Implementing polygenic risk scores in the clinic: Use cases for cardiovascular disease risk management
George Busby, Allelica CSO & Co-Founder
The evidence is undeniable — polygenic risk score (PRS) testing enables healthcare providers to identify more high risk patients at an earlier stage, leading to better risk management and improved outcomes.
As with any medical innovation, there is a need to offer providers guidance and education on how to gain the most benefit from its use. In the case of PRS testing, there are recurring provider questions that the clinical genetics experts at Allelica are here to answer:
Which patients should be offered PRS testing? How should results be communicated? How is clinical management impacted based on PRS results?
The use cases presented here seek to answer these questions and provide guidance to providers in the implementation of this highly advantageous form of genetic risk assessment.
In the following use cases, we cover how Allelica’s Coronary Artery Disease (CAD) PRS can augment the standard of care for risk stratification in cardiovascular prevention: the AHA/ACC 10-year ASCVD Risk Calculator. These form the backbone of lipid management pathways and are the current standard of care when it comes to understanding someone’s risk of Atherosclerotic Cardiovascular Disease (ASCVD).
The calculator puts individuals into one of four groups based on their estimated likelihoods of having an ASCVD risk over the next 10 years:
- Low risk: Individuals with a less than 5% 10-year risk
- Borderline risk: Individuals with a 5% to 7.4% 10-year risk
- Intermediate risk: Individuals with a 7.5% and 20% 10-year risk
- High risk: Individuals with a greater than 20% 10-year risk
The chart below provides an overview of how PRS results increase precision in risk classification and preventive care strategies.
Use Case 1: A healthy, 45-year old patient with no family history of ASCVD visits his physician, wanting to learn more about his personal risk of CAD
John visits his physician’s office seeking an understanding of his ASCVD risk. John has no prior history of ASCVD and does not have a family history of heart disease. However, John has recently been diagnosed with Type 2 Diabetes and wants to ensure he’s taking the necessary steps to maintain a healthy heart. Hearing John’s concerns, his physician, Dr. Smith, decides to perform a 10-year ASCVD risk assessment.
Dr. Smith starts by evaluating all of John’s clinical risk factors. This includes assessing his HDL and LDL cholesterol levels, blood pressure, family history of heart disease, smoking habits, and age. Inputting these values into the Pooled Cohort Equation, the standard 10-year risk ASCVD calculator, Dr. Smith concludes that John is at a 7.4% 10-year risk. None of his clinical risk factors are particularly worrying, but combined together they put John’s risk in the borderline category.
Dr. Smith then shares with John the value of incorporating his genetic risk information to enable a more comprehensive understanding of John’s personal risk factors and recommends a polygenic risk score test for CAD.
Recognizing the potential benefits of a genetic risk assessment, John agrees to take a CAD PRS test. John provides a sample for DNA analysis in the clinic using a noninvasive buccal swab. The sample is sent to an equipped CLIA, CAP laboratory for processing using genome-wide microarray technology. Dr. Smith schedules a follow-up appointment with John in four weeks’ time to discuss his PRS results.
Once the lab completes the analysis, the physician receives a detailed clinical PRS report which outlines John’s polygenic risk score and its implications for his CAD risk. This information is automatically integrated into John’s Electronic Health Record (EHR) for future reference.
John’s PRS is in the 87th percentile, which translates into a greater than twice the population average risk of CAD, based on his PRS. Combining the results of the PRS analysis with his 10-year risk assessment means that John’s ASCVD risk is no longer in the borderline category. The presence of two risk enhancers, his Type 2 Diabetes and a High PRS, means that his risk should be up-classified to High.
Dr. Smith provides John with a personalized risk management plan based on his reclassified risk level. As he is still young, this starts with an aggressive lifestyle and dietary modification plan to drive down cholesterol in adherence to national guidelines for cholesterol management. His physician ensures that John understands the significance of these measures in mitigating his risk of CAD, setting him on a path toward better heart health. If high 10-year risk cannot be reduced on the basis of this plan, Dr. Smith advises that a lipid-lowering therapy such as statins can be initiated in three to six months’ time.
In this case, John’s proactive approach to his health, combined with the integration of genetic insights, enables him to take meaningful steps towards reducing his risk of ASCVD and safeguarding his cardiovascular well-being for years to come.
Use Case 2: A 62-year old patient has suffered a heart attack, but does not present any obvious clinical risk factors and is seeking to understand if polygenic risk can explain the cause of her event
Despite her healthy lifestyle, including daily exercise, a nutritious diet and limited alcohol consumption, Sara suffered a heart attack at the age of 50. Sara does not have a family history of heart disease and does not present any traditional risk factors associated with a heart attack.
In order to understand the cause of the event, Sara visits her physician’s office to seek clarity about which factors could have triggered her cardiac event. Based on an initial assessment of clinical risk factors such as cholesterol and blood pressure, her physician, Dr. Smith, cannot identify the cause of her event.
Due to the unexpected nature and seriousness of Sara’s heart attack, Dr. Smith acknowledges the need for a more thorough investigation and recommends that Sara take a CAD PRS test.
Sara wants some time to think about the testing and gather more information, so she opts to receive the kit at home in the mail. Sara provides a sample for DNA analysis in the clinic using a noninvasive buccal swab. Sara sends her sample into a CLIA, CAP laboratory for processing using genome-wide microarray technology and PRS analysis. Dr. Smith schedules a follow-up appointment with Sara in four weeks’ time to discuss her PRS results.
Once the lab completes the analysis, the physician receives a detailed clinical PRS report which outlines Sara’s polygenic risk score and its implications for her CAD risk. This information is automatically integrated into Sara’s Electronic Health Record (EHR) for future reference.
Sara’s PRS is in the 91st percentile, putting Sara at a greater than 2 times increased genetic risk of CAD, compared to the population average. Sara’s high PRS enables Dr. Smith to provide a possible explanation for her previous cardiac event. Using the insights from the PRS report, Dr. Smith engages in a meaningful dialogue about the potential implications of polygenic risk factors in relation to the cardiac event. This discussion empowers the patient with a deeper understanding of cardiovascular health and the role that genetics may play in her condition.
In cases such as this, where clinical risk factors do not fully explain a cardiac event, PRS is a valuable tool for unraveling the complex interplay between genetics and disease. Family members can also receive PRS testing to determine which therapeutic or lifestyle interventions are right for them as described in this JACC paper.
Use Case 3: A 35-year old patient with a family history of CAD is concerned about her personal risk and wants to learn how she can reduce it
Catherine’s mother and great aunt have both suffered from CAD, and she is concerned that she may suffer the same disease. In an effort to understand her personal risk and learn strategies to reduce it, Catherine visits her cardiologist, Dr. Jones, and expresses her concerns.
Catherine is too young for her risk to be calculated using the standard ASCVD 10-year risk calculator, which is validated for adults between the ages of 40 and 75. However, she has two well established risk factors for ASCVD: her family history and South Asian ethnicity. To enable a more accurate assessment of her risk and ensure the most appropriate preventive measures are taken, Dr. Jones recommends a CAD PRS test, explaining the potential results and benefits of testing to the patient.
Catherine agrees to take a CAD PRS test and provides a sample on-site. The sample is sent to an equipped CLIA, CAP laboratory for processing using genome-wide microarray technology and PRS analysis. Dr. Jones schedules a follow-up appointment with Catherine in four weeks’ time to discuss her results and make shared decisions on the best course of action moving forward.
Once the lab completes the analysis, the physician receives a detailed clinical PRS report which outlines Catherine’s PRS and its implications for her CAD risk.
Catherine’s PRS is in the 99th percentile, putting her at over three times her population’s average risk of CAD. This risk is equivalent to a patient with familial hypercholesterolemia, however Catherine’s LDL-cholesterol levels, while elevated aren’t dangerously high. Based on these results, Catherine and Dr. Jones decide on a therapeutic intervention and Catherine is prescribed a low intensity statin medication and regular cholesterol measurement, reducing her risk of CAD and ultimately improving her heart health in the long term.
In all these use cases, PRS is a crucial health insight which empowers patients with knowledge of their personal risk profiles and enables providers to prescribe the most effective, impactful preventive plans possible.
For more information on implementing PRS testing in your practice, send us a message today.
