Aortic stenosis: 200 newly identified genes raise hope for future treatments

The discovery could improve early detection and accelerate the development of treatments for this incurable heart disease.

A new study on aortic stenosis, the most common form of heart valve disease, has identified more than 200 new genes that predispose individuals to this condition, for which no treatment currently exists. The discovery of these genes, some of which are also associated with faster disease progression, could make it possible to identify individuals at high risk of developing the disease, with a view to offering them earlier intervention. It also opens new avenues into treatments aiming to slow or stop the progression of the disease.

The study published in Nature Genetics was co-led by Dr. George Thanassoulis and Dr. Jamie Engert, respectively senior scientist and scientist in the Cardiovascular Health across the Lifespan research Program at the Research Institute of the McGill University Health Centre (The Institute), in collaboration with colleagues from Harvard University and other international researchers. This study is a meta-analysis integrating genetic data from 2.8 million individuals from diverse populations belonging to different ancestral groups. It is the largest genetic analysis of aortic stenosis conducted to date.

“Our study has several major strengths: the inclusion of a large number of individuals, its multi-ancestral design, and the separate analysis of men and women, which enhanced our ability to detect genetic markers within different populations,” explains Dr. Engert. “This work paves the way for the search for new prevention and treatment strategies, which are greatly needed.”

A widely spread disease

Aortic stenosis affects more than 9 million people worldwide. In Canada, it affects nearly 3% of people aged 65 and older. Aortic stenosis is characterized by thickening, hardening, calcification, and/or narrowing of the aortic valve, the opening between the left ventricle of the heart and the aorta. As a result, the heart has to work harder to pump blood through the body, and over time this extra effort weakens it and causes symptoms that reduce patients' quality of life.

Medications may be prescribed to treat symptoms such as shortness of breath, chest pain, palpitations, and dizziness, but they do not prevent the disease from progressing. When the condition becomes too advanced, the only possible intervention is heart valve replacement, either through open-heart surgery or a catheter.

“Our goal is to treat patients as early as possible and provide access to treatments that avoid heart valve replacement, a procedure that is not without risks and for which not all patients are eligible,” says Dr. Thanassoulis.

The genetics behind aortic stenosis

In total, the researchers identified 241 genes—including 200 previously unknown ones—that predispose individuals to developing aortic stenosis. They then created a risk score that can predict the probability of a person developing the disease based on their genetic profile.

“The tool we have developed could improve screening for people at high risk of developing the disease, even before symptoms appear, which often occur at a late stage. In the long term, the score could also be used to select participants for clinical trials of preventive treatment strategies,” explains Dr. Thanassoulis. 

The team also discovered that certain genes are involved in disrupting biological mechanisms specific to the disease, such as inflammation, calcification, lipid metabolism, adiposity and cell division cycle arrest. The team identified two specific genes which, when deactivated, block calcium accumulation in valve cells. They also identified three other genes that may explain certain differences in the development of the disease in men and women.

 “It is important to better understand the mechanisms regulated by each gene and their link to aortic stenosis,” explains Dr. Thanassoulis, “as this could open up many avenues for testing drugs in preclinical models.”

About the study

Genomic and transcriptomic analyses of aortic stenosis enhance therapeutic target discovery and disease prediction by Dr. George Thanassoulis, Dr. Jamie Engert and coll. was published in Nature Genetics. The study was funded by Canadian Institutes of Health Research (CIHR), Heart and Stroke Foundation of Canada (HSFC) and Fonds de recherche du Québec – Santé (FRQS).

DOI : 10.1038/s41588-025-02417-6


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Evelyne Dufresne
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