Clinical Utility and Practical Considerations of a Coronary Artery Disease Genetic Risk Score

Background Coronary artery disease (CAD) risk traditionally has been assessed using clinical risk factors. We evaluated whether molecular genetic markers for CAD risk could add information to traditional variables. Methods We developed a false discovery rate 267-marker genetic risk score (FDR 267 ) from markers that were significantly associated with CAD in the UK Biobank cohort meta-analysis. FDR 267 was tested in the Atherosclerosis Risk in Communities cohort using logistic regression and Cox proportional hazards analyses in the European and African American groups. Results Our genetic risk score (FDR 267 ) was associated with a 1.45 (95% confidence interval, 1.39-1.51) increase in odds ratio and a 1.32 (95% confidence interval, 1.26-1.38) increase in hazard ratio per standard deviation of the score. The score modestly improved the area under the curve (AUC) statistic when added to a clinical model (ΔAUC = 0.0112, P = 0.0002). FDR 267 predicted incident CAD (C-index = 0.60), although it did not improve on clinical risk factors (ΔAUC = 0.0159, P = 0.0965). Individuals in the top quintile of FDR 267 genetic risk were at approximately 2-fold increased risk compared with the bottom quintile, which is comparable to risk associated with self-reported family history. The performance of FDR 267 was less robust in the African American sample. Conclusions FDR 267 is significantly associated with CAD in the European sample, with an effect size comparable to self-reported family history. FDR 267 discriminated between individuals with and without CAD, but did not improve CAD risk prediction over clinical variables. FDR 267 was less predictive of CAD risk in African Americans.