Causal Links and Immune Mediators Between Blood Cells and Breast Cancer Risk: A Mendelian Randomization Study

Background: Previous studies have indicated a potential association between blood cells and breast cancer risk, but the causal relationships involving specific blood cell metrics and the role of immune cell mediators remain unclear. This study employs Mendelian randomization to explore the causal relationships between diverse blood cell profiles and breast cancer risk, while also seeking to identify potential mediating factors within immune cell metrics. Methods: We utilized Mendelian randomization to explore the causal effects of 91 different blood cell types on breast cancer risk, using genetic variants as instrumental variables. The analysis employed the inverse-variance weighted (GWAS) method, with a significance threshold of 0.05, to evaluate the causal relationships. Multivariate analysis was conducted to determine the mediating effects of immune cells in the association between blood cells and breast cancer. Heterogeneity test and multi-small size test are performed to complete the sensitivity analysis, ensuring the stability and reliability of the results. Results: We identified significant causal relationships between blood cells and breast cancer risk. Specifically, the Neutrophil perturbation response (the ratio of neutrophil 2 to neutrophil 4 in response to KCl perturbation measured by WDF dye) was found to be causally associated with breast cancer risk. Furthermore, CD45RA-CD4+ T cell Absolute Count was identified as a mediator in this relationship. The mediating effect of CD45RA-CD4+ T cell Absolute Count was -0.055 (P=0.022), indicating that the impact of Neutrophil perturbation response on breast cancer risk is mediated through CD45RA-CD4+ T cell Absolute Count. Conclusion: Our study highlights a causal relationship between Neutrophil perturbation response and breast cancer risk, with CD45RA-CD4+ T cell Absolute Count acting as a significant mediator. These findings provide new insights into the role of immune cells in the relationship between blood cell metrics and breast cancer risk, suggesting potential targets for further research and intervention.