Genetically defined elevated homocysteine levels do not result in widespread changes of DNA methylation in leukocytes
Identifieur interne : 002852 ( Pmc/Curation ); précédent : 002851; suivant : 002853Genetically defined elevated homocysteine levels do not result in widespread changes of DNA methylation in leukocytes
Auteurs : Pooja R. Mandaviya [Pays-Bas] ; Roby Joehanes [États-Unis] ; Dylan Aïssi [France] ; Brigitte Kühnel [Allemagne] ; Riccardo E. Marioni [Australie, Royaume-Uni] ; Vinh Truong [Canada] ; Lisette Stolk [Pays-Bas] ; Marian Beekman [Pays-Bas] ; Marc Jan Bonder [Pays-Bas] ; Lude Franke [Pays-Bas] ; Christian Gieger [Allemagne] ; Tianxiao Huan [États-Unis] ; M. Arfan Ikram [Pays-Bas] ; Sonja Kunze [Allemagne] ; Liming Liang [États-Unis] ; Jan Lindemans [Pays-Bas] ; Chunyu Liu [États-Unis] ; Allan F. Mcrae [Australie] ; Michael M. Mendelson [États-Unis] ; Martina Müller-Nurasyid [Allemagne] ; Annette Peters [Allemagne] ; P. Eline Slagboom [Pays-Bas] ; John M. Starr [Royaume-Uni] ; David-Alexandre Trégouët [France] ; André G. Uitterlinden [Pays-Bas] ; Marleen M. J. Van Greevenbroek [Pays-Bas] ; Diana Van Heemst [Pays-Bas] ; Maarten Van Iterson [Pays-Bas] ; Philip S. Wells [Canada] ; Chen Yao [États-Unis] ; Ian J. Deary [Royaume-Uni] ; France Gagnon [Canada] ; Bastiaan T. Heijmans [Pays-Bas] ; Daniel Levy [États-Unis] ; Pierre-Emmanuel Morange [France] ; Melanie Waldenberger [Allemagne] ; Sandra G. Heil [Pays-Bas] ; Joyce B. J. Van Meurs [Pays-Bas]Source :
- PLoS ONE [ 1932-6203 ] ; 2017.
Abstract
DNA methylation is affected by the activities of the key enzymes and intermediate metabolites of the one-carbon pathway, one of which involves homocysteine. We investigated the effect of the well-known genetic variant associated with mildly elevated homocysteine:
Methylation levels were assessed using Illumina 450k arrays on 9,894 individuals of European ancestry from 12 cohort studies. Linear-mixed-models were used to study the association of additive
Meta-analysis revealed that the
Our results do not show widespread changes in DNA-methylation across the genome, and therefore do not support the hypothesis that mildly elevated homocysteine is associated with widespread methylation changes in leukocytes.
Url:
DOI: 10.1371/journal.pone.0182472
PubMed: 29084233
PubMed Central: 5662081
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Mandaviya</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands</addr-line></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands</addr-line></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Internal Medicine, Erasmus University Medical Center, Rotterdam</wicri:regionArea></affiliation></author><author><name sortKey="Joehanes, Roby" sort="Joehanes, Roby" uniqKey="Joehanes R" first="Roby" last="Joehanes">Roby Joehanes</name><affiliation wicri:level="1"><nlm:aff id="aff003"><addr-line>Institute for Aging Research, Hebrew SeniorLife, Harvard Medical School, Boston, MA, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Institute for Aging Research, Hebrew SeniorLife, Harvard Medical School, Boston, MA</wicri:regionArea></affiliation></author><author><name sortKey="Aissi, Dylan" sort="Aissi, Dylan" uniqKey="Aissi D" first="Dylan" last="Aïssi">Dylan Aïssi</name><affiliation wicri:level="1"><nlm:aff id="aff004"><addr-line>Sorbonne Universités, UPMC Univ. Paris 06, INSERM, UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Sorbonne Universités, UPMC Univ. Paris 06, INSERM, UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff005"><addr-line>ICAN Institute for Cardiometabolism and Nutrition, Paris, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>ICAN Institute for Cardiometabolism and Nutrition, Paris</wicri:regionArea></affiliation></author><author><name sortKey="Kuhnel, Brigitte" sort="Kuhnel, Brigitte" uniqKey="Kuhnel B" first="Brigitte" last="Kühnel">Brigitte Kühnel</name><affiliation wicri:level="1"><nlm:aff id="aff006"><addr-line>Research Unit of Molecular Epidemiology, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Research Unit of Molecular Epidemiology, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff007"><addr-line>Institute of Epidemiology II, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Epidemiology II, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg</wicri:regionArea></affiliation></author><author><name sortKey="Marioni, Riccardo E" sort="Marioni, Riccardo E" uniqKey="Marioni R" first="Riccardo E." last="Marioni">Riccardo E. Marioni</name><affiliation wicri:level="1"><nlm:aff id="aff008"><addr-line>Queensland Brain Institute, The University of Queensland, Brisbane, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Queensland Brain Institute, The University of Queensland, Brisbane</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff009"><addr-line>Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff010"><addr-line>Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh</wicri:regionArea></affiliation></author><author><name sortKey="Truong, Vinh" sort="Truong, Vinh" uniqKey="Truong V" first="Vinh" last="Truong">Vinh Truong</name><affiliation wicri:level="1"><nlm:aff id="aff011"><addr-line>Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto</wicri:regionArea></affiliation></author><author><name sortKey="Stolk, Lisette" sort="Stolk, Lisette" uniqKey="Stolk L" first="Lisette" last="Stolk">Lisette Stolk</name><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands</addr-line></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Internal Medicine, Erasmus University Medical Center, Rotterdam</wicri:regionArea></affiliation></author><author><name sortKey="Beekman, Marian" sort="Beekman, Marian" uniqKey="Beekman M" first="Marian" last="Beekman">Marian Beekman</name><affiliation wicri:level="1"><nlm:aff id="aff012"><addr-line>Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands</addr-line></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden</wicri:regionArea></affiliation></author><author><name sortKey="Bonder, Marc Jan" sort="Bonder, Marc Jan" uniqKey="Bonder M" first="Marc Jan" last="Bonder">Marc Jan Bonder</name><affiliation wicri:level="1"><nlm:aff id="aff013"><addr-line>Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands</addr-line></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Genetics, University Medical Center Groningen, Groningen</wicri:regionArea></affiliation></author><author><name sortKey="Franke, Lude" sort="Franke, Lude" uniqKey="Franke L" first="Lude" last="Franke">Lude Franke</name><affiliation wicri:level="1"><nlm:aff id="aff013"><addr-line>Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands</addr-line></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Genetics, University Medical Center Groningen, Groningen</wicri:regionArea></affiliation></author><author><name sortKey="Gieger, Christian" sort="Gieger, Christian" uniqKey="Gieger C" first="Christian" last="Gieger">Christian Gieger</name><affiliation wicri:level="1"><nlm:aff id="aff006"><addr-line>Research Unit of Molecular Epidemiology, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Research Unit of Molecular Epidemiology, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff007"><addr-line>Institute of Epidemiology II, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Epidemiology II, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg</wicri:regionArea></affiliation></author><author><name sortKey="Huan, Tianxiao" sort="Huan, Tianxiao" uniqKey="Huan T" first="Tianxiao" last="Huan">Tianxiao Huan</name><affiliation wicri:level="1"><nlm:aff id="aff014"><addr-line>Framingham Heart Study, Framingham, MA, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Framingham Heart Study, Framingham, MA</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff015"><addr-line>The Population Studies Branch, National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, MD, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>The Population Studies Branch, National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, MD</wicri:regionArea></affiliation></author><author><name sortKey="Ikram, M Arfan" sort="Ikram, M Arfan" uniqKey="Ikram M" first="M. Arfan" last="Ikram">M. Arfan Ikram</name><affiliation wicri:level="1"><nlm:aff id="aff016"><addr-line>Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands</addr-line></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Epidemiology, Erasmus University Medical Center, Rotterdam</wicri:regionArea></affiliation></author><author><name sortKey="Kunze, Sonja" sort="Kunze, Sonja" uniqKey="Kunze S" first="Sonja" last="Kunze">Sonja Kunze</name><affiliation wicri:level="1"><nlm:aff id="aff006"><addr-line>Research Unit of Molecular Epidemiology, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Research Unit of Molecular Epidemiology, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff007"><addr-line>Institute of Epidemiology II, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Epidemiology II, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg</wicri:regionArea></affiliation></author><author><name sortKey="Liang, Liming" sort="Liang, Liming" uniqKey="Liang L" first="Liming" last="Liang">Liming Liang</name><affiliation wicri:level="1"><nlm:aff id="aff017"><addr-line>Harvard T.H. Chan School of Public Health, Boston, MA, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Harvard T.H. Chan School of Public Health, Boston, MA</wicri:regionArea></affiliation></author><author><name sortKey="Lindemans, Jan" sort="Lindemans, Jan" uniqKey="Lindemans J" first="Jan" last="Lindemans">Jan Lindemans</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands</addr-line></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam</wicri:regionArea></affiliation></author><author><name sortKey="Liu, Chunyu" sort="Liu, Chunyu" uniqKey="Liu C" first="Chunyu" last="Liu">Chunyu Liu</name><affiliation wicri:level="1"><nlm:aff id="aff014"><addr-line>Framingham Heart Study, Framingham, MA, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Framingham Heart Study, Framingham, MA</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff015"><addr-line>The Population Studies Branch, National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, MD, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>The Population Studies Branch, National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, MD</wicri:regionArea></affiliation></author><author><name sortKey="Mcrae, Allan F" sort="Mcrae, Allan F" uniqKey="Mcrae A" first="Allan F." last="Mcrae">Allan F. Mcrae</name><affiliation wicri:level="1"><nlm:aff id="aff008"><addr-line>Queensland Brain Institute, The University of Queensland, Brisbane, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Queensland Brain Institute, The University of Queensland, Brisbane</wicri:regionArea></affiliation></author><author><name sortKey="Mendelson, Michael M" sort="Mendelson, Michael M" uniqKey="Mendelson M" first="Michael M." last="Mendelson">Michael M. Mendelson</name><affiliation wicri:level="1"><nlm:aff id="aff014"><addr-line>Framingham Heart Study, Framingham, MA, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Framingham Heart Study, Framingham, MA</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff015"><addr-line>The Population Studies Branch, National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, MD, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>The Population Studies Branch, National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, MD</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff018"><addr-line>Department of Cardiology, Boston Children's Hospital, Boston, MA, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Cardiology, Boston Children's Hospital, Boston, MA</wicri:regionArea></affiliation></author><author><name sortKey="Muller Nurasyid, Martina" sort="Muller Nurasyid, Martina" uniqKey="Muller Nurasyid M" first="Martina" last="Müller-Nurasyid">Martina Müller-Nurasyid</name><affiliation wicri:level="1"><nlm:aff id="aff019"><addr-line>DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff020"><addr-line>Institute of Genetic Epidemiology, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Genetic Epidemiology, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff021"><addr-line>Department of Medicine I, University Hospital Munich, Campus Grosshadern, Ludwig-Maximilians-University, Munich, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Medicine I, University Hospital Munich, Campus Grosshadern, Ludwig-Maximilians-University, Munich</wicri:regionArea></affiliation></author><author><name sortKey="Peters, Annette" sort="Peters, Annette" uniqKey="Peters A" first="Annette" last="Peters">Annette Peters</name><affiliation wicri:level="1"><nlm:aff id="aff006"><addr-line>Research Unit of Molecular Epidemiology, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Research Unit of Molecular Epidemiology, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff007"><addr-line>Institute of Epidemiology II, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Epidemiology II, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff019"><addr-line>DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich</wicri:regionArea></affiliation></author><author><name sortKey="Slagboom, P Eline" sort="Slagboom, P Eline" uniqKey="Slagboom P" first="P. Eline" last="Slagboom">P. Eline Slagboom</name><affiliation wicri:level="1"><nlm:aff id="aff012"><addr-line>Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands</addr-line></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden</wicri:regionArea></affiliation></author><author><name sortKey="Starr, John M" sort="Starr, John M" uniqKey="Starr J" first="John M." last="Starr">John M. Starr</name><affiliation wicri:level="1"><nlm:aff id="aff009"><addr-line>Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh</wicri:regionArea></affiliation></author><author><name sortKey="Tregouet, David Alexandre" sort="Tregouet, David Alexandre" uniqKey="Tregouet D" first="David-Alexandre" last="Trégouët">David-Alexandre Trégouët</name><affiliation wicri:level="1"><nlm:aff id="aff004"><addr-line>Sorbonne Universités, UPMC Univ. Paris 06, INSERM, UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Sorbonne Universités, UPMC Univ. Paris 06, INSERM, UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff005"><addr-line>ICAN Institute for Cardiometabolism and Nutrition, Paris, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>ICAN Institute for Cardiometabolism and Nutrition, Paris</wicri:regionArea></affiliation></author><author><name sortKey="Uitterlinden, Andre G" sort="Uitterlinden, Andre G" uniqKey="Uitterlinden A" first="André G." last="Uitterlinden">André G. Uitterlinden</name><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands</addr-line></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Internal Medicine, Erasmus University Medical Center, Rotterdam</wicri:regionArea></affiliation></author><author><name sortKey="Van Greevenbroek, Marleen M J" sort="Van Greevenbroek, Marleen M J" uniqKey="Van Greevenbroek M" first="Marleen M. J." last="Van Greevenbroek">Marleen M. J. Van Greevenbroek</name><affiliation wicri:level="1"><nlm:aff id="aff022"><addr-line>Department of Internal Medicine and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands</addr-line></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Internal Medicine and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center, Maastricht</wicri:regionArea></affiliation></author><author><name sortKey="Van Heemst, Diana" sort="Van Heemst, Diana" uniqKey="Van Heemst D" first="Diana" last="Van Heemst">Diana Van Heemst</name><affiliation wicri:level="1"><nlm:aff id="aff023"><addr-line>Department of Gerontology and Geriatrics Section, Leiden University Medical Center, Leiden, The Netherlands</addr-line></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Gerontology and Geriatrics Section, Leiden University Medical Center, Leiden</wicri:regionArea></affiliation></author><author><name sortKey="Van Iterson, Maarten" sort="Van Iterson, Maarten" uniqKey="Van Iterson M" first="Maarten" last="Van Iterson">Maarten Van Iterson</name><affiliation wicri:level="1"><nlm:aff id="aff012"><addr-line>Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands</addr-line></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden</wicri:regionArea></affiliation></author><author><name sortKey="Wells, Philip S" sort="Wells, Philip S" uniqKey="Wells P" first="Philip S." last="Wells">Philip S. Wells</name><affiliation wicri:level="1"><nlm:aff id="aff024"><addr-line>Department of Medicine, University of Ottawa, and the Ottawa Hospital Research Institute, Ottawa, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Medicine, University of Ottawa, and the Ottawa Hospital Research Institute, Ottawa</wicri:regionArea></affiliation></author><author><name sortKey="Yao, Chen" sort="Yao, Chen" uniqKey="Yao C" first="Chen" last="Yao">Chen Yao</name><affiliation wicri:level="1"><nlm:aff id="aff014"><addr-line>Framingham Heart Study, Framingham, MA, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Framingham Heart Study, Framingham, MA</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff015"><addr-line>The Population Studies Branch, National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, MD, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>The Population Studies Branch, National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, MD</wicri:regionArea></affiliation></author><author><name sortKey="Deary, Ian J" sort="Deary, Ian J" uniqKey="Deary I" first="Ian J." last="Deary">Ian J. Deary</name><affiliation wicri:level="1"><nlm:aff id="aff009"><addr-line>Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff025"><addr-line>Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Psychology, University of Edinburgh, Edinburgh</wicri:regionArea></affiliation></author><author><name sortKey="Gagnon, France" sort="Gagnon, France" uniqKey="Gagnon F" first="France" last="Gagnon">France Gagnon</name><affiliation wicri:level="1"><nlm:aff id="aff011"><addr-line>Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto</wicri:regionArea></affiliation></author><author><name sortKey="Heijmans, Bastiaan T" sort="Heijmans, Bastiaan T" uniqKey="Heijmans B" first="Bastiaan T." last="Heijmans">Bastiaan T. Heijmans</name><affiliation wicri:level="1"><nlm:aff id="aff012"><addr-line>Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands</addr-line></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden</wicri:regionArea></affiliation></author><author><name sortKey="Levy, Daniel" sort="Levy, Daniel" uniqKey="Levy D" first="Daniel" last="Levy">Daniel Levy</name><affiliation wicri:level="1"><nlm:aff id="aff014"><addr-line>Framingham Heart Study, Framingham, MA, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Framingham Heart Study, Framingham, MA</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff015"><addr-line>The Population Studies Branch, National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, MD, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>The Population Studies Branch, National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, MD</wicri:regionArea></affiliation></author><author><name sortKey="Morange, Pierre Emmanuel" sort="Morange, Pierre Emmanuel" uniqKey="Morange P" first="Pierre-Emmanuel" last="Morange">Pierre-Emmanuel Morange</name><affiliation wicri:level="1"><nlm:aff id="aff026"><addr-line>Laboratory of Haematology, La Timone Hospital, Marseille, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Laboratory of Haematology, La Timone Hospital, Marseille</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff027"><addr-line>Institut National pour la Santé et la Recherche Médicale (INSERM), UMR_S 1062, Inra UMR_1260, Aix-Marseille Université, Marseille, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut National pour la Santé et la Recherche Médicale (INSERM), UMR_S 1062, Inra UMR_1260, Aix-Marseille Université, Marseille</wicri:regionArea></affiliation></author><author><name sortKey="Waldenberger, Melanie" sort="Waldenberger, Melanie" uniqKey="Waldenberger M" first="Melanie" last="Waldenberger">Melanie Waldenberger</name><affiliation wicri:level="1"><nlm:aff id="aff006"><addr-line>Research Unit of Molecular Epidemiology, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Research Unit of Molecular Epidemiology, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff007"><addr-line>Institute of Epidemiology II, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Epidemiology II, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg</wicri:regionArea></affiliation></author><author><name sortKey="Heil, Sandra G" sort="Heil, Sandra G" uniqKey="Heil S" first="Sandra G." last="Heil">Sandra G. Heil</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands</addr-line></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam</wicri:regionArea></affiliation></author><author><name sortKey="Van Meurs, Joyce B J" sort="Van Meurs, Joyce B J" uniqKey="Van Meurs J" first="Joyce B. J." last="Van Meurs">Joyce B. J. Van Meurs</name><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands</addr-line></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Internal Medicine, Erasmus University Medical Center, Rotterdam</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">29084233</idno><idno type="pmc">5662081</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5662081</idno><idno type="RBID">PMC:5662081</idno><idno type="doi">10.1371/journal.pone.0182472</idno><date when="2017">2017</date><idno type="wicri:Area/Pmc/Corpus">002A02</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002A02</idno><idno type="wicri:Area/Pmc/Curation">002852</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">002852</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Genetically defined elevated homocysteine levels do not result in widespread changes of DNA methylation in leukocytes</title><author><name sortKey="Mandaviya, Pooja R" sort="Mandaviya, Pooja R" uniqKey="Mandaviya P" first="Pooja R." last="Mandaviya">Pooja R. Mandaviya</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands</addr-line></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands</addr-line></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Internal Medicine, Erasmus University Medical Center, Rotterdam</wicri:regionArea></affiliation></author><author><name sortKey="Joehanes, Roby" sort="Joehanes, Roby" uniqKey="Joehanes R" first="Roby" last="Joehanes">Roby Joehanes</name><affiliation wicri:level="1"><nlm:aff id="aff003"><addr-line>Institute for Aging Research, Hebrew SeniorLife, Harvard Medical School, Boston, MA, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Institute for Aging Research, Hebrew SeniorLife, Harvard Medical School, Boston, MA</wicri:regionArea></affiliation></author><author><name sortKey="Aissi, Dylan" sort="Aissi, Dylan" uniqKey="Aissi D" first="Dylan" last="Aïssi">Dylan Aïssi</name><affiliation wicri:level="1"><nlm:aff id="aff004"><addr-line>Sorbonne Universités, UPMC Univ. Paris 06, INSERM, UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Sorbonne Universités, UPMC Univ. Paris 06, INSERM, UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff005"><addr-line>ICAN Institute for Cardiometabolism and Nutrition, Paris, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>ICAN Institute for Cardiometabolism and Nutrition, Paris</wicri:regionArea></affiliation></author><author><name sortKey="Kuhnel, Brigitte" sort="Kuhnel, Brigitte" uniqKey="Kuhnel B" first="Brigitte" last="Kühnel">Brigitte Kühnel</name><affiliation wicri:level="1"><nlm:aff id="aff006"><addr-line>Research Unit of Molecular Epidemiology, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Research Unit of Molecular Epidemiology, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff007"><addr-line>Institute of Epidemiology II, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Epidemiology II, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg</wicri:regionArea></affiliation></author><author><name sortKey="Marioni, Riccardo E" sort="Marioni, Riccardo E" uniqKey="Marioni R" first="Riccardo E." last="Marioni">Riccardo E. Marioni</name><affiliation wicri:level="1"><nlm:aff id="aff008"><addr-line>Queensland Brain Institute, The University of Queensland, Brisbane, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Queensland Brain Institute, The University of Queensland, Brisbane</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff009"><addr-line>Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff010"><addr-line>Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh</wicri:regionArea></affiliation></author><author><name sortKey="Truong, Vinh" sort="Truong, Vinh" uniqKey="Truong V" first="Vinh" last="Truong">Vinh Truong</name><affiliation wicri:level="1"><nlm:aff id="aff011"><addr-line>Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto</wicri:regionArea></affiliation></author><author><name sortKey="Stolk, Lisette" sort="Stolk, Lisette" uniqKey="Stolk L" first="Lisette" last="Stolk">Lisette Stolk</name><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands</addr-line></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Internal Medicine, Erasmus University Medical Center, Rotterdam</wicri:regionArea></affiliation></author><author><name sortKey="Beekman, Marian" sort="Beekman, Marian" uniqKey="Beekman M" first="Marian" last="Beekman">Marian Beekman</name><affiliation wicri:level="1"><nlm:aff id="aff012"><addr-line>Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands</addr-line></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden</wicri:regionArea></affiliation></author><author><name sortKey="Bonder, Marc Jan" sort="Bonder, Marc Jan" uniqKey="Bonder M" first="Marc Jan" last="Bonder">Marc Jan Bonder</name><affiliation wicri:level="1"><nlm:aff id="aff013"><addr-line>Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands</addr-line></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Genetics, University Medical Center Groningen, Groningen</wicri:regionArea></affiliation></author><author><name sortKey="Franke, Lude" sort="Franke, Lude" uniqKey="Franke L" first="Lude" last="Franke">Lude Franke</name><affiliation wicri:level="1"><nlm:aff id="aff013"><addr-line>Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands</addr-line></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Genetics, University Medical Center Groningen, Groningen</wicri:regionArea></affiliation></author><author><name sortKey="Gieger, Christian" sort="Gieger, Christian" uniqKey="Gieger C" first="Christian" last="Gieger">Christian Gieger</name><affiliation wicri:level="1"><nlm:aff id="aff006"><addr-line>Research Unit of Molecular Epidemiology, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Research Unit of Molecular Epidemiology, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff007"><addr-line>Institute of Epidemiology II, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Epidemiology II, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg</wicri:regionArea></affiliation></author><author><name sortKey="Huan, Tianxiao" sort="Huan, Tianxiao" uniqKey="Huan T" first="Tianxiao" last="Huan">Tianxiao Huan</name><affiliation wicri:level="1"><nlm:aff id="aff014"><addr-line>Framingham Heart Study, Framingham, MA, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Framingham Heart Study, Framingham, MA</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff015"><addr-line>The Population Studies Branch, National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, MD, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>The Population Studies Branch, National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, MD</wicri:regionArea></affiliation></author><author><name sortKey="Ikram, M Arfan" sort="Ikram, M Arfan" uniqKey="Ikram M" first="M. Arfan" last="Ikram">M. Arfan Ikram</name><affiliation wicri:level="1"><nlm:aff id="aff016"><addr-line>Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands</addr-line></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Epidemiology, Erasmus University Medical Center, Rotterdam</wicri:regionArea></affiliation></author><author><name sortKey="Kunze, Sonja" sort="Kunze, Sonja" uniqKey="Kunze S" first="Sonja" last="Kunze">Sonja Kunze</name><affiliation wicri:level="1"><nlm:aff id="aff006"><addr-line>Research Unit of Molecular Epidemiology, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Research Unit of Molecular Epidemiology, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff007"><addr-line>Institute of Epidemiology II, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Epidemiology II, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg</wicri:regionArea></affiliation></author><author><name sortKey="Liang, Liming" sort="Liang, Liming" uniqKey="Liang L" first="Liming" last="Liang">Liming Liang</name><affiliation wicri:level="1"><nlm:aff id="aff017"><addr-line>Harvard T.H. Chan School of Public Health, Boston, MA, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Harvard T.H. Chan School of Public Health, Boston, MA</wicri:regionArea></affiliation></author><author><name sortKey="Lindemans, Jan" sort="Lindemans, Jan" uniqKey="Lindemans J" first="Jan" last="Lindemans">Jan Lindemans</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands</addr-line></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam</wicri:regionArea></affiliation></author><author><name sortKey="Liu, Chunyu" sort="Liu, Chunyu" uniqKey="Liu C" first="Chunyu" last="Liu">Chunyu Liu</name><affiliation wicri:level="1"><nlm:aff id="aff014"><addr-line>Framingham Heart Study, Framingham, MA, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Framingham Heart Study, Framingham, MA</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff015"><addr-line>The Population Studies Branch, National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, MD, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>The Population Studies Branch, National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, MD</wicri:regionArea></affiliation></author><author><name sortKey="Mcrae, Allan F" sort="Mcrae, Allan F" uniqKey="Mcrae A" first="Allan F." last="Mcrae">Allan F. Mcrae</name><affiliation wicri:level="1"><nlm:aff id="aff008"><addr-line>Queensland Brain Institute, The University of Queensland, Brisbane, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Queensland Brain Institute, The University of Queensland, Brisbane</wicri:regionArea></affiliation></author><author><name sortKey="Mendelson, Michael M" sort="Mendelson, Michael M" uniqKey="Mendelson M" first="Michael M." last="Mendelson">Michael M. Mendelson</name><affiliation wicri:level="1"><nlm:aff id="aff014"><addr-line>Framingham Heart Study, Framingham, MA, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Framingham Heart Study, Framingham, MA</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff015"><addr-line>The Population Studies Branch, National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, MD, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>The Population Studies Branch, National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, MD</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff018"><addr-line>Department of Cardiology, Boston Children's Hospital, Boston, MA, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Cardiology, Boston Children's Hospital, Boston, MA</wicri:regionArea></affiliation></author><author><name sortKey="Muller Nurasyid, Martina" sort="Muller Nurasyid, Martina" uniqKey="Muller Nurasyid M" first="Martina" last="Müller-Nurasyid">Martina Müller-Nurasyid</name><affiliation wicri:level="1"><nlm:aff id="aff019"><addr-line>DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff020"><addr-line>Institute of Genetic Epidemiology, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Genetic Epidemiology, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff021"><addr-line>Department of Medicine I, University Hospital Munich, Campus Grosshadern, Ludwig-Maximilians-University, Munich, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Medicine I, University Hospital Munich, Campus Grosshadern, Ludwig-Maximilians-University, Munich</wicri:regionArea></affiliation></author><author><name sortKey="Peters, Annette" sort="Peters, Annette" uniqKey="Peters A" first="Annette" last="Peters">Annette Peters</name><affiliation wicri:level="1"><nlm:aff id="aff006"><addr-line>Research Unit of Molecular Epidemiology, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Research Unit of Molecular Epidemiology, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff007"><addr-line>Institute of Epidemiology II, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Epidemiology II, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff019"><addr-line>DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich</wicri:regionArea></affiliation></author><author><name sortKey="Slagboom, P Eline" sort="Slagboom, P Eline" uniqKey="Slagboom P" first="P. Eline" last="Slagboom">P. Eline Slagboom</name><affiliation wicri:level="1"><nlm:aff id="aff012"><addr-line>Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands</addr-line></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden</wicri:regionArea></affiliation></author><author><name sortKey="Starr, John M" sort="Starr, John M" uniqKey="Starr J" first="John M." last="Starr">John M. Starr</name><affiliation wicri:level="1"><nlm:aff id="aff009"><addr-line>Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh</wicri:regionArea></affiliation></author><author><name sortKey="Tregouet, David Alexandre" sort="Tregouet, David Alexandre" uniqKey="Tregouet D" first="David-Alexandre" last="Trégouët">David-Alexandre Trégouët</name><affiliation wicri:level="1"><nlm:aff id="aff004"><addr-line>Sorbonne Universités, UPMC Univ. Paris 06, INSERM, UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Sorbonne Universités, UPMC Univ. Paris 06, INSERM, UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff005"><addr-line>ICAN Institute for Cardiometabolism and Nutrition, Paris, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>ICAN Institute for Cardiometabolism and Nutrition, Paris</wicri:regionArea></affiliation></author><author><name sortKey="Uitterlinden, Andre G" sort="Uitterlinden, Andre G" uniqKey="Uitterlinden A" first="André G." last="Uitterlinden">André G. Uitterlinden</name><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands</addr-line></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Internal Medicine, Erasmus University Medical Center, Rotterdam</wicri:regionArea></affiliation></author><author><name sortKey="Van Greevenbroek, Marleen M J" sort="Van Greevenbroek, Marleen M J" uniqKey="Van Greevenbroek M" first="Marleen M. J." last="Van Greevenbroek">Marleen M. J. Van Greevenbroek</name><affiliation wicri:level="1"><nlm:aff id="aff022"><addr-line>Department of Internal Medicine and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands</addr-line></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Internal Medicine and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center, Maastricht</wicri:regionArea></affiliation></author><author><name sortKey="Van Heemst, Diana" sort="Van Heemst, Diana" uniqKey="Van Heemst D" first="Diana" last="Van Heemst">Diana Van Heemst</name><affiliation wicri:level="1"><nlm:aff id="aff023"><addr-line>Department of Gerontology and Geriatrics Section, Leiden University Medical Center, Leiden, The Netherlands</addr-line></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Gerontology and Geriatrics Section, Leiden University Medical Center, Leiden</wicri:regionArea></affiliation></author><author><name sortKey="Van Iterson, Maarten" sort="Van Iterson, Maarten" uniqKey="Van Iterson M" first="Maarten" last="Van Iterson">Maarten Van Iterson</name><affiliation wicri:level="1"><nlm:aff id="aff012"><addr-line>Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands</addr-line></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden</wicri:regionArea></affiliation></author><author><name sortKey="Wells, Philip S" sort="Wells, Philip S" uniqKey="Wells P" first="Philip S." last="Wells">Philip S. Wells</name><affiliation wicri:level="1"><nlm:aff id="aff024"><addr-line>Department of Medicine, University of Ottawa, and the Ottawa Hospital Research Institute, Ottawa, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Medicine, University of Ottawa, and the Ottawa Hospital Research Institute, Ottawa</wicri:regionArea></affiliation></author><author><name sortKey="Yao, Chen" sort="Yao, Chen" uniqKey="Yao C" first="Chen" last="Yao">Chen Yao</name><affiliation wicri:level="1"><nlm:aff id="aff014"><addr-line>Framingham Heart Study, Framingham, MA, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Framingham Heart Study, Framingham, MA</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff015"><addr-line>The Population Studies Branch, National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, MD, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>The Population Studies Branch, National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, MD</wicri:regionArea></affiliation></author><author><name sortKey="Deary, Ian J" sort="Deary, Ian J" uniqKey="Deary I" first="Ian J." last="Deary">Ian J. Deary</name><affiliation wicri:level="1"><nlm:aff id="aff009"><addr-line>Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff025"><addr-line>Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Psychology, University of Edinburgh, Edinburgh</wicri:regionArea></affiliation></author><author><name sortKey="Gagnon, France" sort="Gagnon, France" uniqKey="Gagnon F" first="France" last="Gagnon">France Gagnon</name><affiliation wicri:level="1"><nlm:aff id="aff011"><addr-line>Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto</wicri:regionArea></affiliation></author><author><name sortKey="Heijmans, Bastiaan T" sort="Heijmans, Bastiaan T" uniqKey="Heijmans B" first="Bastiaan T." last="Heijmans">Bastiaan T. Heijmans</name><affiliation wicri:level="1"><nlm:aff id="aff012"><addr-line>Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands</addr-line></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden</wicri:regionArea></affiliation></author><author><name sortKey="Levy, Daniel" sort="Levy, Daniel" uniqKey="Levy D" first="Daniel" last="Levy">Daniel Levy</name><affiliation wicri:level="1"><nlm:aff id="aff014"><addr-line>Framingham Heart Study, Framingham, MA, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Framingham Heart Study, Framingham, MA</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff015"><addr-line>The Population Studies Branch, National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, MD, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>The Population Studies Branch, National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, MD</wicri:regionArea></affiliation></author><author><name sortKey="Morange, Pierre Emmanuel" sort="Morange, Pierre Emmanuel" uniqKey="Morange P" first="Pierre-Emmanuel" last="Morange">Pierre-Emmanuel Morange</name><affiliation wicri:level="1"><nlm:aff id="aff026"><addr-line>Laboratory of Haematology, La Timone Hospital, Marseille, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Laboratory of Haematology, La Timone Hospital, Marseille</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff027"><addr-line>Institut National pour la Santé et la Recherche Médicale (INSERM), UMR_S 1062, Inra UMR_1260, Aix-Marseille Université, Marseille, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut National pour la Santé et la Recherche Médicale (INSERM), UMR_S 1062, Inra UMR_1260, Aix-Marseille Université, Marseille</wicri:regionArea></affiliation></author><author><name sortKey="Waldenberger, Melanie" sort="Waldenberger, Melanie" uniqKey="Waldenberger M" first="Melanie" last="Waldenberger">Melanie Waldenberger</name><affiliation wicri:level="1"><nlm:aff id="aff006"><addr-line>Research Unit of Molecular Epidemiology, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Research Unit of Molecular Epidemiology, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff007"><addr-line>Institute of Epidemiology II, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Epidemiology II, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg</wicri:regionArea></affiliation></author><author><name sortKey="Heil, Sandra G" sort="Heil, Sandra G" uniqKey="Heil S" first="Sandra G." last="Heil">Sandra G. Heil</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands</addr-line></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam</wicri:regionArea></affiliation></author><author><name sortKey="Van Meurs, Joyce B J" sort="Van Meurs, Joyce B J" uniqKey="Van Meurs J" first="Joyce B. J." last="Van Meurs">Joyce B. J. Van Meurs</name><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands</addr-line></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Internal Medicine, Erasmus University Medical Center, Rotterdam</wicri:regionArea></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="sec001"><title>Background</title><p>DNA methylation is affected by the activities of the key enzymes and intermediate metabolites of the one-carbon pathway, one of which involves homocysteine. We investigated the effect of the well-known genetic variant associated with mildly elevated homocysteine: <italic>MTHFR</italic> 677C>T independently and in combination with other homocysteine-associated variants, on genome-wide leukocyte DNA-methylation.</p></sec><sec id="sec002"><title>Methods</title><p>Methylation levels were assessed using Illumina 450k arrays on 9,894 individuals of European ancestry from 12 cohort studies. Linear-mixed-models were used to study the association of additive <italic>MTHFR</italic> 677C>T and genetic-risk score (GRS) based on 18 homocysteine-associated SNPs, with genome-wide methylation.</p></sec><sec id="sec003"><title>Results</title><p>Meta-analysis revealed that the <italic>MTHFR</italic> 677C>T variant was associated with 35 CpG sites in <italic>cis</italic>, and the GRS showed association with 113 CpG sites near the homocysteine-associated variants. Genome-wide analysis revealed that the MTHFR 677C>T variant was associated with 1 <italic>trans</italic>-CpG (nearest gene <italic>ZNF184</italic>), while the GRS model showed association with 5 significant <italic>trans</italic>-CpGs annotated to nearest genes <italic>PTF1A</italic>, <italic>MRPL55</italic>, <italic>CTDSP2</italic>, <italic>CRYM</italic> and <italic>FKBP5</italic>.</p></sec><sec id="sec004"><title>Conclusions</title><p>Our results do not show widespread changes in DNA-methylation across the genome, and therefore do not support the hypothesis that mildly elevated homocysteine is associated with widespread methylation changes in leukocytes.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Ehrlich, M" uniqKey="Ehrlich M">M Ehrlich</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Klutstein, M" uniqKey="Klutstein M">M Klutstein</name></author><author><name sortKey="Nejman, D" 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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS One</journal-id><journal-id journal-id-type="iso-abbrev">PLoS ONE</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosone</journal-id><journal-title-group><journal-title>PLoS ONE</journal-title></journal-title-group><issn pub-type="epub">1932-6203</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, CA USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">29084233</article-id><article-id pub-id-type="pmc">5662081</article-id><article-id pub-id-type="doi">10.1371/journal.pone.0182472</article-id><article-id pub-id-type="publisher-id">PONE-D-17-09339</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and life sciences</subject><subj-group><subject>Cell biology</subject><subj-group><subject>Chromosome biology</subject><subj-group><subject>Chromatin</subject><subj-group><subject>Chromatin modification</subject><subj-group><subject>DNA methylation</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and life sciences</subject><subj-group><subject>Genetics</subject><subj-group><subject>Epigenetics</subject><subj-group><subject>Chromatin</subject><subj-group><subject>Chromatin modification</subject><subj-group><subject>DNA methylation</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and life sciences</subject><subj-group><subject>Genetics</subject><subj-group><subject>Gene expression</subject><subj-group><subject>Chromatin</subject><subj-group><subject>Chromatin modification</subject><subj-group><subject>DNA methylation</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and life sciences</subject><subj-group><subject>Genetics</subject><subj-group><subject>DNA</subject><subj-group><subject>DNA modification</subject><subj-group><subject>DNA methylation</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and life sciences</subject><subj-group><subject>Biochemistry</subject><subj-group><subject>Nucleic acids</subject><subj-group><subject>DNA</subject><subj-group><subject>DNA modification</subject><subj-group><subject>DNA methylation</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and life sciences</subject><subj-group><subject>Genetics</subject><subj-group><subject>Epigenetics</subject><subj-group><subject>DNA modification</subject><subj-group><subject>DNA methylation</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and life sciences</subject><subj-group><subject>Genetics</subject><subj-group><subject>Gene expression</subject><subj-group><subject>DNA modification</subject><subj-group><subject>DNA methylation</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Physical Sciences</subject><subj-group><subject>Chemistry</subject><subj-group><subject>Chemical Reactions</subject><subj-group><subject>Methylation</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Research and Analysis Methods</subject><subj-group><subject>Mathematical and Statistical Techniques</subject><subj-group><subject>Statistical Methods</subject><subj-group><subject>Meta-Analysis</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Physical Sciences</subject><subj-group><subject>Mathematics</subject><subj-group><subject>Statistics (Mathematics)</subject><subj-group><subject>Statistical Methods</subject><subj-group><subject>Meta-Analysis</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Genetics</subject><subj-group><subject>Molecular Genetics</subject></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Molecular Biology</subject><subj-group><subject>Molecular Genetics</subject></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Genetics</subject><subj-group><subject>Genetic Loci</subject></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Cell Biology</subject><subj-group><subject>Cellular Types</subject><subj-group><subject>Animal Cells</subject><subj-group><subject>Blood Cells</subject><subj-group><subject>White Blood Cells</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Cell Biology</subject><subj-group><subject>Cellular Types</subject><subj-group><subject>Animal Cells</subject><subj-group><subject>Immune Cells</subject><subj-group><subject>White Blood Cells</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Immunology</subject><subj-group><subject>Immune Cells</subject><subj-group><subject>White Blood Cells</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Immunology</subject><subj-group><subject>Immune Cells</subject><subj-group><subject>White Blood Cells</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Cell Biology</subject><subj-group><subject>Chromosome Biology</subject><subj-group><subject>Chromosomes</subject><subj-group><subject>Autosomes</subject><subj-group><subject>Chromosome Pairs</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Cell Biology</subject><subj-group><subject>Chromosome Biology</subject><subj-group><subject>Chromosomes</subject><subj-group><subject>Chromosome Pairs</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Social Sciences</subject><subj-group><subject>Sociology</subject><subj-group><subject>Consortia</subject></subj-group></subj-group></subj-group></article-categories><title-group><article-title>Genetically defined elevated homocysteine levels do not result in widespread changes of DNA methylation in leukocytes</article-title><alt-title alt-title-type="running-head">Homocysteine-associated variants and DNA methylation</alt-title></title-group><contrib-group><contrib contrib-type="author" equal-contrib="yes"><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0002-7730-4462</contrib-id><name><surname>Mandaviya</surname><given-names>Pooja R.</given-names></name><role content-type="http://credit.casrai.org/">Conceptualization</role><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Formal analysis</role><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Methodology</role><role content-type="http://credit.casrai.org/">Project administration</role><role content-type="http://credit.casrai.org/">Visualization</role><role content-type="http://credit.casrai.org/">Writing – original draft</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff002"><sup>2</sup></xref><xref ref-type="author-notes" rid="econtrib001"><sup>‡</sup></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Joehanes</surname><given-names>Roby</given-names></name><role content-type="http://credit.casrai.org/">Formal analysis</role><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Resources</role><role content-type="http://credit.casrai.org/">Software</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff003"><sup>3</sup></xref><xref ref-type="author-notes" rid="econtrib001"><sup>‡</sup></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Aïssi</surname><given-names>Dylan</given-names></name><role content-type="http://credit.casrai.org/">Formal analysis</role><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Methodology</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff004"><sup>4</sup></xref><xref ref-type="aff" rid="aff005"><sup>5</sup></xref><xref ref-type="author-notes" rid="econtrib001"><sup>‡</sup></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Kühnel</surname><given-names>Brigitte</given-names></name><role content-type="http://credit.casrai.org/">Formal analysis</role><role content-type="http://credit.casrai.org/">Investigation</role><xref ref-type="aff" rid="aff006"><sup>6</sup></xref><xref ref-type="aff" rid="aff007"><sup>7</sup></xref><xref ref-type="author-notes" rid="econtrib001"><sup>‡</sup></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Marioni</surname><given-names>Riccardo E.</given-names></name><role content-type="http://credit.casrai.org/">Formal analysis</role><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Methodology</role><xref ref-type="aff" rid="aff008"><sup>8</sup></xref><xref ref-type="aff" rid="aff009"><sup>9</sup></xref><xref ref-type="aff" rid="aff010"><sup>10</sup></xref><xref ref-type="author-notes" rid="econtrib001"><sup>‡</sup></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Truong</surname><given-names>Vinh</given-names></name><role content-type="http://credit.casrai.org/">Formal analysis</role><role content-type="http://credit.casrai.org/">Investigation</role><xref ref-type="aff" rid="aff011"><sup>11</sup></xref><xref ref-type="author-notes" rid="econtrib001"><sup>‡</sup></xref></contrib><contrib contrib-type="author"><name><surname>Stolk</surname><given-names>Lisette</given-names></name><role content-type="http://credit.casrai.org/">Conceptualization</role><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Methodology</role><role content-type="http://credit.casrai.org/">Supervision</role><xref ref-type="aff" rid="aff002"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Beekman</surname><given-names>Marian</given-names></name><role content-type="http://credit.casrai.org/">Project administration</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff012"><sup>12</sup></xref></contrib><contrib contrib-type="author"><name><surname>Bonder</surname><given-names>Marc Jan</given-names></name><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Resources</role><xref ref-type="aff" rid="aff013"><sup>13</sup></xref></contrib><contrib contrib-type="author"><name><surname>Franke</surname><given-names>Lude</given-names></name><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Resources</role><xref ref-type="aff" rid="aff013"><sup>13</sup></xref></contrib><contrib contrib-type="author"><name><surname>Gieger</surname><given-names>Christian</given-names></name><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff006"><sup>6</sup></xref><xref ref-type="aff" rid="aff007"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>Huan</surname><given-names>Tianxiao</given-names></name><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff014"><sup>14</sup></xref><xref ref-type="aff" rid="aff015"><sup>15</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ikram</surname><given-names>M. Arfan</given-names></name><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff016"><sup>16</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kunze</surname><given-names>Sonja</given-names></name><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff006"><sup>6</sup></xref><xref ref-type="aff" rid="aff007"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>Liang</surname><given-names>Liming</given-names></name><role content-type="http://credit.casrai.org/">Data curation</role><xref ref-type="aff" rid="aff017"><sup>17</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lindemans</surname><given-names>Jan</given-names></name><role content-type="http://credit.casrai.org/">Conceptualization</role><role content-type="http://credit.casrai.org/">Methodology</role><role content-type="http://credit.casrai.org/">Project administration</role><role content-type="http://credit.casrai.org/">Resources</role><role content-type="http://credit.casrai.org/">Supervision</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff001"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Liu</surname><given-names>Chunyu</given-names></name><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff014"><sup>14</sup></xref><xref ref-type="aff" rid="aff015"><sup>15</sup></xref></contrib><contrib contrib-type="author"><name><surname>McRae</surname><given-names>Allan F.</given-names></name><role content-type="http://credit.casrai.org/">Investigation</role><xref ref-type="aff" rid="aff008"><sup>8</sup></xref></contrib><contrib contrib-type="author"><name><surname>Mendelson</surname><given-names>Michael M.</given-names></name><role content-type="http://credit.casrai.org/">Data curation</role><xref ref-type="aff" rid="aff014"><sup>14</sup></xref><xref ref-type="aff" rid="aff015"><sup>15</sup></xref><xref ref-type="aff" rid="aff018"><sup>18</sup></xref></contrib><contrib contrib-type="author"><name><surname>Müller-Nurasyid</surname><given-names>Martina</given-names></name><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Investigation</role><xref ref-type="aff" rid="aff019"><sup>19</sup></xref><xref ref-type="aff" rid="aff020"><sup>20</sup></xref><xref ref-type="aff" rid="aff021"><sup>21</sup></xref></contrib><contrib contrib-type="author"><name><surname>Peters</surname><given-names>Annette</given-names></name><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff006"><sup>6</sup></xref><xref ref-type="aff" rid="aff007"><sup>7</sup></xref><xref ref-type="aff" rid="aff019"><sup>19</sup></xref></contrib><contrib contrib-type="author"><name><surname>Slagboom</surname><given-names>P. Eline</given-names></name><role content-type="http://credit.casrai.org/">Investigation</role><xref ref-type="aff" rid="aff012"><sup>12</sup></xref></contrib><contrib contrib-type="author"><name><surname>Starr</surname><given-names>John M.</given-names></name><role content-type="http://credit.casrai.org/">Investigation</role><xref ref-type="aff" rid="aff009"><sup>9</sup></xref></contrib><contrib contrib-type="author"><name><surname>Trégouët</surname><given-names>David-Alexandre</given-names></name><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff004"><sup>4</sup></xref><xref ref-type="aff" rid="aff005"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Uitterlinden</surname><given-names>André G.</given-names></name><role content-type="http://credit.casrai.org/">Conceptualization</role><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Project administration</role><role content-type="http://credit.casrai.org/">Resources</role><role content-type="http://credit.casrai.org/">Supervision</role><xref ref-type="aff" rid="aff002"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>van Greevenbroek</surname><given-names>Marleen M. J.</given-names></name><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Project administration</role><role content-type="http://credit.casrai.org/">Resources</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff022"><sup>22</sup></xref></contrib><contrib contrib-type="author"><name><surname>van Heemst</surname><given-names>Diana</given-names></name><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff023"><sup>23</sup></xref></contrib><contrib contrib-type="author"><name><surname>van Iterson</surname><given-names>Maarten</given-names></name><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Resources</role><role content-type="http://credit.casrai.org/">Software</role><xref ref-type="aff" rid="aff012"><sup>12</sup></xref></contrib><contrib contrib-type="author"><name><surname>Wells</surname><given-names>Philip S.</given-names></name><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Project administration</role><xref ref-type="aff" rid="aff024"><sup>24</sup></xref></contrib><contrib contrib-type="author"><name><surname>Yao</surname><given-names>Chen</given-names></name><role content-type="http://credit.casrai.org/">Data curation</role><xref ref-type="aff" rid="aff014"><sup>14</sup></xref><xref ref-type="aff" rid="aff015"><sup>15</sup></xref></contrib><contrib contrib-type="author"><name><surname>Deary</surname><given-names>Ian J.</given-names></name><role content-type="http://credit.casrai.org/">Investigation</role><xref ref-type="aff" rid="aff009"><sup>9</sup></xref><xref ref-type="aff" rid="aff025"><sup>25</sup></xref><xref ref-type="author-notes" rid="econtrib001"><sup>‡</sup></xref></contrib><contrib contrib-type="author"><name><surname>Gagnon</surname><given-names>France</given-names></name><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Supervision</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff011"><sup>11</sup></xref><xref ref-type="author-notes" rid="econtrib001"><sup>‡</sup></xref></contrib><contrib contrib-type="author"><name><surname>Heijmans</surname><given-names>Bastiaan T.</given-names></name><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Project administration</role><role content-type="http://credit.casrai.org/">Resources</role><role content-type="http://credit.casrai.org/">Supervision</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff012"><sup>12</sup></xref><xref ref-type="author-notes" rid="econtrib001"><sup>‡</sup></xref></contrib><contrib contrib-type="author"><name><surname>Levy</surname><given-names>Daniel</given-names></name><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff014"><sup>14</sup></xref><xref ref-type="aff" rid="aff015"><sup>15</sup></xref><xref ref-type="author-notes" rid="econtrib001"><sup>‡</sup></xref></contrib><contrib contrib-type="author"><name><surname>Morange</surname><given-names>Pierre-Emmanuel</given-names></name><role content-type="http://credit.casrai.org/">Investigation</role><xref ref-type="aff" rid="aff026"><sup>26</sup></xref><xref ref-type="aff" rid="aff027"><sup>27</sup></xref><xref ref-type="author-notes" rid="econtrib001"><sup>‡</sup></xref></contrib><contrib contrib-type="author"><name><surname>Waldenberger</surname><given-names>Melanie</given-names></name><role content-type="http://credit.casrai.org/">Investigation</role><xref ref-type="aff" rid="aff006"><sup>6</sup></xref><xref ref-type="aff" rid="aff007"><sup>7</sup></xref><xref ref-type="author-notes" rid="econtrib001"><sup>‡</sup></xref></contrib><contrib contrib-type="author"><name><surname>Heil</surname><given-names>Sandra G.</given-names></name><role content-type="http://credit.casrai.org/">Conceptualization</role><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Methodology</role><role content-type="http://credit.casrai.org/">Project administration</role><role content-type="http://credit.casrai.org/">Resources</role><role content-type="http://credit.casrai.org/">Supervision</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="author-notes" rid="econtrib001"><sup>‡</sup></xref></contrib><contrib contrib-type="author"><name><surname>van Meurs</surname><given-names>Joyce B. J.</given-names></name><role content-type="http://credit.casrai.org/">Conceptualization</role><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Methodology</role><role content-type="http://credit.casrai.org/">Project administration</role><role content-type="http://credit.casrai.org/">Resources</role><role content-type="http://credit.casrai.org/">Supervision</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff002"><sup>2</sup></xref><xref ref-type="author-notes" rid="econtrib001"><sup>‡</sup></xref><xref ref-type="corresp" rid="cor001">*</xref></contrib><contrib contrib-type="author"><collab>on behalf of The CHARGE Consortium Epigenetics group and BIOS Consortium</collab><xref ref-type="author-notes" rid="fn001"><sup>¶</sup></xref></contrib></contrib-group><aff id="aff001"><label>1</label><addr-line>Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands</addr-line></aff><aff id="aff002"><label>2</label><addr-line>Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands</addr-line></aff><aff id="aff003"><label>3</label><addr-line>Institute for Aging Research, Hebrew SeniorLife, Harvard Medical School, Boston, MA, United States of America</addr-line></aff><aff id="aff004"><label>4</label><addr-line>Sorbonne Universités, UPMC Univ. Paris 06, INSERM, UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris, France</addr-line></aff><aff id="aff005"><label>5</label><addr-line>ICAN Institute for Cardiometabolism and Nutrition, Paris, France</addr-line></aff><aff id="aff006"><label>6</label><addr-line>Research Unit of Molecular Epidemiology, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg, Germany</addr-line></aff><aff id="aff007"><label>7</label><addr-line>Institute of Epidemiology II, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg, Germany</addr-line></aff><aff id="aff008"><label>8</label><addr-line>Queensland Brain Institute, The University of Queensland, Brisbane, Australia</addr-line></aff><aff id="aff009"><label>9</label><addr-line>Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom</addr-line></aff><aff id="aff010"><label>10</label><addr-line>Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom</addr-line></aff><aff id="aff011"><label>11</label><addr-line>Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada</addr-line></aff><aff id="aff012"><label>12</label><addr-line>Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands</addr-line></aff><aff id="aff013"><label>13</label><addr-line>Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands</addr-line></aff><aff id="aff014"><label>14</label><addr-line>Framingham Heart Study, Framingham, MA, United States of America</addr-line></aff><aff id="aff015"><label>15</label><addr-line>The Population Studies Branch, National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, MD, United States of America</addr-line></aff><aff id="aff016"><label>16</label><addr-line>Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands</addr-line></aff><aff id="aff017"><label>17</label><addr-line>Harvard T.H. Chan School of Public Health, Boston, MA, United States of America</addr-line></aff><aff id="aff018"><label>18</label><addr-line>Department of Cardiology, Boston Children's Hospital, Boston, MA, United States of America</addr-line></aff><aff id="aff019"><label>19</label><addr-line>DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany</addr-line></aff><aff id="aff020"><label>20</label><addr-line>Institute of Genetic Epidemiology, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg, Germany</addr-line></aff><aff id="aff021"><label>21</label><addr-line>Department of Medicine I, University Hospital Munich, Campus Grosshadern, Ludwig-Maximilians-University, Munich, Germany</addr-line></aff><aff id="aff022"><label>22</label><addr-line>Department of Internal Medicine and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands</addr-line></aff><aff id="aff023"><label>23</label><addr-line>Department of Gerontology and Geriatrics Section, Leiden University Medical Center, Leiden, The Netherlands</addr-line></aff><aff id="aff024"><label>24</label><addr-line>Department of Medicine, University of Ottawa, and the Ottawa Hospital Research Institute, Ottawa, Canada</addr-line></aff><aff id="aff025"><label>25</label><addr-line>Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom</addr-line></aff><aff id="aff026"><label>26</label><addr-line>Laboratory of Haematology, La Timone Hospital, Marseille, France</addr-line></aff><aff id="aff027"><label>27</label><addr-line>Institut National pour la Santé et la Recherche Médicale (INSERM), UMR_S 1062, Inra UMR_1260, Aix-Marseille Université, Marseille, France</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Zeller</surname><given-names>Tanja</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1"><addr-line>Universitatsklinikum Hamburg-Eppendorf, GERMANY</addr-line></aff><author-notes><fn fn-type="COI-statement" id="coi001"><p><bold>Competing Interests: </bold>The authors have declared that no competing interests exist.</p></fn><fn fn-type="other" id="econtrib001"><p>‡ PRM, RJ, DA, BK, REM, and VT are first authors on this work. IJD, FG, BTH, DL, PEM, MW, SGH, and JBJvM also contributed equally as last authors on this work.</p></fn><fn fn-type="other" id="fn001"><p>¶ Membership of the CHARGE Consortium Epigenetics group and BIOS Consortium is provided in the <xref ref-type="supplementary-material" rid="pone.0182472.s015">S1</xref> and <xref ref-type="supplementary-material" rid="pone.0182472.s016">S2</xref> Files, respectively.</p></fn><corresp id="cor001">* E-mail: <email>j.vanmeurs@erasmusmc.nl</email></corresp></author-notes><pub-date pub-type="epub"><day>30</day><month>10</month><year>2017</year></pub-date><pub-date pub-type="collection"><year>2017</year></pub-date><volume>12</volume><issue>10</issue><elocation-id>e0182472</elocation-id><history><date date-type="received"><day>17</day><month>3</month><year>2017</year></date><date date-type="accepted"><day>19</day><month>7</month><year>2017</year></date></history><permissions><license xlink:href="https://creativecommons.org/publicdomain/zero/1.0/"><license-p>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 <ext-link ext-link-type="uri" xlink:href="https://creativecommons.org/publicdomain/zero/1.0/">Creative Commons CC0</ext-link> public domain dedication.</license-p></license></permissions><self-uri content-type="pdf" xlink:href="pone.0182472.pdf"></self-uri><abstract><sec id="sec001"><title>Background</title><p>DNA methylation is affected by the activities of the key enzymes and intermediate metabolites of the one-carbon pathway, one of which involves homocysteine. We investigated the effect of the well-known genetic variant associated with mildly elevated homocysteine: <italic>MTHFR</italic> 677C>T independently and in combination with other homocysteine-associated variants, on genome-wide leukocyte DNA-methylation.</p></sec><sec id="sec002"><title>Methods</title><p>Methylation levels were assessed using Illumina 450k arrays on 9,894 individuals of European ancestry from 12 cohort studies. Linear-mixed-models were used to study the association of additive <italic>MTHFR</italic> 677C>T and genetic-risk score (GRS) based on 18 homocysteine-associated SNPs, with genome-wide methylation.</p></sec><sec id="sec003"><title>Results</title><p>Meta-analysis revealed that the <italic>MTHFR</italic> 677C>T variant was associated with 35 CpG sites in <italic>cis</italic>, and the GRS showed association with 113 CpG sites near the homocysteine-associated variants. Genome-wide analysis revealed that the MTHFR 677C>T variant was associated with 1 <italic>trans</italic>-CpG (nearest gene <italic>ZNF184</italic>), while the GRS model showed association with 5 significant <italic>trans</italic>-CpGs annotated to nearest genes <italic>PTF1A</italic>, <italic>MRPL55</italic>, <italic>CTDSP2</italic>, <italic>CRYM</italic> and <italic>FKBP5</italic>.</p></sec><sec id="sec004"><title>Conclusions</title><p>Our results do not show widespread changes in DNA-methylation across the genome, and therefore do not support the hypothesis that mildly elevated homocysteine is associated with widespread methylation changes in leukocytes.</p></sec></abstract><funding-group><award-group id="award001"><funding-source><institution-wrap><institution-id institution-id-type="funder-id">http://dx.doi.org/10.13039/100000002</institution-id><institution>National Institutes of Health</institution></institution-wrap></funding-source><award-id>N01-HC-25195</award-id></award-group><award-group id="award002"><funding-source><institution>Erasmus Medical Center and Erasmus University, Rotterdam</institution></funding-source></award-group><award-group id="award003"><funding-source><institution>Netherlands Organization for the Health Research and Development (ZonMw)</institution></funding-source></award-group><award-group id="award004"><funding-source><institution>Research Institute for Diseases in the Elderly (RIDE)</institution></funding-source></award-group><award-group id="award005"><funding-source><institution>Ministry of Education, Culture and Science</institution></funding-source></award-group><award-group id="award006"><funding-source><institution>Ministry for Health, Welfare and Sports, the European Commission (DG XII)</institution></funding-source></award-group><award-group id="award007"><funding-source><institution>Municipality of Rotterdam</institution></funding-source></award-group><award-group id="award008"><funding-source><institution>Netherlands CardioVascular Research Initiative (the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organisation for Health Research and Development, and the Royal Netherlands Academy of Sciences) for the GENIUS project “Generating the best evidence-based pharmaceutical targets for atherosclerosis”</institution></funding-source><award-id>CVON2011-19</award-id></award-group><award-group id="award009"><funding-source><institution>BBMRI-NL, a research infrastructure financed by the Dutch government</institution></funding-source><award-id>NWO 184.021.007</award-id></award-group><award-group id="award010"><funding-source><institution>Région Ile de France (CORDDIM)</institution></funding-source></award-group><award-group id="award011"><funding-source><institution>Région Ile de France, Pierre and Marie Curie University</institution></funding-source></award-group><award-group id="award012"><funding-source><institution>ICAN Institute for Cardiometabolism and Nutrition</institution></funding-source><award-id>ANR-10-IAHU-05</award-id></award-group><award-group id="award013"><funding-source><institution>Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health</institution></funding-source></award-group><funding-statement>Rotterdam Study: The generation and management of the Illumina 450K methylation array data (EWAS data) for the Rotterdam Study was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Netherlands. The EWAS data was funded by the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, and by the Netherlands Organization for Scientific Research (NWO; project number 184021007) and made available as a Rainbow Project (RP3; BIOS) of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL). We thank Mr. Michael Verbiest, Ms. Mila Jhamai, Ms. Sarah Higgins, Mr. Marijn Verkerk, and Lisette Stolk PhD for their help in creating the methylation database. The Rotterdam Study is funded by 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 grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. Biobank-Based Integrative Omics Studies (BIOS) Consortium Samples were contributed by LifeLines (<ext-link ext-link-type="uri" xlink:href="http://lifelines.nl/lifelines-research/general">http://lifelines.nl/lifelines-research/general</ext-link>), the Leiden Longevity Study (<ext-link ext-link-type="uri" xlink:href="http://www.leidenlangleven.nl">http://www.leidenlangleven.nl</ext-link>), the Netherlands Twin Registry (<ext-link ext-link-type="uri" xlink:href="http://www.tweelingenregister.org">http://www.tweelingenregister.org</ext-link>), the Rotterdam studies (<ext-link ext-link-type="uri" xlink:href="http://www.erasmus-epidemiology.nl/research/ergo.htm">http://www.erasmus-epidemiology.nl/research/ergo.htm</ext-link>), the CODAM study (<ext-link ext-link-type="uri" xlink:href="http://www.carimmaastricht.nl/">http://www.carimmaastricht.nl/</ext-link>), and the PAN study (<ext-link ext-link-type="uri" xlink:href="http://www.alsonderzoek.nl/">http://www.alsonderzoek.nl/</ext-link>). We thank the participants of all aforementioned biobanks and acknowledge the contributions of the investigators to this study, especially Aaron Isaacs, René Pool, Marian Beekman, P. Mila Jhamai, Michael Verbiest, H. Eka D. Suchiman, Marijn Verkerk, Ruud van der Breggen, Jeroen van Rooij, Nico Lakenberg, Jan Bot, Patrick Deelen, Irene Nooren, Martijn Vermaat, Dasha V. Zhernakova, René Luijk, Freerk van Dijk, Wibowo Arindrarto, Szymon M. Kielbasa, and Morris A. Swertz (S1_File-BIOSconsortiumMembershipList). This work was carried out on the Dutch national e-infrastructure with the support of SURF Cooperative. We acknowledge the support from the Netherlands CardioVascular Research Initiative (the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organisation for Health Research and Development, and the Royal Netherlands Academy of Sciences) for the GENIUS project “Generating the best evidence-based pharmaceutical targets for atherosclerosis” (CVON2011-19). This work was performed within the framework of the Biobank-Based Integrative Omics Studies (BIOS) Consortium funded by BBMRI-NL, a research infrastructure financed by the Dutch government (NWO 184.021.007). MARseille THrombosis Association Study (MARTHA) D.A. was supported by a PhD grant from the Région Ile de France (CORDDIM). Statistical analyses of the MARTHA were performed using the C2BIG computing cluster, funded by the Région Ile de France, Pierre and Marie Curie University, and the ICAN Institute for Cardiometabolism and Nutrition (ANR-10-IAHU-05). Framingham Heart Study (FHS): The Framingham Heart Study is funded by National Institutes of Health contract N01-HC-25195. The laboratory work for this investigation was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health. The analytical component of this project was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute Bethesda, MD. Cooperative health research in the Region of Augsburg (KORA) The KORA study was initiated and financed by the Helmholtz Zentrum München – German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research has been supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. The research leading to these results has received funding fromthe European Union Seventh Framework Programme under grant agreement [n°603288] (Systems Biology to Identify Molecular Targets for Vascular Disease Treatment – SysVasc; <ext-link ext-link-type="uri" xlink:href="http://www.sysvasc.eu/">http://www.sysvasc.eu/</ext-link>). Lothian Birth Cohort (LBC): Phenotype collection in the Lothian Birth Cohort 1921 was supported by the UK’s Biotechnology and Biological Sciences Research Council (BBSRC), The Royal Society and The Chief Scientist Office of the Scottish Government. Phenotype collection in the Lothian Birth Cohort 1936 was supported by Age UK (The Disconnected Mind project). Methylation typing was supported by the Centre for Cognitive Ageing and Cognitive Epidemiology (Pilot Fund award), Age UK, The Wellcome Trust Institutional Strategic Support Fund, The University of Edinburgh, and The University of Queensland. REM, JMS, and IJD are members of the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology (CCACE). CCACE is supported by funding from the BBSRC, the Medical Research Council (MRC), and the University of Edinburgh as part of the cross-council Lifelong Health and Wellbeing initiative (MR/K026992/1). French-Canadian Family Study on Factor V Leiden (F5L) Thrombophilia (F5L Family Study) The F5L Family Study was supported by the Canadian Institutes of Health Research (Grant MOP 86466) and by the Heart and Stroke Foundation of Canada (Grant T6484). F. Gagnon is recipient of a Canada Research Chair.</funding-statement></funding-group><counts><fig-count count="3"></fig-count><table-count count="3"></table-count><page-count count="19"></page-count></counts><custom-meta-group><custom-meta id="data-availability"><meta-name>Data Availability</meta-name><meta-value>We are not allowed to publish the full data on internet because of privacy policy. However, data can be accessed by individual researchers through these contacts for each individual study: Requests for the data from the Rotterdam study may be sent to: Frank van Rooij (<email>f.vanrooij@erasmusmc.nl</email>). Requests for the data from the Lothian Birth Cohort may be sent to Riccardo Marioni (<email>rmarioni@exseed.ed.ac.uk</email>). LBC methylation data have been submitted to the European Genome-phenome Archive -accession number EGAS00001000910. The informed consents given by KORA study participants do not cover data posting in public databases. However, data are available upon request from KORA-gen (<ext-link ext-link-type="uri" xlink:href="https://epi.helmholtz-muenchen.de/">https://epi.helmholtz-muenchen.de/</ext-link>). Data requests can be submitted online and are subject to approval by the KORA Board. Requests for the data from the Framingham Heart Study may be sent to Roby Joehanes (<email>robyjoehanes@hsl.harvard.edu</email>) or from the link: <ext-link ext-link-type="uri" xlink:href="https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000724.v6.p10">https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000724.v6.p10</ext-link>. Requests for the data from the Biobank-Based Integrative Omics Studies (BIOS) Consortium (RS, LLS, LL, CODAM and NTR cohorts) may be sent to Rick Jansen (<email>Ri.Jansen@ggzingeest.nl</email>) and from the accession number EGAC00001000277. Requests for the data from the MARTHA study may be sent to David-Alexandre Trégouët (<email>david.tregouet@upmc.fr</email>). MARTHA Methylation data are already available in the Array Express database (<ext-link ext-link-type="uri" xlink:href="http://www.ebi.ac.uk/arrayexpress">www.ebi.ac.uk/arrayexpress</ext-link>) under accession number E-MTAB-3127. Request for the data from the F5L study may be sent to France Gagnon (<email>france.gagnon@utoronto.ca</email>).</meta-value></custom-meta></custom-meta-group></article-meta><notes><title>Data Availability</title><p>We are not allowed to publish the full data on internet because of privacy policy. However, data can be accessed by individual researchers through these contacts for each individual study: Requests for the data from the Rotterdam study may be sent to: Frank van Rooij (<email>f.vanrooij@erasmusmc.nl</email>). Requests for the data from the Lothian Birth Cohort may be sent to Riccardo Marioni (<email>rmarioni@exseed.ed.ac.uk</email>). LBC methylation data have been submitted to the European Genome-phenome Archive -accession number EGAS00001000910. The informed consents given by KORA study participants do not cover data posting in public databases. However, data are available upon request from KORA-gen (<ext-link ext-link-type="uri" xlink:href="https://epi.helmholtz-muenchen.de/">https://epi.helmholtz-muenchen.de/</ext-link>). Data requests can be submitted online and are subject to approval by the KORA Board. Requests for the data from the Framingham Heart Study may be sent to Roby Joehanes (<email>robyjoehanes@hsl.harvard.edu</email>) or from the link: <ext-link ext-link-type="uri" xlink:href="https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000724.v6.p10">https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000724.v6.p10</ext-link>. Requests for the data from the Biobank-Based Integrative Omics Studies (BIOS) Consortium (RS, LLS, LL, CODAM and NTR cohorts) may be sent to Rick Jansen (<email>Ri.Jansen@ggzingeest.nl</email>) and from the accession number EGAC00001000277. Requests for the data from the MARTHA study may be sent to David-Alexandre Trégouët (<email>david.tregouet@upmc.fr</email>). MARTHA Methylation data are already available in the Array Express database (<ext-link ext-link-type="uri" xlink:href="http://www.ebi.ac.uk/arrayexpress">www.ebi.ac.uk/arrayexpress</ext-link>) under accession number E-MTAB-3127. Request for the data from the F5L study may be sent to France Gagnon (<email>france.gagnon@utoronto.ca</email>).</p></notes></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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