New Genetic Risk Score Identifies Individuals at Risk for Heart Disease Who May Benefit Most from Cholesterol-Lowering Therapies

Researchers analyzed genes associated with endothelial cell function to pinpoint people that were at greater risk of atherosclerosis and who benefited the most from lowered cholesterol levels  

Coronary artery disease (CAD), or the narrowing of the coronary arteries, is the leading cause of morbidity and mortality throughout the world. Atherosclerosis, or the buildup of plaque in the arteries, develops when low-density lipoprotein cholesterol (LDL-C) enters the blood vessel walls through dysfunctional endothelial cells (EC), leading to the formation of plaques. Researchers from Mass General Brigham developed a polygenic risk score that examines genes associated with EC function to identify individuals with higher CAD risk. Their results are published in Nature Medicine.

“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. As a result, patients who are LDL-C sensitive have a much greater benefit from aggressive cholesterol-lowering therapies, creating an opportunity for personalized prevention plans,” said lead author Nicholas Marston, MD, MPH, from the Division of Cardiovascular Medicine at Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system.

The research team identified 35 single nucleotide polymorphisms—single “letter” genetic changes—that were connected to EC function and CAD, to create a risk score that they then used to make predictions while following participants in three separate study populations. They found that individuals with high EC risk benefited greatly from LDL-C lowering therapies, and that the score could be used to predict CAD risk.

One of the main limitations of the risk score that the team developed is that it does not directly measure endothelial cell function. In the future, the researchers would like to assess phenotypes and serum biomarkers, as well as analyze environmental factors like smoking that can adversely affect endothelial cells.

Authorship: In addition to Marston, Mass General Brigham researchers, Frederick K. Kamanu, Giorgio E.M. Melloni, Gavin Schnitzler, Aaron Hakim, Daniel I. Chasman, Robert P. Giugliano, Patrick T. Ellinor, Paul M. Ridker, Marc S. Sabatine, Christian T. Ruff, and Rajat M. Gupta. Additional authors include Rosa X. Ma, Helen Kang, and Jesse M. Engreitz.

Disclosures: Marston reports research grants through BWH: Amgen, Ionis, Pfizer, Novartis, and AstraZeneca. Consultant: Amgen, Beckman Coulter. Honoraria for Lecture/CME Programs: Medical Education Speakers Network (MESN). Additional disclosures can be found in the paper.

Funding: Marston receives grant funding from the National Institutes of Health (NIH) K08HL153950. JPP is supported by NIH K08HL159346.

Paper Cited: Marston, N et al. “Endothelial Cell Genetic Risk Variants Identify LDL Cholesterol-Sensitive Patients Who Benefit from Aggressive Lipid Lowering Therapy” Nature Medicine DOI: 10.1038/s41591-025-03533-w