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HLA–B*08 Identified as the Most Prominently Associated Major Histocompatibility Complex Locus for Anti–Carbamylated Protein Antibody–Positive/Anti–Cyclic Citrullinated Peptide–Negative Rheumatoid Arthritis
Author(s) -
Regueiro Cristina,
CasaresMarfil Desire,
Lundberg Karin,
Knevel Rachel,
AcostaHerrera Marialbert,
RodriguezRodriguez Luis,
LopezMejias Raquel,
PerezPampin Eva,
TrigueroMartinez Ana,
Nuño Laura,
FerrazAmaro Ivan,
RodriguezCarrio Javier,
LopezPedrera Rosario,
RobustilloVillarino Montse,
Castañeda Santos,
RemuzgoMartinez Sara,
Alperi Mercedes,
AlegreSancho Juan J.,
Balsa Alejandro,
GonzalezAlvaro Isidoro,
Mera Antonio,
FernandezGutierrez Benjamin,
GonzalezGay Miguel A.,
Trouw Leendert A.,
Grönwall Caroline,
Padyukov Leonid,
Martin Javier,
Gonzalez Antonio
Publication year - 2021
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.41630
Subject(s) - rheumatoid arthritis , immunology , antibody , medicine , rheumatoid factor , population , allele , major histocompatibility complex , haplotype , antigen , biology , genetics , gene , environmental health
Objective Previously, only the HLA–DRB1 alleles have been assessed in rheumatoid arthritis (RA). The aim of the present study was to identify the key major histocompatibility complex (MHC) susceptibility factors showing a significant association with anti–carbamylated protein antibody–positive (anti‐CarP+) RA. Methods Analyses were restricted to RA patients who were anti–cyclic citrullinated peptide antibody negative (anti‐CCP−), because the anti‐CCP status dominated the results otherwise. Therefore, we studied samples from 1,821 anti‐CCP− RA patients and 6,821 population controls from Spain, Sweden, and the Netherlands. The genotypes for ~8,000 MHC biallelic variants were assessed by dense genotyping and imputation. Their association with the anti‐CarP status in RA patients was tested with logistic regression and combined with inverse‐variance meta‐analysis. Significance of the associations was assessed according to a study‐specific threshold of P < 2.0 × 10 −5 . Results The HLA–B*08 allele and its correlated amino acid variant Asp‐9 showed a significant association with anti‐CarP+/anti‐CCP− RA ( P < 3.78 × 10 −7 ; I 2 = 0). This association was specific when assessed relative to 3 comparator groups: population controls, anti‐CarP−/anti‐CCP− RA patients, and anti‐CCP− RA patients who were positive for other anti–citrullinated protein antibodies. Based on these findings, anti‐CarP+/anti‐CCP− RA patients could be separated from other antibody‐defined subsets of RA patients in whom an association with the HLA–B*08 allele has been previously demonstrated. No other MHC variant remained associated with anti‐CarP+/anti‐CCP− RA after accounting for the presence of the HLA–B*08 allele. Specifically, the reported association of HLA–DRB1*03 was observed at a level comparable to that reported previously, but it was attributable to linkage disequilibrium. Conclusion These results identify HLA–B*08 carrying Asp‐9 as the MHC locus showing the strongest association with anti‐CarP+/anti‐CCP− RA. This knowledge may help clarify the role of the HLA in susceptibility to specific subsets of RA, by shaping the spectrum of RA autoantibodies.