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Hepatology. 2019 Mar 10. doi: 10.1002/hep.30604. [Epub ahead of print]

Genome Wide Association Studies of Specific Antinuclear Autoantibody Sub-phenotypes in Primary Biliary Cholangitis.

Author information

1
Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, 2 Sipailou Road, Nanjing, Jiangsu, 210096, China.
2
Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, HefeiChina & Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China & Key Laboratory of Major Autoimmune Diseases, Anhui Province, Hefei, China.
3
Department of Gastroenterology and Hepatology, Shanghai Institute of Digestive Diseases, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, 145 Shandong Middle Road, Shanghai, 200001, China.
4
Department of Laboratory Medicine, The Third People's Hospital of Zhenjiang, 300 Daijiamen, Zhenjiang, Jiangsu, 212021, China.
5
Department of Laboratory Medicine, The Fifth People's Hospital of Wuxi, 1215 Guangrui Road, Wuxi, Jiangsu, 214000, China.
6
Department of Laboratory Medicine, The 81th Hospital of PLA, 34 Yanggongjing Nanjing, Jiangsu, 210002, China.
7
Department of Laboratory Medicine, The Fifth People's Hospital of Suzhou, Soochow University, 10 Guangqian Road, Suzhou, Jiangsu, 215131, China.
8
Department of Laboratory Medicine, Subei People's Hospital, Clinical Medical College, Yangzhou University, 98 Nantong West Road, Yangzhou, Jiangsu, 225001, China.
9
Department of Laboratory Medicine, Huai'an First People's Hospital, Nanjing Medical University, 1 Huanghe West Road, Huai'an, Jiangsu, 223300, China.
10
Department of Laboratory Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, Jiangsu, 210008, China.
11
Department of Rheumatology, First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, Jiangsu, 215006, China.
12
Department of Hepatology, The Third People's Hospital of Changzhou, 300 Lanling North Road, Changzhou, Jiangsu, 213001, China.
13
Department of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China.
14
Department of Laboratory Medicine, Jiangyin People's Hospital, Southeast University, 163 shoushan Road, Jiangyin, Jiangsu, 214400, China.
15
Department of Laboratory Medicine, Affiliated Wuxi People's Hospital of Nanjing Medical University, 299 Qingyang Road, Wuxi, Jiangsu, 214023, China.
16
Department of Hepatology, The Second Hospital of Nanjing, Southeast University, 1 Zhongfu Road, Nanjing, jiangsu, 210003, China.
17
Department of Gastrointestinal Endoscopy, Eastern Hepatobiliary Surgery Hospital, 700 Moyu North Road, Shanghai, 201800, China.
18
Department of Gastroenterology, Yancheng First People's Hospital, 66 Renmin South Road, Yancheng, Jiangsu, 224005, China.
19
Department of Gastroenterology, Jiangsu University affiliated Kunshan Hospital, 91 Qianjin West Road, Kunshan, Jiangsu, 215300, China.
20
Department of Gastroenterology, Yixing People's Hospital, 75 Tongzhenguan Road, Yixin, Jiangsu, 214200, China.
21
Department of Gastroenterology, Taicang First People's Hospital, Soochow University, 58 Changsheng South Road, Taicang, Jiangsu, 215400, China.
22
Department of Hepatology, Jingjiang Second People's Hospital, 1 Chengxiqiao Jiangping Road, Jingjiang, Jiangsu, 214500, China.
23
Department of Gastroenterology, Taizhou People's Hospital, 210 Yingchun Road, Taizhou, Jiangsu, 225300, China.
24
Department of Laboratory Medicine, Zhongda Hospital, Southeast University, 87 Dingjiaqiao Road, Nanjing, Jiangsu, 210009, China.
25
Institute of Life Sciences, Southeast University, Key Laboratory of Developmental Genes and Human Diseases.
26
Department of Gastroenterology, First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, Jiangsu, 215006, China.
27
Department of Radiology, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, Jiangsu, 215004, China.
28
Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Genome and Biomedical Sciences Facility Building, 451 Health Sciences Drive, Suite 6510, Davis, CA, 95616, USA.
29
Department of Biochemistry and Molecular Medicine, University of California at Davis School of Medicine, 4453 Tupper Hall, Davis, CA, 95616, USA.

Abstract

Anti-nuclear antibodies to sp100 and 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 sub-phenotypes, we performed genome-wide association analysis of 930 PBC cases based on their autoantibody status, followed with a replication study in 1252 PBC cases. We confirmed single-nucleotide polymorphism rs492899 (P = 3.27 × 10-22 ; OR = 2.90; 95% CI: 2.34-3.66) and rs1794280 (P = 5.78 × 10-28 ; OR = 3.89; 95% CI: 3.05-4.96) in human major histocompatibility complex (MHC) region associated with sp100 autoantibody. However, no genetic variant was identified to associate with gp210 autoantibody. To further define specific classical human leukocyte antigen (HLA) alleles or amino acids associated with 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, *15:01, *01 and DPB1*03:01 alleles can explain most of the HLA association with sp100 autoantibody. This study indicated significantly genetic predisposition to sp100 autoantibody, but not gp210 autoantibody, sub-phenotype in PBC patients. Additional studies will be necessary to determine if these findings have clinical significance to PBC pathogenesis and/or therapeutics. This article is protected by copyright. All rights reserved.

KEYWORDS:

autoimmune; gp210; human leukocyte antigen; single nucleotide polymorphism; sp100

PMID:
30854688
DOI:
10.1002/hep.30604

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