Genetically defined elevated homocysteine levels do not result in widespread changes of DNA methylation in leukocytes.

Maarten van Iterson, Chunyu Liu, Allan F McRae, Michael M Mendelson, Martina Müller-Nurasyid, Annette Peters, John M Starr, David-Alexandre Trégouët, Marleen M J van Greevenbroek, Diana van Heemst, Jan Lindemans, Philip S Wells, Chen Yao, Ian J Deary, France Gagnon, Bastiaan T Heijmans, Daniel Levy, Pierre-Emmanuel Morange, Melanie Waldenberger, Riccardo E Marioni, P Eline Slagboom, Joyce B J van Meurs, M Arfan Ikram, Sandra G Heil, Christian Gieger, Pooja R Mandaviya, Roby Joehanes, Dylan Aïssi, Brigitte Kühnel, André G Uitterlinden, Vinh Truong, Lisette Stolk, Marian Beekman, Marc Jan Bonder, Lude Franke, Tianxiao Huan, Sonja Kunze, Liming Liang

Journal: PloS one 2017;12(10):e0182472

PMID: 29084233

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Abstract

BACKGROUND

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: MTHFR 677C>T independently and in combination with other homocysteine-associated variants, on genome-wide leukocyte DNA-methylation.

METHODS

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 MTHFR 677C>T and genetic-risk score (GRS) based on 18 homocysteine-associated SNPs, with genome-wide methylation.

RESULTS

Meta-analysis revealed that the MTHFR 677C>T variant was associated with 35 CpG sites in cis, 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 trans-CpG (nearest gene ZNF184), while the GRS model showed association with 5 significant trans-CpGs annotated to nearest genes PTF1A, MRPL55, CTDSP2, CRYM and FKBP5.

CONCLUSIONS

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.

Address: Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands.; Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.; Institute for Aging Research, Hebrew SeniorLife, Harvard Medical School, Boston, MA, United States of America.; Sorbonne Universités, UPMC Univ. Paris 06, INSERM, UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris, France.; ICAN Institute for Cardiometabolism and Nutrition, Paris, France.; Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.; Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.; Queensland Brain Institute, The University of Queensland, Brisbane, Australia.; Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom.; Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.; Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.; Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands.; Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands.; Framingham Heart Study, Framingham, MA, United States of America.; The Population Studies Branch, National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, MD, United States of America.; Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.; Harvard T.H. Chan School of Public Health, Boston, MA, United States of America.; Department of Cardiology, Boston Children's Hospital, Boston, MA, United States of America.; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.; Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.; Department of Medicine I, University Hospital Munich, Campus Grosshadern, Ludwig-Maximilians-University, Munich, Germany.; Department of Internal Medicine and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands.; Department of Gerontology and Geriatrics Section, Leiden University Medical Center, Leiden, The Netherlands.; Department of Medicine, University of Ottawa, and the Ottawa Hospital Research Institute, Ottawa, Canada.; Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom.; Laboratory of Haematology, La Timone Hospital, Marseille, France.; Institut National pour la Santé et la Recherche Médicale (INSERM), UMR_S 1062, Inra UMR_1260, Aix-Marseille Université, Marseille, France.

DOI: 10.1371/journal.pone.0182472

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MeSH Terms: Adult, Chromosomes, Human, Pair 6, Cohort Studies, CpG Islands, DNA Methylation, Homocysteine, Humans, Leukocytes, Methylenetetrahydrofolate Reductase (NADPH2), Polymorphism, Single Nucleotide, mu-Crystallins