GENETIC PREDISPOSITIONS OF ENDOMETRIOSIS, FROM RISK ALLELES TO CLINICAL INSIGHT

Objective: Endometriosis affects up to 50% of women with infertility, with an average diagnostic delay of 7-11 years. This study investigated if genetic risk alleles linked to inflammation, oxidative stress, estrogen metabolism, and endometrial receptivity are over-represented among infertile women and may contribute to endometriosis pathophysiology. Design: Cross-sectional genetic analysis using data from FERN (Functional Evaluation of Reproductive Nutrigenomics), a clinical nutrigenomic test assessing fertility-related lifestyle genes. Materials and Methods: Candidate genes were selected based on biological relevance and literature. Risk allele frequencies in the FERN data were compared to global reference data (1000 Genomes Project) using one-sample proportion tests and statistically enriched variants were prioritized for pathway-level interpretation. Results: Genetic risk alleles previously associated with endometriosis showed significant enrichment in our infertile cohort. These included IL6 (rs1800795/rs1800797) and CRP (rs1205) for inflammation and immune dysregulation; SOD2 (rs4880) and GSTM1 (null) for oxidative stress; MTHFR (rs1801133) and PEMT (rs7946) for altered methylation and estrogen metabolism; and VDR (rs1544410) associated with impaired endometrial receptivity (vitamin D may modulate inflammation, immune function, and lesion growth). Our data also showed a high prevalence of multi-pathway gene combinations, suggesting gene-gene synergy. SOD2-GSTM1-MTHFR may contribute to mitochondrial stress and epigenetic instability; IL6-CRP-VDR may magnify immune dysregulation and impair implantation and IL6-PEMT may reflect inflammation and impaired estrogen breakdown, worsening pain, lesion growth, and systemic dysfunction. Conclusions: Converging genetic variants may contribute to endometriosis pathophysiology and infertility. Early identification of at-risk women by genetic screening may improve diagnosis and guide personalized reproductive care.