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Distinct HLA Associations with Rheumatoid Arthritis Subsets Defined by Serological Subphenotype
Harvard Med Sch, Brigham & Womens Hosp, Div Rheumatol Inflammat & Immun, Boston, MA 02115 USA;Harvard Med Sch, Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA;Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA;RIKEN, Ctr Integrat Med Sci, Lab Stat & Translat Genet, Yokohama, Kanagawa 2300045, Japan;Shizuoka Prefectural Gen Hosp, Clin Res Ctr, Shizuoka 4208527, Japan;Univ Shizuoka, Sch Pharmaceut Sci, Dept Appl Genet, Shizuoka 4228526, Japan;Karolinska Inst, Inst Environm Med, Dept Translat Epidemiol, S-17176 Stockholm, Sweden.
Karolinska Inst, Inst Environm Med, Dept Translat Epidemiol, S-17176 Stockholm, Sweden;Karolinska Inst, Dept Med Solna, Div Rheumatol, S-17176 Stockholm, Sweden;Karolinska Univ Hosp, S-17176 Stockholm, Sweden.
Karolinska Inst, Inst Environm Med, Dept Translat Epidemiol, S-17176 Stockholm, Sweden.
Karolinska Inst, Inst Environm Med, Dept Translat Epidemiol, S-17176 Stockholm, Sweden.
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2019 (English)In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 105, no 3, p. 616-624Article in journal (Refereed) Published
Abstract [en]

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 (BPpos-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 BPpos-9 was derived from individuals who were positive for non-canonical serologies (omnibus_p = 9.2 x 10(-17)). Similarly, we observed in CCP2(+) RA that associations between subsets of CCP2(+) RA and BPpos-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.

Place, publisher, year, edition, pages
CELL PRESS , 2019. Vol. 105, no 3, p. 616-624
National Category
Rheumatology and Autoimmunity
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URN: urn:nbn:se:uu:diva-394686DOI: 10.1016/j.ajhg.2019.08.002ISI: 000484435700014PubMedID: 31474319OAI: oai:DiVA.org:uu-394686DiVA, id: diva2:1366655
Funder
Swedish Research CouncilForte, Swedish Research Council for Health, Working Life and WelfareAvailable from: 2019-10-30 Created: 2019-10-30 Last updated: 2019-10-30Bibliographically approved

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