Polymorphisms in the genes encoding enzymes in the folate metabolism pathway have been associated with male infertility and chromosome abnormalities. The aim of this study was to analyze the distribution of the methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and methionine synthase reductase (MTRR) polymorphisms in fertile men and infertile men with non-obstructive azoospermia (NOA). A case-control study comprising 85 infertile men with NOA and 246 fertile men as controls was carried out. MTHFR c.677C > T (rs1801133), MTHFR c.1298A > C (rs1801131), MTR c.2756A > G (rs1805087), and MTRR c.66A > G (rs1801394) polymorphisms were determined using the polymerase chain reaction restriction fragment length polymorphism technique. There were significant differences in AC + CC genotype (OR = 1.9, 95% CI = 1.1-3.2) and C allele frequencies (OR = 1.8, 95% CI = 1.2-2.8) of MTHFR c.1298A > C polymorphism between NOA patients and controls after applying the Bonferroni correction. Moreover, the 1298AC genotype, 1298AC + CC genotype, and 1298C allele frequencies were statistically significant in NOA with chromosomal abnormalities and/or a Y chromosome deletion compared to the controls (AC genotype: OR = 3.0; AC + CC genotype: OR = 3.0; C allele: OR = 2.3). Considering the other polymorphisms, no differences were found between cases and controls. Our findings suggest the MTHFR c.1298A > C polymorphism is associated with an increased risk of male infertility, i.e., NOA.
Keywords: MTHFR gene; MTR gene; MTRR gene; Male infertility; non-obstructive azoospermia; outdent gene; outdent polymorphism; polymorphism.