Causal role of immune cells in male infertility: a Mendelian randomization study

Abstract

Background: Epidemiological studies have shown that early immune inflammatory responses are associated with male infertility, and bacteria and viruses interact with the host's immune and inflammatory systems through their unique structures. This study aims to use Mendelian randomization (MR) to investigate the causal relationship between different immune cell types and the risk of male infertility.

Methods: Male infertility data was obtained from the FinnGen database, and immune cell subtypes data were gathered from the Genome-Wide Association Studies (GWAS) catalog. An MR analysis was performed to investigate the causal relationship between immune cells and male infertility. Several MR methods, including inverse-variance weighted (IVW), weighted median, weighted mode, MR-Egger, and simple mode, were employed. Reverse MR analysis was also conducted to explore the reverse causal relationship. Sensitivity analyses, including Cochran's Q test for heterogeneity, MR-Egger regression for pleiotropy, and MR-PRESSO to exclude pleiotropic outliers, were performed to assess the robustness of the findings.

Results: The study identified 23 immune phenotypes causally associated with male infertility, of which six immune phenotypes were protective, and 17 were risk factors. No reverse causal relationship was found between male infertility and immune phenotypes in the reverse MR analysis.

Conclusions: These results suggest that there is a potential causal relationship between some immune cell subtypes and male infertility at the genetic level.

Keywords: Immune cells; Mendelian randomization (MR); immunophenotype; male infertility; single nucleotide polymorphisms (SNPs).

Figure 1

Principle (A) and analytical workflow (B) of MR analysis. The MR analysis in this study comprises two steps. Each step involves three assumptions (assumptions 1, 2, and 3) and five major components of MR analysis (the names of the components are shown in the left boxes, and their specific contents are shown in the right boxes) to investigate the potential causal relationship between exposure and outcome. Step 1: 731 immune cell traits are considered as exposures, and male infertility as the outcome. SNPs derived from immune cell traits are regarded as IVs, and the causal effects of immune cells on male infertility are estimated through MR analysis. Step 2: male infertility is used as the exposure, and immune cells identified as associated with male infertility in Step 1 are considered outcomes. SNPs derived from male infertility are used as IVs to test for reverse causation via MR analysis. IV, instrumental variable; IVW, inverse-variance weighted; MR, Mendelian randomization; SNP, single nucleotide polymorphism.

Figure 2

Forest plot showing the potential causal relationships between immune cell traits and male infertility, identified using MR analyses where (PIVW<0.05) and the OR directions were consistent across five major MR methods. AC, absolute cell counts; cDC, conventional dendritic cells; CI, confidence interval; DC, dendritic cell; HLA DR, Human leukocyte antigen-type DR; IgD, immunoglobulin D; IVW, inverse-variance weighted; MR, Mendelian randomization; nsnp, number of SNPs; OR, odds ratio; SNPs, single nucleotide polymorphisms; TBNK, T cells, B cells, natural killer cells; T/B, T cell to B cell ratio; Treg, regulatory T cell.

Figure 3

The circular heatmap of the results from five Mendelian randomization experiments examining male infertility and 23 male infertility-associated immune cell traits (four groups: B cells, T cells, cDC, other). AC, activated cell; cDC, conventional dendritic cells; IVW, inverse variance weighted; MR, Mendelian randomization; OR, odds ratio.