Harnessing polygenic risk scores for cardiovascular disease prevention: A guide for physicians
George Busby, Allelica CSO & Co-Founder
Atherosclerotic Cardiovascular disease (ASCVD) remains the leading cause of morbidity and mortality worldwide. As we strive to improve prevention strategies, polygenic risk scores (PRS) have emerged as an important tool to enhance risk stratification and guide personalized interventions. This article aims to provide cardiovascular and primary care physicians with practical insights on implementing PRS in clinical practice so that you can improve patient outcomes.
Why use Polygenic Risk Scores?
In short, clinical risk assessments that do not take genetic risk into account are at best incomplete and at worst inaccurate.
Despite the widespread use of clinical risk assessments for ASCVD, a significant proportion of people who have heart attacks are missed by current risk assessments. Some of these individuals have no identifiable risk factors and are therefore not picked up by standard assessments. In fact, up to 30% of individuals who have a heart attack in the absence of clincal risk factors.
Others may have some level of clinical risk which remains too low for mitigation strategies to be applied. Studies of prospective cohort data have repeatedly shown that clinical risk assessments that incorporate PRSs are better at identifying individuals who go on to have ASCVD events than those that do not use PRS.
In both of these cases, PRSs provide a key additional component of risk which can help physicians identify those at increased risk because of their genetics. Importantly, risk from PRS is independent of clinical risk, and so assessing a patient’s PRS provides a unique and essential perspective of ASCVD risk that needs to be accounted for.
Understanding Polygenic Risk Scores
Polygenic risk scores aggregate the effects of multiple genetic variants associated with a particular condition, providing a comprehensive measure of an individual’s genetic predisposition to that condition. For cardiovascular diseases, PRSs can offer valuable information about a patient’s inherited risk, complementing traditional risk factors and potentially improving risk prediction.
But how can we use them in clinical practice?
The Scientific Basis for PRS in ASCVD
Recent large-scale genome-wide association studies have confirmed the polygenic nature of cardiometabolic diseases, demonstrating that numerous single nucleotide variants (SNVs) across the genome contribute to ASCVD risk. While each variant individually confers a small risk, their cumulative effect can be substantial.
Studies have shown that PRSs are independently associated with various cardiovascular diseases, including coronary artery disease (CAD), atrial fibrillation (AF), and venous thromboembolism. This independent association suggests that PRS can enhance current risk prediction models and inform more targeted prevention strategies.
Clinical implementation of PRS
When it comes to the clinical implementation of PRSs for ASCVD, there is a range of scenarios where these genomic-powered insights can provide real, immediate value.
Risk Stratification and Prevention
PRSs are particularly valuable in identifying individuals at high genetic risk who may benefit from earlier or more aggressive preventive measures. For example, patient groups where PRSs support clinical decision making include:
- Individuals with family history of ASCVD
Approximately 10–20% of the U.S. population has a family history of ASCVD. On its own, family history increases ASCVD risk by 1.5–2 times and is an established clinical risk factor for ASCVD. A similar proportion of the U.S. population has a genetic risk factor for ASCVD, which doubles their risk of ASCVD irrespective of the presence or absence of family history or other clinical risk factors.
For the 1 in 5 individuals with a family history who also carry high genetic risk, overall ASCVD risk doubles again, reaching 3–4 times the population average. This translates to 2–4% of the U.S. population who are at significantly higher risk but who are invisible without genetic testing. Allelica’s CAD PRS test is essential for identifying these high-risk individuals.
- As a risk enhancer in individuals with intermediate clinical risk
ASCVD risk models such as the Pooled Cohort Equations (PCE) fail to identify 1 in 5 individuals with borderline/intermediate 10-year clinical risk (5–20%) who also possess genetic risk factors for ASCVD. As a result, many high-risk individuals are undertreated by clinicians, resulting in more preventable disease in patients and higher healthcare costs for payers than would be the case if this key genetic information was utilized.
Using the PCE risk model, around 40–50% of the population aged 40 and 79 will be classified as having either borderline (5–7.5%) or intermediate (7.5–20%) 10-year ASCVD risk (BIR). Within this risk group, Allelica’s CAD PRS test identifies those with high genetic risk for disease (1 in 5), treating this as a “risk enhancing factor”. The ACC/AHA Cardiovascular Risk Guidelines recommend initiating or escalating lipid-lowering treatment in BIR individuals with a risk enhancing factor. We estimate appropriate treatment of BIR individuals with the genetic risk factor in the US could avert up to 20,000 (15%) of ASCVD cases annually.
- Early detection of high risk in younger individuals
ASCVD is a long term process with disease developing over decades. The pace of this development, which involves the development of atherosclerotic plaques in blood vessels, varies. PRSs are one tool that can be used to identify younger individuals at high risk so that mitigation strategies can be implemented to slow down or even stop subclinical development of ASCVD.
Equivalence to risk from hypercholesterolemia genetic variants
A now classic study by Khera et al. demonstrated that individuals with high polygenic risk for CAD had a risk equivalent to that conferred by monogenic mutations. This finding shows that PRS identifies a broader slice of the population that might benefit from early intervention.
The mechanics of CAD PRS in atherosclerosis
We now understand why a high CAD PRS can lead to increased risk. PRSs identify individuals in whom LDL cholesterol has a dangerous effect. For example, research published in Circulation by Allelica has demonstrated that individuals with a high PRS and potentially safe levels of LDL cholesterol actually have risk equivalent to individuals with an average PRS and hypercholesterolemia (>190 mgdL).
Additional research has supported this notion: individuals with high PRS had a higher atherosclerotic plaque burden and features of advanced atherosclerosis. PRSs are useful as a method for CAD risk stratification, especially in younger subjects. Moreover, PRSs have also been strongly associated with future long-term plaque progression in patients suspected of having CAD.
Importantly, individuals with a high PRS — who have a higher atherosclerotic plaque burden — respond better to statins, meaning that much of the increased risk in ASCVD in individuals with a high PRS can be mitigated with lipid management if their genetic risk is known.
Integrating PRS into Clinical Practice
To effectively implement PRS in clinical practice, consider the following approaches:
- Use PRS as an adjunct to traditional risk factors: Incorporate PRS into existing risk assessment tools to refine risk stratification.
- Focus on high-risk individuals: Prioritize PRS testing for patients with intermediate risk based on traditional factors (e.g. family history), where additional information could guide management decisions.
- Tailor interventions: Use PRS information to personalize prevention strategies, such as earlier initiation of statins or more aggressive lifestyle modifications for high-risk individuals.
- Patient education: Utilize PRS as a tool to enhance patient understanding of their risk and motivate behavior changes.
Guidelines and Recommendations
Several professional organizations have addressed the role of PRS in ASCVD management:
- The American Heart Association (AHA) has published a scientific statement on the use of PRS in cardiovascular health, acknowledging their potential to improve risk prediction and guide prevention strategies.
- The European Society of Cardiology (ESC) guidelines highlight the emerging role of polygenic risk scores as an additional tool to personalize cardiovascular disease prevention strategies, especially for those with borderline risk profiles.
Conclusion
Polygenic risk scores offer a promising avenue to enhance cardiovascular disease prevention by providing a more comprehensive assessment of individual risk. The potential benefits of PRS in improving risk stratification and guiding personalized prevention strategies are substantial. As cardiovascular and primary care physicians, embracing this technology and integrating it thoughtfully into clinical practice can lead to significant improvements in patient care and outcomes.
By staying informed about the latest developments in PRS implementation with Allelica and following evolving guidelines, we can harness the power of genomics to advance cardiovascular disease prevention and provide more personalized, effective care to our patients.
