Eythor Bjornsson1, Daniel F Gudbjartsson1, Anna Helgadottir1, Thorarinn Gudnason1, Tomas Gudbjartsson1, Kristjan Eyjolfsson1, Riyaz S Patel1, Nima Ghasemzadeh1, Gudmar Thorleifsson1, Arshed A Quyyumi1, Unnur Thorsteinsdottir1, Gudmundur Thorgeirsson1, Kari Stefansson2. 1. From the Faculty of Medicine (E.B., A.H., T.G., U.T., G.T., K.S.) and Department of Engineering and Natural Sciences (D.F.G.), University of Iceland, Reykjavik, Iceland; deCODE Genetics, Reykjavik, Iceland (E.B., D.F.G., A.H., G.T., U.T., K.S.); Department of Medicine (T.G., K.E., G.T.), and Department of Surgery (T.G.), Landspitali University Hospital, Reykjavik, Iceland; Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA (R.S.P., N.G., A.A.Q.); and Institute of Cardiovascular Sciences, University College London, London, United Kingdom (R.S.P.). 2. From the Faculty of Medicine (E.B., A.H., T.G., U.T., G.T., K.S.) and Department of Engineering and Natural Sciences (D.F.G.), University of Iceland, Reykjavik, Iceland; deCODE Genetics, Reykjavik, Iceland (E.B., D.F.G., A.H., G.T., U.T., K.S.); Department of Medicine (T.G., K.E., G.T.), and Department of Surgery (T.G.), Landspitali University Hospital, Reykjavik, Iceland; Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA (R.S.P., N.G., A.A.Q.); and Institute of Cardiovascular Sciences, University College London, London, United Kingdom (R.S.P.). kstefans@decode.is.
Abstract
OBJECTIVE: Single-nucleotide polymorphisms predisposing to coronary artery disease (CAD) have been shown to predict cardiovascular risk in healthy individuals when combined into a genetic risk score (GRS). We examined whether the cumulative burden of known genetic risk variants associated with risk of CAD influences the development and progression of coronary atherosclerosis. APPROACH AND RESULTS: We investigated the combined effects of all known CAD variants in a cross-sectional study of 8622 Icelandic patients with angiographically significant CAD (≥ 50% diameter stenosis). We constructed a GRS based on 50 CAD variants and tested for association with the number of diseased coronary arteries on angiography. In models adjusted for traditional cardiovascular risk factors, the GRS associated significantly with CAD extent (difference per SD increase in GRS, 0.076; P=7.3 × 10(-17)). When compared with the bottom GRS quintile, patients in the top GRS quintile were roughly 1.67× more likely to have multivessel disease (odds ratio, 1.67; 95% confidence interval, 1.45-1.94). The GRS significantly improved prediction of multivessel disease over traditional cardiovascular risk factors (χ(2) likelihood ratio 48.1; P<0.0001) and modestly improved discrimination, as estimated by the C-statistic (without GRS versus with GRS, 64.0% versus 64.8%) and the integrated discrimination improvement (0.52%). Furthermore, the GRS associated with an earlier age at diagnosis of angiographic CAD. These findings were replicated in an independent sample from the Emory Biobank study (n=1853). CONCLUSIONS: When combined into a single GRS, known genetic risk variants for CAD contribute significantly to the extent of coronary atherosclerosis in patients with significant angiographic disease.
OBJECTIVE: Single-nucleotide polymorphisms predisposing to coronary artery disease (CAD) have been shown to predict cardiovascular risk in healthy individuals when combined into a genetic risk score (GRS). We examined whether the cumulative burden of known genetic risk variants associated with risk of CAD influences the development and progression of coronary atherosclerosis. APPROACH AND RESULTS: We investigated the combined effects of all known CAD variants in a cross-sectional study of 8622 Icelandic patients with angiographically significant CAD (≥ 50% diameter stenosis). We constructed a GRS based on 50 CAD variants and tested for association with the number of diseased coronary arteries on angiography. In models adjusted for traditional cardiovascular risk factors, the GRS associated significantly with CAD extent (difference per SD increase in GRS, 0.076; P=7.3 × 10(-17)). When compared with the bottom GRS quintile, patients in the top GRS quintile were roughly 1.67× more likely to have multivessel disease (odds ratio, 1.67; 95% confidence interval, 1.45-1.94). The GRS significantly improved prediction of multivessel disease over traditional cardiovascular risk factors (χ(2) likelihood ratio 48.1; P<0.0001) and modestly improved discrimination, as estimated by the C-statistic (without GRS versus with GRS, 64.0% versus 64.8%) and the integrated discrimination improvement (0.52%). Furthermore, the GRS associated with an earlier age at diagnosis of angiographic CAD. These findings were replicated in an independent sample from the Emory Biobank study (n=1853). CONCLUSIONS: When combined into a single GRS, known genetic risk variants for CAD contribute significantly to the extent of coronary atherosclerosis in patients with significant angiographic disease.
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