Integrated clinical and polygenic coronary artery disease risk score predicts 10-year progression of coronary artery plaque

Background Coronary artery disease (CAD) is highly heritable and clinical risk scores may insufficiently capture the full spectrum of individual risk. We investigated whether integrated polygenic risk score (iPRS) derived from a combination of genetic and clinical risk factors is associated with coronary plaque phenotypes and 10-year coronary plaque progression. Methods Patients suspected of CAD (N=288, mean age 58 ± 7 years; 60% male) underwent AI-analyzed serial coronary CTA at baseline and after a median of 10.2 years follow-up. We evaluated the association of iPRS - which combines a CAD PRS with pooled cohort equations (PCE) into an absolute 10 year risk estimate – with baseline burden and 10-year progression of percent atheroma volume (PAV) and percent non-calcified plaque volume (PNCP). Patients were stratified into low/borderline (<7.5%), intermediate (≥7.5% to <20%), and high (≥20%) 10-year risk categories. Clinical utility was assessed using a reclassification matrix and continuous net reclassification improvement (NRI) to investigate the benefit of iPRS compared to PCE alone for prediction of above-median plaque progression. Results iPRS was a robust, independent predictor of both baseline plaque burden and 10-year plaque progression. After adjustment for genetic principal components, iPRS was significantly associated with baseline PAV (Beta: 0.211 [95% CI: 0.128-0.294]; P<0.001) and PNCP (Beta: 0.094 [95% CI: 0.044-0.143]; P<0.001). For longitudinal changes, iPRS was significantly associated with 10-year progression of PAV (Beta: 0.118 [95% CI: 0.075-0.162]; P<0.001) and PNCP (Beta: 0.074 [95% CI: 0.045-0.102]; P=<0.001). Compared to PCE, iPRS reclassified 57 patients (19.8%) across clinical risk levels (28 higher, 29 lower). For 10-year PNCP progression, the iPRS demonstrated a significant continuous NRI of 0.403 (95% CI: 0.184–0.619; P<0.001). This improvement was predominantly driven by the superior identification of true progressors (NRI+ Cases: 0.389). Conclusion Integrating genetic data with clinical risk scores significantly improves prediction of both baseline coronary plaque and 10-year plaque progression. iPRS is effective at identifying patients with a genetic predisposition for high-risk non-calcified plaque progression, providing an opportunity for targeted prevention strategies.iprs_table