Use of a polygenic risk score to enhance early detection of coronary atherosclerosis

Background Coronary CT angiography (CCTA) enables early noninvasive detection of coronary atherosclerosis, but its use in younger adults is limited by low pretest probability. Coronary artery disease polygenic risk score (CAD-PRS) may help identify individuals with increased likelihood of coronary plaque. Methods We conducted a retrospective cohort study of patients without prior coronary artery disease who underwent CCTA between 2004 and 2021 and were genotyped through the Mass General Brigham Biobank (n=1,991), with follow-up through 2024. CAD-PRS was analyzed continuously and by risk categories (high [top decile], intermediate, low [bottom decile]). Plaque was classified as absent (CAD-RADS 0), non-obstructive (CAD-RADS 1–2), or obstructive (CAD-RADS 3–5). Extensive plaque was defined as ≥3-vessel involvement. Relative risk regression evaluated associations with plaque stratified by age. Kaplan–Meier and Cox proportional hazards models evaluated associations with adverse cardiovascular outcomes. Results Plaque was present in 65.6%, extensive plaque in 32.2%, and obstructive disease in 24.6%. Compared with the low-PRS group, high CAD-PRS was associated with greater risk of any plaque (RR 1.68), extensive plaque (RR 2.62), and obstructive disease (RR 2.82) (all P<.001). Associations were strongest among younger individuals (PRS–age interaction P=.017). CAD-PRS improved discrimination beyond age, sex, and traditional risk factors (C-statistic 0.832 [95% CI, 0.814–0.851] vs 0.803 [0.782–0.823]). High CAD-PRS was independently associated with increased cardiovascular events (log-rank P<.005). Conclusions High CAD-PRS was independently associated with greater presence, extent, and severity of CAD on CCTA. The impact of genetic risk was strongest in younger adults—a group for whom identifying early atherosclerotic plaque may have the greatest impact.