HLA–DRB1 Amino Acid Positions 11/13, 71, and 74 Are Associated With Inflammation Level, Disease Activity, and the Health Assessment Questionnaire Score in Patients With Inflammatory Polyarthritis

OBJECTIVE:
Rheumatoid arthritis susceptibility HLA-DRB1 haplotypes based on amino acid (AA) positions 11/13, 71 and 74 predict radiographic damage. The mechanism of action is unknown, but may be mediated by inflammation. However, the effect of these AA on non-radiographic measures of disease activity/outcomes has not been systematically investigated.
METHODS:
We tested the association of HLA-DRB1 susceptibility AA with inflammatory marker levels, tender joint count (TJC), swollen joint count (SJC), DAS28 and HAQ score in the Norfolk Arthritis Register (NOAR) and Early Rheumatoid Arthritis Study (ERAS). Longitudinal modelling of disease activity/outcomes was performed using Generalised Linear Latent and Mixed Models. Mediation analysis was performed using directed acyclic graphs to investigate the paths from genetic factors to outcome.
RESULTS:
2,158 patients were available for analysis in NOAR. Valine at position 11 showed the strongest association with CRP (p=2.21E-06), SJC (p=7.51E-06) and DAS28 (p=0.002), was marginally associated with HAQ (p=0.044), but not with TJC. The same AA and haplotype risk hierarchy observed for susceptibility and radiographic severity was observed for CRP and non-radiographic measures of disease activity/outcome, apart from TJC. The results replicated in ERAS. The effect of Val11 on SJC was mainly mediated by anti-CCP, the effect of which was mainly mediated by inflammation; however, the effect of Val11 was also independent of CRP (p=1.6E-04).
CONCLUSION:
Genetic markers of rheumatoid arthritis susceptibility located within HLA-DRB1 determine the level of clinical and laboratory inflammation independently, and all objective measures of disease activity and outcome.