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Am J Hum Genet. 2019 Sep 5;105(3):616-624. doi: 10.1016/j.ajhg.2019.08.002. Epub 2019 Aug 29.

Distinct HLA Associations with Rheumatoid Arthritis Subsets Defined by Serological Subphenotype.

Author information

1
Division of Rheumatology, Inflammation, and Immunity, 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; Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Kanagawa 230-0045, Japan; Clinical Research Center, Shizuoka General Hospital, Shizuoka 420-8527, Japan; The Department of Applied Genetics, The School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan.
2
Department of Translational Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Solna, 171 76 Stockholm, Sweden; Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, 171 76 Stockholm, Sweden.
3
Department of Translational Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Solna, 171 76 Stockholm, Sweden.
4
Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, 171 76 Stockholm, Sweden.
5
Charité Universitätsmedizin Berlin, Humboldt University of Berlin, 10117 Berlin, Germany.
6
UDEAR, UMRS 1056 Inserm - Université Toulouse III, Toulouse, France.
7
Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden.
8
Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden; Thermo Fischer Scientific Uppsala, 751 37 Uppsala, Sweden.
9
Department of Public Health and Clinical Medicine/Rheumatology, University of Umeå, 90187 Umeå, Sweden.
10
Robert S. Boas Center for Genomics and Human Genetics, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.
11
Versus Arthritis Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, Oxford Road, Manchester M13 9PT, UK.
12
Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, 171 76 Stockholm, Sweden. Electronic address: lars.klareskog@ki.se.
13
Division of Rheumatology, Inflammation, and Immunity, 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; Versus Arthritis Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, Oxford Road, Manchester M13 9PT, UK; Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: soumya@broadinstitute.org.

Abstract

Rheumatoid arthritis (RA) is the most common immune-mediated arthritis. Anti-citrullinated peptide antibodies (ACPA) are highly specific to RA and assayed with the commercial CCP2 assay. Genetic drivers of RA within the MHC are different for CCP2-positive and -negative subsets of RA, particularly at HLA-DRB1. However, aspartic acid at amino acid position 9 in HLA-B (Bpos-9) increases risk to both RA subsets. Here we explore how individual serologies associated with RA drive associations within the MHC. To define MHC differences for specific ACPA serologies, we quantified a total of 19 separate ACPAs in RA-affected case subjects from four cohorts (n = 6,805). We found a cluster of tightly co-occurring antibodies (canonical serologies, containing CCP2), along with several independently expressed antibodies (non-canonical serologies). After imputing HLA variants into 6,805 case subjects and 13,467 control subjects, we tested associations between the HLA region and RA subgroups based on the presence of canonical and/or non-canonical serologies. We examined CCP2(+) and CCP2(-) RA-affected case subjects separately. In CCP2(-) RA, we observed that the association between CCP2(-) RA and Bpos-9 was derived from individuals who were positive for non-canonical serologies (omnibus_p = 9.2 × 10-17). Similarly, we observed in CCP2(+) RA that associations between subsets of CCP2(+) RA and Bpos-9 were negatively correlated with the number of positive canonical serologies (p = 0.0096). These findings suggest unique genetic characteristics underlying fine-specific ACPAs, suggesting that RA may be further subdivided beyond simply seropositive and seronegative.

KEYWORDS:

HLA; MHC; citrullinated peptides; genetics; major histocompatability complex; rheumatoid arthritis

PMID:
31474319
PMCID:
PMC6731376
[Available on 2020-03-05]
DOI:
10.1016/j.ajhg.2019.08.002
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