Key result
The rs6903956 A allele is linked to ~1-point lower flow-mediated vasodilation via PHACTR1 upregulation.
Why the study?
Although rs6903956 has been identified as a CAD susceptibility locus in East Asian populations, its functional role has not been fully elucidated.
Does the CAD risk variant rs6903956 'A' allele worsen endothelial function compared to the 'G' allele?
Does the CAD risk variant rs6903956 'A' allele worsen endothelial function compared to the 'G' allele?
This translational study provides a mechanistic link between the CAD-associated rs6903956 non-coding variant and endothelial dysfunction through an allele-specific enhancer regulation of PHACTR1.
Answers are grounded in this paper and cite their sources.
Does not warrant clinical action; hypothesis-generating for PHACTR1-targeted CAD therapies.
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 elevated ICAM-1 expression and increased monocyte adhesion compared to the ‘G’ allele, indicating allele-specific endothelial inflammatory activation. These findings propose a model in which rs6903956 influences PHACTR1 expression via HOX-MEIS cooperative binding, thereby modulating endothelial function and contributing to CAD susceptibility. This study provides mechanistic insights into the role of rs6903956 in endothelial dysfunction and CAD, informing potential therapeutic targets arising from genetic determinants in cardiovascular pathogenesis.
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Tay et al. (2025) studied Coronary artery disease susceptibility / Endothelial dysfunction (n=566). rs6903956 'A' risk allele vs. rs6903956 'G' non-risk allele was evaluated on Flow-mediated vasodilation (FMD) (%) (p=0.015). The rs6903956 'A' risk allele is associated with reduced flow-mediated vasodilation compared to the 'G' allele and drives endothelial dysfunction via HOX-MEIS-mediated PHACTR1 upregulation.
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