It is sometimes difficult to measure the impact of scientific research on people and society. But it is very clear with Connie Bezzina: her research has important consequences for people who can die at a young age from sudden cardiac arrest without any warning. Bezzina’s research makes it possible to identify them in time and to treat them preventively.

In 1997, Bezzina began her genetic research on hereditary heart disease. This disease carries a high risk of sudden cardiac arrest and cardiac death in apparently healthy, young people. Usually, they have not even reached age 40 when it happens. If someone goes into cardiac arrest — due to the heart beating too quickly or slowly, for example — there is a high risk of death or permanent neurological damage. Bezzina gave herself the task to identify these people before they experience their first arrhythmia or cardiac arrest.

“We are looking at 2 types of disorders,” the professor of Molecular Cardiogenetics explains. “On the one hand, abnormalities in the electrical activity of the heart, which causes it to beat too quickly or slowly. And on the other hand, problems with the heart muscle itself, which can sometimes be too thin and weak or too thick and stiff. We call those cardiomyopathies. So this means, we are looking for genetic mutations that can cause cardiac arrest due to electrical or muscular problems.”

Family research

Initially, the investigation focused on families in which several young individuals had experienced arrhythmias and sometimes died of sudden cardiac arrest. “We determined which part of the chromosomes was shared by the affected family members and we then looked for the gene responsible in this part.” The classical genetic approach turned out to be very successful. Together with colleagues from Amsterdam UMC, Bezzina identified many new mutated genes that could cause sudden cardiac death like this.
This was also quickly received in health care. Cardiogenetic clinics were set up, where genetic testing became standard and patients and their families were seen by a comprehensive team of specialists including at least one cardiologist and one clinical geneticist.

Genetic modifiers

But in the process, it became clear that there was more to it. Bezzina sometimes saw that people with the same genetic defect had very different symptoms. While one experienced almost no discomfort from the mutation, the other had serious heart problems. They sometimes saw older people who had never experienced arrhythmias and who showed little to no abnormalities on an ECG or MRI as well as children who experienced cardiac arrest very early on. It is the same genetic mutation with completely different symptoms.

We thought that maybe there were many more genetic factors that played a role. A smaller role, but still: a role
Connie Bezzina
Professor Molecular Cardiogenetics

Bezzina: “Initially, we considered environmental factors, such as gender differences or if someone moves a lot or not — things like that. Those certainly have an influence, but they could only explain parts of the large differences we saw. At the same time, we often saw people with a heightened risk who did not have family members with the same problem. Truly individual cases. Both factors have led us to look at the problem from a different angle. We thought that maybe there were many more genetic factors that played a role. A smaller role, but still: a role. These additional factors, also called genetic modifiers, formed an important new hypothesis that once again added quite a bit of depth to our work.”

Looking at hereditary heart disease in a new way

So, what did they find? Genetic modifiers exist. Some genetic mutations have a lot of influence, others have less. Slowly but steadily, a new model emerges. Bezzina: “In large families we often see genetic mutations that are enough to cause heart disease on their own. This is called a monogenetic disease. But there are also genetic mutations that are slightly below the ‘disease threshold’. Those need the help of several genetic modifiers to pass the threshold and in turn, cause cardiac arrhythmias. Some modifiers increase the risk for disease, but others decrease it. That's the idea.”
“So, we are looking at a complex story, in which heart problems on the one hand are caused by just one genetic mutation, and on the other hand by a large number of genes with a small risk, which add up to a similar effect. With all kinds of variations in between.”

Publications in Nature Genetics

In 2013, Bezzina had already published a paper in Nature Genetics, in which she pointed to the role of genetic modifiers in Brugada syndrome, a hereditary condition in which the electrical activity of the heart is disturbed. With this she showed that the idea is correct. Recently, two new papers were added, again in Nature Genetics, and this time for the relatively more common heart disease hypertrophic cardiomyopathy, or HCM (thickened heart muscle). At least 16 genetic modifiers were named in the first paper. In the second paper, which was published in collaboration with scientists from Oxford, the role of additional genetic factors for this heart disease was further underscored. There will soon be a publication in the same journal, which focuses on the role of genetic modifiers in Brugada syndrome, based on a larger study of nearly 3,000 patients.

Large databases

This has moved the research into a new phase. The focus has shifted from research in families to large-scale research at a national and preferably even international level. Large databases that record genetic data and clinical information from large groups — preferably over longer periods of time — will be used. This costs a lot of money and organizational power. But it has to happen, because it is the only way to map out the tens, maybe even hundreds of genetic modifiers, each with their own impact.
What helps is that medical and technical developments have not been at a standstill in the meantime. In the beginning of the study, they only looked for mutations in genes that could cause heart problems. They only looked for genes that ‘coded’ for proteins. But all of the genes responsible for the production of proteins only make up about 2 percent of the total DNA (the genome). The remaining 98 percent of the non-coding DNA (initially called junk DNA, because it was thought to not have any function) appears to have an influence on the risk of cardiac arrest and cardiac death. Bezzina: “With a technique called whole genome sequencing, we have now found the first genetic modifiers within this non-coding DNA as well. In this way, we are getting closer and closer to a comprehensive array of risk factors.

Personal risk profile

This is what Bezzina ultimately wants to achieve: the creation of a personal risk profile for everyone who is at risk for sudden cardiac arrest. A risk profile based on all of the individual genetic factors, from the monogenetic disorders to the complex accumulation of all genetic modifiers present. With this knowledge you can then decide on a treatment for each individual patient that fits seamlessly into their profile.

Original text (in Dutch): Pieter Lomans
Photo: Martijn Gijsbertsen