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Coronary artery disease (CAD), the leading cause of morbidity and mortality worldwide, results from the narrowing of coronary arteries due to the buildup of plaques, a process known as atherosclerosis. This occurs when low-density lipoprotein cholesterol (LDL-C) infiltrates blood vessel walls through dysfunctional endothelial cells (EC), leading to plaque formation and an increased risk of cardiovascular events.
In a groundbreaking study published in Nature Medicine, researchers from Mass General Brigham have developed a polygenic risk score that analyzes genes linked to endothelial cell function to better predict CAD risk. The tool could help identify individuals who are particularly sensitive to LDL-C levels and who may benefit most from aggressive cholesterol-lowering therapies.
Understanding Individual Risk
Dr. Nicholas Marston, MD, MPH, from the Division of Cardiovascular Medicine at Brigham and Women’s Hospital, explained the significance of their findings. “We have been trying to understand why two patients with similarly high cholesterol can have very different degrees of CAD. Our work suggests that intact endothelial function may provide protection in some, while in other patients, EC dysfunction may increase their sensitivity to LDL-C concentrations and amplify their risk of cardiovascular events.”
Marston emphasized that this discovery presents an opportunity for personalized prevention plans. “Patients who are LDL-C sensitive have a much greater benefit from aggressive cholesterol-lowering therapies,” he said.
Developing the Risk Score
The research team identified 35 single nucleotide polymorphisms (SNPs), which are small genetic variations, linked to endothelial cell function and CAD. These SNPs were used to create a risk score that was then tested across three separate study populations. Their findings showed that individuals with high EC-related risk derived significant benefits from LDL-C-lowering treatments and that the score effectively predicted CAD risk.
Future Research and Limitations
One of the key limitations of the current polygenic risk score is that it does not directly measure endothelial cell function. To improve accuracy, future research will explore phenotypic assessments, serum biomarkers, and environmental factors such as smoking that negatively impact endothelial cells.
Implications for Precision Medicine
This study underscores the growing role of genetic insights in tailoring treatment plans for cardiovascular disease. By identifying individuals who are genetically predisposed to CAD due to EC dysfunction, doctors may be able to intervene earlier and more effectively, ultimately reducing the burden of heart disease worldwide.
For more information, refer to the original study: Nicholas A. Marston et al, Endothelial cell-related genetic variants identify LDL cholesterol-sensitive individuals who derive greater benefit from aggressive lipid lowering, Nature Medicine (2025). DOI: 10.1038/s41591-025-03533-w.
Disclaimer: This article is for informational purposes only and does not constitute medical advice. Readers should consult a qualified healthcare professional before making any decisions regarding their health based on this information.
