Nrf2 mRNA in the First Trimester as a Predictive Biomarker for Gestational Diabetes Mellitus

Objective: This study aimed to explore the role of the nuclear factor E2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1)-antioxidant response element (ARE)/heme oxygenase-1 (HO-1) signaling pathway in the development of GDM during the first trimester and to evaluate its potential as an early predictor biomarker. Methods: A prospective nested case-control study including 97 matched pairs of GDM patients and healthy controls was conducted. Peripheral blood collected between gestational weeks 8 and 12 was analyzed for mRNA levels of Nrf2, Keap1, and HO-1 using quantitative real-time PCR (qRT-PCR) analysis. Results: During the first trimester, the GDM group showed significantly higher levels of Nrf2 and HO-1 mRNA, while Keap1 expression was comparable to controls. Elevated Nrf2 mRNA levels were associated with a higher GDM risk (odds ratio (OR) = 2.369, 95% confidence interval (CI): 1.700-3.302, p < 0.001), with increased Nrf2 mRNA levels being positively linked to GDM development. Receiver operating characteristic (ROC) curve analysis indicated that first-trimester Nrf2 mRNA expression could predict mid-gestation GDM diagnosis with an area under curve (AUC) of 0.770 (95%CI: 0.704-0.827). Conclusions: In the early trimester of pregnancy, individuals with GDM show a significant increase in the mRNA expression of Nrf2 and HO-1. Nrf2 mRNA serves as an independent predictor of GDM development, supporting its possible role in pathogenesis and potential utility for early screening.