Mendelian randomization and mediation analysis reveal the role of immune cells in the pathways between inflammatory factors and glioblastoma.

Abstract

ObjectiveInflammatory factors and immune cells play crucial roles in glioblastoma multiforme pathophysiology. However, the relationships between these factors and the underlying mechanisms are not fully understood. This study employed Mendelian randomization to investigate the effects of inflammatory factors and immune cells on glioblastoma multiforme risk, specifically focusing on the mediating role of immune cells.MethodsGenetic data on 91 inflammatory factors (e.g. interleukins, CXCL, and fibroblast growth factor; N = 14,824), 731 immune cell phenotypic traits (e.g. CD39⁺ secreting Treg absolute count, IgD^-CD38^- absolute count, and T cell absolute count; N = 3,757), and glioblastoma multiforme risk (6,183 cases and 18,169 controls) were obtained from a genome-wide association study database. All data were derived from individuals of European ancestry. Inverse variance weighting was employed as the primary Mendelian randomization method to estimate causal effects.ResultsMendelian randomization analysis revealed significant associations between two inflammatory factors and glioblastoma multiforme risk. Furthermore, 22 immune cell phenotypic traits were associated with glioblastoma multiforme risk. Notably, Mendelian randomization mediation analysis identified two significant mediation pathways: (a) double-negative (CD4^-CD8^-) T cells mediate the causal effect of transforming growth factor β1 on glioblastoma multiforme risk and (b) human leukocyte antigen-DR⁺ T cells mediate the causal effect of CXCL10 on glioblastoma multiforme risk.ConclusionThis study provides genetic evidence supporting the complex interplay among inflammatory factors, immune cells, and glioblastoma multiforme risk, highlighting key mediation mechanisms. These findings offer novel insights into the therapeutic potential of targeting inflammatory factors within the tumor microenvironment to regulate immune cell responses.