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Genetic Loci for Retinal Arteriolar Microcirculation

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Genetic Loci for Retinal Arteriolar Microcirculation Genetic Loci for Retinal Arteriolar Microcirculation Xueling Sim1., Richard A. Jensen2,3., M. Kamran Ikram4,5., Mary Frances Cotch6., Xiaohui Li7, Stuart MacGregor8, Jing Xie9, Albert Vernon Smith10,11, Eric Boerwinkle12, Paul Mitchell13, Ronald Klein14, Barbara E. K. Klein14, Nicole L. Glazer2,15,16, Thomas Lumley2,17,18, Barbara McKnight2,17, Bruce M. Psaty2,3,15,19,20, Paulus T. V. M. de Jong21,22,23, Albert Hofman23, Fernando Rivadeneira23,24, Andre G. Uitterlinden23,24,25, Cornelia M. van Duijn23, Thor Aspelund10,11, Gudny Eiriksdottir10, Tamara B. Harris26, Fridbert Jonasson27,28, Lenore J. Launer26, The Wellcome Trust Case Control Consortium2"a, John Attia29,30, Paul N. Baird9, Stephen Harrap31, Elizabeth G. Holliday29, Michael Inouye32,33, Elena Rochtchina13, Rodney J. Scott34, Ananth Viswanathan35,36, Global BPGen Consortium"b, Guo Li2, Nicholas L. Smith3,20,37, Kerri L. Wiggins2,15, Jane Z. Kuo7, Kent D. Taylor7, Alex W. Hewitt9, Nicholas G. Martin8, Grant W. Montgomery8, Cong Sun38, Terri L. Young39, David A. Mackey9,40, Natalie R. van Zuydam41, Alex S. F. Doney41, Colin N. A. Palmer41, Andrew D. Morris41, Jerome I. Rotter7, E. Shyong Tai42,43,44", Vilmundur Gudnason10,11", Johannes R. Vingerling5,23", David S. Siscovick2,3,15", Jie Jin Wang9,13", Tien Y. Wong4,9,45*" 1 Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, United States of America, 2 Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, United States of America, 3 Department of Epidemiology, University of Washington, Seattle, Washington, United States of America, 4 Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore, 5 Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands, 6 Division of Epidemiology and Clinical Applications, National Eye Institute, Intramural Research Program, National Institutes of Health, Bethesda, Maryland, United States of America, 7 Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America, 8 Genetics and Population Health, Queensland Institute of Medical Research, Brisbane, Queensland, Australia, 9 Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia, 10 Icelandic Heart Association, Kopavogur Capital Region, Iceland, 11 Department of Medicine, University of Iceland, Reykjavik, Iceland, 12 Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, United States of America, 13 Centre for Vision Research, Department of Ophthalmology and the Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia, 14 Department of Ophthalmology and Visual Sciences, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, United States of America, 15 Department of Medicine, University of Washington, Seattle, Washington, United States of America, 16 Department of Medicine, Boston University, Boston, Massachusetts, United States of America, 17 Department of Biostatistics, University of Washington, Seattle, Washington, United States of America, 18 Department of Statistics, University of Auckland, Auckland, New Zealand, 19 Department of Health Services, University of Washington, Seattle, Washington, United States of America, 20 Group Health Research Institute, Group Health Cooperative, Seattle, Washington, United States of America, 21 Department of Clinical and Molecular Ophthalmogenetics, The Netherlands Institute of Neuroscience, Amsterdam, The Netherlands, 22 Department of Ophthalmology, Academic Medical Center, Amsterdam, The Netherlands, 23 Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands, 24 Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands, 25 Department of Clinical Chemistry, Erasmus Medical Center, Rotterdam, The Netherlands, 26 Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, Intramural Research Program, National Institutes of Health, Bethesda, Maryland, United States of America, 27 Department of Ophthalmology, University of Iceland, Reykjavik, Iceland, 28 Department of Ophthalmology, Landspitalinn University Hospital, Reykjavik, Iceland, 29 School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia, 30 Department of Medicine, John Hunter Hospital and Hunter Medical Research Institute, Newcastle, New South Wales, Australia, 31 Department of Physiology, University of Melbourne, Melbourne, Victoria, Australia, 32 Immunology Division, Walter and Eliza Hall Institute of Medical Research, Victoria, Australia, 33 Department of Medical Biology, University of Melbourne, Victoria, Australia, 34 School of Biomedical Sciences, University of Newcastle, Newcastle, New South Wales, Australia, 35 National Institutes of Health Research (NIHR) Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital, London, United Kingdom, 36 University College London Institute of Ophthalmology, London, United Kingdom, 37 Seattle Epidemiologic Research and Information Center, Veterans Affairs Office of Research and Development, Seattle, Washington, United States of America, 38 Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, Victoria, Australia, 39 Center for Human Genetics, Duke University Medical Center, Durham, North Carolina, United States of America, 40 Lions Eye Institute, University of Western Australia, Centre for Ophthalmology and Visual Science, Perth, Western Australia, Australia, 41 Medical Research Institute, University of Dundee, Dundee, Scotland, United Kingdom, 42 Department of Medicine, National University of Singapore, Singapore, Singapore, 43 Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore, 44 Duke-National University of Singapore Graduate Medical School, Singapore, Singapore, 45 Department of Ophthalmology, National University of Singapore, Singapore, Singapore Abstract Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value ,561028. This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value = 2.11610212 in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined. PLOS ONE | www.plosone.org 1 June 2013 | Volume 8 | Issue 6 | e65804 Genetic Loci for Retinal Arteriolar Caliber Citation: Sim X, Jensen RA, Ikram MK, Cotch MF, Li X, et al. (2013) Genetic Loci for Retinal Arteriolar Microcirculation. PLoS ONE 8(6): e65804. doi:10.1371/ journal.pone.0065804 Editor: Graham R. Wallace, University of Birmingham, United Kingdom Received February 20, 2013; Accepted April 19, 2013; Published June 12, 2013 This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Funding: This work was supported by multiple funding agencies and details for each cohort were given below. The Age, Gene/Environment Susceptibility – Reykjavik Study was funded by the Intramural Research Program of the National Institute on Aging (ZIAAG007380, National Institutes of Health (NIH) contract N01- AG-12100); and the National Eye Institute (ZIAEY000401) at the NIH in the United States; Hjartavernd (the Icelandic Heart Association); and the Althingi (the Icelandic Parliament). The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C,HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. The Cardiovascular Health Study research reported in this article was supported by the National Heart, Lung,
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