What makes some people more susceptible to heart disease?
- Coronary artery disease is characterized by a
dysfunction of the endothelial cells that form the innermost lining of all
blood vessels.
- A new study has identified five biological
pathways regulated by a few genes that could potentially play a prominent
role in coronary artery disease through their involvement in endothelial
cell function.
- Notably, these pathways included genes whose
role in coronary artery disease has not been previously demonstrated.
- One of the genes in these pathways, TLNRD1,
plays an essential role in endothelial function, cardiovascular health,
and potentially coronary artery disease, according to the study.
- These findings could lead to the development of
novel therapies targeting endothelial cell dysfunction in coronary artery
disease.
Coronary
artery disease is the
These effects of statins are mediated, in part, by
improving blood vessel health. However, there is a lack of therapies for
coronary artery disease that directly target the
Identifying genetic risk factors associated with
endothelial cell function could help develop therapeutics that target blood
vessels.
Research has shown that specific
However, methodological limitations have impeded the
identification of major pathways associated with coronary artery disease
variants.
A new study using a combination of high-throughput
molecular biology techniques and computational methods has identified major
biological pathways and novel genes involved in endothelial cell function that
could contribute to the risk of coronary artery disease.
The paper reporting the study findings appears in
Study author Dr. Jesse Engreitz, assistant professor at
Stanford University, CA, explained the findings to Medical News Today:
“We found that genetic risk
factors for coronary artery disease converge onto a particular pathway in
endothelial cells. One of the known roles of this pathway is to tune
endothelial cell responses to blood flow, and includes genes that could prove
to be good targets for therapies that directly target blood vessels.”
“We also found a new understudied gene, TLNRD1,
that plays a key role in this pathway in humans and zebrafish but has
previously eluded notice. The list of genes we identified might also prove
helpful in identifying individuals who are genetically predisposed to having
poor vascular health and, therefore, may respond better to existing
medications,” added Dr. Engreitz.
How researchers pinpointed genetic risk factors for heart
disease
Advances in genome sequencing technologies have
facilitated the discovery of genetic variants associated with several diseases.
These
Several of these genetic variants associated with a
disease likely regulate a small number of biological pathways, with each
pathway consisting of several genes that work together.
Although genetic variants have been identified for
several diseases, linking genetic variants to a few converging biological
pathways has been challenging.
A majority of these genetic variants identified by
genome-wide association studies do not code for proteins. Instead, these
noncoding variants regulate the expression of multiple genes nearby that are
involved in biological pathways associated with the disease.
However, identifying the specific genes regulated by
each variant and playing a role in disease-associated pathways remains
challenging.
Moreover, multiple cells contribute to the development
and progression of a disease. Different biological pathways operate in each
cell type and contribute to the disease. The specific biological pathways in a
particular cell type impacted by disease-associated variants have not been
fully characterized.
In other
words, how genetic variants identified using genome-wide association studies
affect biological function is not well understood. In the present study, the
researchers investigated the biological pathways associated with genetic
variants that are involved in coronary artery disease.
Dr . Engreitz said: “Human genetics has been immensely
successful over the last decades in identifying variants that influence risk
for disease — there are now 100,000s of associations between genetic loci and
particular human diseases and traits. This vast trove of insights could reveal
genes that mediate disease and guide therapeutic development.”
“But, it has proven extremely difficult to find the
genes, cell types, and pathways underlying each of these associations.
Sometimes, it can take a decade to solve this “variant-to-function” problem for
even one association,” he added.
254 genes linked to coronary artery disease
More than 300 genetic variants have been identified for
coronary artery disease using genome-wide association studies. These coronary
artery disease-associated variants are known to impact cells associated with
blood vessels and hepatocytes in the liver.
In the
present study, the authors specifically examined the variants impacting the
function of endothelial cells that are present in the walls of blood vessels.
The researchers used laboratory cultures of
genetically modified endothelial cells obtained from the human aorta, the blood
vessel that carries oxygenated blood to the rest of the body.
The genome of these endothelial cells was sequenced,
and then a computational model was used to map genes whose expression was
influenced by the coronary artery disease-associated variant.
With the help of data on coronary artery
disease-associated variants identified by previous studies, the researchers
identified nearly 2,000 genes close to these variants.
Among
these genes, the expression of 254 genes was regulated by the coronary artery
disease-associated variants.
The researchers then identified the programs or
pathways associated with coronary artery disease. They used
Subsequently, the researchers examined the changes in
the gene expression profile of the endothelial aorta cells upon the inhibition
of individual candidate genes.
Using computational methods, genes that showed similar
patterns of changes in expression profile were categorized as coregulated
genes.
These coregulated genes were classified as a
biological program or pathway. The analysis generated 50 such programs, several
of which were involved in processes that were not specific to endothelial cells
or coronary artery disease.
Gene involved in blood flow regulation may be key
The researchers then examined programs in which the 254
genes regulated by coronary artery disease-associated variants were
overrepresented. They identified five such programs, which encompassed 41
coronary artery disease-associated genes and 43 variants.
While these programs included genes that have been
implicated in coronary artery disease, a majority of genes in these pathways
have not yet been identified as risk factors for this condition.
In
addition, all five programs were regulated by genes associated with the pathway
associated with cerebral cavernous malformations (CCM), a
condition involving the formation of tiny, abnormal clusters of blood vessels
in the brain.
Specifically, the analysis revealed that the CCM2 gene
and other genes in the CCM pathway were involved in the regulation of all five
coronary artery disease pathways.
Previous studies have shown that the CCM pathway
However, CCM2 and other CCM pathway
genes have not been shown to be involved in coronary artery disease. The
present study found that inhibiting the expression of CCM pathways modulated
the expression of genes that have been shown to be involved in coronary artery
disease. These findings indicate the involvement of genes in the CCM pathway in
coronary artery disease.
The researchers further examined the role of one of
the novel CCM pathway genes, TLNRD1. They focused on TLNRD1 because the gene is one of the strongest
regulators of the five coronary artery disease pathways. The role of TLNRD1 in
endothelial cell function has not been characterized so far.
The researchers found that TLNRD1 interacts with CCM2 and, consequently, examined whether TLNRD1 performed
a function similar to CCM2. The disruption of TLNRD1 in cells cultured in the laboratory
altered the barrier function of endothelial cells. Such an impaired barrier
function of endothelial cells has been implicated in cardiovascular diseases.
In addition, the disruption of the TLNRD1 expression
in zebrafish also adversely impacted heart and blood vessel development in a
zebrafish model.
These
results support the role of the TLNRD1 gene in
sustaining blood flow and could be a risk factor for coronary artery disease
development.
New
approach to genetic research of heart disease
Besides aiding the identification of new therapeutic
targets for coronary artery disease, the methodological approach used by the
study could facilitate the discovery of novel biological pathways associated
with other diseases.
Dr. Engrietz said: “In this study, we developed a new
methodology to extract lessons from human genetic data. Here, we took a new
approach leveraging CRISPR tools, which we use to simultaneously break every
candidate gene 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 are working together in pathways.”
“With this comprehensive and systematic data, we are
able to much better interpret genetic associations and here identify likely
causal genes for 40 out of [approximately] 300 loci for coronary artery disease
in a single pass. We think this tool will be a powerful approach for studying
many other heritable diseases in the future,” added Dr. Engrietz.
Dr. Cheng-Han Chen, board-certified
interventional cardiologist and medical director of the Structural Heart
Program at MemorialCare Saddleback Medical Center in Laguna Hills, CA, not
involved in this study, commented that:
“This research has the
potential to open an entirely new field of research, as it might be able to
identify the molecular connections more efficiently between gene variants and
clinical disease. With such a strategy, researchers would then be able to
target the biological pathways through therapeutics to improve clinical
outcomes.”
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