Dynamic Importance of Genomic and Clinical Risk for Coronary Artery Disease Over the Life Course.

Summary

Across two large longitudinal cohorts (FOS and UK Biobank), CAD polygenic risk had its greatest predictive value at younger ages, outperforming pooled cohort equations especially in the 40–45 age group. Adding PRS increased AUC overall by 5.1% and by 6.5% in individuals under 55, supporting age-tailored precision prevention.

Key Findings

• CAD PRS hazard ratio was 3.58 at age 19 (FOS) and 1.51 by age 70 (UKB), indicating age-dependent diminishing effect.
• In ages 40–45, PRS identified 3.2-fold more subsequent CAD events than pooled cohort equations.
• Adding PRS improved AUC by +5.1% overall and by +6.5% in individuals <55 years.

Clinical Implications

Consider incorporating PRS for CAD risk assessment in adults under 55 to identify high-risk individuals earlier than traditional models, enabling earlier statin/lifestyle interventions and targeted follow-up.

Limitations

• Observational design limits causal inference and may be influenced by unmeasured confounding.
• Predominantly European ancestry may limit generalizability to other populations.

Future Directions

Prospective implementation studies to test PRS-guided prevention pathways, evaluation in diverse ancestries, and cost-effectiveness analyses for earlier-life screening.