Multi-omics identification of quantitative trait loci associated with vascular pathogenesis and diagnostic potential in chronic venous disease

Abstract

Chronic venous disease (CVD) is a prevalent vascular disorder with a poorly characterized genetic basis. In this study, we employed an integrative omics strategy combining genome-wide association studies (GWAS), expression quantitative trait loci (eQTL) mapping, endothelial cell functional assays, and transcriptomic correlation analysis to elucidate the molecular architecture of CVD. A GWAS conducted in a Taiwanese population identified two CVD-associated single nucleotide polymorphisms: VSTM2L rs1998049 and DPYSL2 rs1442887. Through eQTL analysis and endothelial functional assays, four QTLs (VSTM2L, RPRD1B, SAMHD1, and PNMA2) were found to significantly affect VEGF consumption, vWF expression, and endothelial tube formation. Co-expression and correlation analyses further linked these QTLs to key vascular effector genes, including VEGF, vWF, MMP9, and CCM2. A logistic regression model based on QTL expression profiles demonstrated high diagnostic performance (area under the curve, AUC = 0.898), highlighting their translational potential. These findings offer novel insights into the functional genomics of CVD, particularly in relation to vascular remodeling, endothelial dysfunction, and inflammation. They also demonstrate the utility of multi-omics integration for biomarker discovery in complex vascular disorders.