lin Maosong,
Li Li,
Li You,
Chen Sufang,
Shu Lixin,
Qiu Fang,
Wu Qiuyuan,
Zhang Mingming,
Chen Ru,
Jawed Rohil,
Zhang Yu,
Shi Xingjuan,
Zhu Zhen,
Pei Hao,
Huang Lihua,
Zhao Weifeng,
Tian Ye,
Zhu Xiang,
Qiu Hong,
Gershwin M. Eric,
Chen Weichang,
Seldin Michael F.,
Liu Xiangdong,
Sun Liangdan,
Ma Xiong
Publication year - 2019
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.30604
Subject(s) - autoantibody , medicine , anti nuclear antibody , genome wide association study , gastroenterology , biology , genetics , immunology , antibody , gene , genotype , single nucleotide polymorphism
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.