Abstract 13054: Predictive Utility of a CAD Polygenic Risk Score in a Low-Risk Primary Prevention Cohort

Abstract

Background: Statin initiation is not recommended for individuals at low clinical risk of ASCVD as defined by the Pooled Cohort Equations (PCE). We sought to evaluate whether CAD PRS can be used to reclassify low ASCVD risk to a range in which a statin should be considered. Methods: We performed a longitudinal cohort study of low-risk participants from the UK Biobank excluding those on lipid-lowering therapy. The PCE was used to identify participants with low risk for ASCVD. We evaluated the actual 10-year ASCVD event rate as a function of the PCE risk score and a previously validated 2.3 million-SNP CAD PRS. The top 10%, 5%, and 1% of CAD PRS were used to depict estimates across PCE predicted risk and the Net Reclassification Index (NRI) was calculated for risk thresholds ≥5% and ≥7.5%. Results: 294,371 participants were included with mean age of 56 ± 8 years and 56% female. High CAD PRS elevated a subset of clinically low-risk individuals to higher risk categories ( Figure ). The top 10% of CAD PRS reclassified individuals with a PCE estimated risk of ≥3.7% to ≥5% risk (borderline risk). For the top 5% and top 1% of CAD PRS, the PCE estimated risk thresholds to be reclassified to ≥5% risk dropped to ≥2.9% and ≥1.3%, respectively (p<0.001). Patients in the top 5% and 1% CAD PRS cross into intermediate risk (≥7.5% risk) at PCE risk estimates of ≥4.2% and ≥2.7%. In these low-risk individuals, the addition of the CAD PRS resulted in a NRI of 0.12 (CI 0.11-0.14) with 14% (CI 0.13-0.16) correctly upclassified to risk ≥5% and 5% (CI 0.04-0.06) correctly upclassified to risk ≥7.5%. Based on the 2021 US census, this corresponds to ~10.4 and ~3.7 million people reclassified, respectively. Incorrect upclassification occurred in 2% (CI 0.02-0.02) and 0.6% (CI 0.005-0.006) at these risk thresholds. Conclusion: In low-risk individuals, a CAD PRS can be used to identify individuals with a higher ASCVD risk than expected based on conventional clinical risk stratification who may merit consideration of statin initiation.