Abstract
Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10−8). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events.
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Acknowledgements
The Age, Gene/Environment Susceptibility (AGES) Reykjavik Study was funded by US National Institutes of Health (NIH) contract N01-AG-12100, the National Institute on Aging (NIA) Intramural Research Program, Hjartavernd (the Icelandic Heart Association) and the Althingi (the Icelandic Parliament).
The Old Order Amish Studies were supported by grants and contracts from the NIH including R01 AG18728 (Amish Longevity Study), R01 HL088119 (Amish Calcification Study), U01 GM074518-04 (The Amish Pharmacogenomics of Anti-Platelet Intervention (PAPI) study) and U01 HL072515-06 (the Heredity and Phenotype Intervention (HAPI) heart study), the University of Maryland General Clinical Research Center grant M01 RR 16500, the Baltimore Veterans Administration Medical Center Geriatrics Research and Education Clinical Center and the Paul Beeson Physician Faculty Scholars in Aging Program. We thank our Amish research volunteers for their long-standing partnership in research and the research staff at the Amish Research Clinic for their hard work and dedication.
The Atherosclerosis Risk in Communities Study (ARIC) was carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and US National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Study infrastructure was partly supported by grant number UL1RR025005, a component of the US National Institutes of Health and NIH Roadmap for Medical Research.
The Erasmus Rucphen Family Study was supported by grants from The Netherlands Organisation for Scientific Research, Erasmus Medical Center and the Centre for Medical Systems Biology (CMSB). We are grateful to all study participants and their relatives, the general practitioners and neurologists for their contributions and to P. Veraart for her help in genealogy, J. Vergeer for the supervision of the laboratory work and P. Snijders for his help in data collection.
The Cardiovascular Health Study research reported in this article was supported by National Heart, Lung, and Blood Institute (NHLBI) contracts N01-HC-85239, N01-HC-85079 through N01-HC-85086; N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133 and NHLBI grants HL080295, HL075366, HL087652, HL105756 with additional contribution from National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through AG-023629, AG-15928, AG-20098 and AG-027058 from the National Institute of Aging. See also http://www.chs-nhlbi.org/pi.htm. DNA handling and genotyping was supported in part by National Center for Research Resources grant M01RR00069 to the Cedars-Sinai General Clinical Research Center Genotyping core and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center.
The Framingham Heart Study of the National Heart, Lung, and Blood Institute of the US National Institutes of Health and Boston University School of Medicine was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (Contract No. N02-HL-6-4278) and by grants from the National Institute of Neurological Disorders and Stroke (NS17950, P.A.W.) and the National Institute of Aging (AG08122, AG16495, P.A.W. and AG033193, S.S.). A portion of this research used the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project.
Rotterdam Study I and II (RS I and RS II): The Rotterdam GWAS was funded by the Netherlands Organisation of Scientific Research (NWO, De Nederlandse Organisatie voor Wetenschappelijk Onderzoek) Investments (number 175.010.2005.011, 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) project number 050-060-810. This study was further supported by an NWO grant (vici, 918-76-619). The Rotterdam Study was funded by the Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The authors are very grateful to the participants and staff from the Rotterdam Study, the participating general practioners and the pharmacists. We thank P. Arp, M. Jhamai, M. Moorhouse, M. Verkerk and S. Bervoets for their help in creating the GWAS database. We would like to thank T.A. Knoch, L.V. de Zeeuw, A. Abuseiris and R. de Graaf as well as their institutions the Erasmus Computing Grid, Rotterdam, The Netherlands, and especially the National German MediGRID and Services@MediGRID part of the German D-Grid, both funded by the German Bundesministeriumfuer Forschung und Technology under grants #01 AK 803 A-H and #01 IG 07015 G, for access to their grid resources.
The SardiNIA Study: This work was supported by the Intramural Research Program of the National Institute on Aging, NIH. The SardiNIA ('Progenia') team was supported by Contract NO1-AG-1–2109 from the National Institute on Aging. The efforts of G.R.A. were supported in part by contract 263-MA-410953 from the National Institute on Aging to the University of Michigan and by research grants HG005581 and HL084729 from the National Institutes of Health (to G.R.A.).
We thank M. Piseddu, Bishop of Ogliastra; E. Lai and his administration in Lanusei for providing and furnishing the clinic site; the mayors of Ilbono, Arzana and Elini; the head of the local Public Health Unit Ar1; and the residents of the towns for their volunteerism and cooperation. We also thank H. Spurgeon and P. Pullen for invaluable help with equipment and readings and M. Evans and D. Longo for helpful discussions.
The Study of Health in Pomerania (SHIP) is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants number 01ZZ9603, 01ZZ0103 and 01ZZ0403), and the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany, and the Federal State of Mecklenburg-West Pomerania. The SHIP authors are grateful to the contribution of A. Teumer, A. Hoffmann and A. Petersmann in generating the SNP data. The University of Greifswald is a member of the 'Center of Knowledge Interchange' program of the Siemens AG.
The Austrian Stroke Prevention Study (ASPS): The research reported in this article was funded by the Austrian Science Fond (FWF) grant number P20545-P05 and P13180. The Medical University of Graz supports the databank of the ASPS.
The Coronary Artery Progression Study: Research leading these results has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 201668; AtheroRemo.
The Gutenberg Heart Study was funded through the government of Rheinland-Pfalz ('Stiftung Rheinland Pfalzfür Innovation', contract number AZ 961-386261/733), the research programs 'Wissenschafft Zukunft' and 'Schwerpunkt Vaskuläre Prävention' of the Johannes Gutenberg-University of Mainz and its contract with BoehringerIngelheim and Philips Medical Systems, including an unrestricted grant for the Gutenberg Heart Study. Specifically, the research reported in this article was supported by the National Genome Network 'NGFNplus' (contract number project A3 01GS0833) by the Federal Ministry of Education and Research, Germany.
Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA)/Cooperative Health Research in the Region of Augsburg (KORA) studies were financed by the Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany, and supported by grants from the German Federal Ministry of Education and Research (BMBF). Part of this work was financed by the German National Genome Research Network (NGFNplus, project number 01GS0834) and through additional funds from the University of Ulm. Furthermore, the research was supported within the Munich Center of Health Sciences (MC Health) as part of Ludwig-Maximilians-Universität Munich (LMU) innovative. IMT measurement of the KORA cohort was funded by a grant of the Karl-Wilder Foundation. Finally, part of this work was financed by the German Diabetes Center, which is funded by the German Federal Ministry of Health and the Ministry of Innovation, Science, Research and Technology of the State of North Rhine Westphalia.
The Orkney Complex Disease Study (ORCADES) was supported by the Chief Scientist Office of the Scottish Government, the Royal Society and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh. We would like to acknowledge the invaluable contributions of L. Anderson and the research nurses in Orkney, the administrative team in Edinburgh and the people of Orkney.
The Cardiovascular Risk in Young Finns Study was supported by the Academy of Finland (grant numbers 117797, 121584 and 126925), the Social Insurance Institution of Finland, University Hospital Medical funds to Tampere, and Turku University Hospitals, the Finnish Foundation of Cardiovascular Research.
CARDIoGRAM: We acknowledge the contributions of all of the authors of the CARDIoGRAM report, as listed in their primary analysis publication14.
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Study concept and design: J.C.B., M. Kavousi, N.F., G.R.A., L.A.C., T.L., S.R.H., K.N., C.H., O.R., C.S.F., V.N., R.B.S., T.A., M.S., M. Kähönen, P.S.W., A.R.S., J.I.R., J.S., D.H.O., E.G.L., B.M.P., M.U., E.B., J.V., W.K., S. Blankenberg, A.B.N., J.W., C.v.D., A. Scuteri, V.G., C.J.O.
Acquisition of the data: J.C.B., A.I., G.R.A., U.S., W.S.P., H.S.M., R.S., T.L., B.O., S. Bevan, E.-M.S., O.R., C.M., H.V., B.T., F.R., K.E.P., H.E.W., R.B.S., M.D., A.P., T.A., S.K., M.P.R., K.T., A.U., M.S., M. Kähönen, T.I., P.S.W., M.O., J.L., A.R.S., G.E., J.I.R., A.H., J.S., T.Z., G.U., F.E., L.J.L., R.B.D., D.H.O., J.T., T.B.H., P.A.W., B.M.P., J.F.P., W.R., E.B., N.K., H.S., J.F.W., J.V., W.K., S. Blankenberg, A.B.N., G. Heiss, C.v.D., A. Scuteri, G. Homuth, B.D.M., V.G., C.J.O.
Statistical analysis and interpretation of the data: J.C.B., M. Kavousi, N.F., A.I., G.R.A., A.V.S., L.A.C., J.E.H., T.L., J.B., S.R.H., A.D., K.N., C.H., O.R., A. Schillert, S.S., Y.-C.C., K.R., V.N., E.H., K.E.P., T.A., S.D., S.K., P.S.W., C.C.W., R.B.D., A.Z., R.K.C., H.S., C.J.O.
Drafting of the manuscript: J.C.B., M. Kavousi, N.F., A.I., K.N., O.R., M. Kähönen, J.F.P., J.V., C.J.O.
Critical revision of the manuscript: J.C.B., M. Kavousi, N.F., A.I., G.R.A., U.S., W.S.P., L.A.C., H.S.M., R.S., T.L., J.B., T.M., S.R.H., A.D., K.N., O.R., C.M., H.V., B.T., K.R., F.R., V.N., H.E.W., R.B.S., M.D., A.P., S.D., M.P.R., K.T., A.U., D.J.C., M.S., M. Kähönen, T.I., J.L., G.E., J.I.R., A.H., J.S., F.E., L.J.L., R.B.D., D.H.O., C.B., A.Z., E.G.L., R.K.C., T.B.H., B.M.P., J.F.P., X.L., W.R., E.B., J.V., W.K., S. Blankenberg, J.W., C.v.D., A. Scuteri, G. Homuth, B.D.M., V.G., C.J.O.
Obtained funding: G.R.A., U.S., H.S.M., R.S., T.L., O.R., H.V., L.P., M.D., S.K., A.U., M.S., M. Kähönen, P.S.W., A.R.S., J.I.R., A.H., J.S., A.Z., P.A.W., B.M.P., J.F.P., W.R., M.U., E.B., H.S., J.F.W., J.V., W.K., A.B.N., G. Heiss, C.v.D., G. Homuth, B.D.M., V.G., C.J.O.
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V.N. has a non-financial research collaboration with General Electric and Medipattern Inc.
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Bis, J., Kavousi, M., Franceschini, N. et al. Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque. Nat Genet 43, 940–947 (2011). https://doi.org/10.1038/ng.920
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DOI: https://doi.org/10.1038/ng.920
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