Association Between Metabolic Signature of Adherence to Healthy Lifestyle, Genetic Predisposition, and Risk of Rheumatoid Arthritis: Observational and Mendelian Randomization Analyses of UK Biobank

Background: Metabolomics defines novel metabolic phenotypes and identifies biomarkers of chronic diseases. We aimed to identify the metabolic signature of adherence to a healthy lifestyle and investigate its observational and causal association with incident rheumatoid arthritis (RA).Methods: We calculated a healthy lifestyle score (5-point scale including diet, physical activity, smoking status, alcohol consumption and body mass index) among 87,258 UK Biobank participants. Utilising 249 metabolic biomarkers measured by NMR spectrometry, we used elastic net regression to constructed a metabolic signature in response to a healthy lifestyle. We assessed the prospective and causal associations between metabolic signatures and incident RA using the Cox proportional hazards model and Mendelian randomisation (MR) analysis, respectively. We constructed the polygenic risk score to characterized the genetic risk of RA, then used population attributable fraction (PAF) to quantify the contribution of lifestyle, genetic and metabolic factors to disease burden.Findings: A total of 557 incident RA cases were recorded during a median follow-up of 8.1 years. The metabolic signature comprising of 81 metabolites mainly presented larger average diameter of HDL, increase in total cholines, citrate, linoleic and omega-3 fatty acids, and reduced phosphatidylcholines and glycoprotein acetyls. The metabolic signature was inversely associated with the risk of RA (hazard ratio, HR [95% CI] per SD increment: 0.76 [0.70, 0.83]). MR analysis further supported the link (odds ratio, OR [95% CI] per SD increment: 0.82 [0.67, 0.99]). Compared to the low genetic risk and ideal/moderate metabolic signature group, the risk of incident RA in high genetic risk and poor metabolic signature group elevated by 2-fold (Incidence rate: 138.88 per 100,000 person-years, HR (95% CI): 3.00 [2.20, 4.06]). The metabolic signature was predominant in the impact on RA incidence compared to lifestyle and genetic factors (PAF=0.355, P =2.42×10−7).Interpretation: Our findings suggest that the beneficial impact of a healthy lifestyle on RA is associated with systematic metabolic changes, and highlight that early lifestyle intervention and metabolic status tracking may contribute to RA prevention.Funding Information: The Fund of Anhui Provincial Laboratory of Inflammation and Immune Mediated Diseases (Population Epidemiology Study).Declaration of Interests: All authors declare no actual or potential competing interests.Ethics Approval Statement: All participants provided written informed consent and ethical approval was obtained from the North West MultiCenter Research Ethics Committee. The study was approved under UK Biobank Project 62663.