Gene-Dosage Effect of V89L Variants in Steroid 5α-Reductase Type 2 and Increased Risk of 46, XY Disorders of Sex Development: A Systematic Review and Meta-Analysis

A BSTRACT Background: Disorders of sex development (DSD) and isolated hypospadias are congenital conditions characterized by atypical male genital differentiation, often linked to impaired androgen biosynthesis or signaling. The steroid 5α-reductase type 2 (SRD5A2) gene, encoding SRD5A2, is crucial for dihydrotestosterone biosynthesis, and its V89L polymorphism has been investigated as a potential risk factor for DSD. However, the results across the studies have been inconsistent. This synthesis was conducted to assess the association between the SRD5A2 V89L polymorphism and the risk of 46, XY DSD and isolated hypospadias through a systematic review and meta-analysis, clarifying its inheritance pattern and clinical significance. Materials and Methods: PubMed, Scopus, and Google Scholar were queried systematically for relevant studies. Meta-analysis was performed under five genetic models: allelic (V vs. L), dominant (LL + VL vs. VV), recessive (LL vs. VL + VV), codominant (LL vs. VV and VL vs. VV), and overdominant (VL vs. LL + VV). Pooled odds ratios (OR) with 95% confidence intervals (CIs) were calculated using a random effects model. Publication bias and heterogeneity were assessed through funnel plots, Begg’s test, and sensitivity analyses. Results: Nine case-control studies comprising 1232 cases and 1616 controls were included. Significant associations were found in the allelic (OR = 2.05, 95% CI: 1.28–3.28, P = 0.003), dominant (OR = 2.14, 95% CI: 1.23–3.73, P = 0.007), and recessive models (OR = 2.46, 95% CI: 1.29–4.67, P = 0.006). The codominant model analysis demonstrated a dose-dependent gene effect, where heterozygous VL carriers had a moderate risk (OR = 1.66, 95% CI: 1.01–2.72, P = 0.04) while homozygous LL carriers exhibited the highest risk (OR = 3.38, 95% CI: 1.51–7.56, P = 0.003) compared to VV carriers. The overdominant model showed no significant association (OR = 1.10, 95% CI: 0.80–1.51, P = 0.57). The robustness of the findings was demonstrated through sensitivity analyses. Conclusion: This meta-analysis provides strong evidence for a codominant inheritance pattern of the SRD5A2 V89L polymorphism with a stepwise increase in the risk of DSD per L allele. The results support the role of V89L as a genetic susceptibility factor in 46, XY DSD and isolated hypospadias. The findings have clinical implications for genetic counseling, early diagnosis, and potential therapeutic targeting.