Metabolic signature of healthy lifestyle and risk of rheumatoid arthritis

While substantial evidence suggests that healthy lifestyle behaviours are associated with a lower risk of rheumatoid arthritis (RA), the underlying metabolic mechanisms remain unclear.
A study aimed to identify the metabolic signature reflecting a healthy lifestyle and investigate its observational and genetic linkage with rheumatoid arthritis risk.
The study included 87,258 UK Biobank participants (557 cases of incident RA) aged 37 to 73 years with complete lifestyle, genotyping and nuclear magnetic resonance (NMR) metabolomics data. A healthy lifestyle was assessed based on five factors: healthy diet, regular exercise, not smoking, moderate alcohol consumption, and normal body mass index. The metabolic signature was developed by summing selected metabolites’ concentrations weighted by the coefficients using elastic net regression. The associations between metabolic signatures and rheumatoid arthritis risk were assessed and the mediating role of the metabolic signature in the impact of a healthy lifestyle on rheumatoid arthritis was examined. Genome-wide association analysis (GWAS) was performed to obtain genetic variants associated with the metabolic signature, then Mendelian randomization (MR) analyses were conducted to detect causality.
The metabolic signature comprised of 81 metabolites, robustly correlated with healthy lifestyle. The metabolic signature was inversely associated with RA risk (HR per standard deviation 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. One and two-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 OR: 0.84, 95% CI: 0.73-0.97 respectively).
The findings implicate the metabolic signature reflecting healthy lifestyle as a potential causal mediator in the development of RA, highlighting the importance of early lifestyle intervention and metabolic tracking for precise prevention of RA.
Source: Zhang J, Fang XY, Leng R, Chen HF, Qian TT, Cai YY, Zhang XH, Wang YY, Mu M, Tao XR, Leng RX, Ye DQ. Metabolic signature of healthy lifestyle and risk of rheumatoid arthritis: observational and Mendelian randomization study. Am J Clin Nutr. 2023 Apr 29:S0002-9165(23)48892-2.