Elucidating the Causal Impact of Plasma Proteins on Osteoporosis Risk and the Mediating Role of Immune Cells through Integrated Multi-omics Data Analysis

Recent evidence increasingly suggests that plasma proteins and immune factors play crucial roles in bone metabolism. However, the specific mechanisms of how plasma proteins impact osteoporosis (OP) and whether immune factors mediate the process remain largely unknown. In this study, we employed a two sample mendelian randomization (TSMR) model and bidirectional analysis to identify plasma proteins linked to OP, explore whether immune phenotypes mediate OP risk associated with these proteins. Our findings revealed that plasma MGP and TMEM38B proteins were negatively correlated with OP (p < 0.001), while CD14, RUFY1, and IL6ST were positively associated with the risk of OP (p < 0.001). Further validation using whole blood eQTL data revealed a positive association between CD14 and OP risk (OR = 1.254, 95% CI: 1.016–1.547, p < 0.05). The analysis of the GEO dataset further corroborated this finding. Analysis revealed 62 immune phenotypes related to OP. Bidirectional TSMR analysis showed a positive correlation between plasma protein CD14 and IgD + CD38-%B cells (Ivw beta = 0.349, OR = 1.418, 95% CI: 1.068–1.882, p < 0.05). In addition, mediation analysis results showed that IgD + CD38-%B cells mediates 12% of the effect of CD14 on OP risk. Furthermore, Bayesian colocalization analysis reinforced our findings. Finally, in the drug target MR study and Phe-MR analysis, anti-CD14 exhibited a protective effect against OP (OR = 0.798, 95%CI: 0.646–0.984, p < 0.05). Our study provides evidence that elevated plasma CD14 is linked to OP risk, partially mediated by IgD + CD38-%B cells. Blocking CD14 shows potential in preventing or delaying OP. Further research is warranted to elucidate the underlying physiological and pathological mechanisms.