Genetically predicted circulating immune cells and cytokines reveal the causal role of immune factors on female infertility: a two-sample mendelian randomization study.

Objectives: Previous studies suggested that immune factors may play critical roles in female infertility, but their causal links remain unclear. To address this gap, this study employs the Mendelian randomization (MR) to delineate the causal association between circulating immune factors and female infertility.

Methods: This study employed summary-level data from three genome-wide association studies (GWAS) encompassing 731 peripheral immune cell signatures, 41 circulating cytokines, and five female infertility phenotypes to reveal the causal relationship between immune factors and female infertility. Causalities of exposure-outcome pairs were explored mainly using two-sample MR, and comprehensive sensitivity analyses were deployed to validate the reliability of the results. Multi-variable Mendelian randomization (MVMR) was further employed to examine the potential mediating effects between significant exposures.

Results: Following false discovery rate (FDR) correction and sensitivity analyses, univariable Mendelian randomization identified distinct causal immune signatures across infertility subtypes. Peripheral levels of Naive CD8br %CD8br, MIP1B and IL17 were causally associated with general female infertility, and higher circulating MIP1B level decreased the risk of ovarian infertility. Furthermore, peripheral levels of CD80 on monocyte and MIP1B were causally associated with a higher risk of tubal infertility, three peripheral immune cell features (CD86 + myeloid DC AC, HLA DR + NK %NK, CD16 on CD14- CD16 + monocyte) were causal for uterine factor infertility, and three cytokines (MIP1B, IL18, IL17) were genetic causes of cervical infertility, vaginal infertility, other or unspecified origin infertility (FIOTHNAS). MVMR further revealed that MIP1B's effects on general female infertility and FIOTHNAS were substantially attenuated upon adjusting for circulating levels of IL17 and IL18.

Conclusion: Our results highlight that immune response contributes to female infertility risk through subtype-specific mechanisms, providing clues for following clinical research and treatment.