Revealing hidden genetic risk in CAD prevention: how PRS identifies individuals who behave clinically like those with LDL-C ≥190 mg/dL, despite non-elevated LDL-C

Coronary artery disease remains the leading cause of preventable morbidity and mortality, and many first events still occur in individuals previously assessed as low risk. Clinicians routinely encounter patients with optimal LDL cholesterol values, low pooled cohort equation (PCE) estimates, or a calcium score of zero who nonetheless who nonetheless experience their first coronary event. These situations highlight a central limitation in contemporary prevention: traditional assessments describe current physiologic status but provide no direct measure of inherited genetic susceptibility. CAD has a strong genetic foundation, with 40–60% heritability. Genetic factors contribute substantially to lifetime CAD risk, and polygenic scores quantify this inherited component by capturing the combined influence of many common variants. This genetic signal is present from birth, remains stable across the lifespan, and provides insight that cannot be derived from lipid measurements, short term risk calculations, or coronary calcium imaging. The American Heart Association recognizes polygenic risk as an independent cardiovascular risk factor and supports its use alongside established clinical tools.

Inherited risk is particularly informative when traditional metrics lack precision. Some adults maintain normal lipid profiles or have reassuring PCE or CAC results despite carrying meaningful genetic predisposition. Identifying these individuals early allows clinicians to initiate preventive therapy while the disease process is still modifiable. Genetic information also clarifies risk when family history is incomplete or unreliable, offering an objective measure where clinical uncertainty often exists. Younger adults represent another important group because age-driven ten-year estimates frequently underestimate lifetime risk despite clear inherited vulnerability.

Invisible hypocholesterolemia 

Hypercholesterolemia has long been defined by LDL-C levels. Clinicians typically flag LDL-C levels above 190 mg/dL as “severe,” triggering aggressive treatment and intensive follow-up. But PRS reveals a second category of high-risk individuals: people whose LDL-C is only mildly elevated, often around 130 mg/dL, yet whose inherited genetic predisposition causes them to behave clinically as if they had LDL-C levels above 190 mg/dL. This condition can be thought of as “invisible hypercholesterolemia.” This means millions of seemingly “normal” patients carry a hidden, severe risk that traditional tools fail to detect. Genetically informed risk assessment using PRS is essential because it uncovers this silent danger and guides therapy where standard cholesterol thresholds offer insufficient resolution.

Clinical scenarios and PRS enhanced clinical interpretation

In routine cardiovascular practice, clinicians often encounter patients whose current risk profile does not fully reflect their long term cardiovascular risk. Traditional risk calculators and imaging are valuable, but they capture only the patient’s present state and may overlook inherited susceptibility that influences outcomes over time. PRS closes this gap by quantifying underlying genetic predisposition, giving clinicians a deeper insight when traditional assessments do not capture the full extent of risk.

Family history presents another challenge in daily clinical care. Many patients are unable to provide accurate information regarding the age of onset or specific diagnoses among relatives with coronary disease, reducing the predictive utility of family history alone. PRS offers an objective, reproducible quantification of inherited risk that does not depend on the accuracy of patient reported information, thereby strengthening clinical decision-making when historical details are incomplete.

Younger adults represent a particularly important group for enhanced risk stratification. Ten-year risk calculators are heavily age-oriented and often underestimate true cardiovascular vulnerability in this population. Because polygenic risk is present from birth and remains constant across the lifespan, PRS identifies genetically high-risk individuals who may benefit from earlier lifestyle modification, closer surveillance, or initiation of pharmacologic prevention even when routine clinical parameters appear reassuring.

The following table summarizes these clinical scenarios and outlines how PRS augments interpretation, supported by representative evidence from the literature.

How PRS strengthens preventive decisions

From a clinical standpoint, genetically informed risk assessment resolves uncertainty in situations where traditional tools do not provide enough resolution to guide therapy. These individuals represent a large proportion of the population (>30%). Patients with borderline or intermediate clinical profiles but a high inherited risk may benefit from earlier statin initiation, lower LDL-C thresholds, or closer clinical follow up. Conversely, individuals with intermediate PCE risk and reassuring genetic profiles may be suitable for more conservative management. This added precision supports guideline-aligned care by reducing both undertreatment in genetically susceptible patients and unnecessary escalation in those with lower inherited risk.

Polygenic information also improves shared decision making. Many asymptomatic adults hesitate to begin therapy when their short-term risk appears not extremely high. Demonstrating a clear inherited predisposition often provides the clarity patients need to understand the rationale for preventive strategies and improves adherence over time. Because genetic susceptibility is stable across the lifespan, it becomes a durable component of the risk profile that can support preventive planning long before structural disease develops.

Integrating PRS into preventive cardiology workflows

In practice, genetic risk assessment fits naturally within existing workflows. It is most valuable when:

• The clinical profile does not fully explain a patient’s risk,

• Family history is incomplete or difficult to interpret,

• Lifetime risk estimation influences treatment decisions, or

• Middle-aged individuals present with early signs of metabolic change.

PRS results are interpreted alongside LDL-C, PCE, CAC, and other standard assessments. It does not replace these tools but enhances their effectiveness by identifying inherited vulnerability earlier in the disease course. This makes genetic evaluation particularly relevant in primary prevention, where the greatest clinical impact is achieved through early recognition and intervention.

Conclusion

Clinicians involved in cardiovascular prevention increasingly rely on tools that offer greater diagnostic resolution than traditional risk factors alone. Polygenic risk assessment delivers that clarity by quantifying inherited susceptibility that remains invisible to conventional risk models. It strengthens risk stratification, supports confident initiation of preventive therapy, and enhances the precision of guideline- and prescriber-based care. Integrating genetic information into cardiovascular risk evaluation enables clinicians to identify individuals who benefit most from early intervention long before coronary disease becomes clinically apparent.