Heart Disease Risk: New Genetic Score & Cholesterol Therapy
- A novel polygenic risk score may help predict an individual's likelihood of developing coronary artery disease (CAD), the world's leading cause of death.
- The research suggests that some individuals' endothelial function protects them, while others' EC dysfunction heightens sensitivity to LDL-C concentrations, amplifying cardiovascular event risk.
- The team pinpointed 35 single nucleotide polymorphisms tied to EC function and CAD.
New Risk Score Predicts Coronary Artery Disease Risk
Updated June 02, 2025
A novel polygenic risk score may help predict an individual’s likelihood of developing coronary artery disease (CAD), the world’s leading cause of death. Mass General Brigham researchers developed the score by examining genes linked to endothelial cell (EC) function, according to a study published in Nature Medicine. The score aims to identify those at higher risk of CAD, which arises from atherosclerosis, or plaque buildup in arteries.
The research suggests that some individuals’ endothelial function protects them, while others’ EC dysfunction heightens sensitivity to LDL-C concentrations, amplifying cardiovascular event risk. According to Nicholas Marston, MD, MPH, of Brigham and Women’s Hospital, those with LDL-C sensitivity benefit more from aggressive cholesterol-lowering therapies, allowing for personalized prevention.
The team pinpointed 35 single nucleotide polymorphisms tied to EC function and CAD. They used these to create a risk score and make predictions across three study populations. Results showed that individuals at high EC risk saw significant benefits from LDL-C lowering treatments, and the score effectively predicted CAD risk.
“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. Consequently, patients who are LDL-C sensitive have a much greater benefit from aggressive cholesterol-lowering therapies, creating an prospect for personalized prevention plans,” said lead author Nicholas Marston, MD, MPH, from the Division of Cardiovascular Medicine at Brigham and Women’s Hospital.
What’s next
Future research will focus on directly measuring endothelial cell function, as the current risk score does not. The researchers plan to assess phenotypes, serum biomarkers, and environmental factors like smoking, which can negatively impact endothelial cells.