Polygenic Risk Score Predicts Sudden Death in Patients With Coronary Disease and Preserved Systolic Function

Background: A familial predisposition to sudden and/or arrhythmic death (SAD) in the setting of coronary artery disease (CAD) exists; however, the genetic basis is poorly understood. Objective: To determine whether a genome-wide polygenic score for CAD (GPSCAD) might have utility in SAD risk stratification in CAD patients without severe systolic dysfunction. Methods: A previously validated GPSCAD was generated utilizing genome-wide genotyping in 4698 PREDETERMINE participants of European ancestry with CAD and left ventricular ejection fraction (LVEF)>30–35%. The population was dichotomized according to top GPSCAD decile as defined by the general population, and absolute, proportional, and relative risks for SAD and non-SAD were estimated using competing risk analyses. Results: Over a median follow-up of 8.0 years, participants in the top GPSCAD decile were at elevated absolute SAD risk (8.0%; 95% CI, 5.1–12.4 versus 4.8%; 95% CI,3.3–7.0; p=0.005) and proportional SAD risk (29% vs 16%; p=0.0003) compared to the remainder. After controlling for LVEF, clinical factors, and ECG parameters, the top GPSCAD decile was associated with SAD (sHR1.77; 95% CI, 1.23–2.54; p=0.002) but not non-SAD (sHR 1.00, 95% CI 0.80–1.25; p=0.98) (p for Δ =0.003). The addition of the top GPSCAD decile to the multivariable model significantly improved net reclassification indexes (continuous NRI 14.0%, p=0.024 and categorical NRI 6.6%, p=0.005) but not the C-Index (difference in C-Index 0.007; p=0.143). Conclusion: Among CAD patients without severe systolic dysfunction, high GPSCAD specifically predicted SAD and enriched for both absolute and proportional SAD risk, identifying a population who might benefit from defibrillator therapy.