Clinical Utility of Multi-marker Genetic Risk Scores for Prediction of Incident Coronary Heart Disease: A Cohort Study among over 51 Thousand Individuals of European Ancestry

Background —We evaluated whether including multi-locus genetic risk scores (GRS's) into the Framingham Risk Equation improves the predictive capacity, discrimination and reclassification of asymptomatic individuals with respect to coronary heart disease (CHD) risk. Methods and Results —We performed a cohort study among 51,954 European-ancestry members of a Northern California integrated health care system (67% female; mean age 59) free of CHD at baseline (2007-08). Four GRS's were constructed using between 8 and 51 previously identified genetic variants. After a mean (± SD) follow-up of 5.9 (± 1.5) years, 1,864 incident CHD events were documented. All GRS's were linearly associated with CHD in a model adjusted by individual risk factors: HR [95%CI] per SD unit: 1.21 [1.15-1.26] for GRS\_8, 1.20 [1.15-1.26] for GRS\_12, 1.23 [1.17-1.28] for GRS\_36 and 1.23 [1.17-1.28] for GRS\_51. Inclusion of the GRS's improved the C-statistic (Δc-statistic=0.008 for GRS\_8 and GRS\_36; 0.007 for GRS\_12; and 0.009 for GRS\_51; all p<0.001). The net reclassification improvement (NRI) was 5% for GRS\_8, GRS\_12 and GRS\_36 and 4% for GRS\_51 in the entire cohort, and was (after correcting for bias) 9% for GRS\_8 and GRS\_12, and 7% for GRS\_36 and GRS\_51 when analyzing those classified as intermediate Framingham risk (10-20%). The number required to treat to prevent 1 CHD after selectively treating with statins up-reclassified subjects on the basis of genetic information was 36 for GRS\_8 and GRS\_12, 41 for GRS\_36 and 43 for GRS\_51. Conclusions —Our results demonstrate significant and clinically relevant incremental discriminative/predictive capability of four multi-locus GRS's for incident CHD among subjects of European ancestry.