In a breakthrough discovery, researchers have identified the biological drivers behind the risk of developing heart disease. For the past 15 years, scientists have identified numerous regions in the human genome that are associated with an increased risk of heart attacks. However, until now, there has been a lack of efficient methods to explore how these genetic variants are connected to cardiovascular disease on a molecular level. This limitation has hindered the development of effective therapeutics for heart disease.
To address this issue, a team of researchers from Brigham and Women’s Hospital, in collaboration with the Broad Institute of MIT and Harvard and Stanford Medicine, used a combination of sequencing and experimental techniques to map the relationship between known genetic variants associated with coronary artery disease (CAD) and the biological pathways they affect. Their findings were published in the journal Nature.
The researchers focused on endothelial cells, which line the blood vessels, as these cells play a crucial role in cardiovascular health. By analyzing hundreds of genome regions individually or in groups, the team aimed to uncover the mechanisms through which these variants influence the risk of heart attacks. Rajat Gupta, MD, corresponding author of the study and from the Divisions of Genetics and Cardiovascular Medicine at Brigham and Women’s Hospital, explained the motivation behind the research: “We decided we needed to have better maps showing how genetic variants affect gene expression and how genes affect biological function. If we could combine those two kinds of maps, we could make the bigger connection from variant to biological function.”
To achieve this, the researchers developed a mapping technique called the Variant-to-Gene-to-Program (V2G2P) approach. They began by linking CAD regions previously identified through genome-wide association studies to the genes affected by these genetic variants, in collaboration with Stanford Medicine. Next, they utilized CRISPRi-Perturb-seq, a technology developed at the Broad Institute of MIT and Harvard, to delete thousands of CAD-associated genes one by one. This allowed them to observe how each deletion affected the expression of all other genes in the cell.
In total, the researchers sequenced 215,000 endothelial cells to determine the impact of 2,300 deletions on the expression of 20,000 other genes in each cell. By employing machine learning algorithms, they were able to identify consistent biological mechanisms related to CAD-associated variants. Interestingly, they discovered that 43 out of 306 CAD-associated variants in endothelial cells were linked to genes in the cerebral cavernous malformations (CCM) signaling pathway.
CCM is a rare, devastating vascular disease that primarily affects the brain. However, the researchers hypothesized that subtle mutations in the genes involved in CCM may also contribute to the risk of developing CAD. These mutations could potentially influence vascular inflammation, thrombosis, and the structural integrity of the endothelium. Furthermore, the researchers highlighted the previously unrecognized role of the TLNRD1 gene in regulating the CCM pathway, alongside other known CCM regulators. They suggested that TLNRD1 may be involved in both CAD, a common disease, and CCM, a rare one.
This groundbreaking research provides valuable insights into the biological mechanisms underlying heart disease risk. By understanding how genetic variants impact gene expression and biological function, researchers can develop targeted therapeutics to potentially mitigate the risk of heart attacks. Additionally, the study sheds new light on the connection between CAD and CCM, opening up possibilities for further investigation and potential treatment strategies for both diseases.
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1. Source: Coherent Market Insights, Public sources, Desk research
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