Pathogenetic interrelationship between genetic factors and oxidative stress in the development of early preeclampsia in multiple pregnancy

BACKGROUND: Early-onset preeclampsia in multifetal pregnancy is a major clinical challenge associated with high maternal and perinatal morbidity and mortality. Its pathogenesis is complex and is thought to arise from interactions between genetic susceptibility and environmental factors, with oxidative stress representing a key mechanistic component. Although the genetic basis of oxidative stress has been investigated in a number of domestic and international research centers, comprehensive studies that integrate the epistatic interactions between genes and their relationship to oxidative status in patients with multifetal pregnancy remain scarce. AIM: The aim of this study was to assess the frequency of polymorphic variants in genes involved in hemostasis and folate metabolism, identify significant epistatic interactions, and evaluate oxidative status markers in patients with multifetal pregnancy complicated by early-onset preeclampsia. METHODS: This single-center case-control study included patients with multifetal pregnancy, with or without preeclampsia. Genotyping of 12 single nucleotide variants in hemostasis related genes (F2, F5, F7, F13, FGB, ITGA2, ITGB3, SERPINE1) and folate cycle genes (MTHFR, MTRR, MTR) was performed using real-time polymerase chain reaction. Oxidative status was assessed by total antioxidant capacity, lipid peroxidation index (PerOx), and the integral oxidative stress index (OxyStat). Epistasis was explored using the generalized multifactor dimensionality reduction (GMDR) method. RESULTS: The study included 157 women (main group: 38 women with early-onset preeclampsia; control group: 119 women without preeclampsia). The carriage of minor alleles in the SERPINE1 −6755G4G, ITGA2 807CT, and MTRR 66AG gene variants was associated with an increased risk of early-onset preeclampsia in multifetal pregnancy. The GMDR method identified significant epistatic interactions; the most predictive three-locus model (ITGA2 + SERPINE1 + MTRR genes) achieved a balanced accuracy of 0.8902 with a sensitivity of 97.5%. Patients with preeclampsia exhibited a marked oxidative imbalance, with a 4.2-fold decrease in total antioxidant capacity and nearly 3-fold increases in PerOx and OxyStat compared to control values. The carriage of the SERPINE1 4G allele and the ITGA2 T allele was associated with more pronounced impairment of oxidative status. CONCLUSION: The data obtained support a plausible pathogenic link between genetic susceptibility and oxidative stress in early-onset preeclampsia in multifetal pregnancy. Unfavorable genotype combinations in the SERPINE1, ITGA2, and MTRR genes may confer a high genetic risk that, in the context of multifetal gestation, is realized through hypercoagulability, endothelial dysfunction, and placental ischemia-reperfusion, culminating in severe oxidative stress and clinical manifestation of preeclampsia. The results substantiate the rationale for a comprehensive risk stratification approach integrating genetic testing and oxidative status assessment.