Causality Between Immune Cells, Metabolites and Breast Cancer: Mendelian Randomization and Mediation Analysis

Previous studies have shown that immune cells and metabolites are associated with the development of breast cancer, but the causal relationship is unclear. We use Mendelian randomization (MR) to explore potential connections between them. Based on two sample MR studies, we evaluated the causal relationship between 731 immune cell traits, 1400 metabolites and breast cancer. In addition, we evaluated the mediating role of metabolites between immune cells and breast cancer using two-step MR Studies. Pooled GWAS data on 731 immune cell traits (n = 3757), 1400 metabolites (n = 8299) and breast cancer (ncase = 122,977, ncontrol = 105,974) were obtained from publicly available authoritative databases. We mainly used inverse variance weighted (IVW) method combined with Bayesian weighted MR (BWMR), MR-Egger, weighted median, simple mode, and weighted mode methods. The results of MR Studies showed that 3 immune cells and 15 metabolites were associated with an increased risk of breast cancer. 8 immune cells and 11 metabolites are associated with a reduced risk of breast cancer. Mediating MR Analysis showed that 6 metabolites, Tricosanoyl sphingomyelin (d18:1/23:0) levels(Mediated proportion:17.5%), N-palmitoyl-heptadecasphingosine (d17:1/16:0) levels(8.74%), Inosine 5'-monophosphate (IMP) to phosphate ratio(11.3%), Glutamine to asparagine ratio(5.43%), Oleoyl-linoleoyl-glycerol (18:1/18:2) [2] levels(8.48%), and Sphinganine-1-phosphate levels(8.68%), were found to mediate the relationship between immune cells and breast cancer. Our study reveals a potential causal relationship among multiple immune cells traits, metabolites, and breast cancer. It provides valuable clues and potential therapeutic targets for breast cancer biomarker discovery and breast cancer treatment.