Many studies have shown that PRS (Polygenic Risk Scores) have similar or greater accuracy in predicting cardiovascular health issues compared to individual clinical risk factors. For example, a 2018 UK Biobank (UKBB) study conducted on European participants showed that PRS had greater predictive accuracy than any clinical risk factor [PRS C-statistic: 0.623 (95% CI 0.615-0.631), compared to 0.550 to 0.594 range for clinical risk factors like smoking, type 2 diabetes, family history of heart disease, body mass index (BMI), hypertension, high cholesterol levels]. However, PRS has a slightly lower predictive value for cardiovascular health compared to combined clinical risk factors. In the UKBB study, the set of clinical risk factors summed as a clinical risk tool showed a C-statistic value of 0.670 (0.663–0.678), compared to 0.623 (0.615–0.631) for PRS alone. A 2020 analysis showed that based on PRS, an additional 4% of the population could be considered high-risk and could be offered statin treatment if PRS is included in risk stratification. This improved risk classification by having PRS in conventional clinical risk models is visible across different genders and age groups and increasingly for other ethnic groups, with the most significant benefit achieved in younger patients before clinical risk emerges. Additionally, evidence suggests that including PRS in the American ACC/AHA cardiovascular health risk assessment is generally more cost-effective than the ACC/AHA clinical risk assessment alone and results in fewer cardiovascular events.
It is important to emphasize that polygenic risk scores indicate how an individual’s risk compares to others with different genetic constitutions. Polygenic results do not provide a baseline or timeframe for disease progression. For instance, two individuals with high PRS values for cardiovascular health require additional risk information regarding the occurrence of cardiovascular events over their lifetime. It is known that one person is in their twenties and another is over the age of 80. However, they have the same polygenic risk score, and their risk of developing cardiovascular health issues will differ over a lifetime. It is necessary to consider exposures to additional risk factors over several decades.
Previous studies have shown that PRS in cardiovascular health can lead to a reclassification of about 12% of individuals from the general medium-risk category to the high-risk category, translating into a stronger recommendation for therapeutic interventions in primary prevention. Furthermore, after presenting the genetic risk of coronary disease, individuals with higher genetic risk more often started and adhered to statin therapy. It has been shown that high polygenic risk for cardiovascular health is associated with similar risk as monogenic variants in LDLR (gene coding for LDL cholesterol receptor), APOB (gene coding for apolipoprotein B), and PCSK9 (gene coding for proprotein convertase subtilisin/kexin type 9). For example, in the UKBB, carriers of familial hypercholesterolemia (FH) had a 3.2-fold (1.7–6.0) increased risk of cardiovascular health issues compared to a 2.3-fold (2.1–2.5) increase in non-carriers in the top 20% PRS group. Moreover, existing data indicate that whole-genome PRS identifies the top 2.5% of individuals who have a 400% increased risk of cardiovascular health issues, equivalent to the risk of adverse coronary incidents associated with familial hypercholesterolemia.
Based on: ElliottJ,BodinierB,BondTA,etal.Predictive accuracy of a polygenic risk score–enhanced prediction model vs a clinical risk score for coronary artery disease. JAMA. 2020;323(7):636-645 Based on: IsgutM,SunJ,QuyyumiAA,GibsonG.Highly elevated polygenic risk scores are better predictors of myocardial infarction risk early in life than later. Genome Med. 2021;13(1):13.