The rise of genetic research has transformed our understanding of diseases, offering new insights into their mechanisms and risk factors.
Among these advancements, polygenic risk scores (PRS) have emerged as a powerful tool for predicting an individual’s susceptibility to complex conditions such as aortic stenosis, a common cardiovascular disease.
A polygenic risk score, (also called a genome-wide association score) estimates the extent to which your genes influence traits such as height, cholesterol levels, or the risk of certain diseases.
For patients and healthcare providers alike, PRS represent a shift toward more personalized medicine, enabling earlier interventions and preventative strategies. Such paradigms are already starting to be implemented for heart attack risk at Mass General Brigham.
However, integrating genetic insights into routine clinical practice also raises important questions about risk communication, cost-effectiveness, actionability, and access to genetic testing.
In this Q&A, Pradeep Natarajan, MD, MMSC, director of preventative cardiology at Massachusetts General Hospital, discusses the significance of PRS in understanding and addressing cardiovascular diseases.
He shares his exciting research findings, the potential for developing targeted therapies, and the implications for improving patient outcomes through informed risk assessment.
Q: Why are genetics—and specifically polygenic risk scores—such a powerful tool for understanding diseases like aortic stenosis?
Pradeep Natarajan, MD, MMSC
Natarajan: Genetics, and specifically polygenic risk scores, help us identify and quantify the cumulative effects of multiple genetic variants on an individual’s risk of developing a certain condition.
Unlike lifestyle risk factors, such as diet quality and exercise levels that can change throughout life, genetic factors remain constant from conception, providing a stable basis for understanding disease mechanisms.
Identifying individuals at high genetic risk for aortic stenosis, a disease where the aortic valve narrows, restricting blood flow to the body, allows for the possibility of significantly altering the disease trajectory.
Since aortic stenosis generally appears in older age and is associated with severe health outcomes, understanding genetic risk can help prioritize those who may benefit from extra monitoring and early interventions.
This proactive approach is vital, especially in conditions such as aortic stenosis, where it can only be treated with invasive surgical procedures.
Q: What originally drew you to explore the intersection between cardiovascular medicine and genetics?
Natarajan: I’ve always had a strong interest in coronary artery disease, the root cause of heart attack, because this condition is so prevalent and impactful on public health.
I often think, “Why would anyone study anything else?” considering that heart disease remains the leading cause of death globally.
During my training, I saw firsthand how common heart disease is, particularly in South Asian communities, which motivated me to delve deeper into the genetic factors underlying these conditions.
As advancements in genetic technology emerged in parallel with my clinical training, I became excited about the opportunity to explore cardiovascular disease through this lens.
Human genetics began to enable an unprecedented way to understand human health and disease directly in humans.
Ultimately, my commitment to this field is driven by a desire to improve patient outcomes and tackle the challenges these diseases pose.
Q: Where do you expect PRS to have the earliest clinical impact?
Natarajan: I expect polygenic risk scores to have their maximal impact on younger adults, where current methods for assessing cardiovascular risk remain limited.
By integrating PRS into routine assessments for younger patients, we can identify individuals at higher genetic risk before traditional symptoms arise.
This proactive approach would allow for tailored lifestyle interventions, monitoring strategies, and consideration of preventive medicines.
Q: What is being done to make PRS tests more accessible to people who want to take a deep dive into their personal cardiovascular disease risk?
Natarajan: At Mass General Brigham, we have developed a clinically validated assay that assesses multiple cardiovascular conditions and risk factors.
This test is continually expanding to include additional conditions as our understanding of genetics evolves.
Education is also a key focus. We’re prioritizing the training of healthcare providers to ensure they feel comfortable discussing genetic risks with patients and helping them interpret their scores, while taking into consideration the psychological toll such results may have on an individual.
Additionally, we’re exploring ways to integrate PRS testing into routine clinical practice, particularly in scenarios where it may meaningfully augment risk assessment.
By doing so, we aim to empower individuals with knowledge about their genetic risk and promote earlier interventions for those who may be at high risk.
While genetics remain the same, cardiovascular disease is heavily influenced by non-genetic factors, allowing for improved prevention.
Q: What kinds of early interventions might be possible once it's known that a patient has a high genetic susceptibility for a heart condition? How will this change the status quo for cardiovascular care?
Natarajan: Around 60% of people will have a high polygenic risk score for at least one major cardiovascular condition or risk factor, according to our recent analysis in the Mass General Brigham Biobank.
Once we know that a patient has a high genetic susceptibility for a heart condition, additional investigations and potential early interventions become possible.
We can implement rigorous monitoring of cardiovascular health, including regular screenings for blood pressure and cholesterol levels, and emphasize lifestyle modifications like dietary changes and increased physical activity.
Cardiac imaging to evaluate for early signs of heart disease can also be pursued.
Additionally, earlier pharmacological interventions may be considered for a subset, such as initiating statin therapy before traditional guidelines would recommend because this risk signal would be missed.
A shift in how we provide cardiovascular care to young adults could transform care from a reactive approach to a proactive one, ultimately improving outcomes and public health.
Q: Where do you expect PRS to go from here over the next 3-5 years?
Natarajan: I expect polygenic risk scores to become increasingly integrated into routine clinical practice. We’re developing assays that assess multiple cardiovascular conditions, and as our understanding of genetics improves, these tests will expand to include even more conditions and risk factors.
I also see a greater emphasis on educating healthcare providers on how to communicate genetic results to patients. This will empower more individuals to understand their genetic risk and engage in proactive health management.
Ultimately, I anticipate cardiovascular care to begin moving increasingly toward preventative approaches to reduce the burden of heart disease on a larger scale.
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