Mediterranean diet, metabolic signature, genetic predisposition, and risk of rheumatoid arthritis: a large-scale population-based prospective cohort study.

Background: While the Mediterranean (MED) diet has been associated with reduced rheumatoid arthritis (RA) risk, the underlying metabolic mechanisms and the role of genetic susceptibility in this relationship remain unknown.

Objectives: To identify a metabolic signature linked to the MED diet and examine its association with the risk of RA, while accounting for genetic predispositions.

Methods: We analyzed data from 109,565 participants in the UK Biobank. Elastic net regression was applied to generate a MED-related metabolic signature. Cox proportional hazards models were used to assess the associations between MED diet score, its derived metabolic signature, and incident RA. A polygenic risk score (PRS) for RA was incorporated to evaluate joint associations and potential interactions between genetic susceptibility and MED diet score or its metabolic signature in relation to RA risk. Mediation analysis was conducted to estimate the extent to which metabolic signature mediates the MED diet-RA association.

Results: Over a median follow-up of 11.6 years, 1,123 participants developed RA. We identified a MED diet-related metabolic signature comprising 66 metabolites. Both MED diet score and metabolic signature were inversely associated with RA risk - comparing the 90^th to the 10^th percentiles, hazard ratios (HRs) for RA were 0.73 (95%CI: 0.63, 0.84) for MED diet score and 0.60 (95%CI: 0.50, 0.70) for metabolic signature. These associations remained consistent across all strata of genetic risk. Joint analyses indicated that favorable metabolic profiles may attenuate genetic predisposition to RA. Mediation analysis showed that the metabolic signature explained 22.4% (95%CI: 11.8%, 44.8%) of the MED diet-RA association.

Conclusions: We identified a robust metabolic signature reflecting the metabolic response to the MED diet. This signature was inversely associated with RA risk and partially mitigated the genetic susceptibility to RA. These findings highlight the potential of metabolic signature for enhancing dietary assessment and guiding personalized nutritional intervention.