Researchers have developed a method to link knowledge about genetic variants to the cellular signalling pathways that increase the risk of developing coronary artery disease. A researcher says that this vastly improves understanding of how genetic variants influence the risk of developing coronary artery disease and provides new drug targets.
Research within the past 15 years has shown that many genetic variants are linked with an increased risk of developing coronary artery disease.
Although these genetic variants have been known, researchers have not yet been able to link them to cellular signalling pathways and thus their function in cells, leading to incomplete knowledge of the links between the identified genetic variants and understanding the development of disease.
Researchers have now established this link in a new study showing which cellular signalling pathways many of the genetic variants influence.
This gives researchers new understanding of the mechanisms that increase some people’s risk of coronary artery disease but not others – and provides new targets for drug development.
“Existing small molecules can affect the most relevant signalling pathway, and we now need to investigate whether these small molecules can be further improved to reduce the risk of developing coronary artery disease,” explains a researcher behind the study, Jesse Engreitz, Assistant Professor, Department of Genetics, Stanford University, Palo Alto, CA, USA and investigator in the Novo Nordisk Foundation Center for Genomic Mechanisms of Disease at the Broad Institute, Cambridge, MA, USA.
The research, which was carried out in collaboration with Professor Rajat Gupta from Brigham Women’s Hospital and Harvard Medical School, has been published in Nature.
300 genetic variants associated with coronary artery disease
The researchers focused on coronary artery disease, the most common cause of death in Denmark.
Statins are the standard treatment for people who risk developing coronary artery disease. However, for many people, statins alone cannot prevent either coronary artery disease or other cardiovascular diseases.
The researchers therefore investigated the role of 300 genetic variants associated with an increased risk of developing coronary artery disease in the endothelial cells surrounding the blood vessels.
These 300 genetic variants are known from genome-wide association studies using large data sets comprising many hundreds of thousands of people to identify genetic variants linked to the risk of developing specific diseases.
“Although we know which genetic variants are linked with increased risk of developing coronary artery disease, we do not know which genes they affect and thus which signalling pathways they influence. This study aimed to establish this link,” says Jesse Engreitz.
He adds that previous studies have identified the significance of some of these genetic variants, but this took many years.
“We need to be able to accelerate this process so that we can identify the significance of all genetic variants at the same time. This applies not only to coronary artery disease but also to many other diseases,” explains Jesse Engreitz.
A new genetic tool
The researchers used a variant-to-gene-to-programme approach that combines CRISPR technology and computational modelling to investigate how changing all possible candidate disease-linked genes affects the expression of all other genes in endothelial cells.
This enabled the researchers to determine which genes and thus which signalling pathways the genetic variants influence.
The researchers sequenced 215,000 endothelial cells to determine how 2,300 disturbances in the DNA affected the expression of 20,000 genes in each cell.
Then the researchers used an algorithm to organise all the data and thereby identify the genes and signalling pathways that were most affected by the genetic variants and thus were most strongly linked to coronary artery disease.
Many genes influence the same signalling pathway
The results showed that 43 of the genetic variants were linked to the function of a single signalling pathway – the cerebral cavernous malformation signalling pathway.
“Cerebral cavernous malformation is a very rare disease with abnormally formed blood vessels in the brain and it has previously been shown that the loss of function of this signalling pathway causes the malformations in the brain and spinal cord. However, we were surprised that common genetic variants linked to the risk of developing coronary artery disease are also linked to the function of this signalling pathway,” says Jesse Engreitz.
Marker genes detect blood flow
The researchers also found that some of the genes involved in the cerebral cavernous malformation signalling pathway have specific roles in vascular health.
One such gene is nitric oxide synthase (NOS3), which increases the production of nitric oxide when the endothelial cells detect the blood flow in the arteries.
“Atherosclerosis predominantly develops in regions of disrupted or turbulent blood flow. We identified genetic variants linked to genes that enable the endothelial cells to detect how blood flows. This links the genetic variants to genes and their function to the risk of disease,” explains Jesse Engreitz.
May lead to novel treatments
Jesse Engreitz says the study provides much better understanding of how genetic variants lead to disease.
Armed with this new knowledge, the researchers are now focusing on understanding these interactions better and developing new treatments and are planning to investigate the potential of existing preclinical small molecules to influence the signalling pathway identified.
These molecules were actually developed to treat people with some types of cancer but may have a role in treating people with increased risk of coronary artery disease.
“This new knowledge might enable us to identify people with an increased risk of developing coronary artery disease but not benefitting from statins. These people need a new type of treatment, and we may have identified a relevant signalling pathway for future drug development,” says Jesse Engreitz.
He elaborates that additional research will also determine the role of genetic variants in signalling pathways in relevant cells other than endothelial cells.
“The variant-to-gene-to-programme approach can also be used to identify the influence of genetic variants on signalling pathways linked to other types of diseasess and cells– including how genetic variants are linked to the function of signalling pathways in the fat cells or liver cells of people with an increased genetic risk of developing type 2 diabetes,” concludes Jesse Engreitz.
