Large-Scale Proteomics Reveals New Candidate Biomarkers for Late-Onset Preeclampsia

BACKGROUND: Preeclampsia is classified as either a more severe early onset or a more prevalent late-onset form. Lower PlGF (placental growth factor) and increased sFlt-1 (fms-like tyrosine kinase-1) in maternal circulation are promising biomarkers, yet they lack specificity for preeclampsia. METHODS: We quantified ≈7000 proteins in 673 samples collected from 89 patients with late-onset preeclampsia and 91 controls at T1 (15-22), T2 (22-30), and T3 (30-42) weeks. Elastic net and random forest models were fitted and evaluated by cross-validation. Differential abundance analysis followed by functional profiling, was used to identify and interpret protein changes. RESULTS: An increase in protein differential abundance in late-onset preeclampsia was observed with advancing gestation, reaching 806 proteins at T3 related to angiogenesis, cell adhesion, and extracellular matrix remodeling. FAAH2 (fatty acid amide hydrolase 2), SIGLEC6 (sialic acid-binding Ig-like lectin-6), IL17RC (interleukin-17 receptor C), HTRA1 (serine protease), sFlt-1, and 47 other proteins dysregulated at T3 were validated in a reanalysis of a ≈5000 protein Norwegian data set. Random forest models with 20 proteins showed high accuracy at T3 (area under the curve [AUC], 0.83 [0.77-0.89], sensitivity 59%) even in cases not yet diagnosed at sampling (n=31, AUC, 0.80 [0.71-0.90], sensitivity 58%), outperforming sFlt-1 and PlGF. Moderate accuracy was obtained at T1 (AUC, 0.63 [0.54-0.72], sensitivity 33%) and T2 (AUC, 0.59 [0.50-0.68], sensitivity 17%). Combining maternal characteristics and obstetric history with proteomics data increased accuracy at T1 (AUC, 0.68 [0.59-0.77], sensitivity 28%), T2 (AUC, 0.68 [0.60-0.77], sensitivity 31%), and T3 (AUC, 0.87 [0.81-0.92], sensitivity 69%). CONCLUSIONS: The findings confirm the involvement of abnormal trophoblast invasion, angiogenesis, and extracellular matrix remodeling in late-onset preeclampsia, while highlighting new protein alterations consistent across diverse cohorts.