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Abstract
Aim: Homocysteine (Hcy) is a sensitive marker of one-carbon metabolism. Higher Hcy levels have been associated with global DNA hypomethylation. We investigated the association between plasma Hcy and epigenome-wide DNA methylation in leukocytes. Methods: Methylation was measured using Illumina 450 k arrays in 2035 individuals from six cohorts. Hcy-associated differentially methylated positions and regions were identified using meta-analysis. Results: Three differentially methylated positions cg21607669 (SLC27A1), cg26382848 (AJUBA) and cg10701000 (KCNMA1) at chromosome 19, 14 and 10, respectively, were significantly associated with Hcy. In addition, we identified 68 Hcy-associated differentially methylated regions, the most significant of which was a 1.8-kb spanning domain (TNXB/ATF6B) at chromosome 6. Conclusion: We identified novel epigenetic loci associated with Hcy levels, of which specific role needs to be further validated.
Acknowledgements
The authors thank Michael Verbiest, Mila Jhamai, Sarah Higgins and Marijn Verkerk for their help in creating the methylation database. The authors also thank Wilma Verbree and Wim Schilleman for measuring homocysteine. The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. The authors thank all participants of the Leiden Longevity Study. The authors also thank V Soo for his assistance with laboratory work. EGCUT data analyses were carried out in part in the High Performance Computing Center of University of Tartu.
The Rotterdam Study (RS)
The generation and management of the Illumina 450 K 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). Homocysteine analysis was funded by the Department of Clinical Chemistry.
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 Leiden Longevity Study (LLS)
This study received funding from the European Union’s Seventh Framework Programme (FP7/2007–2011) under grant agreement no. 259679, from the Innovation-Oriented Research Program on Genomics (SenterNovem IGE05007), the Centre for Medical Systems Biology, from the Netherlands Consortium for Healthy Ageing (grant 050–060–810), and from the Biobank-Based Integrative Omics Studies (BIOS) Consortium funded by BBMRI-NL, a research infrastructure financed by the Dutch government (NWO 184.021.007), all in the framework of the Netherlands Genomics Initiative, Netherlands Organization for Scientific Research (NWO).
The MARseille THrombosis Association Study (MARTHA)
The MARTHA project was supported by grants from the Program Hospitalier de Recherche Clinique. The methylation array typing was funded by the Canadian Institutes of Health Research (grant MOP 86466) and the Heart and Stroke Foundation of Canada (grant T6484). Statistical analyses of the MARTHA dataset were performed using the C2BIG computing cluster funded by the Region Ile de France, Pierre and Marie Curie University and the ICAN Institute for Cardiometabolism and Nutrition (ANR-10-IAHU-05). D Aïssi was financially supported by grants from the Region Ile de France (CORDDIM) and La Nouvelle Société Française d’Athérosclérose.
Estonian Genome Center of the University of Tartu (EGCUT)
This research was supported by the European Union through the European Regional Development Fund in the framework of the Centre of Excellence for Genomics and Translational Medicine (Project No. 2014–2020.4.01.15–0012), ePerMed - EU 2020 (grant no. 692145), and the Estonian Research Council (grant IUT20–60).
French-Canadian Family Study on Factor V Leiden (F5L) thrombophilia
The French-Canadian Family Study on Factor V Leiden (F5L) Thrombophilia (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.
The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Ethical conduct of research
All participants provided a written informed consent, and each study was approved at the relevant organizations by their respective ethics review committees (RS, Institutional review board [Medical Ethics Committee] of the Erasmus Medical Center; LLS, Ethical committee of the Leiden University Medical Center; CODAM, Medical Ethical Committee of the Maastricht University; MARTHA, ‘Departement santé de la direction générale de la recherche et de l’innovation du ministère’ [Projects DC: 2008–880 & 09.576]; EGCUT; Research Ethics Committee of the University of Tartu; F5L, Research ethics boards of the University of Toronto and the Ottawa Hospital Research Institute).
Supplementary data
To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/full/10.2217/epi-2017-0038