A bidirectional Mendelian randomization analysis of the causal relationship between immune cells and high-grade squamous intraepithelial lesion.

High-grade squamous intraepithelial lesions (HSIL), critical precursors to cervical cancer, are associated with persistent human papillomavirus infection and immune dysregulation, yet the causal role of specific immune cell phenotypes remains unclear. To investigate bidirectional causal relationships, we performed a 2-sample Mendelian randomization (MR) analysis using European genome-wide association study data: 731 immune cell phenotypes and HSIL. Instrumental variables (P < 1 × 10⁻⁵) were selected under MR assumptions, with inverse-variance weighted as the primary method. Forward MR (immune cells to HSIL) identified 67 phenotypes nominally associated (P < .05); after FDR correction (FDR < 0.20), IgD on transitional B cells were protective, while increased CD3 on CD39+ Tregs elevated risk. Reverse MR (HSIL to immune cells) indicated HSIL causally reduces naïve CD4- CD8- T cell, HVEM on effector memory CD8+ T cells, FSC-A on lymphocyte and FSC-A on T cells (FDR < 0.20). This study provides genetic evidence for causal roles of specific immune phenotypes in HSIL pathogenesis, suggesting immunotherapeutic targets, while revealing HSIL-induced immune exhaustion patterns.