Causal association of immune cell phenotypes with osteosarcoma and the mediation role of blood metabolites: A two-steps, two-samples Mendelian randomization study

Abstract

Background: Immunogenic nature of osteosarcoma is well-established, but the precise roles of immune cells and the potential influence of blood metabolites on its advancement remain unclear. Methods: Two-step, two-sample Mendelian randomization (MR) strategy was employed to investigate causal relation between osteosarcoma risk and immune cell distribution, we sought to uncover and measure the potential mediating role of blood metabolites. Our analysis incorporated a diverse range of MR estimation techniques, encompassing inverse variance weighting (IVW), MR-Egger regression, weighted median, weighted mode, and simple mode. Additionally, we conducted sensitivity analyses to assess the reliability of our results. Results: MR analysis revealed that three immune cell phenotypes exhibited positive relation with osteosarcoma risk (CX3CR1 on CD14^- CD16^-, CD25 on CD45RA^- CD4 not Treg, and CD45 on HLA DR⁺ CD8^br), while four immune cell phenotypes illustrated negative relation to osteosarcoma risk (BAFF^-R on IgD⁺ CD38^- unsw mem, CD20 on IgD^- CD38^-, Naive CD4⁺ %T cell, and CD28⁺ CD45RA⁺ CD8br %CD8^br). Moreover, mediation MR analysis demonstrated causal effect of CX3CR1 on CD14^- CD16^- within monocyte panel on osteosarcoma (Total effect IVW: OR = 0.3330) was predominantly mediated by dimethyl sulfone (0.0288, constituting 8.70% of Total effect) and unidentified metabolite X-12680 (0.0524, constituting 15.74% of Total effect). Conclusions: This investigation unveiled a causal link between immune cells and osteosarcoma, potentially mediated by blood metabolites.