From categorical labels to quantitative risk: a practical framework for coronary risk assessment in cardiology
Inherited coronary artery disease risk is rarely binary. In routine practice, cardiologists see patients with the same genetic diagnosis present with different ages of onset, disease severity, and long-term outcomes.1 This variability is not an anomaly. It reflects the underlying biology of coronary disease.
Rare, high-impact pathogenic variants do not act in isolation. Their clinical expression is shaped by a patient’s broader genetic background. Accurate risk assessment therefore requires integrating monogenic and polygenic risk, rather than interpreting either alone.
Importantly, pathogenic monogenic variants that directly cause inherited coronary artery disease are rare in the general population. Even within preventive cardiology and lipid clinics, only a small fraction of patients carry high-impact variants in genes such as LDLR, APOB, PCSK9, or LDLRAP1.2,3 As a result, while monogenic findings are clinically important when present, they account for only a limited portion of inherited coronary risk overall. Incorporating a polygenic risk score captures the far more common genetic contributors to coronary disease, allowing inherited risk to be assessed comprehensively rather than inferred from rare variants alone.
AbsoluteDx™ CAD was developed to operationalize this principle in clinical practice, delivering quantitative, patient-specific coronary risk estimates that directly support prevention, treatment selection, and follow-up decisions.
Why gene-only risk assessment falls short in clinical care
Traditional cardiovascular genetic testing has focused on identifying monogenic causes of disease. This approach remains essential for diagnosis, particularly in familial hypercholesterolemia. However, monogenic testing alone cannot explain the wide variability in coronary risk observed among patients who carry the same pathogenic variant.
Binary genetic results create practical challenges for clinicians. They can inflate perceived risk in some patients, underestimate risk in others, and promote uniform management strategies that do not reflect true disease biology.4 As a result, cardiologists are often left uncertain about how aggressively to intervene, how closely to monitor, and how to communicate risk to patients and families
Polygenic risk provides the missing context. By capturing the cumulative effect of common genetic variants, it explains why genetically similar patients experience very different clinical trajectories and allows risk to be treated as a measurable continuum rather than a categorical label.
Familial hypercholesterolemia as a model for precision coronary risk
Familial hypercholesterolemia illustrates the clinical value of integrated risk assessment. FH is driven by pathogenic variants in LDLR, APOB, PCSK9, and LDLRAP1, yet FH carriers do not share a uniform risk of coronary artery disease.
Large-scale analyses from the All of Us Research Program and UK Biobank demonstrate that polygenic background strongly modifies CAD risk among FH carriers. When a validated, multi-ancestry CAD polygenic risk score is integrated with monogenic FH status, carriers separate into a broad and clinically meaningful risk spectrum.
A substantial proportion of FH-positive individuals fall below commonly used CAD risk thresholds once polygenic risk is incorporated, with risk approaching that of the general population. Approximately one quarter remain below a two-fold CAD risk threshold. At the opposite end of the spectrum, a clearly defined subgroup exhibits markedly elevated risk, in some cases exceeding a ten-fold increase.5,6
This heterogeneity has direct clinical consequences. It explains why some FH carriers develop premature coronary disease despite treatment, while others remain event-free well into adulthood.
AbsoluteDx™ CAD: turning genetic information into clinical decisions
AbsoluteDx™ CAD integrates monogenic and polygenic genetics into a single standardized test designed specifically for inherited coronary artery disease risk assessment.
It combines ACMG-recommended analysis of LDLR, APOB, PCSK9, and LDLRAP1 with a clinically validated, multi-ancestry CAD polygenic risk score. This unified framework quantifies how much coronary risk a pathogenic variant confers in the context of the patient’s full genetic profile.
For cardiologists, this means genetic testing no longer stops at diagnosis. It becomes a tool for risk stratification that directly informs care.
Clinical utility in everyday practice
AbsoluteDx™ CAD supports clinical decision-making across multiple points in the patient journey.
Guiding preventive therapy
By quantifying inherited coronary risk, AbsoluteDx™ CAD helps cardiologists determine which patients are most likely to benefit from early, intensive lipid-lowering therapy and aggressive prevention. At the same time, it provides reassurance when lower-risk FH carriers can be managed with guideline-directed therapy without unnecessary escalation.7,8,9,10
Informing surveillance and follow-up
Risk stratification allows clinicians to tailor surveillance intensity and follow-up intervals based on true inherited risk rather than genetic status alone. Higher-risk patients can be monitored more closely, while lower-risk individuals avoid excessive testing and clinic visits.
Improving risk communication
Quantitative risk estimates improve discussions with patients and families. Explaining risk as a measurable gradient rather than a binary label helps patients understand why treatment recommendations differ among individuals with the same genetic diagnosis and supports shared decision-making.
Identifying high-risk individuals earlier
AbsoluteDx™ CAD can identify patients with disproportionately high inherited risk who may not yet have overt disease. This enables earlier intervention, when preventive strategies are most effective.11,12
Reliable, calibrated risk you can trust
For genetic risk assessment to influence care, results must be reliable and well calibrated. Analyses of PRS-informed CAD risk among FH carriers show close alignment between predicted and observed outcomes across the risk spectrum. This calibration confirms that polygenic risk captures a true quantitative gradient of coronary risk.13
Integrated monogenic and polygenic assessment provides estimates that better reflect real-world outcomes and support confident clinical decisions.
Designed for preventive cardiology workflows
AbsoluteDx™ CAD is performed in a CLIA-certified, CAP-accredited laboratory and is designed to integrate seamlessly into preventive cardiology and lipid clinic workflows. It combines whole-exome sequencing for high-confidence detection of rare pathogenic variants with low-coverage whole-genome sequencing for accurate polygenic risk calculation.
Reports are standardized and clinically focused, emphasizing actionable risk information rather than technical complexity.
AbsoluteDx™ CAD provides the quantitative insight needed to practice precision prevention with confidence.
Reference materials
1 Di Taranto & Fortunato, Int J Mol Sci 2023
2 Rocheleau et al., Nature Communications 2024
5 Allelica AbsoluteDxTM Product Specifications
6 Fahed et al., Nature Communications 2020
7 Natarajan et al., Circulation 2017
8 Oni-Orisan et al., Clin Pharm Ther 2023
9 MI-GENES Trial (Kullo et al., Circulation 2016)
10 MI-GENES Trial Results (Naderian et al., Circulation: Geno Precis Med 2025)
11 AHA Scientific Statement, Circulation 2022
12 Cornelissen et al., ATVB 2023
13 Busby et al., Nature Communications 2023