Abstract
OBJECTIVE: Rheumatoid arthritis (RA) susceptibility HLA-DRB1 haplotypes based on amino acid positions 11/13, 71, and 74 predict radiographic damage. The mechanism of action is unknown, but it may be mediated by inflammation. We undertook this study to systematically investigate the effect of these amino acids on nonradiographic measures of disease activity/outcomes. METHODS: We tested the association of RA susceptibility HLA-DRB1 amino acids with the C-reactive protein (CRP) level, the tender joint count (TJC), the swollen joint count (SJC), the Disease Activity Score in 28 joints (DAS28), and the Health Assessment Questionnaire (HAQ) score in the Norfolk Arthritis Register (NOAR) and Early Rheumatoid Arthritis Study (ERAS) cohorts. Longitudinal modeling of disease activity/outcomes was performed using generalized linear latent and mixed models. Mediation analysis was performed using directed acyclic graphs to investigate the paths from genetic factors to outcome. RESULTS: A total of 2,158 patients were available for analysis in the NOAR cohort. Valine at position 11 showed the strongest association with the CRP level (P = 2.21 × 10(-6) ), the SJC (P = 7.51 × 10(-6) ), and the DAS28 (P = 0.002); it was marginally associated with the HAQ score (P = 0.044) but not with the TJC. The same amino acid and haplotype risk hierarchy observed for susceptibility and radiographic severity was observed for the CRP level and nonradiographic measures of disease activity/outcome, apart from the TJC. The results were replicated in the ERAS cohort. The effect of valine at position 11 on the SJC was mainly mediated by anti-citrullinated protein antibody status, the effect of which was mainly mediated by inflammation; however, the effect of valine at position 11 was also independent of the CRP level (P = 1.6 × 10(-4) ). CONCLUSION: Genetic markers of RA susceptibility located within HLA-DRB1 determine the levels of clinical and systemic inflammation independently, and also determine all objective measures of disease activity and outcome.