Effects of Immune Cells and Plasma Metabolites on Osteoarthritis: A Mediation Mendelian Randomization Study

OBJECTIVE: Recent studies suggest that immune cells and plasma metabolites may play significant roles in osteoarthritis pathogenesis. However, the causal relationships between these factors and osteoarthritis are unclear. METHODS: Based on the genome-wide association study (GWAS) database, 731 immune cell phenotypes and 1400 metabolites were evaluated for their possible mediating effects on osteoarthritis via two-step Mendelian randomization (MR). Sensitivity analyses were conducted to assess the robustness of our findings. RESULTS: Our findings revealed that 17 immune cell phenotypes were positively associated with osteoarthritis, suggesting their potential as risk factors. Conversely, 23 immune cell phenotypes exhibited a negative association, indicating possible protective roles against osteoarthritis. Furthermore, we identified 51 metabolites as potential risk factors for osteoarthritis. Conversely, 34 metabolites were deemed protective factors. Notably, 49 plasma metabolites partially mediated the relationship between 35 immune cell phenotypes and osteoarthritis, with leucine levels showing the highest mediation proportion (19.3%) between HLA DR+ CD4+ %lymphocytes and osteoarthritis. CONCLUSION: Our study revealed a substantial impact of specific immune cell phenotypes and plasma metabolites on the progression of osteoarthritis, enhancing the understanding of the complex interplay between immunity and metabolism in osteoarthritis pathogenesis. Further research is necessary to clarify the underlying mechanisms driving these associations.