Genetic-Epigenetic Interactions in Uterine Leiomyomas: MED12 Mutations as Predictors of Aberrant DNA Methylation.

Objective: The study was conducted to investigate the frequency of MED12 gene (rs5030619) mutations and to evaluate DNA methylation patterns in uterine leiomyomas among women at a tertiary care hospital in Karachi, Pakistan. Methods: In this cross-sectional study, 200 women with uterine fibroids and 50 controls were recruited from tertiary care hospitals after ethical approval. Baseline data and history were collected. Serum levels of estradiol, progesterone, and FSH were measured. Genomic DNA was extracted from fibroid and myometrial tissues and analyzed using allele-specific PCR for MED12 genotyping. DNA methylation profiling was conducted to evaluate epigenetic modifications. Statistical analyses were performed using the Statistical Package for social sciences (SPSS) version 27.0. Results: The majority of cases were aged 31-50 years, with 41.5% overweight and 24.5% obese. An increased WHR was observed in 65% of cases, compared to only 36% of controls. Serum estradiol, progesterone, and FSH levels were significantly higher in cases across all menstrual phases (p < 0.01). The MED12 A/C genotype was significantly associated with fibroid risk (OR = 11.72, 95% CI: 5.59-24.57, p < 0.001), and the C/C genotype conferred the highest risk (OR = 18.17, 95% CI: 4.00-82.54, p = 0.001). C allele was associated with increased disease susceptibility (OR = 4.65, 95% CI: 2.69-8.03, p < 0.001). Hyper-methylation was the most prevalent finding, observed in 125 cases of leiomyomas (69.4%). Multivariable logistic regression identified age (OR = 1.04, p = 0.012), BMI (OR = 1.09, p = 0.004), multiple fibroids (OR = 2.31, p = 0.005), intramural fibroid location (OR = 1.88, p = 0.041), and positive family history (OR = 2.74, p = 0.003) as significant independent predictors. Conclusions: Uterine leiomyomas may be influenced by a combination of hormonal, metabolic, genetic, and epigenetic factors. Overall findings suggest that MED12 C allele and A/C genotype variation was significantly associated with increased DNA methylation in uterine leiomyomas.