A polygenic risk score predicts atrial fibrillation in patients with coronary artery disease without severe systolic dysfunction

Abstract

Abstract Background Genome-wide polygenic risk scores (GPS) comprised of multiple common variants can identify individuals within the general population at significantly higher risk for developing atrial fibrillation AF; however, the clinical utility in general populations is limited by the low absolute risk of AF. Purpose To determine whether a genome-wide polygenic score for AF (GPSAF) can be utilized to identify a patient population at high absolute risk for the development of AF among older patients with established coronary artery disease (CAD) and left ventricular ejection fraction (LVEF) > 30-35%. Methods Participants in the PREDETERMINE study without a prior history of AF who had claims data available in Centers for Medicare and Medicaid Services (CMS) database were followed for incident AF defined as International Classification of Diseases codes 427.3 and I48. A recently validated GPSAF comprised of 1.1 million variants was generated and participants were divided into quintiles based upon the distribution of the GPSAF in the general population. The population was separated into 3 categories of genetic risk, with the top quintile classified as high risk, the second through fourth quintiles classified as intermediate risk, and the bottom quintile classified as low risk. Cumulative incidence curves for incident AF were plotted stratified by the GPSAF categories and the association between GPSAF and incident AF were estimated using Cox proportional hazard models with and without adjusting for established AF risk factors and biomarkers (N-terminal pro-B-type natriuretic peptide, high-sensitivity Troponin I, high sensitivity c-reactive protein). Results Over a median follow-up of 8.0 years, there were 482 incident AF events among 2272 study participants. Overall, median age was 67 [62,73] years and 73.5% were men. Baseline AF risk factors and biomarkers did not differ across GPSAF risk categories. The unadjusted cumulative incidence of AF over the course of the study was 39.2% (29.2%-47.8%) in the high GPSAF risk group, 32.5% (25.8%-38.5%) in the intermediate GPSAF risk group, and 21.6% (13.4%-29.9%) in the low GPSAF risk group (Figure 1). Compared with the participants with low GPSAF risk, participants with high and intermediate GPSAF risk had respectively t 2.32-fold (95% CI, 1.71-3.14; p=0.001) and 1.64-fold (95% CI, 1.27-2.10; p=0.001) increased risk for incident AF, adjusted for age and sex. Both remained significantly elevated after controlling for clinical factors, and biomarkers (Table 1). Conclusion A polygenic risk score for AF is strongly associated with incident AF risk among patients with CAD without severe systolic dysfunction, and clinically meaningful elevations in absolute risk of developing AF were observed in those in the highest quintile of risk. Future research is needed to determine if genetic risk assessment and targeted screening strategies will result in reduce morbidity from AF in this high-risk population.