Genetic insights into the immunological basis of male infertility: A translational perspective.

Abstract

Objective: To clearly elaborate the causal relationships between specific immunocyte phenotypes and male infertility.

Design: Mendelian randomization using genome-wide association study data.

Setting: Publicly available genome-wide association study data.

Subjects: Large cohorts of European ancestry.

Exposure: 731 immunocyte phenotypes or male infertility.

Main outcomes measures: Genetic variants were used as instrumental variables to infer causality, minimizing confounding and bias. The causal associations were assessed using the inverse variance-weighted (IVW) method for primary analysis and validated the findings using MR-Egger, Weighted Median, Simple Mode, and Weighted Mode approaches. Additional sensitivity analyses were performed to validate the robustness of findings.

Results: Our analysis identified significant causal associations between specific immunocyte phenotypes and male infertility. Phenotypes such as Naive-mature B cell %lymphocyte (OR = 1.257, P = 0.009) and IgD- CD38dim %B cell (OR = 1.100, P = 0.021) were positively associated with increased infertility risk, while phenotypes like CD39+ CD8br %T cell (OR = 0.856, P = 0.021) and BAFF-R on transitional (OR = 0.833, P = 0.002) were negatively associated, suggesting a protective effect. Additionally, reverse MR analysis revealed that male infertility might causally affect certain immunocyte phenotypes, including CD14- CD16+ monocyte %monocyte (OR = 1.049, P = 0.007).

Conclusions: This study provides robust evidence for the causal role of specific immunocyte phenotypes in male infertility and highlights the bidirectional relationship between immune function and reproductive health. These findings provide new insights into the immunological factors contributing to male infertility and suggest potential biomarkers and therapeutic targets for future research and clinical interventions.