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Meta-analysis of epigenome-wide association studies of carotid intima-media thickness |
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| Authors: | Portilla-Fernández Eliana Hwang Shih-Jen Wilson Rory Maddock Jane Hill W David Teumer Alexander Mishra Pashupati P Brody Jennifer A Joehanes Roby Ligthart Symen Ghanbari Mohsen Kavousi Maryam Roks Anton J M Danser A H Jan Levy Daniel Peters Annette Ghasemi Sahar Schminke Ulf Dörr Marcus Grabe Hans J Lehtimäki Terho Kähönen Mika Hurme Mikko A Bartz Traci M Sotoodehnia Nona Bis Joshua C Thiery Joachim Koenig Wolfgang Ong Ken K Bell Jordana T Meisinger Christine Wardlaw Joanna M Starr John M Seissler Jochen Then Cornelia Rathmann Wolfgang Ikram M Arfan Psaty Bruce M Raitakari Olli T Völzke Henry Deary Ian J Wong Andrew Waldenberger Melanie O’Donnell Christopher J Dehghan Abbas |
| Institution: | 1.Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands ;2.Department of Internal Medicine, Division of Vascular Medicine and Pharmacology, Erasmus University Medical Center, Rotterdam, The Netherlands ;3.Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA ;4.Framingham Heart Study, Framingham, MA, USA ;5.Research Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany ;6.MRC Unit for Lifelong Health and Ageing at UCL, Institute of Cardiovascular Science, University College London, London, UK ;7.Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK ;8.Department of Psychology, University of Edinburgh, Edinburgh, UK ;9.Intitute for Community Medicine, University Medicine Greifswald, Greifswald, Germany ;10.DZHK (German Centre for Cardiovascular Research), Partner Site Griefswald, Greifswald, Germany ;11.Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland ;12.Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA ;13.Institute for Medical Information Processing, Biometry, and Epidemiology, Faculty of Medicine, Ludwig-Maximilians-Universit?t München, Munich, Germany ;14.German Center for Diabetes Research, Neuherberg, Germany ;15.Department of Neurology, University Medicine Greifswald, Greifswald, Germany ;16.Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany ;17.Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany ;18.Department of Clinical Physiology, Tampere University Hospital, and Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland ;19.Department of Microbiology and Immunology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland ;20.Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital, Leipzig, Leipzig, Germany ;21.DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany ;22.Deutsches Herzzentrum München, Technische Universit?t München, Munich, Germany ;23.Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany ;24.MRC Epidemiology Unit and Department of Paediatrics, Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK ;25.Department of Twin Research and Genetic Epidemiology, King’s College London, London, UK ;26.Independent Research Group, Clinical Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany ;27.Ludwig-Maximilians-Universit?t München, UNIKA-T, Augsburg, Germany ;28.Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK ;29.Edinburgh Imaging, University of Edinburgh, Edinburgh, UK ;30.UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK ;31.Diabetes Zentrum, Medizinische Klinik und Poliklinik IV – Campus Innenstadt, Klinikum Der Ludwig-Maximilians-Universit?t München, Munich, Germany ;32.Clinical Cooperation Group Diabetes, Ludwig-Maximilians-Universit?t München and Helmholtz Zentrum München, Munich, Germany ;33.Institute of Biometrics and Epidemiology, German Diabetes Center, Leibniz Institute at Heinrich Heine University Düsseldorf, Düsseldorf, Germany ;34.Department of Epidemiology, University of Washington, Seattle, WA, USA ;35.Department of Health Services, University of Washington, Seattle, WA, USA ;36.Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA ;37.Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland ;38.Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland ;39.Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland ;40.Cardiology Section and Center for Population Genomics, VA Boston Healthcare System, Boston, MA, USA ;41.Department of Medicine, Harvard Medical School, Boston, MA, USA ;42.Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, Room 157, Norfolk Place, St Mary’s Campus, London, UK ;43.UK Dementia Research Institute at Imperial College London, London, UK ;44.MRC Centre for Environment and Health, School of Public Health, Imperial College London, London, UK ; |
| Abstract: | Common carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta?=??0.0264, p value?=?3.5?×?10–8) in the discovery panel and was replicated in replication panel (beta?=??0.07, p value?=?0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (AHRR). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of ALOX12 showed the strongest association with cIMT (p value?=?1.4?×?10–13). In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease. |
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