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.

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.

• Authors: Cristina Regueiro, Desire Casares-Marfil, Karin Lundberg, Rachel Knevel, Marialbert Acosta-Herrera, Luis Rodriguez-Rodriguez, Raquel Lopez-Mejias, Eva Perez-Pampin, Ana Triguero-Martinez, Laura Nuño, Ivan Ferraz-Amaro, Javier Rodriguez-Carrio, Rosario Lopez-Pedrera, Montse Robustillo-Villarino, Santos Castañeda, Sara Remuzgo-Martinez, Mercedes Alperi, Juan J Alegre-Sancho, Alejandro Balsa, Isidoro Gonzalez-Alvaro, Antonio Mera, Benjamin Fernandez-Gutierrez, Miguel A Gonzalez-Gay, Leendert A Trouw, Caroline Grönwall, Leonid Padyukov, Javier Martin, Antonio Gonzalez
• Journal: Arthritis & rheumatology (Hoboken, N.J.) (Arthritis Rheumatol) Vol. 73 Issue 6 Pg. 963-969 (06 2021) ISSN: 2326-5205 [Electronic] United States
• PMID: 33381897 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020, American College of Rheumatology.

Chemical References

• Anti-Citrullinated Protein Antibodies
• Autoantibodies
• HLA-B8 Antigen
• Aspartic Acid

Topics

• Alleles
• Anti-Citrullinated Protein Antibodies (immunology)
• Arthritis, Rheumatoid (genetics, immunology)
• Aspartic Acid (genetics)
• Autoantibodies (immunology)
• Genetic Predisposition to Disease
• HLA-B8 Antigen (genetics, immunology)
• Humans
• Protein Carbamylation (immunology)