Integrative transcriptomics and scpagwas analysis predicts immune-related markers of preeclampsia.
INTRODUCTION Preeclampsia (PE) pathogenesis involves immune dysregulation, but key drivers remain unclear. This study aimed to identify placental immune regulators in PE using integrative transcriptomics and scPagwas analysis. METHODS We integrated single-cell RNA sequencing (GSE173193, n = 4) and bulk transcriptomic data (GSE75010, n = 157) from placental tissues. scPagwas algorithm assessed genetic associations. Pseudotime trajectory was constructed using Monocle. Key genes were identified by intersecting LASSO and random forest algorithms. Immune infiltration was evaluated by CIBERSORT, pathway enrichment by GSEA/GSVA, and regulatory networks/drug interactions predicted using RcisTarget, miRcode, and CTD. RESULTS Ten placental cell subtypes were characterized. Macrophages showed the highest genetic correlation with PE and exhibited abnormal stemness in lesions. Three hub genes (ARL4C, SLC16A10, DAB2) were significantly dysregulated in PE macrophages, correlating with altered immune infiltration (elevated eosinophils/plasma cells; reduced M2 macrophages/neutrophils). They were enriched in TNF signaling, PI3K-AKT-mTOR, oxidative phosphorylation, and complement cascades, and correlated with established PE genes (FLT1, FURIN). Upstream transcription factors, 128 miRNA-mRNA pairs, and candidate drugs were identified. DISCUSSION This study identifies macrophages as central immune mediators in PE and pinpoints ARL4C, SLC16A10, and DAB2 as key regulators of macrophage polarization, representing promising diagnostic and therapeutic targets.