Decoding genes to save more hearts

What if your DNA could predict your risk of a heart attack many years before it happens — and what if you could change that risk?

Dr. Guillaume Paré, a clinician and a Heart & Stroke–funded researcher at McMaster University, is on a mission to tackle those questions. At his clinic in Hamilton, Ontario where he practices as a cardiologist, he sees people in their 30s and 40s blindsided by severe heart attacks, with no obvious cause.

“When we asked these patients about their family history, they would say, ‘Oh, you know I had a heart attack at 42, and my brother had one at 44,’ and we thought it has to be genetics, right? And yet, we didn't find anything striking when we looked at their individual genes. It was frustrating.”

Dr. Paré is investigating the issue as both a doctor and a DNA detective: In his clinic, he sees young people who’ve had an early-onset heart attack. Some have joined his research study, helping Paré decode the puzzle behind their bafflingly early heart attacks. And in his lab, he hunts for more clues, hidden in the genetic code of others who did not survive. 

He and his team pioneered polygenic risk scoring, a breakthrough that the American Heart Association named one of the top ten advances in cardiovascular research. Polygenic risk means that lots of tiny genetic changes — each barely making a difference on its own — can add up to a big impact on your chances of getting a disease like heart disease.  

Polygenic risk scores now inform much genetic research into heart disease, but Paré is investigating further. He’s tracking down the rarest genetic clues to refine these scores and build a clearer picture of what drives early-onset heart disease.

His most recent work goes even further. For the past five years, Paré has been investigating accelerated aging — when the body acts and feels older than its years.  It’s an ongoing line of inquiry with life-saving potential — not just for heart disease and stroke, but for other serious conditions.

In this conversation, Dr. Guillaume Paré explains why early-onset heart disease demands urgent attention — and what it could mean for care if we routinely identified high-risk people decades before disease strikes. Best of all? He provides new insights on how the choices you make every day can help rewrite your genetic story.

What makes early onset heart disease different from heart disease in older people — and so important to study?

Heart disease is catastrophic, whatever your age, but it’s particularly striking in younger individuals. Oftentimes these people have young children, active careers and so much to live for. I think the impact can be felt even more on their loved ones.

Also, if someone has a first heart attack in their 30s or 40s, we know we're facing an aggressive disease that is very likely to strike again, so we should try hard to better understand, so we can act on it.

How are the ripples of a cardiac emergency felt throughout the family?

All the family members are reasonably very worried about this. If someone's brother has a first heart attack at age 41, it just sends a chill through the whole family. The siblings might be thinking “Could I be next?” And “what do we need to do with this?”

You work in both a clinical setting and in the laboratory. How does your work with young heart patients inspire your research?

We see patients with very early-onset heart disease — and their families. It’s distressing to see them suffering from heart events at such a young age. It’s also frustrating, because right now in our healthcare system there are no real guidelines about what we should be doing differently for these young patients. When we started our research, we realized we needed more data about this group — there had to be a reason why this disease manifested itself so early in these people.

How does the research affect you?

It can get very emotional. Because we're talking about, in many cases parents that have lost their sons or daughters to this disease at an early age, and it's very demanding on their families. It's very demanding on the study team as well because these stories are… they're just so sad.

What exactly is polygenic risk?

Our team proposed that the risk for these young people having a heart attack in their 30s may not be due to one significant gene mutation, as was once believed, but rather a very large number of genes with very small mutations. Polygenic risk is the combined effect of hundreds or thousands or even tens of thousands of smaller genetic variants. Alone, these variants increase the risk of heart disease by just a tiny bit. In combination, they put people at very high risk.

And what led you to research polygenic risk?

At first, we were focusing on a single mutation — familial hypercholesterolemia (a lipid disorder where the ‘bad’ cholesterol is too high in your blood). That’s really important, but it only explains 2–5% of these cases. That is what sparked our next investigation: to look beyond searching for our answer in a single gene or mutation.

What is the polygenic risk score?

It’s a way to capture hereditary risk — the impact of hundreds or thousands of tiny genetic variants on heart health — in a single number. We add up the number of variants that increase the risk of heart disease, and we give different weight to different variants, because they don’t all have the same impact. That formula gives us a person’s polygenic risk score.

How did your team decide which genetic variants to include in the risk score for early-onset heart disease?

We looked at large genetic studies of coronary artery disease and pooled data from a lot of very large international studies that try to identify the genetic variants and genes associated with many specific diseases. The results are publicly released so everyone can use them.

Many people think our genes determine our future. What have your research and experience with heart patients taught you about this?

Obviously, genetics are very important, but it’s the combination of genetics and how we live that truly determines our risk — our environment, our lifestyle, our diet, and how we exercise. Whether we smoke or not plays an equal role in genetics.

Learning you’re at high risk for a potentially fatal illness could weigh heavy. Does it make sense for everyone to know at a young age?

My answer is personal — others may feel differently, and that’s fine. I envision a future where we can identify the risk of most major diseases — early or late onset — at a young age.

Why do you think it is so important to make genetic testing widely accessible?

At 20, everyone looks fit; everyone looks healthy. Without genetic testing, it’s really difficult to know who the 20-year-olds are going to be in trouble when they are 50, 60 and 70.

Polygenic risk is of the same order of magnitude as smoking or even diabetes, so it really is worth testing for it, as a major risk factor. We should be identifying polygenic risk and treating it more aggressively with safe and effective interventions. We could have a greater impact if we were to act on risk factors much earlier in life and in a more targeted way.  

When might polygenic risk testing become available in our healthcare system?

I’d say these tests could be ready in about five to 10 years. There’s been progress: The results of tests are even more accurate now, and the technology is even better than when we started our study. These scores have become so good that now we can identify that up to 20% of the population has a three-fold increase in risk, just based on their genetics, which is massive, right?

If someone tests high for polygenic risk, there wouldn’t be medication they could take for that, would there?

That’s correct — there’s no single medication for this type of risk. But here’s what’s interesting: People with high polygenic risk for coronary artery disease seem to benefit more than average from cholesterol-lowering treatments. We think this genetic risk makes arteries more prone to plaque buildup, so reducing cholesterol gives them an outsized advantage.

Your study on polygenic risk was named one of the American Heart Association’s top ten advances in cardiovascular research in 2018. What did that recognition mean to you and your team at McMaster University and Hamilton Health Sciences? 

We were truly honoured. I’m proud this came from a local study in Hamilton, based on my own patients and a real clinical question. Seven years later, it’s clear this work opened doors for our research team. And since we made that discovery, the concept has been widely adopted and refined by other groups working other fields, such as cancer, diabetes and dementia.

Your latest research looks at accelerated biological aging. How would you explain ‘biological age’ in simple terms?

We all know our chronological age, the number of years since we were born, but instinctively we also all realize that we might not all be aging at the same pace. Some people look much younger or older than their age.

Our biological age reflects how our body is aging on the inside. Scientists measure it using markers like DNA methylation — chemical changes on the DNA molecule that act like decorations, turning genes on or off. These changes follow predictable patterns as we age, so by analyzing them in a DNA sample, we can estimate a person’s biological age. That’s mind-blowing, because not long ago this wasn’t possible.

Beyond the passing of time, what else can make our body age faster?

I don’t think it will come as a surprise that the biggest environmental factor is smoking. We can distinguish smokers from non-smokers almost perfectly using DNA methylation.

So why is understanding biological age important?

If someone is 40 and their biological age is 45, do they have the health risk of a 45-year-old? Essentially, yes! When biological age is higher than chronological age, that person is at increased risk of disease. If it’s lower, they’re more protected.

Understanding how aging affects heart disease risk helps us spot problems in healthy young people and find ways to slow down aging. If we don't have good signs or tests to measure aging, we can't see if our efforts to slow it down are working until it's too late. 

Where will your research go next in this area?

We’re now asking if people with very early coronary disease also show signs of accelerated aging, beyond single-gene mutations and polygenic risk. So, the next big hypothesis we’re testing is: Could it be that these individuals have accelerated aging, and they're getting a first heart attack in their 30s or 40s because their arteries are aging faster?

We want to test the hypothesis and then I think if it pans out, it's going to give us further lines of investigation and say, well, OK, now that we know this: Is there a way that we could detect this before a catastrophe happens? And what can we do to try to prevent accelerated aging? There are tons of people who are interested in slowing aging, so we would love to solve that problem.

Right now, biological aging is not ever discussed in relation to predicting coronary artery disease. So, if we can show this has an impact, I think that we would be opening up a whole new risk factor.

In the context of your latest Heart & Stroke-funded research, tell us about your unique collaboration with the Ontario Forensic Pathology Service.

We're working with terabytes of data they’re providing about all the Ontarians that have passed because of very early coronary artery disease. This represents the most severe cases. We focus on this group, because the more extreme the severity of the disease, the easier it is to pick up biological signals.

And then obviously the goal is to apply our findings to a broader population. We’re looking to identify the biological factors that explain why these people developed this disease so young.

What has Heart & Stroke funding and the support of our donors meant to you as a researcher?

Heart & Stroke funding has made it possible for me to pursue research that would simply not exist without this support. Knowing that these funds come directly from the generosity of donors makes the work feel even more meaningful and deeply connected to the patients and families we aim to help.

Dr. Paré, is there anything else about your current and future research that you'd like to share with us?

Yes! We’re doing a lot of research on gene–environment interactions, which ties back to the idea that heart disease isn’t just your destiny — even if you have genetic risk. We’re asking: On one side, you have lifestyle and environment; on the other, genetics – what’s the crosstalk between the two? That’s a big conversation we’re having right now.

We’re also doing a lot of work on blood biomarkers, which is a new phase for us. One project we’ve developed is what we call the “death score”— a score that predicts mortality with a very high level of accuracy. Honestly, it’s a little scary how accurate it is!

And we’re working on new methodologies for pharmacogenetics — how our genes may affect how we process medications. We have many projects on the go that align with the broader mission of improving heart and brain health.

Dr. Pare's expertise runs deep
Thanks to donors, we fund the best medical minds in Canada. Dr. Pare is one of them: A clinician and researcher, his  roles include director, Genetic and Molecular Epidemiology Laboratory – Clinical Research Laboratory and Biobank; senior scientist, Population Health Research Institute, a joint institute of McMaster University and Hamilton Health Sciences; scientist, Thrombosis and Atherosclerosis Research Institute, a joint institute of McMaster University and Hamilton Health Sciences; and university scholar and professor of Pathology and Molecular Medicine, McMaster University.