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

• Published in: Journal of the American College of Cardiology Vol. 80; no. 9; pp. 873 - 883
• Main Authors: Sandhu, Roopinder K., Dron, Jacqueline S., Liu, Yunxian, Moorthy, M. Vinayaga, Chatterjee, Neal A., Ellinor, Patrick T., Chasman, Daniel I., Cook, Nancy R., Khera, Amit V., Albert, Christine M.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 30.08.2022
• Subjects: Cardiovascular; coronary artery disease; polygenic risk score; sudden death; coronary artery disease; NRI; CAD; ECG; LVEF; GPSCAD; ICD; IDI; VF; sudden death; NNT; SAD; MI; polygenic risk score; VT; myocardial infarction; left ventricular ejection fraction; electrocardiogram; implantable cardioverter-defibrillator; sudden and/or arrhythmic death; ventricular fibrillation; net reclassification improvement; integrated discrimination improvement; GPS CAD; ventricular tachycardia; genome-wide polygenic score for coronary artery disease; number needed to treat
• ISSN: 0735-1097; 1558-3597; 1558-3597
• DOI: 10.1016/j.jacc.2022.05.049

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. The purpose of this study was to determine whether a genome-wide polygenic score for coronary artery disease (GPSCAD) might have utility in SAD risk stratification in CAD patients without severe systolic dysfunction. A previously validated GPSCAD was generated utilizing genome-wide genotyping in 4,698 PRE-DETERMINE participants of European ancestry with CAD and left ventricular ejection fraction >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. 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% vs 4.8%; 95% CI: 3.3%-7.0%; P = 0.005) and proportional SAD risk (29% vs 16%; P = 0.0003) compared with the remainder. After controlling for left ventricular ejection fraction, clinical factors, and electrocardiogram parameters, the top GPSCAD decile was associated with SAD (subdistribution HR: 1.77; 95% CI: 1.23-2.54; P = 0.002) but not non-SAD (subdistribution HR: 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 (NRIs) (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). 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. [Display omitted]