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.
González, Antonio; Regueiro, Cristina; Casares-Marfil, Desire; Lundberg, Karin; Knevel, Rachel; Acosta-Herrera, Marialbert; Rodriguez-Rodriguez, Luis; Lopez-Mejias, Raquel; Pérez Pampín, Eva; Triguero-Martinez, Ana; Nuño, Laura; Ferraz-Amaro, Ivan; Rodriguez-Carrio, Javier; Lopez-Pedrera, Rosario; Robustillo-Villarino, Montse; Castañeda, Santos; Remuzgo-Martinez, Sara; Alperi, Mercedes; Alegre-Sancho, Juan J; Balsa, Alejandro; Gonzalez-Alvaro, Isidoro; Mera Varela, Antonio; Fernandez-Gutierrez, Benjamin; Gonzalez-Gay, Miguel A; Trouw, Leendert A; Grönwall, Caroline; Padyukov, Leonid; Martin, Javier; González Martínez-Pedrayo, Antonio
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Identificadores
URI: http://hdl.handle.net/20.500.11940/17701
PMID: 33381897
DOI: 10.1002/art.41630
ISSN: 2326-5191
ESSN: 2326-5205
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Fecha de publicación
2021-06Título de revista
Arthritis and Rheumatology
Tipo de contenido
Artigo
DeCS
autoanticuerpos | antígeno HLA-B8 | Carbamilación de Proteína | alelos | reumatología | cadenas HLA-DRB1 | artritis reumatoide | artritisMeSH
Anti-Citrullinated Protein Antibodies | Arthritis, Rheumatoid | Autoantibodies | Rheumatology | Arthritis | Population | Protein Carbamylation | HLA-DRB1 Chains | HLA-B8 Antigen | AllelesResumen
[EN] 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.
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