Transcriptomic analysis identifies immune-related clusters and PPP2R1A as a candidate gene associated with venous...

Venous thromboembolic disease (VTE), encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE), is associated with substantial morbidity, mortality, and recurrence risk. However, immune-related transcriptomic heterogeneity and recurrence-associated molecular features in VTE remain incompletely defined. This study aimed to explore immune-related transcriptomic clusters associated with VTE recurrence and to prioritize recurrence-associated candidate genes. Public GEO datasets were analyzed, with GSE19151 used as the discovery cohort and GSE48000 used for external validation. Consensus clustering, WGCNA, differential expression analysis, GO/KEGG enrichment, and random forest-based exploratory gene prioritization were performed. The functional relevance of PPP2R1A was further evaluated using a mouse inferior vena cava thrombosis model and endothelial cell experiments, including western blotting, qRT-PCR, CCK-8, Transwell, flow-cytometry, and endothelial-immune co-culture assays. Two exploratory immune-related clusters were identified among VTE patients. Compared with subtype I, subtype II showed stronger IFN-gamma, monocyte, and IL-6 enrichment and a higher recurrence proportion (61.4% vs. 41.7%). Random forest analysis prioritized 23 recurrence-associated candidate genes, including PPP2R1A, although external validation showed modest discriminatory performance (AUC = 0.615). In experimental systems, PPP2R1A expression was associated with thrombus burden, endothelial cell proliferation, migration, apoptosis, inflammatory activation, and altered p-MEK/p-ERK signaling. These findings identify exploratory immune-related clusters in VTE and support PPP2R1A as a recurrence-associated candidate gene linked to endothelial MEK/ERK signaling. Larger prospective cohorts and cell-specific mechanistic studies are needed before these findings can be translated into clinical biomarkers or therapeutic targets.