In This Article
- Genome interpretation can improve our ability to understand risk of heart attack and impact its prevention
- State-of-the-art genome interpretation for heart attack risk includes both monogenic risk—due to a single gene defect—as well as polygenic risk—due to the cumulative effect of many variations across the DNA
- The recent study developed and implemented a framework for combined monogenic and polygenic risk assessment to assess heart attack risk in a preventive genomics clinic
- The study concluded that combined monogenic and polygenic risk assessment for heart attack risk is feasible, understandable, and is likely to impact clinical management
- In this Q&A, senior author Akl C. Fahed, MD, MPH, discusses the study and how it paves the way for larger studies to investigate the clinical use of polygenic scores to inform disease risk
Akl C. Fahed, MD, MPH, interventional cardiologist and physician-scientist at Massachusetts General Hospital and affiliate scientist at the Broad Institute of MIT and Harvard, together with the Preventive Genomics Clinic co-founder Amit V. Khera, MD, MSc, co-led a study focused on using genome risk interpretation for heart attack risk, which was recently published in the journal JACC: Advances. The team developed and implemented a framework for reporting monogenic and polygenic risk for heart attack that influenced participants to make healthy lifestyle changes and led their providers to adjust clinical management to prevent the disease.
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In this Q&A, Dr. Fahed explains the goals of the study and its impact.
Q: What is a polygenic risk score?
Fahed: We've known for quite some time that single variations in our DNA can affect traits like the color of our eyes and skin, but these monogenic variations can also affect a person's risk of disease such as heart attack. Over the past five years, we started to understand that while a single variation often has a small, almost negligible effect on a person's disease risk, when you add together the effect of many small variations across the genome, you can create what we call a polygenic risk score. It's a number that indicates where the person is on the risk spectrum, giving a more meaningful insight into their potential treatment or necessary lifestyle changes to prevent the disease.
Q: What is the Preventive Genomics Clinic at Mass General?
Fahed: The Preventive Genomics Clinic at Mass General provides genome risk interpretation to evaluate disease risk. This clinic is unique in that it follows a "genome-first" approach to prevention—meaning the person's DNA could be analyzed to determine if they are at a higher risk of certain diseases, regardless of whether they have existing risk factors or disease. The promise of the genome first approach is that it can potentially detect disease earlier in life but also it augments existing methods for risk prediction using our conventional risk measures.
For example, diabetes and smoking are risk factors for heart disease. A patient may develop diabetes in their 40s and gain weight from smoking throughout their life. Since you are born with your DNA, we can know this information earlier and enable the patient to have better control of their risk factors down the line.
Q: Can you discuss your recent study implementing genomic risk assessment for heart attacks?
Fahed: Within the infrastructure of the Preventive Genomics Clinic, we invited participants who were interested in learning how their DNA might affect their risk of heart disease. Currently, how we determine a person's risk of heart attack is to first identify their conventional risk factors, such as asking about their family history, diet, exercise, and smoking habits, and then measuring their cholesterol and body mass index. This study introduced, in addition to all that, a state-of-the-art genomic risk assessment. This included a monogenic assessment for rare single gene defects that are known to increase the risk of heart attacks and a polygenic risk score consisting of millions of DNA variations.
Q: What was the goal of this study?
Fahed: The overall goal of the study was to develop a proof-of-concept framework of comprehensive genomic risk assessment for heart attack, implement it in clinic, and show that it can positively impact management.
The first step towards that goal was to establish a method for communicating the monogenic and polygenic risk information to patients in an effective and educational manner. This is a new genetic test, and we haven't had the infrastructure to determine how we communicate that risk or what the report looks like when it's returned to the patient. It's a concept that's not necessarily straightforward because we wanted to see if participants understood the information, if they had intent to make positive lifestyle changes, and if their provider treated them differently as a result.
It really takes a village with expertise across multiple disciplines to implement a study like this. To create the polygenic risk report, we worked with visual designers to design the educational tools and make sure the participants would really understand the results. And the co-first author on the paper, Deanna Brockman, is a genetic counselor who spearheaded the plan for how we communicated risk results to the patients. Bringing in people from different disciplines, such as geneticists, cardiologists, and genetic counselors, was necessary to truly implement this project.
Q: What were the findings of this study?
Fahed: Overall, the framework was successfully implemented, identifying 35% of participants at high genetic risk. Most participants felt they learned something very valuable about their health and strongly intended to make positive changes to their lifestyle. Almost no one reported a sense of fear from seeing a high genetic risk.
The last thing we looked at was if doctors managed these patients after they received the risk assessment. About 40% of the participants changed their clinical management after their result was returned, such as starting a cholesterol-lowering medicine, increasing their dosage if they were already prescribed, or conducting additional testing to determine if treatment was needed.
Q: What do you believe is the impact of this study?
Fahed: The concept of this study was really to show that this is feasible and could change management for the patients who receive a high-risk score. We worked with a relatively small sample size of individuals who were early adopters of genetic testing, predominately of European ancestry and of higher socioeconomic status. This study opens the door to larger, more controlled studies such as randomized trials that compare more diverse groups of people to see if these findings hold true for the general population.
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