Abstract
INTRODUCTION: Numerous evidence have highlighted a robust association between inflammatory proteins, gut microbiotas, and immune cells and leukemia. However, the causal relationship remains poorly defined. To delve into this connection, we implemented a bidirectional Mendelian randomization (MR) study. MATERIALS AND METHODS: This study utilized genetic variation data from publicly accessible genome-wide association study (GWAS) datasets. We used methods such as inverse variance weighting (IVW) to assess the causal relationship between exposure and the outcome of leukemia. Mediation analyses were applied to investigate the associations between immunophenotypes, gut microbiotas and inflammatory proteins and leukemia. Instrumental variables (IVs) mapping genes were identified, and functional analyses of the related genes were subsequently carried out. Sensitivity analyses was implemented to fortify the robustness of methods and results. RESULTS: This study uncovered four inflammatory proteins exhibiting significant associations with elevated leukemia risk, while leukemia exerted discernible effects on six inflammatory cytokines. IVW analysis revealed two immune cell subtypes with opposing roles on leukemia risk. One gut microbiota subtypes exhibited a pro-leukemogenic association, contrasted by four subtypes displaying protective influences. Enrichment analysis further identified three differentially expressed genes between malignant and adjacent normal tissues, with related genes demonstrated pronounced pathway enrichment in the mitogen-activated protein kinase (MAPK) signaling pathway. CONCLUSION: These findings shed new light on the genetic associations between circulating inflammatory proteins, gut microbiotas, and immune cells and leukemia. It may not only enrich the understanding but also guide deeper clinical and basic research in this domain.