June 10, 2020 -- Polygenic risk scoring may benefit some middle-aged people at borderline risk for cardiovascular events and has potential as a one-time test for those who are younger, a primary prevention study has concluded.
The retrospective study evaluated the value of polygenic risk scores (PRSs) in a total of 47,108 middle-aged people (mean, 60 years) treated at hospitals affiliated with three different U.S. institutions on the East Coast: Partners HealthCare (MA), the University of Pennsylvania Health System (PA), and the Mount Sinai Health System (NY).
Using electronic health records, researchers assessed a range of measures, including clinical risk factors and prescriptions for statins, to calculate a PRS, which captures many small genetic changes that contribute to susceptibility for heart disease. Results of the study were reported by Massachusetts General Hospital cardiologist Dr. Krishna Aragam and colleagues in the June issue of the Journal of the American College of Cardiology (Vol. 75, pp. 2769-2780).
A key part of the assessment was to see what the PRS adds on top of standard care, which guides patients to treatment with statins based on a 10-year risk score that takes into account a range of clinical factors, including race, age, sex, and low-density lipoprotein cholesterol (LDL-C). Statins have been proved to reduce the risk for cardiovascular events.
Those with a PRS in the top 20% were almost two times more likely to develop coronary artery disease (CAD) as those in the bottom 80%, a statistically significant result. Furthermore, a high-risk score did not correlate with recommendations for statin therapy based on clinical practice guidelines or a higher number of prescriptions for statins.
The overall primary prevention population did not appear likely to benefit over and beyond clinical risk calculations supported by clinical practice guidelines. But the researchers identified a subset -- those with borderline or intermediate risk who did not receive statins -- who might benefit if the PRS were considered.
"An additional 4.1% of primary prevention patients may be recommended for statin therapy if high CAD PRS were considered a guideline-based risk-enhancing factor," they wrote.
What genetic testing adds
The authors noted that when the level of risk is intermediate, guidelines advise that "risk-enhancing factors" that are independently associated with significantly higher risk for developing CAD can be taken into account when considering options for management. Wider popularity and use of direct-to-consumer genetic testing, including for heart disease, means that polygenic risk scoring is well positioned as a risk-enhancing factor in making the right call, in the authors' view.
"Therefore, there is broad interest in understanding how a CAD PRS may be incorporated into current guideline-based frameworks to inform clinical care," they wrote.
The PRS for 6,630,150 common (minor allele frequency > 1%) genetic variants was developed using genetic data from a published genome-wide association study. The researchers wanted to assess the value of the PRS in a clinical as opposed to research-based setting in order to understand its role in real-world practice.
Some experts have questioned the value of the PRS in cardiology practice. Two studies published in February concluded that polygenic scores did not show a clinically meaningful benefit for risk stratification in heart disease beyond conventional tools for estimating risk. However, Aragam counters that there is value in even a modest benefit, particularly for those in the "gray zone," i.e., with borderline or intermediate risk for cardiovascular disease and events, where genetics could help break the tie and determine the need for statin therapy. One in 25 individuals in primary prevention fall into that gray zone of risk, so it's not an insignificant number, Aragam said in an interview.
Aragam also noted that studies that have found little benefit for adding the PRS on top of clinical risk classification also concluded that the two tools compare well head to head.
"For younger individuals one would argue that there is a real opportunity there to act based on risk that is calculatable well before onset of those other risk factors," he said.
Furthermore, as risk scoring for heart diseases becomes increasingly available -- along with other types of genetic testing -- physicians need a framework for knowing what to do with scores presented by patients.
"Do you completely toss it because you think it's useless? Or does it actually have some value?" Aragam asked. "Are there cases that warrant its incorporation into the way we currently go about defining risk based on clinical metrics?"
The answers to those questions will become clearer over time with more research and experience. Aragam acknowledged that there can be hype around genetic testing and that it should not be oversold, but he sees opportunities to include these data alongside clinical risk assessments in the future.