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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; I2 = 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. [ABSTRACT FROM AUTHOR]

Objective: Recognition of a new type of rheumatoid arthritis (RA)–specific autoantibody, the anti–carbamylated protein antibodies (anti‐CarP), has provided an opportunity to improve the management and understanding of RA. The current study was undertaken to assess the relationship between anti‐CarP antibodies and HLA–DRB1 alleles in RA. Methods: Serum samples were obtained from 3 different collections, comprising a total of 1,126 RA patients. Serum reactivity against in vitro carbamylated fetal calf serum proteins was determined by enzyme‐linked immunosorbent assay. HLA–DRB1 alleles were determined using either hybridization techniques or imputation from HLA‐dense genotypes. Results of these analyses were combined in a meta‐analysis with data from 3 previously reported cohorts. The carrier frequencies of the common HLA–DRB1 alleles were compared between the antibody‐positive RA subgroups and the double‐negative subgroup of RA patients stratified by anti–citrullinated protein antibody (ACPA)/anti‐CarP antibody status, and also between the 4 RA patient strata and healthy controls. Results: Meta‐analysis was conducted with 3,709 RA patients and 2,305 healthy control subjects. Results revealed a significant increase in frequency of HLA–DRB1*03 carriers in the ACPA−/anti‐CarP+ subgroup as compared to ACPA−/anti‐CarP− RA patients and healthy controls; this was consistently found across the 6 sample collections. This association of HLA–DRB1*03 with ACPA−/anti‐CarP+ RA was independent of the presence of the shared allele (SE) and any other confounders analyzed. No other allele was specifically associated with the ACPA−/anti‐CarP+ RA patient subgroup. In contrast, frequency of the SE was significantly increased in the ACPA+/anti‐CarP− and ACPA+/anti‐CarP+ RA patient subgroups, without a significant distinction between them. Furthermore, some alleles (including HLA–DRB1*03) were associated with protection from ACPA+ RA. Conclusion: These findings indicate a specific association of HLA–DRB1*03 with ACPA−/anti‐CarP+ RA, suggesting that preferential presentation of carbamylated peptides could be a new mechanism underlying the contribution of HLA alleles to RA susceptibility. [ABSTRACT FROM AUTHOR]