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

New research into aortic valve stenosis, the most common form of heart valve disease, has identified more than 200 new genes that predispose people to the condition, for which there is currently no treatment. The discovery of these genes, some of which are associated with faster disease progression, may make it possible to identify individuals at high risk of developing the disease for the purpose of early intervention. It also opens new avenues for treatments aimed at slowing or stopping the progression of the disease.

The study, published in Nature Genetics, was co-authored with Dr. George Thanassoulis. Dr. Jamie Engert, They are respectively senior scientists and scientists in the McGill University Health Center Research Institute (Institute)’s Cardiovascular Health Research Program across the lifespan, in collaboration with colleagues at Harvard University and other international researchers. This study is a meta-analysis that integrates genetic data from 2.8 million people from diverse populations belonging to different ancestral groups. This is the largest genetic analysis of aortic stenosis ever performed.

“Our study has several major strengths: the inclusion of a large number of individuals, the multi-ancestral design, and the separate analysis of males and females improved our ability to detect genetic markers within different populations,” explains Dr. Engert. “This study paves the way for the search for much-needed new prevention and treatment strategies.”

widely spread disease

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

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

“Our goal is to treat patients as early as possible and provide access to treatments that avoid heart valve replacement surgery, which is not without risk and not available to all patients,” Dr. Tanaslees says.

The genetics behind aortic stenosis

Researchers identified a total of 241 genes, including 200 previously unknown genes, that predispose people to developing aortic stenosis. They then created a risk score that can predict a person’s chances of developing the disease based on their genetic profile.

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

The research team also found that specific genes are involved in the disruption of biological mechanisms characteristic of the disease, including inflammation, calcification, lipid metabolism, obesity, and cell division cycle arrest. The research team identified two specific genes that, when inactivated, 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 relationship to aortic stenosis. This could open many avenues for testing drugs in preclinical models,” explains Dr. Tanasreece.

About research

Genomic and transcriptomic analysis of aortic stenosis enhances therapeutic target discovery and disease prediction Written by Dr. George Thanassoulis, Dr. Jamie Engert, and coll. Published in natural genetics. This research was funded by Canadian Institutes of Health Research (CIHR), Heart and Stroke Foundation of Canada (HSFC), and Fondation du Québec Santé (FRQS).

Doi: 10.1038/s41588-025-02417-6

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Evelyn Dufresne
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McGill University Health Center (MUHC)
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