A preeclampsia prediction model incorporating methylenetetrahydrofolate reductase, vitamin D receptor, and uterine artery pulsatility index

OBJECTIVE: This study evaluated the predictive value of methylenetetrahydrofolate reductase (MTHFR) rs1801133 and vitamin D receptor (VDR) FokI rs2228570 polymorphisms combined with uterine artery pulsatility index (PI) for preeclampsia (PE), and explored mediating pathways underlying genetic risk. METHODS: A two-phase prospective study was conducted. Phase I (n = 73) screened PE-related single nucleotide polymorphisms (SNPs) via targeted sequencing; Phase II (n = 195) validated the candidates and collected clinical and ultrasound metrics. Independent predictors were identified by multivariate logistic regression to build a nomogram, and the nomogram was evaluated by receiver operating characteristic (ROC) curve, calibration, and decision curve analyses. Mediation analysis was performed to quantify the contribution of serum biomarkers. RESULTS: The T allele of MTHFR rs1801133 showed a marginal association with PE risk under dominant model (OR = 1.82, 95% CI: 0.96-3.44, P = 0.067), while VDR rs2228570 was not significantly associated (OR = 1.74, 95% CI: 0.89-3.39, P = 0.104). Pre-pregnancy body mass index (BMI) ≥25 kg/m² (OR = 2.75, 95% CI: 1.45-5.21, P = 0.002) and elevated uterine artery PI (OR = 4.75, 95% CI: 1.38-16.41, P = 0.014) were independent risk factors. The nomogram achieved an area under the curve (AUC) of 0.711 (95% CI: 0.640-0.783), with sensitivity of 75.53% and specificity of 59.41%. Asymmetric dimethylarginine (ADMA) and 8-iso-PGF2α mediated 77.5% and 26.0% of the effect of MTHFR on PE risk, respectively. CONCLUSION: Pre-pregnancy BMI and uterine artery PI are independent predictors of PE. The integrated model offers moderate predictive value. ADMA-mediated endothelial dysfunction may be involved in MTHFR-related PE risk.