ATHENA: Atherosclerosis targets from human genetics and functional genomic approaches | 26CVD02

• Thomas QUERTERMOUS, Stanford University (USA)
• Helle F. JØRGENSEN, Cambridge University (UK)

The build-up of atherosclerotic plaque in the blood vessels of the heart and neck can cause heart attack and stroke. Despite current preventive treatments, these diseases remain the leading causes of death and disability worldwide, highlighting a need for new therapeutic drugs. However, we lack drugs that directly target disease pathways in these vessels because the causes of atherosclerosis remain unknown. This LeDucq grant would fund ATHENA, a transatlantic network of experts in human genetics, vascular biology, and cutting-edge genomics that will work together to discover which genes and pathways drive the disease process and integrate these discoveries with patient information to yield better ways to predict and prevent cardiovascular disease.

ATHENA investigators will start by analyzing very large genetic studies, including a unique biobank with over half a million participants and decades of health records, to pinpoint DNA variants that either increase risk of, or protect against, heart attacks and strokes. Next, the ATHENA network will study individual cells in diseased arteries to understand exactly how DNA risk variants act in the vessel wall. This work will create maps in both heart and neck arteries of detailed gene networks to reveal how groups of genes interact in different cell types and disease stages. This type of information will then be fed back into genetic studies to improve how we can predict an individual’s risk of heart attack or stroke.

Finally, ATHENA will test the most promising genes and pathways in experimental models to see which ones truly drive plaque build-up and therefore represent the best drug targets. High-throughput approaches will allow the team to switch hundreds of genes off in mice or human cells and then determine how each change affects cell behavior and plaque buildup. ATHENA’s systematic pipeline, moving from human genetics to artery wall cells to animal models, will generate a prioritized list of validated targets and pathways that future work can leverage to develop new drugs and to more accurately predict risk of disease.