The causal relationship between circulating inflammatory proteins, gut microbiotas, immune cells and leukemia: a bidirectional Mendelian randomization study

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.

Keywords: Causal relationship; Circulating inflammatory proteins; Genome-wide association study; Leukemia; Mendelian randomization.

Fig. 1

The flowchart of the whole process

Fig. 2

The causal impact of: A) inflammatory proteins on leukemia; B) leukemia on inflammatory proteins

Fig. 3

Causal relationships between immunophenotypes and leukemia through MR analysis. (A) A circular heatmap illustrated the MR-derived causal associations between immunophenotypes and leukemia, incorporating five distinct methods of MR analysis. (B) Volcano plots of the results of IVW in causal estimates between immunophenotypes and leukemia. (C) Forest plot of significant MR results regarding the causal links between immunophenotypes and leukemia

Fig. 4

MR-derived causal estimates of significant gut microbiotas and inflammatory factors in leukemia. (A) A circular heatmap illustrated the MR-based causal associations between gut microbiotas and leukemia, incorporating five different methods of MR analysis. (B) IVW results for gut microbiotas-leukemia causal estimates were visualized through volcano plots. (C) Significant MR findings regarding gut microbiotas-leukemia associations were presented in a forest plot. (D) A heatmap displayed causal estimates between inflammatory factors and leukemia using five MR methods. (E) A forest plot summarized significant MR results of casual associations between inflammatory factors and leukemia

Fig. 5

The results of genes association and enrichment analysis. (A) The expression of the related genes of immune cells-leukemia, gut microbiotas-leukemia, and inflammatory proteins-leukemia in DLBC. (B) KEGG pathway analysis of immune cells-leukemia related genes. (C) KEGG pathway analysis of gut microbiotas-leukemia related genes. (D) KEGG enrichment analysis of inflammatory proteins-leukemia related genes