Abstract
This study explored the potential causal relationship between circulating immune cells and breast cancer incidence through a 2-sample Mendelian randomization (MR) approach using inverse-variance weighting, Weighted Median and MR-Egger regression analyses. Pooled statistical datasets from publicly accessible genome-wide association studies on individuals of European ancestry (n = 563085) were used as a base resource for exposure variables. Meanwhile, breast cancer registry codes extracted from the UK Biobank (n = 6563)were used as outcome measures. A total of 132 single-nucleotide polymorphisms of genome-wide significance were selected as instrumental variables from genome-wide association studies focusing on circulating immune cells. The association between the CD4RA gene pair terminally differentiated CD4+ lymphocyte ratio and breast cancer risk was estimated by MR analysis. An odds ratio of 0.9809 (95% CI: 0.9668-0.9952) and a P-value of .0089 were obtained using the inverse-variance weighting method, indicating a statistically significant protective association. This protective effect was also consistently supported in weighted median and simple mode analyses, but did not show significance in weighted mode analyses. Cochran Q test and funnel plot assessment did not reveal significant heterogeneity or asymmetry, suggesting no directional pleiotropy. This suggests that circulating immune cells may play a protective role in breast carcinogenesis through the CD4RA gene. These findings may provide valuable insights for the development of risk prediction models and preventive strategies, and may also inform functional studies to elucidate underlying mechanisms and identify potential therapeutic targets.