A Bidirectional Two-Sample Mendelian Randomization Study: Exploring Causal Relationships Between 731 Immune Cell Phenotypes and Breast Cancer Subtypes

Objective: Investigating the causal relationship between immune cells and the various molecular subtypes of breast cancer(BC) using two-sample Mendelian randomisation(MR).
Methods: This study employed a two-sample MR analysis with 731 immune cell types from the GWAS Catalogue as the exposure factors and four BC molecular subtypes (HR+/HER2-, HR+/HER2+, HR-/HER2+, and HR-/HER2-) from the BCAC Consortium as the outcome variables. For causal inference, inverse variance weighting(IVW) was employed as the primary analytical method, alongside multiple consistency validation approaches, including MR-Egger, weighted median, weighted mode, simple mode and Bayesian weighted Mendelian randomization(BWMR). Positive results were defined as meeting both of the following criteria: an IVW P-value that passed false discovery rate (FDR) correction, and statistical significance in BWMR (P < 0.05). To further ensure robustness, we conducted a reverse MR analysis and a series of sensitivity analyses to effectively evaluate and exclude potential biases and interference from reverse causality.
Results: The study identified significant causal associations for specific immune cell phenotypes across subtypes. In HR+ BC, the HER2+ subtype was associated with 7 immunophenotypes (5 protective, 2 risk-increasing), while the HER2- subtype was associated with 8 immunophenotypes (4 protective, 4 risk-increasing). In HR- BC, the HER2+ subtype was associated with 5 immunophenotypes (1 protective, 4 risk-increasing), and the HER2- subtype (triple-negative BC) was associated with 7 immunophenotypes (6 protective, 1 risk-increasing). Notably, a bidirectional causal relationship was observed between Naive CD8+ T cells and HR+/HER2+ BC. Furthermore, CD4-CD8- NKT cells exhibited opposing effect directions in HER2+ versus HER2- subtypes.
Conclusion: From a genetic perspective, this study confirms the existence of subtype-specific causal associations between immune cell phenotypes and distinct molecular subtypes of BC, revealing heterogeneity in immune regulation. These findings provide novel insights into the immunopathological mechanisms of BC and establish a theoretical foundation for developing subtype-specific immunotherapeutic strategies.