Cristina Regueiro1, Desire Casares-Marfil2, Karin Lundberg3, Rachel Knevel4, Marialbert Acosta-Herrera2, Luis Rodriguez-Rodriguez5, Raquel Lopez-Mejias6, Eva Perez-Pampin1, Ana Triguero-Martinez7, Laura Nuño8, Ivan Ferraz-Amaro9, Javier Rodriguez-Carrio10, Rosario Lopez-Pedrera11, Montse Robustillo-Villarino12, Santos Castañeda7, Sara Remuzgo-Martinez6, Mercedes Alperi13, Juan J Alegre-Sancho12, Alejandro Balsa8, Isidoro Gonzalez-Alvaro7, Antonio Mera1, Benjamin Fernandez-Gutierrez5, Miguel A Gonzalez-Gay6, Leendert A Trouw14, Caroline Grönwall3, Leonid Padyukov3, Javier Martin2, Antonio Gonzalez1. 1. Instituto de Investigacion Sanitaria and Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain. 2. Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, Granada, Spain. 3. Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden. 4. Leiden University Medical Center, Leiden, The Netherlands, and Brigham and Women's Hospital, Boston, Massachusetts. 5. Hospital Clínico San Carlos, Instituto Investigación Sanitaria San Carlos, Madrid, Spain. 6. Valdecilla Biomedical Research Institute, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain. 7. Instituto de Investigación Sanitaria la Princesa and Hospital Universitario de la Princesa, Madrid, Spain. 8. Instituto de Investigación del Hospital Universitario La Paz, Madrid, Spain. 9. Hospital Universitario de Canarias, Tenerife, Spain. 10. University of Oviedo, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias, Instituto Reina Sofía de Investigación Nefrológica, REDinREN del ISCIII, Oviedo, Spain. 11. Maimonides Institute for Research in Biomedicine of Cordoba, Reina Sofia University Hospital, University of Córdoba, Córdoba, Spain. 12. Hospital Universitario Doctor Peset, Valencia, Spain. 13. Hospital Universitario Central de Asturias, and Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain. 14. Leiden University Medical Center, Leiden, The Netherlands.
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.
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 RApatients 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- RApatients 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 RApatients 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- RApatients, and anti-CCP- RApatients who were positive for other anti-citrullinated protein antibodies. Based on these findings, anti-CarP+/anti-CCP- RApatients could be separated from other antibody-defined subsets of RApatients 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.