George Hindy1, Krishna G Aragam1, Kenney Ng1, Mark Chaffin1, Luca A Lotta1, Aris Baras1, Isabel Drake1, Marju Orho-Melander1, Olle Melander1, Sekar Kathiresan1, Amit V Khera1. 1. Department of Population Medicine, Qatar University College of Medicine, QU Health, Doha (G.H.). Program of Medical and Population Genetics, Broad Institute, Cambridge, MA (K.G.A., M.C., S.K., A.V.K.). Center for Genomic Medicine (K.G.A., A.V.K.) and Division of Cardiology, Department of Medicine (S.K., A.V.K.), Massachusetts General Hospital, Boston. Department of Medicine, Harvard Medical School, Boston, MA (K.G.A., S.K., A.V.K.). Center for Computational Health, IBM Research, Cambridge, MA (K.N.). Regeneron Genetics Center, Tarrytown, NY (L.A.L., A.B.). Department of Clinical Sciences in Malmö, Lund University, Malmö, Sweden (I.D., M.O.-M., O.M.).
Abstract
OBJECTIVE: To determine the relationship of a genome-wide polygenic score for coronary artery disease (GPSCAD) with lifetime trajectories of CAD risk, directly compare its predictive capacity to traditional risk factors, and assess its interplay with the Pooled Cohort Equations (PCE) clinical risk estimator. Approach and Results: We studied GPSCAD in 28 556 middle-aged participants of the Malmö Diet and Cancer Study, of whom 4122 (14.4%) developed CAD over a median follow-up of 21.3 years. A pronounced gradient in lifetime risk of CAD was observed-16% for those in the lowest GPSCAD decile to 48% in the highest. We evaluated the discriminative capacity of the GPSCAD-as assessed by change in the C-statistic from a baseline model including age and sex-among 5685 individuals with PCE risk estimates available. The increment for the GPSCAD (+0.045, P<0.001) was higher than for any of 11 traditional risk factors (range +0.007 to +0.032). Minimal correlation was observed between GPSCAD and 10-year risk defined by the PCE (r=0.03), and addition of GPSCAD improved the C-statistic of the PCE model by 0.026. A significant gradient in lifetime risk was observed for the GPSCAD, even among individuals within a given PCE clinical risk stratum. We replicated key findings-noting strikingly consistent results-in 325 003 participants of the UK Biobank. CONCLUSIONS: GPSCAD-a risk estimator available from birth-stratifies individuals into varying trajectories of clinical risk for CAD. Implementation of GPSCAD may enable identification of high-risk individuals early in life, decades in advance of manifest risk factors or disease.
OBJECTIVE: To determine the relationship of a genome-wide polygenic score for coronary artery disease (GPSCAD) with lifetime trajectories of CAD risk, directly compare its predictive capacity to traditional risk factors, and assess its interplay with the Pooled Cohort Equations (PCE) clinical risk estimator. Approach and Results: We studied GPSCAD in 28 556 middle-aged participants of the Malmö Diet and Cancer Study, of whom 4122 (14.4%) developed CAD over a median follow-up of 21.3 years. A pronounced gradient in lifetime risk of CAD was observed-16% for those in the lowest GPSCAD decile to 48% in the highest. We evaluated the discriminative capacity of the GPSCAD-as assessed by change in the C-statistic from a baseline model including age and sex-among 5685 individuals with PCE risk estimates available. The increment for the GPSCAD (+0.045, P<0.001) was higher than for any of 11 traditional risk factors (range +0.007 to +0.032). Minimal correlation was observed between GPSCAD and 10-year risk defined by the PCE (r=0.03), and addition of GPSCAD improved the C-statistic of the PCE model by 0.026. A significant gradient in lifetime risk was observed for the GPSCAD, even among individuals within a given PCE clinical risk stratum. We replicated key findings-noting strikingly consistent results-in 325 003 participants of the UK Biobank. CONCLUSIONS: GPSCAD-a risk estimator available from birth-stratifies individuals into varying trajectories of clinical risk for CAD. Implementation of GPSCAD may enable identification of high-risk individuals early in life, decades in advance of manifest risk factors or disease.
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