Metabolic Signature of Healthy Lifestyle and Risk of Rheumatoid Arthritis: Observational and Mendelian Randomization Study

Although substantial evidence reveals that healthy lifestyle behaviors are associated with a lower risk of rheumatoid arthritis (RA), the underlying metabolic mechanisms remain unclear. This study aimed to identify the metabolic signature reflecting a healthy lifestyle and investigate its observational and genetic linkage with RA risk. This study included 87,258 UK Biobank participants (557 cases with incident RA) aged 37–73 y with complete lifestyle, genotyping, and nuclear magnetic resonance (NMR) metabolomics data. A healthy lifestyle was assessed based on 5 factors: healthy diet, regular exercise, not smoking, moderate alcohol consumption, and normal body mass index. The metabolic signature was developed by summing the selected metabolites' concentrations weighted by the coefficients using elastic net regression. We used the multivariate Cox model to assess the associations between metabolic signatures and RA risk, and examined the mediating role of the metabolic signature in the impact of a healthy lifestyle on RA. We performed genome-wide association analysis (GWAS) to obtain genetic variants associated with the metabolic signature and then conducted Mendelian randomization (MR) analyses to detect causality. The metabolic signature comprised 81 metabolites, robustly correlated with a healthy lifestyle (r = 0.45, P = 4.2 × 10−15). The metabolic signature was inversely associated with RA risk (HR per standard deviation (SD) increment: 0.76; 95% CI: 0.70–0.83), and largely explained the protective effects of healthy lifestyle on RA with 64% (95% CI: 50.4–83.3) mediation proportion. 1- and 2-sample MR analyses also consistently showed the associations of genetically inferred per SD increment in metabolic signature with a reduction in RA risk (HR: 0.84; 95% CI: 0.75–0.94; and P = 0.002 and OR: 0.84; 95% CI: 0.73–0.97; and P = 0.02, respectively). Our findings implicate that the metabolic signature reflecting healthy lifestyle is a potential causal mediator in the development of RA, highlighting the importance of early lifestyle intervention and metabolic status tracking for precise prevention of RA.