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PLoS One. 2017 Oct 30;12(10):e0182472. doi: 10.1371/journal.pone.0182472. eCollection 2017.

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

Author information

1
Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands.
2
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
3
Institute for Aging Research, Hebrew SeniorLife, Harvard Medical School, Boston, MA, United States of America.
4
Sorbonne Universités, UPMC Univ. Paris 06, INSERM, UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris, France.
5
ICAN Institute for Cardiometabolism and Nutrition, Paris, France.
6
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
7
Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
8
Queensland Brain Institute, The University of Queensland, Brisbane, Australia.
9
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom.
10
Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
11
Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.
12
Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands.
13
Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands.
14
Framingham Heart Study, Framingham, MA, United States of America.
15
The Population Studies Branch, National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, MD, United States of America.
16
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
17
Harvard T.H. Chan School of Public Health, Boston, MA, United States of America.
18
Department of Cardiology, Boston Children's Hospital, Boston, MA, United States of America.
19
DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
20
Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
21
Department of Medicine I, University Hospital Munich, Campus Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
22
Department of Internal Medicine and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands.
23
Department of Gerontology and Geriatrics Section, Leiden University Medical Center, Leiden, The Netherlands.
24
Department of Medicine, University of Ottawa, and the Ottawa Hospital Research Institute, Ottawa, Canada.
25
Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom.
26
Laboratory of Haematology, La Timone Hospital, Marseille, France.
27
Institut National pour la Santé et la Recherche Médicale (INSERM), UMR_S 1062, Inra UMR_1260, Aix-Marseille Université, Marseille, France.

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.

PMID:
29084233
PMCID:
PMC5662081
DOI:
10.1371/journal.pone.0182472
[Indexed for MEDLINE]
Free PMC Article

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