EAT ‐Lancet Diet Modifies the Risk of Rheumatoid Arthritis Through Metabolomic Signature

OBJECTIVE: To investigate the association between the EAT-Lancet diet and rheumatoid arthritis (RA) and the underlying metabolic mechanisms. METHODS: This prospective cohort study included 205,439 participants who were free of RA at baseline from the UK Biobank. The EAT-Lancet diet index was constructed based on dietary data collected via Oxford WebQ. A metabolomic signature was developed using elastic net regression. The impact of the EAT-Lancet diet index and the metabolomic signature on the risk of incident RA was assessed using Cox proportional hazards models. Causal mediation analysis was performed to assess the mediating effects of the metabolomic signature and metabolites. A genome-wide gene-environment interaction study was conducted to identify genes interacting with the EAT-Lancet diet for RA. RESULTS: Over a mean follow-up of 13 years, 1,897 RA cases were identified. The hazard ratios were 0.93 (95% confidence interval [CI] 0.90-0.96) and 0.80 (95% CI 0.70-0.93) for 10-point increment of EAT-Lancet diet score and the corresponding metabolomic signature. The metabolomic signature mediated 34.07% (95% CI 21.44%-47.00%), primarily through pathways related to inflammation, fatty acids, and fluid balance. Key mediators included glycoprotein acetyls, docosahexaenoic acid, degree of unsaturation, omega-3 fatty acids, and albumin. Genes B2M, SLC30A4, SHF, SORD, CASC4, SPG11, CRIP2, BTBD6, and TEX22 were found to interact with the EAT-Lancet diet score. CONCLUSION: Greater adherence to the EAT-Lancet diet is linked to a reduced risk of RA, with significant mediation by the metabolomic signature, suggesting the potential of dietary interventions targeting specific metabolic pathways for RA prevention.