NRF2 Gene Polymorphisms, Preconception BMI and Their Interplay in Preeclampsia

This study aimed to explore the correlations of nuclear factor erythroid 2-related factor-2 (NRF2) gene polymorphisms, prepregnancy body mass index (BMI) and the interaction between them with the risk of preeclampsia (PE). A case-control study was conducted in which pregnant women with PE (n = 198) and normotensive pregnant women (n = 396) were recruited as the case group and control group, respectively, from two tertiary hospitals in Hunan Province. Data collection was achieved through face-to-face interviews utilizing a standardized questionnaire, along with perinatal health care records. Blood samples were also collected, and genotyping of nine single-nucleotide polymorphisms (SNPs) in the NRF2 gene was subsequently performed using the MassArray platform. Both univariate and multivariate logistic regression analyses were employed to assess the associations of NRF2 gene polymorphisms with prepregnancy BMI and their interactions with the risk of PE. Multivariate logistic regression analyses revealed a significant association between prepregnancy BMI and PE susceptibility. Specifically, prepregnancy overweight/obesity (BMI ≥ 24.0 kg/m²) was associated with an elevated risk of PE (adjusted OR = 4.59, 95% CI: 2.82-7.45), whereas underweight status (BMI < 18.5 kg/m²) was correlated with a reduced PE risk (adjusted OR = 0.38, 95% CI: 0.18-0.78). The NRF2 polymorphism rs13005431 exhibited a protective effect against PE under the additive genetic model (adjusted OR = 0.59, 95% CI: 0.37-0.93). Furthermore, logistic regression analyses revealed a significant effect of the multiplicative interaction between prepregnancy overweight/obesity and polymorphisms rs35652124 (adjusted OR = 0.24, 95% CI: 0.06-0.89) and rs2627765 (adjusted OR = 3.62, 95% CI: 1.07-12.23) on susceptibility to PE. These findings collectively underscore the critical and independent roles of prepregnancy BMI, NRF2 polymorphisms, and their interactions in modulating PE susceptibility, suggesting that the combined effects of metabolic profiles and genetic determinants may act synergistically to shape PE risk.