Ó³»­´«Ã½

BACKGROUND: Coronary artery disease (CAD) is a complex condition and remains the leading cause of mortality worldwide. Genome-wide association studies have identified a CAD risk locus on chromosome 10q23 that is independent of traditional risk factors, providing an opportunity to uncover novel molecular mechanisms contributing to CAD pathogenesis.METHODS: Improved fine-mapping approaches were used to prioritize noncoding variants at the 10q23 locus within the intronic region of (tetraspanin 14). Regulatory elements harboring lead variants were functionally interrogated using chromatin accessibility, 3-dimensional chromatin organization, and clustered regularly interspaced short palindromic repeats-mediated deletion approaches in endothelial cells (ECs). Subsequently, function in ECs was assessed using transcriptomic profiling, Notch signaling activation assays, and EC functional assay using gene knockout (KO) cell lines.RESULTS: Fine-mapping identified 2 lead variants, rs17680741 and rs12260962, located within regulatory elements predicted to affect expression in monocytes and ECs, respectively. Chromatin accessibility, organization, and enhancer deletion assays demonstrated EC-specific function for the rs12260962-harboring regulatory element in expression regulation. Loss of resulted in significant transcriptomic changes related to Notch signaling, heart morphogenesis, cell adhesion, and wound healing. Functionally, ECs exhibited impaired cell-cell junction integrity, reduced repair capacity, and diminished mechanosensitive responses.CONCLUSIONS: Together, these data identify a regulatory element harboring CAD-associated variants at the 10q23 locus that modulates TSPAN14 expression and downstream Notch signaling in ECs, thereby linking genetic risk to endothelial dysfunction relevant to CAD pathogenesis.