The causal role of plasma metabolites in breast cancer susceptibility mediated by immune cells: A two-sample Mendelian randomization analysis

Breast carcinoma (BC) is a significant oncological issue, categorized based on estrogen receptor (ER) status into ER-positive and ER-negative types. The ER-positive variant relies on hormonal signaling, whereas the ER-negative form is characterized by increased aggressiveness. There exists a potential interplay between plasma metabolites and immune effectors that may influence BC susceptibility, although the underlying mechanisms remain largely undefined. This study employs Mendelian randomization (MR) to elucidate the causal pathways through which plasma metabolites affect both ER-positive and ER-negative BC susceptibility via immune mediators. In the context of ER-positive BC, sphingolipid metabolites (e.g., Sphingomyelin [d18:1/17:0] concentrations, odds ratio [OR] = 1.299, 95% confidence interval [CI]: 1.140-1.480) exhibited positive associations, whereas bile acid metabolites (e.g., Glycochenodeoxycholate 3-sulfate concentrations, OR = 0.876, 95% CI: 0.818-0.938) displayed negative correlations; immune phenotypes such as CD8br % leukocyte (OR = 1.165, 95% CI: 1.005-1.351) were positively linked. For ER-negative BC, the phosphate-to-tryptophan ratio (OR = 1.371, 95% CI: 1.047-1.796) showed a positive correlation, while indolepropionate (OR = 0.762, 95% CI: 0.647-0.896) had an inverse relationship; CD28 on CD39 + CD8br (OR = 1.052, 95% CI: 1.016-1.090) demonstrated a positive association. Mediation analyses revealed pathways: In ER-positive BC, 2R,3R-dihydroxybutyrate was mediated through EM DN (CD4-CD8-) %T cell (intermediation fraction 23.4%), and Sphingomyelin via CD38 on transitional cells (7.41%); in ER-negative BC, Dihomo-linoleoylcarnitine was mediated through human leukocyte antigen-DR on CD14+ CD16+ monocytes (9.98%), and homocitrulline through human leukocyte antigen-DR on plasmacytoid dendritic cells (12.7%). Plasma metabolites significantly influence susceptibility to different BC variants by modifying immune effector functions. This study provides genetic evidence supporting interventions targeting the metabolic-immune interface to improve prevention and management strategies. Utilizing publicly available genome-wide association study datasets, we examined 1440 plasma metabolites (identifiers GCST90199621 to GCST90201020), 731 immune phenotypes (ebi-a-GCST90001391 to ebi-a-GCST90002121), and the FinnGen R12 BC cohorts. Instrumental variables were selected based on criteria of P < 5 × 10-8/10-7, r2 < 0.001, and F-statistic > 10. We employed bidirectional two-sample MR, primarily using inverse-variance weighted methods, supplemented by MR-Egger and other techniques, to assess causal relationships and intermediary roles.