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Am J Hum Genet. 2016 Aug 4;99(2):366-74. doi: 10.1016/j.ajhg.2016.06.019.

Contribution of a Non-classical HLA Gene, HLA-DOA, to the Risk of Rheumatoid Arthritis.

Author information

  • 1Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 113-0034 Tokyo, Japan; Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan; Department of Statistical Genetics, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan. Electronic address: yokada@sg.med.osaka-u.ac.jp.
  • 2Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
  • 3Institute of Rheumatology, Tokyo Women's Medical University, Tokyo 162-0054, Japan; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo 162-0054, Japan.
  • 4Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan; Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto 606-8501, Japan.
  • 5Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo 162-0054, Japan.
  • 6Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
  • 7Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
  • 8Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
  • 9Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
  • 10Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 113-0034 Tokyo, Japan; Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
  • 11Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 113-0034 Tokyo, Japan; Pharmaceutical Discovery Research Laboratories, Teijin Pharma, Hino 191-8512, Japan.
  • 12Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 113-0034 Tokyo, Japan; Advanced Medicinal Research Laboratories, Tsukuba Research Institute, Ono Pharmaceutical, Tsukuba 300-4247, Japan.
  • 13Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117549.
  • 14Department of Rheumatology and Immunology, Shanghai Changzheng Hospital and The Second Military Medical University, Shanghai 200433, China.
  • 15Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 04763, South Korea.
  • 16Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, 108-8639 Tokyo, Japan.
  • 17Institute of Rheumatology, Tokyo Women's Medical University, Tokyo 162-0054, Japan.
  • 18University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland 4072, Australia.
  • 19Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Partners Center for Personalized Genetic Medicine, Boston, MA 02115, USA; Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9PL, UK.
  • 20Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan; Department of Allergy and Rheumatology, Graduate School of Medicine, the University of Tokyo, Tokyo 113-0033, Japan.

Abstract

Despite the progress in human leukocyte antigen (HLA) causal variant mapping, independent localization of major histocompatibility complex (MHC) risk from classical HLA genes is challenging. Here, we conducted a large-scale MHC fine-mapping analysis of rheumatoid arthritis (RA) in a Japanese population (6,244 RA cases and 23,731 controls) population by using HLA imputation, followed by a multi-ethnic validation study including east Asian and European populations (n = 7,097 and 23,149, respectively). Our study identified an independent risk of a synonymous mutation at HLA-DOA, a non-classical HLA gene, on anti-citrullinated protein autoantibody (ACPA)-positive RA risk (p = 1.4 × 10(-9)), which demonstrated a cis-expression quantitative trait loci (cis-eQTL) effect on HLA-DOA expression. Trans-ethnic comparison revealed different linkage disequilibrium (LD) patterns in HLA-DOA and HLA-DRB1, explaining the observed HLA-DOA variant risk heterogeneity among ethnicities, which was most evident in the Japanese population. Although previous HLA fine-mapping studies have identified amino acid polymorphisms of the classical HLA genes as driving genetic susceptibility to disease, our study additionally identifies the dosage contribution of a non-classical HLA gene to disease etiology. Our study contributes to the understanding of HLA immunology in human diseases and suggests the value of incorporating additional ancestry in MHC fine-mapping.

PMID:
27486778
PMCID:
PMC4974094
DOI:
10.1016/j.ajhg.2016.06.019
[PubMed - in process]
Free PMC Article
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