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Specific association of HLA-DRB1*03 with anti-carbamylated protein antibodies in patients with rheumatoid arthritis

AuthorsRegueiro, Cristina; Rodríguez-Rodríguez, Luis; Triguero-Martínez, Ana; Nuño, Laura; Castaño-Nunez, Angel L.; Villalva, Alejandro; Pérez-Pampin, Eva; López-Golan, Yolanda; Abasolo, Lydia; Ortiz, Ana M.; Herranz, Eva; Pascual-Salcedo, Dora; Martínez-Feito, Ana; Boveda, María Dolores; Gómez-Reino, Juan J.; Martín, Javier; González-Escribano, María Francisca; Fernández-Gutiérrez, Benjamín; Balsa, Alejandro; González-Álvaro, Isidoro; González, Antonio
Issue DateMar-2019
PublisherJohn Wiley & Sons
CitationArthritis and Rheumatology 71(3): 331-339 (2019)
Abstract[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.
Publisher version (URL)https://doi.org/10.1002/art.40738
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