Association of MTHFD1G1958A, MTHFD1T401C, and DHFR-19bp variants with sperm criteria and unexplained male infertility: a case–control study on Algerian population

Abstract Background Methylenetetrahydrofolate dehydrogenase (MTHFD1) and Dihydrofolate reductase (DHFR) are pivotal enzymes in the folate metabolic pathway, playing essential roles in DNA synthesis, repair, and methylation processes critical for spermatogenesis. Numerous studies have implicated genetic variations in their encoding genes in the susceptibility to diverse diseases, including reproductive disorders. Objective The aim of our study is to investigate the potential association between MTHFD1G1958A , MTHFD1T401C , and DHFR -19bp polymorphisms, sperm parameters, and the risk of idiopathic male infertility. Methods We conducted a case–control study involving 104 infertile men and 104 controls. Genomic DNA was extracted from blood samples using a commercially kit, and molecular analyses were carried out through direct PCR and PCR–RFLP. Results Statistical analysis showed significant associations of MTHFD1G1958A and MTHFD1 T401C mutant genotypes with male infertility ( P < 0.05). The MTHFD1 958AA polymorphism was linked to reduced sperm mobility, vitality, and normal morphology ( P = 0.001, P = 0.048, P ≤ 0.0001, respectively). MTHFD1 T401C was significantly associated with vital sperm ( P = 0.009). No significant association was found for the DHFR -19bp polymorphism. Conclusion This study suggests that MTHFD1G1958A and MTHFD1T401C polymorphisms may contribute to unexplained male infertility, with the MTHFD1 1958GA linked to defects sperm parameters.