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Common Coronary Artery Disease Risk Variants in Endothelial Regulatory Elements Modulate Tetraspanin 14 Expression
Vivian S Lee-Kim1,2,3,4, Gavin R Schnitzler1,2, Shi Fang1,2
1Broad Institute of MIT and Harvard, Cambridge, MA (V.S.L.-K., G.R.S., S.F., R.C., M.Z., J.M.E., R.M.G.).
Arteriosclerosis, Thrombosis, and Vascular Biology
|April 23, 2026
Summary
Coronary artery disease (CAD) genetic risk is linked to TSPAN14 gene expression in endothelial cells. This study identifies a regulatory element influencing TSPAN14 and Notch signaling, revealing new insights into CAD pathogenesis.
Area of Science:
- Genetics
- Cardiovascular Disease Research
- Molecular Biology
Background:
- Coronary artery disease (CAD) is a leading global cause of death.
- A specific CAD risk locus on chromosome 10q23, independent of traditional factors, offers insight into novel pathogenic mechanisms.
Purpose of the Study:
- To fine-map the 10q23 CAD risk locus and functionally characterize variants within regulatory elements.
- To investigate the role of TSPAN14 (tetraspanin 14) in endothelial cells (ECs) and its connection to CAD pathogenesis.
Main Methods:
- Utilized fine-mapping, chromatin accessibility, 3D chromatin organization, and CRISPR-mediated deletion in ECs.
- Assessed TSPAN14 function via transcriptomic profiling, Notch signaling assays, and gene knockout (KO) in ECs.
Main Results:
- Identified lead variants rs17680741 and rs12260962 within regulatory elements affecting TSPAN14 expression.
- Demonstrated EC-specific regulation of TSPAN14 by rs12260962, impacting Notch signaling, cell adhesion, and wound healing.
- TSPAN14 KO ECs showed impaired cell junctions, reduced repair, and diminished mechanosensitive responses.
Conclusions:
- A regulatory element at 10q23 harboring CAD variants modulates TSPAN14 expression and Notch signaling in ECs.
- This links genetic risk to endothelial dysfunction, a key factor in CAD pathogenesis.
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