Yingchang Lu1, Latchezar Dimitrov2, Shyh-Huei Chen3, Lawrence F Bielak4, Joshua C Bis5, Mary F Feitosa6, Lingyi Lu3, Maryam Kavousi7, Laura M Raffield8, Albert V Smith9,10,11, Lihua Wang6, Stefan Weiss12,13, Jie Yao14, Jiaxi Zhu6, Elias F Gudmundsson10,11, Valborg Gudmundsdottir10,11, Daniel Bos7,15, Mohsen Ghanbari7, M Arfan Ikram7, Shih-Jen Hwang16,17, Kent D Taylor14, Matthew J Budoff18, Gauti K Gíslason10,11, Christopher J O'Donnell19,20,21, Ping An6, Nora Franceschini22, Barry I Freedman23, Yi-Ping Fu24,17, Xiuqing Guo14, Gerardo Heiss22, Sharon L R Kardia4, James G Wilson25,26, Carl D Langefeld2,3, Ulf Schminke27, André G Uitterlinden7,28, Leslie A Lange29, Patricia A Peyser4, Vilmundur G Gudnason10,11, Bruce M Psaty30, Jerome I Rotter14, Donald W Bowden2,31, Maggie C Y Ng1,2. 1. Division of Genetic Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN (Y.L., M.C.Y.N.). 2. Center for Precision Medicine (L.D., C.D.L., D.W.B., M.C.Y.N.), Wake Forest School of Medicine, Winston-Salem, NC. 3. Department of Biostatistics and Data Science (S.-H.C., L.L., C.D.L.), Wake Forest School of Medicine, Winston-Salem, NC. 4. Department of Epidemiology (L.F.B., S.L.R.K., P.A.P.). 5. Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services (J.C.B.), University of Washington, Seattle. 6. Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, Farrell Learning Center, St Louis, MO (M.F.F., L.W., J.Z., P.A.). 7. Department of Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands (M.K., D.B., M.G., M.A.I., A.G.U.). 8. Department of Genetics (L.M.R.), University of North Carolina, Chapel Hill. 9. Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI (A.V.S.). 10. Faculty of Medicine, University of Iceland, Reykjavik (A.V.S., E.F.G., V.G., G.K.G., V.G.G.). 11. Icelandic Heart Association, Kopavogur (A.V.S., E.F.G., V.G., G.K.G., V.G.G.). 12. Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University of Greifswald and University Medicine Greifswald, Germany (S.W.). 13. DZHK (German Center for Cardiovascular Research), Partner Site Greifswald, Germany (S.W.). 14. Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA (J.Y., K.D.T., X.G., J.I.R.). 15. Department of Radiology and Nuclear Medicine (D.B.). 16. The Population Sciences Branch, Division of Intramural Research (S.-J.H), National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD. 17. The Framingham Heart Study, National Heart, Lung and Blood Institute, National Institutes of Health, Framingham, MA (S.-J.H., Y.-P.F.). 18. Division of Cardiology, Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA (M.J.B.). 19. VA Boston Healthcare System (C.J.O.), Harvard Medical School, Boston, MA. 20. Department of Medicine, Brigham Women's Hospital (C.J.O.), Harvard Medical School, Boston, MA. 21. Department of Medicine (C.J.O.), Harvard Medical School, Boston, MA. 22. Department of Epidemiology (N.F., G.H.), University of North Carolina, Chapel Hill. 23. Department of Internal Medicine (B.I.F.), Wake Forest School of Medicine, Winston-Salem, NC. 24. Office of Biostatistics Research (Y.-P.F.), National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD. 25. Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson (J.G.W.). 26. Department of Cardiology, Beth Israel Deaconess Medical Center, Boston, MA (J.G.W.). 27. Department of Neurology, University Medicine Greifswald, Germany (U.S.). 28. Department of Internal Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands (A.G.U.). 29. Division of Biomedical Informatics and Personalized Medicine, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora (L.A.L.). 30. Departments of Epidemiology and Health Services (B.M.P.), University of Washington, Seattle. 31. Department of Biochemistry (D.W.B.), Wake Forest School of Medicine, Winston-Salem, NC.
Abstract
BACKGROUND: Coronary artery calcification (CAC) and carotid artery intima-media thickness (cIMT) are measures of subclinical atherosclerosis in asymptomatic individuals and strong risk factors for cardiovascular disease. Type 2 diabetes (T2D) is an independent cardiovascular disease risk factor that accelerates atherosclerosis. METHODS: We performed meta-analyses of genome-wide association studies in up to 2500 T2D individuals of European ancestry (EA) and 1590 T2D individuals of African ancestry with or without exclusion of prevalent cardiovascular disease, for CAC measured by cardiac computed tomography, and 3608 individuals of EA and 838 individuals of African ancestry with T2D for cIMT measured by ultrasonography within the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium. RESULTS: We replicated 2 loci (rs9369640 and rs9349379 near PHACTR1 and rs10757278 near CDKN2B) for CAC and one locus for cIMT (rs7412 and rs445925 near APOE-APOC1) that were previously reported in the general EA populations. We identified one novel CAC locus (rs8000449 near CSNK1A1L/LINC00547/POSTN at 13q13.3) at P=2.0×10-8 in EA. No additional loci were identified with the meta-analyses of EA and African ancestry. The expression quantitative trait loci analysis with nearby expressed genes derived from arterial wall and metabolic tissues from the Genotype-Tissue Expression project pinpoints POSTN, encoding a matricellular protein involved in bone formation and bone matrix organization, as the potential candidate gene at this locus. In addition, we found significant associations (P<3.1×10-4) for 3 previously reported coronary artery disease loci for these subclinical atherosclerotic phenotypes (rs2891168 near CDKN2B-AS1 and rs11170820 near FLJ12825 for CAC, and rs7412 near APOE for cIMT). CONCLUSIONS: Our results provide potential biological mechanisms that could link CAC and cIMT to increased cardiovascular disease risk in individuals with T2D.
BACKGROUND: Coronary artery calcification (CAC) and carotid artery intima-media thickness (cIMT) are measures of subclinical atherosclerosis in asymptomatic individuals and strong risk factors for cardiovascular disease. Type 2 diabetes (T2D) is an independent cardiovascular disease risk factor that accelerates atherosclerosis. METHODS: We performed meta-analyses of genome-wide association studies in up to 2500 T2D individuals of European ancestry (EA) and 1590 T2D individuals of African ancestry with or without exclusion of prevalent cardiovascular disease, for CAC measured by cardiac computed tomography, and 3608 individuals of EA and 838 individuals of African ancestry with T2D for cIMT measured by ultrasonography within the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium. RESULTS: We replicated 2 loci (rs9369640 and rs9349379 near PHACTR1 and rs10757278 near CDKN2B) for CAC and one locus for cIMT (rs7412 and rs445925 near APOE-APOC1) that were previously reported in the general EA populations. We identified one novel CAC locus (rs8000449 near CSNK1A1L/LINC00547/POSTN at 13q13.3) at P=2.0×10-8 in EA. No additional loci were identified with the meta-analyses of EA and African ancestry. The expression quantitative trait loci analysis with nearby expressed genes derived from arterial wall and metabolic tissues from the Genotype-Tissue Expression project pinpoints POSTN, encoding a matricellular protein involved in bone formation and bone matrix organization, as the potential candidate gene at this locus. In addition, we found significant associations (P<3.1×10-4) for 3 previously reported coronary artery disease loci for these subclinical atherosclerotic phenotypes (rs2891168 near CDKN2B-AS1 and rs11170820 near FLJ12825 for CAC, and rs7412 near APOE for cIMT). CONCLUSIONS: Our results provide potential biological mechanisms that could link CAC and cIMT to increased cardiovascular disease risk in individuals with T2D.
Entities:
Keywords:
atherosclerosis; carotid intima-media thickness; coronary artery disease; genetics; genome-wide association study
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