Causal association of genetically determined plasma metabolites with osteoarthritis: a two-sample Mendelian randomization study.

Abstract

We aimed to elucidate the causal relationship between plasma metabolites and the vulnerability to Osteoarthritis (OA), encompassing both hip OA and knee OA. We conducted a two-way two-sample Mendelian randomization (MR) analysis to investigate the association of 1,400 plasma metabolites with OA. The Inverse Variance Weighted (IVW) model served as the primary two-sample MR Analysis method, with supplementary analysis using the Weighted Median (WM) and MR Egger methods. To ensure the robustness of our findings, sensitivity analyses were performed, incorporating Cochran's Q test, MR-Egger intercept test, MR-PRESSO, and Leave-One-Out analyses. To validate the identified metabolites, we utilized the Steiger test and linkage disequilibrium score regression. A total of 94 plasma metabolites were associated with osteoarthritis, with 60 associated with hip OA and 106 associated with knee OA. IVW analysis revealed that tryptophan levels showed the strongest positive association with hip OA (OR [95% CI]: 1.119 [1.024, 1.223]), while X-24757 levels exhibited the highest positive association with knee osteoarthritis (OR [95% CI]: 1.095 [1.032, 1.162]). Ethylparaben sulfate levels were found to have the greatest positive association with hip OA (OR [95% CI]: 1.118 [1.015, 1.231]). Notably, the plasma metabolite X-2475 showed a strong robust random effect across all three types of osteoarthritis. Metabolic pathway analysis revealed that the pathogenesis of osteoarthritis in the hip was mediated by acetylarginine, specifically in four important metabolic pathways: ethanol degradation (p = 0.044), amino sugar metabolism (p = 0.090), fatty acid biosynthesis (p = 0.095), and aspartate metabolism (p = 0.097816). There is a significant association between tryptophan levels and the risk of hip OA, as well as X-24757 levels and the risk of knee osteoarthritis. Additionally, X-24757 levels are also linked to the risk of hip OA. Moreover, this study has identified four crucial metabolic pathways in hip osteoarthritis, which are all regulated by acetylarginine. These findings provide valuable insights into potential biomarkers for OA and highlight potential pathways for its prevention and clinical intervention.