Genetic prioritization and multi-omic characterization of GNS-associated thromboinflammatory signatures in venous thromboembolism

Abstract

Venous thromboembolism (VTE) remains a major cause of cardiovascular morbidity and mortality. Beyond dysregulated coagulation, accumulating evidence implicates immune and inflammatory pathways in thromboinflammatory susceptibility. However, the genetic determinants of VTE and their links to immune dysregulation remain incompletely characterized. We performed a proteome-wide two-sample Mendelian randomization analysis integrating cis-pQTL instruments and Bayesian colocalization to prioritize plasma proteins associated with VTE, deep vein thrombosis (DVT), and pulmonary embolism (PE). Independent whole-blood transcriptomic cohorts stratified by recurrence history or recurrence-risk categories were analyzed to provide contextual information on recurrence-associated immune transcriptional states. Multi-omic analyses, including phenome-wide association analysis, single-cell transcriptomics, and experimental validation, were conducted to characterize prioritized candidates and evaluate their associations with macrophage-related thromboinflammatory phenotypes. Among 20 plasma proteins showing genome-wide significant MR associations with VTE-related outcomes, six (BCAM, VWF, GNS, ABO, TUFT1, and CHST15) demonstrated strong colocalization evidence (PP.H4 > 0.8). GNS showed directionally consistent protective associations across VTE, DVT, and PE, supported by shared genetic signals. Transcriptomic analyses demonstrated reduced GNS expression in recurrence-associated higher-risk groups. Phenome-wide analysis did not identify genome-wide significant phenotypic associations. Multi-omic analyses localized GNS expression predominantly to macrophage and fibroblast populations within thrombus tissue. Experimental validation demonstrated that bidirectional GNS modulation was associated with altered macrophage polarization, inflammatory responses, and thromboinflammatory phenotypes in vitro and in vivo. GNS emerged as a genetically prioritized and biologically plausible candidate associated with VTE-related outcomes and thromboinflammatory immune signatures. Integrative multi-omic analyses and experimental studies support a potential association between GNS, macrophage-associated immune regulation, and venous thrombosis, although the underlying mechanisms remain to be established. Further mechanistic and prospective studies are required to determine the biological and clinical relevance of GNS-associated pathways in VTE. Not applicable.