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

Area of Science:

• Cardiovascular Genetics
• Molecular Biology
• Endothelial Cell Biology

Background:

• Ischemic heart disease, including coronary artery disease (CAD), is a major global health concern.
• The single nucleotide polymorphism rs6903956 (chromosome 6p24.1) is linked to CAD susceptibility in East Asian populations.
• The precise functional mechanisms of rs6903956 in CAD pathogenesis remain largely unknown.

Purpose of the Study:

• To elucidate the mechanistic role of rs6903956 in CAD pathogenesis, focusing on endothelial cell dysfunction.
• To investigate how the rs6903956 risk allele impacts gene expression and endothelial cell inflammatory responses.

Main Methods:

• Cohort studies to associate rs6903956 with blood pressure and endothelial responsiveness (flow-mediated dilation).
• Single-base editing in patient-derived induced pluripotent stem cell-endothelial cells and expression quantitative trait loci analysis.
• In silico modeling (AlphaFold 3), functional assays (promoter activity), and assessment of inflammatory markers (ICAM-1) and monocyte adhesion.

Main Results:

• The rs6903956 'A' risk allele is associated with altered blood pressure phenotypes and reduced endothelial responsiveness.
• The 'A' allele demonstrates cis-acting regulatory effects on PHACTR1 and EDN1 expression, with enhanced binding to HOXA4/MEIS1 transcription factors.
• rs6903956 'A' allele increases PHACTR1 promoter activity, leading to elevated ICAM-1 expression and monocyte adhesion in endothelial cells under pathological flow.

Conclusions:

• rs6903956 influences PHACTR1 expression through HOX-MEIS cooperative binding, modulating endothelial cell function.
• Allele-specific regulation of PHACTR1 by rs6903956 contributes to endothelial dysfunction and increased CAD susceptibility.
• These findings provide mechanistic insights into genetic determinants of cardiovascular disease and suggest potential therapeutic targets.