A polygenic risk score (PRS) for coronary artery disease (CAD) is a numerical assessment of an individual’s genetic predisposition to the condition.
Unlike tests for rare single-gene mutations (like familial hypercholesterolemia), a PRS aggregates the small effects of millions of common genetic variants—typically single nucleotide polymorphisms (SNPs)—identified through large-scale genome-wide association studies (GWAS).
Individuals in the top 1% to 5% of the PRS distribution can have a 3- to 5-fold higher risk of CAD compared to the average population.
Predictive Strength: For every one standard deviation (SD) increase in a typical CAD PRS, the risk of incident myocardial infarction (MI) increases by approximately 40% to 90%.
Age Factor: The predictive power is significantly stronger in younger adults (under age 50), where genetics plays a larger relative role before traditional risk factors like high blood pressure or cholesterol fully accumulate.
The relative contribution of polygenic risk to overall long-term risk is greater earlier in life when traditional risk factors have lower prevalence, making this information particularly relevant since preventive therapies like statins are anticipated to be more effective when implemented earlier.
PRSs are not intended to replace traditional risk tools but to complement them:
PRS is often used as a “risk enhancer” for individuals at borderline (5%–7.5%) or intermediate (7.5%–20%) clinical risk.
High genetic risk can reclassify these patients into a high-risk category where statin therapy is recommended.
Studies show that individuals with high genetic risk may derive the greatest relative and absolute benefit from statin therapy.
PRS provides a lifetime risk estimate from birth, coronary artery calcium (CAC) scoring remains a more robust predictor of short-term (10-year) events in older adults because it measures actual plaque build-up.
Current Limitations
Most PRSs were developed using data from individuals of European ancestry, which can lead to significantly lower accuracy when applied to other groups, particularly those of African descent.
Individual Variability: While PRSs are accurate at the population level, different scoring methods can produce inconsistent results for an individual.
Polygenic risk scores (PRS) for coronary artery disease are most informative when combined with baseline clinical risk assessment, with the relative risk from the PRS used to multiply the absolute risk from clinical risk scores.
The review identifies three specific populations where PRS assessment holds particular value.
For persons at intermediate clinical risk (5-10% 10-year risk of myocardial infarction or stroke), the PRS for coronary artery disease identifies approximately 10% who fall into a high-risk category, with twice the risk of cardiovascular events compared to those without high polygenic risk.
This strategy could prevent 1 additional cardiovascular event for every 340 persons screened, representing approximately 7% of all events.
Young adults represent another key population, as clinical risk scores are poorly calibrated in this age group and identify only approximately 1 in 4 persons who subsequently experience major cardiovascular events.
At age 40, an average man with no clinical risk factors in the highest quintile of polygenic risk has a 30-40% risk of developing coronary artery disease by age 70, compared with 10% risk for those in the lowest quintile.
Retrospective analyses of randomized trials have consistently shown that persons with high PRS for coronary artery disease derive greater absolute and relative benefit from lipid-lowering therapy than those with average polygenic risk.
A single-site randomized trial demonstrated that disclosure of polygenic risk scores to adults at intermediate risk led to a reduction in major adverse cardiovascular events over nearly 10 years.
Current polygenic risk scores do not predict risk equally well across ancestries since underpinning data are predominantly derived from persons of European ancestry.
The top 95th percentile of a CAD PRS is associated with 3-fold odds for CAD, similar to familial hypercholesterolemia but without severe hypercholesterolemia.
Contemporary scores predict CAD risk independently and are comparable to or more powerful than individual clinical risk factors like smoking, diabetes, or hypertension.
Addition of PRS to the AHA/ACC ASCVD risk calculator significantly improves prediction for cardiovascular events, independent of conventional clinical risk factors.
This enhanced prediction is detectable before emergence of clinical risk factors and is appreciable across ages, sexes, and increasingly diverse ancestries.
Among asymptomatic middle-aged adults at borderline/intermediate risk, a high CAD PRS aids in reclassifying statin prescriptions.
Among younger adults, high CAD PRS may prompt more intensive earlier lifestyle modification and potentially earlier statin initiation to mitigate high lifetime risk.
Lifestyle and medication efficacy correlate with PRS risk.
Adherence to a healthful diet mitigates CAD risk regardless of PRS, though absolute risk reduction may be greater among those with high PRS.
Patients with high CAD PRS derived greater relative and absolute benefit from statins versus placebo (46% versus 26%; without differences in LDL-C reduction.
Similarly, among individuals with established ASCVD on statins, greater benefit from PCSK9 inhibitors was observed with high versus low CAD PRS (37% versus 13%).