- Coronary artery disease is characterized by dysfunction of endothelial cells, which form the innermost lining of all blood vessels.
- A new study identifies five biological pathways controlled by several genes that may play an important role in coronary artery disease by implicating endothelial cell function.
- Notably, these pathways included genes with no previously demonstrated role in coronary artery disease.
- One of the genes in these pathways is TLNRD1Studies have shown that this protein plays an important role in endothelial function, cardiovascular health, and potentially coronary artery disease.
- These findings may lead to the development of new therapies targeting endothelial dysfunction in coronary artery disease.
Coronary artery disease
These effects of statins are mediated in part by improving vascular health, but therapies that directly target coronary artery disease are lacking.
Identifying genetic risk factors associated with endothelial cell function may aid in the development of vascular-targeted therapeutics.
Research has shown that certain
However, methodological limitations have hindered the identification of key pathways associated with CHD mutations.
A new study combining high-throughput molecular biology techniques and computational methods has identified key biological pathways and novel genes involved in endothelial cell function that may contribute to coronary artery disease risk.
The paper reporting the research results is
Study author Dr Jesse Englerts, assistant professor at Stanford University in California, explained the findings: Today’s Medical News:
“We found that genetic risk factors for coronary artery disease cluster together in a specific pathway in endothelial cells. One of the known roles of this pathway is to regulate the response of endothelial cells to blood flow, and it contains genes that may be excellent targets for therapies that directly target blood vessels.”
“We also discovered new genes that are less well studied. TLNRD1“The vascular endothelial cell line (VEC) plays a key role in this pathway in humans and zebrafish, but has not received much attention until now. The list of genes we identified may also help identify individuals who are genetically predisposed to poor vascular health and who may respond well to existing drugs,” Dr. Engleitz added.
Advances in genome sequencing technology have made it easier to discover genetic mutations associated with several diseases.
Some of these disease-associated genetic variants may control a small number of biological pathways, with each pathway consisting of multiple genes working together.
Although genetic mutations have been identified for several diseases, linking genetic mutations to several converging biological pathways has been difficult.
The majority of these genetic variants identified by genome-wide association studies do not code for proteins: instead, these non-coding variants control the expression of multiple nearby genes involved in biological pathways related to the disease.
However, identifying the specific genes regulated by each mutation and that play a role in disease-related pathways remains challenging.
Additionally, multiple cells are involved in disease onset and progression. Different biological pathways function in each cell type and contribute to disease. The specific biological pathways in specific cell types affected by disease-associated mutations are not fully understood.
In other words, how genetic variants identified in genome-wide association studies affect biological functions is not fully understood.In this study, the researchers investigated the biological pathways associated with genetic variants involved in coronary artery disease.
“Over the past few decades, human genetics has made great strides in identifying variants that influence disease risk,” said Dr. Engleitz. “There are now hundreds of thousands of associations between genetic loci and specific human diseases and traits. This vast repository of knowledge can reveal disease-transmitting genes and potentially lead to the development of treatments.”
“But finding the genes, cell types and pathways that underlie these associations has proven extremely difficult. Sometimes it can take up to 10 years for just one association to solve this ‘mutation-to-function’ problem,” he added.
Genome-wide association studies have identified over 300 genetic variants associated with coronary artery disease. These variants are known to affect cells related to blood vessels and hepatocytes in the liver.
In this study, the authors specifically looked for mutations that affect the function of endothelial cells present in the blood vessel wall.
The researchers used laboratory cultures of genetically modified endothelial cells taken from the human aorta, the blood vessel that carries oxygenated blood to the rest of the body.
The genomes of these endothelial cells were sequenced, and computational modeling was used to map genes whose expression is affected by coronary artery disease-associated mutations.
Using data on coronary artery disease-associated mutations identified in previous studies, the researchers identified approximately 2,000 genes close to these mutations.
Of these genes, expression of 254 genes was regulated by CHD-associated mutations.
The researchers identified programs or pathways that are associated with coronary artery disease.
The researchers then examined changes in gene expression profiles in aortic endothelial cells when individual candidate genes were inhibited.
Using computational methods, genes that showed similar patterns of change in expression profiles were classified as co-regulated genes.
These co-regulated genes were classified as biological programs or pathways. The analysis generated 50 such programs, some of which were involved in processes not specific to endothelial cells or coronary artery disease.
The researchers next looked for over-represented programs of 254 genes controlled by CHD-associated mutations. They identified five programs containing 41 CHD-associated genes and 43 mutations.
These programs included genes implicated in coronary artery disease, but the majority of genes in these pathways have yet to be identified as risk factors for the disease.
What’s more, all five programs were regulated by genes linked to pathways associated with cerebral cavernous hemangiomas (CCMs), a condition in which clusters of small abnormal blood vessels form in the brain.
Specifically, the analysis results showed that: CCM2 Genes in the CCM pathway, along with other genes, were involved in regulating all five coronary artery disease pathways.
Previous studies have shown that the CCM pathway
but, CCM2 No other CCM pathway genes have been shown to be involved in coronary artery disease. In this study, we found that inhibiting expression of the CCM pathway modulated the expression of genes shown to be involved in coronary artery disease. These findings indicate that genes in the CCM pathway are involved in coronary artery disease.
The researchers further identified a new CCM pathway gene, TLNRD1They are, TLNRD1 This gene is one of the most powerful regulators of five coronary artery disease pathways; TLNRD1 Its role in endothelial cell function has not been elucidated so far.
The researchers: TLNRD1 Interact CCM2 And as a result, TLNRD1 Performed a similar function CCM2Confusion of TLNRD1 In laboratory-cultured cells, the barrier function of endothelial cells was altered, and this impaired barrier function is thought to be linked to cardiovascular disease.
moreover, TLNRD1 Expression in zebrafish also had adverse effects on cardiac and vascular development in a zebrafish model.
These results are TLNRD1 This gene maintains blood flow and may be a risk factor for developing coronary artery disease.
The methodological approach used in this study may not only help identify new therapeutic targets for coronary artery disease but also facilitate the discovery of new biological pathways relevant to other diseases.
Dr Englietz said: “In this study, we developed a new methodology to draw lessons from human genetic data. Here, we took a novel approach that leverages the CRISPR tool, which we use to simultaneously disrupt all candidate genes in different endothelial cells in a dish and measure what happens to these cells. From there, we use computational models to learn which sets of genes work together in a pathway.”
“This comprehensive and systematic data allows us to better interpret the genetic associations and identify the causative gene among the 40 genes. [approximately] “We can look at 300 genetic loci for coronary artery disease in one go, and we think this tool will be a powerful approach to study many other genetic diseases in the future,” Dr. Englietz added.
“The results are encouraging,” said Dr. Cheng-Han Chen, a board-certified interventional cardiologist and medical director of the structural heart program at MemorialCare Saddleback Medical Center in Laguna Hills, California, who was not involved in the study.
“This work has the potential to open up an entirely new field of research, as it may be possible to more efficiently identify molecular links between genetic mutations and clinical disease. Such a strategy would enable researchers to target biological pathways through treatments and improve clinical outcomes.”
