Coronary Artery Disease Risk Variant rs6903956 Links to Endothelial Dysfunction via PHACTR1 Regulation

作者：Kai Yi Tay, H. Wee, Nhi Nguyen, Matias I. Autio, V. Wazny, Khang Leng Lee, D. Tay, Yuting Wang, Xu Gao, C. Heng, Mark Yan Yee Chan, Roger Sik Yin Foo, Jimmy Lee, Marie Loh, Christine Cheung · 发表于：bioRxiv · 年份：2025 · DOI：10.1101/2025.05.11.653298 · 研究领域：Biology、Medicine

Ischemic heart disease, particularly coronary artery disease (CAD), remain leading causes of mortality worldwide. The single nucleotide polymorphism rs6903956 on chromosome 6p24.1 has been identified as a susceptibility locus for CAD in East Asian populations through genome-wide association studies. However, its functional role has not been fully elucidated. This study investigates the mechanistic basis of rs6903956 and its contribution to CAD pathogenesis, focusing on endothelial cell dysfunction. We first conducted cohort studies, revealing an association between the rs6903956 ‘A’ risk allele and blood pressure phenotypes, along with impaired endothelial responsiveness indicated by reduced flow-mediated dilation. Single-base editing of induced pluripotent stem cell-derived endothelial cells obtained from patients with CAD and expression quantitative trait loci analysis highlighted a cisacting impact of the ‘A’ allele on PHACTR1 and EDN1 expression, suggesting allelespecific regulatory effects. Using in silico modeling by AlphaFold 3 platform, the ‘A’ allele exhibited enhanced binding affinity for HOXA4 and MEIS1 transcription factors, forming a stable ternary complex that promoted transcriptional activation of PHACTR1. Functional assays demonstrated the enhancer role of rs6903956 ‘A’ in PHACTR1 promoter activity, supporting its locus-specific regulatory function in endothelial cells. Under pathological flow conditions, endothelial cells harboring the ‘A’ allele display elev...