Enhanced Risk Prediction for Coronary Heart Disease by Leveraging Polygenic Risk Score and Clinical Risk Score in the Hypertensive Population

Background: Coronary heart disease (CHD) is the leading cause of premature mortality. The incremental value of polygenic risk score (PRS) to clinical risk score towards improving CHD prediction is controversial. Meanwhile, the effect of PRS on CHD prediction in the chronic disease population is unclear. Methods: Utilizing publicly available summary statistic data, we developed several PRSs using genome data of European ancestry from the Atherosclerosis Risk in Communities Study. Furthermore, we investigated the association of CHD with best-performing PRS in both the overall and chronic disease cohorts. Additionally, we evaluated whether adding best-performing PRS to clinical risk score improves the risk prediction. Results: A total of 6,152 subjects (767 CHD cases) were included in this study. The developed best-performing PRS was significantly associated with increased risk of CHD, with a stronger association in the hypertensive population (interaction P = 0.0144). Compared with individuals in the bottom 20% of PRS, those in the top 20% were more than 3-fold more likely to develop CHD in overall cohort, rising to 5-fold in the hypertensive cohort. Adding PRS to the clinical risk score significantly improved the C-index (0.72 to 0.74; P = 0.004) with a 10% net reclassification improvement overall. The hypertensive population showed the greatest improvements. Furthermore, we observed significant gradient of 10-year and lifetime risk of CHD based on PRS within each clinical risk category. Conclusions: Compared to the clinical risk score, integrating PRS significantly improved CHD prediction and better identified CHD risk trajectories, especially in the hypertensive population.