The 9p21.3 Coronary Artery Disease Risk Locus Modulates Vascular Cell-State Transitions via Enhancer-Driven...

The 9p21.3 locus is the strongest genetic association with coronary artery disease (CAD), yet its causal mechanisms remain unresolved. We map the regulatory architecture of 9p21.3 in disease-relevant vascular cells, identifying 12 enhancers within the CAD risk haplotype that respond dynamically to inflammatory and metabolic stress in fibroblasts and smooth muscle cells. These activated states are enriched for CAD heritability, implicating stress-responsive vascular wall cells in disease pathophysiology. Dense CRISPRi tiling integrated with fine-mapping and genomic constraint across >500,000 individuals nominates MTAP as the effector gene, with rs1537371 as a likely causal variant. Perturbation and multi-modal analyses show that MTAP loss induces pro-fibrotic and angiogenic programs and sensitizes vascular cells to TGF-β-driven pathological transitions. Our findings reveal a vascular-specific enhancer network through which noncoding variation at 9p21.3 modulates CAD risk via MTAP-a previously unrecognized regulator of vascular remodeling located 269 kb from the risk haplotype.