1. 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
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Regueiro C, Casares-Marfil D, Lundberg K, Knevel R, Acosta-Herrera M, Rodriguez-Rodriguez L, Lopez-Mejias R, Perez-Pampin E, Triguero-Martinez A, Nuño L, Ferraz-Amaro I, Rodriguez-Carrio J, Lopez-Pedrera R, Robustillo-Villarino M, Castañeda S, Remuzgo-Martinez S, Alperi M, Alegre-Sancho JJ, Balsa A, Gonzalez-Alvaro I, Mera A, Fernandez-Gutierrez B, Gonzalez-Gay MA, Trouw LA, Grönwall C, Padyukov L, Martin J, and Gonzalez A
- Subjects
- Alleles, Anti-Citrullinated Protein Antibodies immunology, Arthritis, Rheumatoid immunology, Aspartic Acid genetics, Genetic Predisposition to Disease, HLA-B8 Antigen immunology, Humans, Arthritis, Rheumatoid genetics, Autoantibodies immunology, HLA-B8 Antigen genetics, Protein Carbamylation immunology
- Abstract
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.)- Published
- 2021
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