Elucidating new causes of heart disease and cerebrovascular disorders

overview:

• Research shows how genetic mutations can affect the biology of cells lining blood vessel walls and increase the risk of heart disease.
• The study identified genes involved in both cerebrovascular malformations, a rare disease, and heart disease, the number one cause of death worldwide.
• The findings could help design new diagnostic tools and precisely targeted treatments for these conditions.

Over the past 15 years, scientists have identified hundreds of regions in the human genome that are associated with heart attacks, but scientists are unsure how genetic mutations can alter biological function and ultimately lead to cardiovascular disease. I couldn’t pinpoint exactly what it is. This makes it impossible to design precisely targeted therapies that treat heart disease at its root, at the cells in the blood vessel walls where the disease originates.

Now, a new approach developed by scientists at Harvard Medical School at Brigham and Women’s Hospital and colleagues at the Broad Institute of MIT, Harvard University, and Stanford Medicine promises to close this gap.

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A new technology, the variant-to-gene-to program, combines several tools of genetic analysis to study how changes in genetic structure alter the biology and function of the epithelial cells lining blood vessel walls. , reveal what causes the dysfunction.

Research conducted on human blood vessel cells and published February 7th Nature, establishes ways to link genetic changes to biological function and dysfunction. Equally important, the findings suggest treatments that affect the cells lining blood vessels and have the potential to prevent and treat the dysfunction that causes disease.

Additionally, the study found that previously unsuspected changes in specific genes implicated in cardiovascular disease may contribute to the development of heart disease, the leading cause of death in the United States, and a rare but often fatal disease. found that it may promote both the formation of heart disease. Cerebral vascular malformations.

“Studying how hundreds of regions of the genome influence heart attack risk, individually or in groups, can be a painstaking process,” said the study’s co-senior authors. Ta rajat gupta HMS Assistant Professor of Medicine and Physician genetics and Cardiology at Brigham and Women’s Hospital.

“We decided that we needed a better map of how genetic variation affects gene expression and how genes affect biological function. “If we can combine the two types of maps, we will be able to make larger connections from variation to biological function,” he added.

Combining gene editing, AI, etc. to find the cause of pranks

The researchers first looked at regions of the human genome previously associated with coronary artery disease and then linked these regions to the function of specific genes.

Then, using a tool developed at the Broad Institute called CRISPRi-Perturb-seq, the researchers “delete” thousands of genes associated with heart disease in individual cells one at a time. did. In doing so, scientists were able to determine how deletions in individual genes affect the activity of all other genes within a given cell.

In total, the researchers analyzed 215,000 blood vessel lining cells to see how the 2,300 deletions affected the expression of the other 20,000 genes within each cell. Then, with the help of AI, the researchers were able to link consistently occurring changes in the biological function of blood vessels to genetic mutations already associated with heart disease.

The analysis showed that 43 of the 306 genetic variants associated with heart disease were also associated with genes involved in the development of heart disease. cerebral cavernous malformationa group of rare but devastating vascular disorders characterized by abnormally formed and malfunctioning blood vessels in the brain.

Furthermore, the researchers found that certain genes TLNRD1 Its biological function was previously unknown, but it appears to play a dual role in the development of cerebrovascular malformations and heart disease.