Causal Relationship Between Immune Cells and Female Infertility: A Mendelian Randomisation Study

Background: Observational and retrospective studies have demonstrated that aberrant immune responses and dysregulation of immune cell populations may be implicated in female infertility. However, the precise relationship between distinct subtypes of immune cells and female infertility remains elusive. Method: In this study, we conducted a two-sample Mendelian randomization (MR) analysis to examine the causal relationship between 731 immune phenotypes and female infertility. The inverse variance weighting method was employed as the primary estimator, complemented by MR-Egger and weighted median approaches. To address potential bias from single nucleotide polymorphisms (SNPs), we utilized MR-PRESSO. Additionally, Cochran's Q test and MR-Egger intercept analysis were performed to detect heterogeneity and horizontal pleiotropy. Results: We detected a causal role of fourteen immune phenotypes with female infertility, including CD11c+ CD62L- monocyte AC (OR=1.042,95%CI=1.002-1.083,P=0.037), CD62L-CD86+myeloid DC AC (OR=1.048,95%CI=1.010-1.088,P=0.013),CD62L-CD86+myeloid DC %DC(OR=1.052,95%CI=1.012-1.094,P=0.010), HLA DR++ monocyte AC(OR=1.038,95%CI=1.000-1.078,P=0.049),Activated&restingTregAC(OR=0.900,95%CI=1.838-0.959,P=0.001), Activated&secreting Treg%CD4 Treg(OR=1.009,95%CI=1.001-1.017,P=0.028),CD25hi%CD4+(OR=0.936,95%CI=0.895-0.978,P=0.004),TCRgd AC(OR=1.053,95%CI=1.003-1.106,P=0.039),HLA DR+CD4+%T cell(OR=0.922,95%CI=0.869-0.978,P=0.007),HLA DR+NKAC(OR=0.926,95%CI=0.864-0.993,P=0.031),CD28-DN(CD4-CD8-)%T cell(OR=1.048,95%CI=1.000-1.098,P=0.049),CD19 on IgD+ CD38- unsw mem(OR=1.056; 95%CI=1.026-1.087; p=0.0002),CD24 on IgD+ CD38- unsw mem(OR=0,967,95%CI=0.937-0.997,P=0.033) and CD25 on IgD+CD38- unsw mem(OR=0,977,95%CI=0.964-1.000,P=0.049). Conclusion: The study demonstrates a causal association between 14 genetically determined immune cell phenotypes and female infertility, thereby identifying novel drug targets for the prevention and treatment of this condition.