Don’t Forget The Highest Risk: Why Polygenic Risk Scores Alone Aren’t Enough

June 21, 2023

A recent New York Times article drew attention to the utility of a new genetic test called polygenic risk scores (PRS) as a tool for risk stratification and informing treatment to prevent heart attacks. This article highlights the growing role of genetics in healthcare, supported by studies that demonstrate the significant contribution of genetic testing in identifying the risk of heart disease. For example, individuals with very high polygenic risk (top 95th percentile) have been found to have a 3-fold risk of coronary artery disease relative to the remainder of the population studied¹.

We now have the capability to personalize risk assessments by incorporating genomics to identify individuals at increased risk of cardiac conditions who could significantly benefit from early interventions such as statins. The advent of affordable clinical-grade sequencing is revolutionizing predictive medicine, making life-saving genetic tests accessible to many. The effectiveness of these genetic tests on broader populations is further confirmed through the rise of dedicated community health research programs such as the Healthy Nevada Project, In Our DNA SC, Tapestry and myGenetics. By examining the genetic predisposition to heart disease, a more personalized approach to preventive care is enabled, well ahead of the first cardiac symptoms.

While the article brings much-needed attention to the use of polygenic risk scores in early intervention, there is a stronger genetic correlation that is critical to understand. For individuals presenting with early-onset high cholesterol and a strong family history of heart conditions, testing for rare pathogenic variants including Familial Hypercholesterolemia (FH) is crucial.

According to established guidelines, these monogenic risks should ideally be examined before or alongside polygenic risks, especially in cases of individuals with very high levels of LDL cholesterol and significant family history. The addition of genetic information can offer a more precise assessment of risk than simply looking at LDL levels on their own.

While the article brings much-needed attention to the use of polygenic risk scores… there is a stronger genetic correlation critical to understand.

For example, individuals with a pathogenic variant in an FH gene and an LDL cholesterol level ≥190 milligrams per deciliter (mg/dL) have a 22-fold increased risk for coronary artery disease when compared to those with LDL levels of 130 and no genetic variant. In the same study, it was found that in participants with LDL cholesterol levels ≥190 and no FH mutation, the odds of coronary artery disease were only increased 6-fold2.

Furthermore, relying on cholesterol levels alone is insufficient for identifying high-risk patients. Both a prior study and our research programs have shown 40-45% of FH variant carriers have an LDL level <1903. FH carrier’s elevated risks make them eligible for additional treatment even if they have low LDL cholesterol. This key point was not mentioned in the New York Times article, which could potentially lead to an incomplete understanding of the best practices for genetic testing.

The true potential of genetic testing is realized when we use it as part of a comprehensive suite of assessments.

Indeed, the future of predictive medicine could very well lie in the effective combination of both rare and common variant testing. This approach could extend beyond coronary artery disease and be utilized for conditions such as breast cancer 4 or diabetes. The true potential of genetic testing is realized when we use it not as a standalone risk assessment tool, but as part of a comprehensive suite of assessments, considering all risk factors including age, lifestyle, and personal and family medical histories.

Balancing traditional risk assessments with innovative genetic tests provide a more holistic view of an individual’s health profile and help patients, like Katie Elkins in the article, who are unsure of whether to take additional preventative action without a more clear understanding of what their odds of actually developing coronary artery disease may be.

Integrating the use of genetic testing more broadly is reinforced by the shortcomings of the current screening approach. This approach relies on LDL levels and family history, and has resulted in a significant underdiagnosis and undertreatment of FH, thereby failing to identify a large number of at-risk individuals5. In contrast, population-based screening offers an alternative approach that improves detection by removing the reliance on clinical indications to initiate testing and ensures all patients have equal access to the ability to act upon testing results.

At the population level, Helix screens for three CDC Tier 1 conditions, including FH, and has demonstrated notable outcomes for healthcare providers and their patients. Our real-world experience with Renown and the Healthy Nevada Project has shown 1 in 75 patients screened carried pathogenic variants for the CDC Tier 1 diseases, 90% of which would have remained undetected through routine care6. Additionally, the research-backed nature of Helix’s programs fill a critical need mentioned in the article for longitudinal studies that focus on younger individuals, enabling the generation of valuable data on risk scores and the long-term impact of genetic testing.

Population-based screening offers an alternative approach that ensures all patients have equal access to testing results.

While polygenic risk scores are a valuable risk stratification tool, it is important to recognize the significance of screening for rare pathogenic variants, such as FH alongside and even prior to this method. The adoption of population-based screening enables early diagnosis and provides physicians with the ability to make informed decisions on timely interventions that can significantly impact patient outcomes.

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