Evaluating the Impact of Folate on Male Infertility Using Mendelian Randomization: A Comprehensive Analysis

Purpose: In recent decades, the incidence of male infertility has been increasing annually. In clinical practice, the question of whether to supplement folic acid is common among patients. Given the limited guidelines and research on the impact of folic acid on male infertility, this study aims to assess the effect of folic acid on male infertility using Mendelian randomization (MR) analysis. Materials and Methods: We conducted a two-sample bidirectional MR study using IEU database data for folate levels and supplementation. Male infertility genome-wide association study (GWAS) data were obtained from the FinnGen Consortium R8 dataset. To evaluate the causal relationship between folate, folate supplementation, and the risk of male infertility, we employed various MR methods, including inverse-variance weighted (IVW), MR-Egger, and Maximum Likelihood. The analysis results were assessed using MR-PRESSO, MR-Egger, and leave-one-out analysis. Genes related to folate metabolism were sourced from the MSigDB database, and the Expression Quantitative Trait Loci (eQTL) information of related genes was obtained from the IEU database. Single nucleotide polymorphism data for other male infertility risk factors, such as diabetes and obesity, were also analyzed. Results: According to the MR analysis, there is no causal relationship between serum folate levels and male infertility in the general population. However, reverse Mendelian analysis indicated that male infertility may promote elevated serum folate levels. Folate supplementation appears to act as a protective factor against male infertility, while reverse MR analysis shows no causal relationship between male infertility and folate supplementation. Furthermore, we identified SERPINE1 and LDLR as potential causal genes in the folate metabolism pathway related to male infertility. Hypertension and hyperlipidemia also showed causal relationships with these two genes. Conclusions: This study used MR to discover that folate supplementation is a protective factor against male infertility, and that SERPINE1 and LDLR may be influential genes in folate metabolism affecting male infertility.