Abstract 12224: Predictive Power and Value of a CAD Polygenic Risk Score in Primary Prevention Based on Age and Clinical Risk

Abstract

Background: The clinical utility of polygenic risk scores (PRS) for CAD has not yet been established. We investigated the ability of a CAD PRS to potentially guide statin initiation after accounting for age and clinical risk. Methods: We performed a prospective cohort study in the UK Biobank that included all individuals without a history of CAD and who were not on lipid-lowering therapy. The CAD PRS was comprised of 241 genome-wide significant SNPs. Genetic risk categories were defined as low (bottom 20%), intermediate, and high (top 20%). HRs were calculated as a function of age. Next, 10-year ASCVD risk score was used to classify individuals as low, borderline, intermediate, or high risk. Each ASCVD risk group was further stratified by genetic risk to determine whether genetics could reclassify individuals to help guide decisions regarding statin initiation with more precision. ASCVD events were defined as incident clinical CAD (including MI), stroke, or CV death. Results: The 333,245 patients included in this study were ages 40-74 years (avg 57) and 57% were female. Over the 10-yr follow-up, there were 4,552 MIs. The CAD PRS significantly predicted MI in all age groups but had significantly stronger risk prediction at younger ages (p-int <0.001) ( Figure, A ). This gradient of risk was especially pronounced under 50 years of age, where those with high PRS approached a 6-fold increased risk of MI compared with those in the low PRS category. When CAD PRS testing was added to the 71,534 patients <50 years old, 20% of borderline risk patients were reclassified into intermediate risk, warranting initiation of statin therapy to reduce LDL-C, and 20% of borderline and intermediate risk patients were reclassified as low risk, thus not warranting therapy ( Figure, B ). Conclusion: The predictive ability of a CAD PRS is especially strong in individuals under the age of 50 and can be used to identify more precisely who should be initiated on statin therapy.