Association of human blood metabolites with rheumatoid arthritis: A Mendelian randomization study

Rheumatoid arthritis (RA) is a common autoimmune disease, but its specific biological mechanisms, especially the link between metabolites and RA, have not been conclusively hypothesized. This study used a Mendelian randomization (MR) analysis approach to assess the association between 1400 human blood metabolites and risk of RA. Pooled statistics of 1400 blood metabolites were used as exposure factors and genome-wide association studies of RA as endpoints, and MR analysis was used to analyze the relationship between the 2. Inverse-variance weighting (IVW) was the preferred method, and 4 methods, MR-Egger method, weighted median method, simple mode method and weighted mode method, were used as supplements to the analysis process. Cochran Q test, MR-Egger intercept test, MR-PRESSO, and leave-one-out method analysis were also selected for sensitivity analysis. The validity of the results was verified by Bonferroni correction (P < .0357 × 10-3) and false discovery rate (FDR) test. In addition, reverse causality was excluded by Steiger test. A total of 77 metabolites were analyzed by MR to obtain a causal relationship with RA. Forty-seven known metabolites, 20 metabolite ratios, and 10 unknown metabolites were involved. Under the strict screening of Bonferroni correction and FDR test, docosatrienoate (22:3n3) levels i.e. docosatrienoic acid (DTA; PIVW = 1.63 × 10-5, OR = 0.8859, CI = 0.8384-0.9361, PFDR = .0229) was significantly associated with a reduced risk of RA. The results of the Cochran Q test (MR-Egger, Q's = 14.5184, P = .8463; IVW.Q = 14.8882, P = .8670) and the MR-Egger regression intercept term of -0.0042, se = 0.0070, P = .5496 suggested that the absence of heterogeneity (P > .05) and horizontal pleiotropy (P > .05) among single nucleotide polymorphisms, the funnel plot and MR-PRESSO method further demonstrated the robustness of the results. In addition, Steiger test (P = 3.0752 × 10-138) excluded the presence of reverse causality. The present study provides evidence for the existence of a causal relationship between 77 especially DTA and RA by screening 1400 human blood metabolites. This study helps to reveal the biological mechanisms of RA and provides new ideas for the prevention and treatment of RA.