HLA-B*08 identified as the most associated MHC locus for anti-carbamylated protein antibody-positive/anti-CCP-negative rheumatoid arthritis

Autor: Regueiro, Cristina, Casares-Marfil, Desiré, Lundberg, Karin, Knevel, Rachel, Acosta-Herrera, Marialbert, Rodríguez-Rodríguez, Luis, López-Mejías, Raquel, Pérez-Pampin, Eva, Triguero-Martínez, Ana, Nuño, Laura, Ferraz-Amaro, Iván, Rodríguez-Carrio, Javier, López-Pedrera, Rosario, Robustillo-Villarino, Montserrat, Castañeda, Santos, Remuzgo-Martínez, Sara, Alperi, Mercedes, Alegre-Sancho, Juan-José, Balsa, Alejandro, González-Álvaro, Isidoro, Mera, Antonio, Fernández-Gutiérrez, B., González-Gay, M. A., Trouw, Leendert A, Grönwall, Caroline, Padyukov, Leonid, Martín, Javier, González, Antonio
Rok vydání: 2021
Předmět:
Zdroj: Digital.CSIC: Repositorio Institucional del CSIC
Consejo Superior de Investigaciones Científicas (CSIC)
Digital.CSIC. Repositorio Institucional del CSIC
instname
Popis: 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. © 2020, American College of Rheumatology.
Databáze: OpenAIRE
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