Abstract
Previous studies have explored the role of the immune system in osteoporosis. This Mendelian randomization (MR) study further evaluated the causal relationship between 731 immune cell phenotypes and osteoporosis, exploring the mediating role of serum metabolites based on genetic prediction. Bidirectional two-sample Mendelian randomization was used to investigate the relationship between 731 immune cell phenotypes and osteoporosis. The 731 immune cell phenotypes, serum metabolites, and osteoporosis data used in this study were obtained from respective genome-wide association studies (GWAS). Inverse variable weighting (IVW) was used as the primary analysis method, and the P values were further corrected for false discovery rate (FDR). In addition, MR-Egger, weighted mode, simple mode, and weighted median analyses were performed to demonstrate the robustness of the results. In sensitivity analysis, the potential impact of horizontal pleiotropy was assessed by examining the intercept in MR-Egger regression, and the heterogeneity between SNPs was evaluated using Cochran's Q test, which was further supplemented with MR PRESSO analysis to detect pleiotropy. The analysis revealed significant associations between seven immune cell phenotypes and osteoporosis (OP). Furthermore, we identified several serum metabolites mediating immune cell phenotypes' effects on osteoporosis. For example, HLA DR++ monocyte %leukocyte promotes the occurrence of osteoporosis through the ratio of citrulline/dimethylarginine (SDMA + ADMA). Mediating effect ratios further elucidate the complex dynamics between immune cell phenotypic exposure, serum metabolites, and their combined effects on OP. We demonstrated the causal relationship between multiple immune cell phenotypes and osteoporosis through a bidirectional two-sample MR analysis. This study further elucidated the mediation effect of serum metabolites through mediation analysis, providing important insights into further understanding the pathogenesis of osteoporosis.