Genetic Aspects of Reproductive Function Disorders in Men with Impaired Semen Parameters

Background: Male infertility is a pressing clinical and social issue, affecting approximately 30–50% of infertile couples. Despite extensive research, the etiology remains unknown in a considerable proportion of cases, underscoring the need for molecular genetic investigations into spermatogenesis disorders. Methods: the study enrolled 187 European men (68 fertile, 119 infertile). Infertile patients were stratified into four subgroups: azoospermia (n = 28), asthenozoospermia (n = 32), teratozoospermia (n = 25), and oligozoospermia (n = 34). Genotyping was performed for polymorphisms in folate metabolism (MTHFR C677T, MTHFR A1298C, MTR A2756G, MTRR A66G), redox system (CAT-262C > T, GSTP1 Ile105Val, GSTP1 Ala114Val), phosphodiesterase (PDE7B G/A), and selenoprotein (SEPS1 G-105A) genes. Statistical analyses included χ2 tests, logistic regression, genetic risk score (GRS) calculation, and ROC analysis, with Benjamini–Hochberg correction for multiple comparisons (FDR, q < 0.05 considered significant). Groups were comparable in age, BMI, and hormonal profiles. Results: in oligozoospermia, nominal associations were detected with MTR A2756G (OR = 2.70; p = 0.003), CAT-262T (OR = 3.12; p = 0.0005), and SEPS1 G-105A (OR = 3.45; p = 0.0001); after FDR correction, only CAT and SEPS1 remained significant. Multivariate regression, adjusting for age, BMI, and hormones, confirmed independent associations for CAT (aOR = 2.34; p = 0.002; q = 0.04) and SEPS1 (aOR = 2.89; p = 0.0001; q = 0.002). MTR A2756G showed nominal associations with astheno-, terato-, and oligozoospermia, but none survived FDR correction. CAT-262T was associated with oligozoospermia (q = 0.04) and borderline with asthenozoospermia (q = 0.08); SEPS1 was significantly associated with both asthenozoospermia (q = 0.04) and oligozoospermia (q = 0.004). GRS was highest in oligozoospermia (3.4 ± 1.5) and significantly elevated in asthenozoospermia and teratozoospermia (3.1 ± 1.2 and 3.2 ± 1.4, respectively), but not in azoospermia (2.3 ± 1.1; p = 0.087). GRS ≥ 3 was found in 64.7% of infertile men vs. 26.5% of fertile controls, corresponding to a 5-fold increased risk (χ2 = 22.4; p < 0.001). The combined GRS achieved an AUC of 0.74 (95% CI 0.67–0.81), with 68.2% sensitivity and 76.5% specificity at a cut-off of ≥3. No associations with azoospermia reached significance for any polymorphism; this subgroup had limited power (n = 28). Conclusions: in this exploratory study, CAT and SEPS1 polymorphisms demonstrated FDR-significant associations with oligozoospermia and asthenozoospermia in European men. The cumulative genetic score (AUC = 0.74) may serve as a useful tool for risk stratification, but these findings require replication in larger independent cohorts before clinical translation.