Causal Relationship between Immune Cells and Gynecological Cancers through Bidirectional and Multivariable Mendelian Randomization Analyses

Abstract

Abstract Background: Evidence suggests potential associations between gynecological malignancies and various immune cell chemicals and systems. However, establishing a causal relationship remains uncertain, as a comprehensive investigation into their interplay has yet to be undertaken. Methods: We conducted a two-sample bidirectional Mendelian Randomization (MR) analysis to assess the potential link between immune cell traits and the risk of gynecological cancers, aiming to identify relevant factor. This work employed the inverse-variance weighted method (IVW) for multiple SNPs (Single Nucleotide Polymorphisms) or Wald ratio for one SNP to ascertain the causal association between exposure and outcome by utilizing genome-wide association study (GWAS) data on 731 immunophenotypes and gynecologic malignancies. Bidirectional two-sample MR and multivariable MR analyses were conducted to illustrate the causality. In addition, we use sensitivity analyses for assessment of the robustness of the results and colocalization for further validation. Results: In IVW analysis, increases in relative counts of circulating CD11c+ HLA-DR++ monocyte was associated with an elevated risk of breast cancer (OR [95% CI], 1.1295 [1.0632-1.2000], P = 8.044 × 10-5), while elevated levels of HLA-DR on plasmacytoid DC and HLA-DR on DC cell were protective against breast cancer (OR [95% CI], 0.9541 [0.9324-0.9762], P = 5.876 × 10-5) (OR [95% CI], 0.9414, [0.9188-0.9646], P = 1.101 × 10-6). In addition, cell counts of CD39+ resting Treg and CD28+ CD45RA- CD8+ T cell were also shown to be causally associated with the development of ovarian and cervical cancer, respectively. Colocalization analysis showed the lead SNP, rs780094, suggesting HLA-DR GWAS shared a common genetic mechanism with breast cancer. Conclusions: We identified a significant causal relationship between multiple immunophenotypes and breast cancer. Circulating immunophenotypes suggestive of breast cancer development can provide us with a basis for forecasting and predicting cancer.