Causality of genetically determined metabolites and metabolic pathways on joint diseases: a two-sample mendelian randomization study

Abstract

OBJECTIVE: Infectious arthropathies, inflammatory polyarthropathy, osteoarthropathies, and many other joint diseases are now prevalent worldwide. A large number of studies have suggested an association between metabolites and joint diseases, but due to the limitations of routine observational studies, its significance is not clear. In this paper, we used Mendelian randomization to assess potential causal associations between metabolites and a variety of joint diseases. METHODS: By screening publicly available data from non-overlapping genome-wide association studies with 1400 metabolites as exposure data and 11 joint diseases as outcome data, the inverse-variance weighted (IVW) method was used as the study to assess the causal effect, MR-Egger, weighted median, weighted mode, and simple mode were used as supplementary methods, and Cochran's Q, MR-Egger- intercept, and MR-PRESSO for sensitivity analysis. RESULTS: Positive correlations were found between N-formyl anthranilic acid levels and Arthropathies (P_FDR=0.019) after FDR correction. Glycine levels (P_FDR=0.016), N-acetylglycine levels (P_FDR=0.010), Glycine to serine ratio (P_FDR=0.018), Propionylcarnitine (c3) levels (P_FDR=0.015) were positively correlated with Gonarthrosis. Cystine levels (P_FDR=0.017), N-acetylglycine levels (P_FDR<0.001), Glycine to serine ratio (P_FDR<0.001), and X-24757 levels (P_FDR=0.021) were positively associated with Gonarthrosis, primary, with knee surgery. Correlation. There was a negative correlation between Taurine to cysteine ratio and Arthropathies (P_FDR=0.035) and a negative correlation between Docosatrienoate (22:3n3) levels and Rheumatoid arthritis (P_FDR=0.013). There was a negative correlation between taurine to cysteine ratio and Other joint disorders (P_FDR=0.011). Cysteinylglycine to taurine ratio (P_FDR=0.005), Adenosine 3',5'-cyclic monophosphate (cAMP) to adenosine 5'-monophosphate (AMP) ratio (P_FDR=0.034) were negatively correlated with Other arthrosis. adenosine 5'-monophosphate (AMP) to histidine ratio (P_FDR=0.024), and Glycohyocholate levels (P_FDR=0.011) were negatively associated with Gonarthrosis, primarily, with knee surgery. Sensitivity analyses did not reveal the presence of heterogeneity as well as level pleiotropy (P>0.05), suggesting that the findings were not biased, and the leave-one-out method also suggested robust results. Six significant metabolic pathways were identified by metabolic pathway analysis. CONCLUSION: This study provides new evidence of a causal relationship between metabolites and a variety of joint diseases. Metabolites are important markers in the progression of joint diseases, which is clinically important for the prevention and treatment of joint diseases.