Evidence map›Paper›PMID 26568774›Full record

ArticleClinical epigenetics2015

The effects of long-term daily folic acid and vitamin B12 supplementation on genome-wide DNA methylation in elderly subjects.

Dieuwertje E G Kok, Rosalie A M Dhonukshe-Rutten, Carolien Lute, Sandra G Heil, André G Uitterlinden, Nathalie van der Velde, Joyce B J van Meurs, Natasja M van Schoor, Guido J E J Hooiveld, Lisette C P G M de Groot and 2 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Clinical epigenetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 86 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
86citing papers in PubMed, 2 pooled it
10.7field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

86 citing papers in PubMed, 2 syntheses or guidelines pooled it, 158 citations in OpenAlex.

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  15. International journal of molecular medicine · 2026
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26 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors at 3 institutions in 1 country.

Dieuwertje E G KokDivision of Human Nutrition, Wageningen University, PO Box 8129, 6700 EV Wageningen, The Netherlands.
Rosalie A M Dhonukshe-RuttenDivision of Human Nutrition, Wageningen University, PO Box 8129, 6700 EV Wageningen, The Netherlands.
Carolien LuteDivision of Human Nutrition, Wageningen University, PO Box 8129, 6700 EV Wageningen, The Netherlands.
Sandra G HeilDepartment of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands.
André G UitterlindenGenetic Laboratory Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands ; Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Nathalie van der VeldeGenetic Laboratory Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands ; Department of Internal Medicine, Section of Geriatrics, Academic Medical Center, Amsterdam, The Netherlands.
Joyce B J van MeursGenetic Laboratory Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
Natasja M van SchoorDepartment of Epidemiology and Biostatistics, EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands.
Guido J E J HooiveldDivision of Human Nutrition, Wageningen University, PO Box 8129, 6700 EV Wageningen, The Netherlands.
Lisette C P G M de GrootDivision of Human Nutrition, Wageningen University, PO Box 8129, 6700 EV Wageningen, The Netherlands.
Ellen KampmanDivision of Human Nutrition, Wageningen University, PO Box 8129, 6700 EV Wageningen, The Netherlands.
Wilma T SteegengaDivision of Human Nutrition, Wageningen University, PO Box 8129, 6700 EV Wageningen, The Netherlands.
Wageningen University & Research · NLErasmus MC · NLEMGO Institute for Health and Care Research · NL

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundFolate and its synthetic form folic acid function as donor of one-carbon units and have been, together with other B-vitamins, implicated in programming of epigenetic processes such as DNA methylation during early development. To what extent regulation of DNA methylation can be altered via B-vitamins later in life, and how this relates to health and disease, is not exactly known. The aim of this study was to identify effects of long-term supplementation with folic acid and vitamin B12 on genome-wide DNA methylation in elderly subjects. This project was part of a randomized, placebo-controlled trial on effects of supplemental intake of folic acid and vitamin B12 on bone fracture incidence (B-vitamins for the PRevention Of Osteoporotic Fractures (B-PROOF) study). Participants with mildly elevated homocysteine levels, aged 65-75 years, were randomly assigned to take 400 μg folic acid and 500 μg vitamin B12 per day or a placebo during an intervention period of 2 years. DNA was isolated from buffy coats, collected before and after intervention, and genome-wide DNA methylation was determined in 87 participants (n = 44 folic acid/vitamin B12, n = 43 placebo) using the Infinium HumanMethylation450 BeadChip.

resultsAfter intervention with folic acid and vitamin B12, 162 (versus 14 in the placebo group) of the 431,312 positions were differentially methylated as compared to baseline. Comparisons of the DNA methylation changes in the participants receiving folic acid and vitamin B12 versus placebo revealed one single differentially methylated position (cg19380919) with a borderline statistical significance. However, based on the analyses of differentially methylated regions (DMRs) consisting of multiple positions, we identified 6 regions that differed statistically significantly between the intervention and placebo group. Pronounced changes were found for regions in the DIRAS3, ARMC8, and NODAL genes, implicated in carcinogenesis and early embryonic development. Furthermore, serum levels of folate and vitamin B12 or plasma homocysteine were related to DNA methylation of 173, 425, and 11 regions, respectively. Interestingly, for several members of the developmental HOX genes, DNA methylation was related to serum levels of folate.

conclusionsLong-term supplementation with folic acid and vitamin B12 in elderly subjects resulted in effects on DNA methylation of several genes, among which genes implicated in developmental processes.

Indexed as

B-vitaminsCancerDevelopmentDNA methylationElderlyEpigeneticsFolic acidInfinium 450k BeadChipIntervention trialOne-carbon metabolismVitamin B12

Identifiers

PMID26568774
PMCPMC4644301
OpenAlexW2172972224

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.