Genome-first recall of healthy individuals by polygenic risk score reveals differences in coronary artery calcium

Area of Science:

• Cardiovascular Genetics
• Medical Imaging
• Preventive Cardiology

Background:

• Polygenic risk scores (PRS) are established for assessing genetic predisposition to coronary artery disease (CAD).
• The association between PRS and subclinical atherosclerotic burden, such as coronary artery calcium (CAC) scores, in individuals without high clinical risk remains underexplored.
• Current clinical risk assessments may not fully capture the risk indicated by extreme genetic predispositions.

Discussion:

• A novel recall-by-PRS strategy was employed to prospectively assess CAC in healthy individuals stratified by extreme high and low PRS.
• The study identified a significantly higher CAC burden in individuals with extreme high PRS compared to those with low PRS, even after adjusting for traditional risk factors.
• This suggests that PRS can identify individuals with increased subclinical atherosclerosis irrespective of their calculated clinical risk score.

Key Insights:

• Individuals with extreme high PRS exhibit a substantially greater coronary artery calcium burden compared to those with low PRS.
• A higher proportion of individuals with extreme high PRS had CAC scores exceeding 300 HU, indicating significant calcified plaque.
• PRS effectively identifies heightened CAD risk in seemingly healthy individuals, demonstrating its potential as a screening tool.

Outlook:

• The findings support the utility of PRS in identifying individuals at elevated risk for CAD who might be missed by conventional risk stratification methods.
• Prospective validation in larger, diverse cohorts is warranted to further establish the clinical utility of recall-by-PRS strategies.
• This approach could refine personalized screening protocols and preventive strategies for coronary artery disease.