Causal Association Between Female Infertility and Circulating Immune Cells: A Bidirectional Mendelian Randomization Study

Abstract

Background

Female infertility (FI) is a global health issue. The etiology remains incompletely understood, but immunologic factors play important roles. This study aims to elucidate the causal association between FI and immune cells (ICs) via Mendelian randomization (MR) analysis.

Methods

The MR analyses employ genetic variants as instrumental variables to evaluate exposure's causal impact on outcomes. In this study, the two-sample MR method was performed to investigate the causal correlation of FI with 731 immunophenotypes of human peripheral blood lymphocytes. Complementary MR methods performed included the weighted median estimator (WME) and inverse variance weighted (IVW). In addition, sensitivity analyses were performed to assess and minimize heterogeneity and horizontal pleiotropy, and reverse MR analysis was used to assess reverse causality.

Results

The results revealed that four immune phenotypes were substantially linked with the risk of developing FI: CD33^dim HLA DR+CD11b+%CD33^dim HLA DR + (IVW: p = 0.0396, OR: 0.98 and WME: p = 0.0208, OR: 0.97), CD39+CD4+AC (IVW: p = 0.0031, OR: 1.03 and WME: p = 0.0264, OR: 1.03), CD27 on IgD-CD38^bright (IVW: p = 0.0401, OR: 0.93 and WME: p = 0.0194, OR: 0.90), CD28 on resting Treg (IVW: p = 0.0019, OR: 0.91 and WME: p = 0.0128, OR: 0.92). The main findings were validated by the sensitivity analyses, indicating data reliability.

Conclusions

In summary, this investigation carried out MR analysis to provide evidence suggesting a causal association between ICs and FI, thereby furnishing new literature on the disease as well as a basis for the establishment of immunomodulatory therapeutic avenues.