New Study Reveals Heart Disease Triggered by Complex Networks of Genes

Victor Chang Cardiac Research Institute

Scientists have revealed how heart disease can be triggered by complex networks of genes that interact on a scale never known before.

The findings from an international team of scientists including the Victor Chang Cardiac Research Institute in Sydney, the Icahn School of Medicine at Mount Sinai in New York, and the Karolinska Institute in Sweden, present a whole new avenue for screening conditions such as coronary heart disease, Australia’s biggest killer.

The study published in the launch issue of Nature Cardiovascular Research, a new journal in the prestigious Nature portfolio, found that up to 60 percent of the risk associated with coronary artery disease may be explained by changes in the activity of hundreds of genes working together in networks across several organs in the body.

The genes of hundreds of patients with coronary artery disease were studied from data collected in the STARNET study and it was also found that fat processing hormones may play a central role in coordinating the gene activity.

Co-author Professor Jason Kovacic, Executive Director at the Victor Chang Cardiac Research Institute, says they now have a clear picture of how these networks of genes work together to cause heart disease.

“We have long suspected that the genes we inherit play a far larger role in our chances of developing conditions such as coronary heart disease, but until now we didn’t know just how these genes were working together,” says Professor Kovacic.

“It turns out that there are vast and complex networks of genes at work, which are signalling to one another and for the first time we now have a comprehensive map of how they are operating. This has never been accounted for until now and shines a whole new light on how and why we are predisposed to heart disease.

“This opens up the possibility of being able to far more accurately predict a person’s risk of heart disease, which would allow for earlier assessments and potentially better treatments.”

Coronary heart disease is a complex disease caused by thousands of genes that interact with other risk factors like smoking and obesity – which means screening for the condition has long been a difficult and unreliable process. The new findings could significantly change that.

The work was led by senior author Dr Johan L.M. Bjorkegren, from Icahn School of Medicine, who began the study 20 years ago when working as a heart surgeon.

Six hundred of the patients who were studied had coronary artery disease whereas the other 250 did not. Tissue samples were collected by researchers in the lab of Arno Ruusalepp, MD, PhD, who is chief vascular surgeon at the Tartu University Hospital in Estonia.

Gene activity was analyzed from the following tissue samples: blood, liver, skeletal muscle, visceral abdominal and subcutaneous fat, and two pieces of the arterial wall taken from different parts of the heart.

Researchers tested out the different ways that gene activity may be associated with the development of coronary artery disease They used advanced computer programs to test out how the activity of all of the disease-related genes were grouped together in different combinations.

Although recent studies have shown that about 20 percent of the risk associated with this disease may be linked to slight differences in a person’s DNA sequences, the new results showed that an additional 54-60 percent of the risk associated with coronary artery disease could be explained by 224 of these gene regulatory networks and that many of these networks could help explain the status of arteriosclerosis severity in individual cases. Of those networks, 135 were located within one type of tissue whereas the remaining 89 represented coordinated gene activity across multiple tissues.

The multi-tissue networks appeared to have the greatest impact. On average they could explain three times more of the disease risk than the single-tissue ones. One example of a multi-tissue network, called GRN165, accounted for 4.1 percent of the risk for coronary artery disease and involved 709 genes active in the arterial wall as well as the subcutaneous fat tissue.

“We found that gene networks work like airplane traffic patterns. Just as a delay at one airport in a key state can disrupt flights in the entire nation, we found that a slight change in the activity of key genes in one tissue can disrupt the activity of other genes throughout rest body,” said Dr. Bjorkegren, from Icahn School of Medicine at Mount Sinai.

Finally, the analysis suggested that hormones that help fat cells communicate with other organs—particularly the liver—play a critical role in coordinating the multi-organ networks. Support for this idea was, in part, based on experiments in mice when injections of some of these hormones altered blood fat and sugar levels.

“This research will be central to the development of ‘precision medicine’ – where patients are diagnosed and treated depending on how their unique genetics interact with risk factors in the environment,” says Professor Kovacic.

“Here, gene-regulatory networks may play a central role as an explanatory model to be used with the increasingly sophisticated molecular screening tools we have at our disposal today.

“We expect our findings will be translated into the clinical work of diagnosing and treating patients. Indeed, we are already working on this. We believe it’s highly likely that we will be able to map a patient’s gene networks and detect their disease risk.”

This research could also lead to the development of specific therapies for many of the new gene targets that have been found, and also allow for the possibility of being able to alter the most important, or apex genes in each network.

“It may also eventually see us altering problem genes at the top of the gene network, which can impact the hundreds or thousands of genes below, and lessen the risk from certain conditions,” adds Professor Kovacic. “In addition, it’s almost certain that these gene networks are critical to many other human diseases like high blood pressure, diabetes and stroke. So this is the beginnings of a whole new way of working to better understand and treat diseases. The future implications for our patients are enormous.”

/Public Release.