Evidence map›Paper›PMID 31165884›Full record

ArticleThe American journal of clinical nutrition2019

Association of dietary folate and vitamin B-12 intake with genome-wide DNA methylation in blood: a large-scale epigenome-wide association analysis in 5841 individuals.

Pooja R Mandaviya, Roby Joehanes, Jennifer Brody, Juan E Castillo-Fernandez, Koen F Dekkers, Anh N Do, Mariaelisa Graff, Ismo K Hänninen, Toshiko Tanaka, Ester A L de Jonge and 37 more

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In one paragraph

Article in The American journal of clinical nutrition, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers, 4 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
39citing papers in PubMed, 4 pooled it
3.2field-weighted citation impact, top 7% 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

39 citing papers in PubMed, 4 syntheses or guidelines pooled it, 65 citations in OpenAlex.

  1. Pooled it
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  6. Article
  7. International journal of molecular medicine · 2026
    Review
  8. Article
  9. Nutrition as a systems regulator of brain aging trajectories.Frontiers in molecular neuroscience · 2026
    Review
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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

47 authors at 20 institutions in 6 countries.

Pooja R MandaviyaDepartment of Internal Medicine.
Roby JoehanesInstitute for Aging Research, Hebrew SeniorLife, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
Jennifer BrodyDepartment of Medicine, University of Washington, Seattle, WA.
Juan E Castillo-FernandezDepartment of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
Koen F DekkersMolecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands.
Anh N DoInstitute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY.
Mariaelisa GraffDepartment of Epidemiology, University of North Carolina, Chapel Hill, NC.
Ismo K HänninenDepartment of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Pirkanmaa, Finland.
Toshiko TanakaTranslational Gerontology Branch, National Institute on Aging, Baltimore, MD.
Ester A L de JongeDepartment of Internal Medicine.
Jessica C Kiefte-de JongDepartment of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Devin M AbsherHudsonAlpha Institute of Biotechnology, Huntsville, AL.
Stella AslibekyanDepartment of Epidemiology, University of Alabama at Birmingham, Birmingham, AL.
Yolanda B de RijkeDepartment of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands.
Myriam FornageBrown Foundation Institute of Molecular Medicine and Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX.
Dena G HernandezLaboratory of Neurogenetics, National Institute on Aging, Bethesda, MD.
Mikko A HurmeDepartment of Microbiology and Immunology, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Pirkanmaa, Finland.
M Arfan IkramDepartment of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Paul F JacquesUSDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA.
Anne E JusticeBiomedical and Translational Informatics, Geisinger Health, Danville, PA.
Douglas P KielInstitute for Aging Research, Hebrew SeniorLife, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
Rozenn N LemaitreDepartment of Medicine, University of Washington, Seattle, WA.
Michael M MendelsonFramingham Heart Study, National Heart, Lung, and Blood Institute, NIH, Framingham, MA.
Vera MikkiläDivision of Nutrition, Department of Food and Environmental Sciences, Helsinki, Uusimaa, Finland.
Ann Z MooreTranslational Gerontology Branch, National Institute on Aging, Baltimore, MD.
Tess PallisterDepartment of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
Olli T RaitakariDepartment of Clinical Physiology and Nuclear Medicine, Turku University Hospital, and Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Southwest Finland, Finland.
Casper G SchalkwijkDepartment of Internal Medicine, Maastricht University Medical Centre and CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands.
Jin ShaPerelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
Eline P E SlagboomMolecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands.
Caren E SmithUSDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA.
Coen D A StehouwerDepartment of Internal Medicine, Maastricht University Medical Centre and CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands.
Pei-Chien TsaiDepartment of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
André G UitterlindenDepartment of Internal Medicine.
Carla J H van der KallenDepartment of Internal Medicine, Maastricht University Medical Centre and CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands.
Diana van HeemstDepartment of Internal Medicine, Section Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
Donna K ArnettCollege of Public Health, University of Kentucky, Lexington, KY.
Stefania BandinelliGeriatric Unit, Azienda Sanitaria di Firenze, Florence, Tuscany, Italy.
Jordana T BellDepartment of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
Bastiaan T HeijmansMolecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands.
Terho LehtimäkiDepartment of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Pirkanmaa, Finland.
Daniel LevyFramingham Heart Study, National Heart, Lung, and Blood Institute, NIH, Framingham, MA.
Kari E NorthDepartment of Epidemiology, University of North Carolina, Chapel Hill, NC.
Nona SotoodehniaDepartment of Medicine, University of Washington, Seattle, WA.
Marleen M J van GreevenbroekDepartment of Internal Medicine, Maastricht University Medical Centre and CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands.
Joyce B J van MeursDepartment of Internal Medicine.
Sandra G HeilDepartment of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands.
Erasmus MC · NLLeiden University Medical Center · NLKing's College London · GBMaastricht University Medical Centre · NLNational Institute on Aging · USUniversity of Washington · USBroad Institute · USTampere University · FITufts University · USUniversity of North Carolina at Chapel Hill · US358 (Finland) · FIAzienda Sanitaria di Firenze · ITBoston Children's Hospital · USBrown Foundation · USChang Gung University · TWGeisinger Health System · USHudsonAlpha Institute for Biotechnology · USIcahn School of Medicine at Mount Sinai · USLeiden University · NLNational Heart Lung and Blood Institute · US

Funding

UCLA Clinical and Translational Science InstituteUL1TR000124 · NCATS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI DUBINETT, STEVEN M. · 2012 to 2015
$57.0M
Framingham Project/LevyZIAHL006001 · NHLBI · NATIONAL HEART, LUNG, AND BLOOD INSTITUTE · PI LEVY, DANIEL · 2009 to 2025
$51.1M
Transgenic & Knock-out MouseP30DK063491 · NIDDK · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI PETER J TONTONOZ · 2003 to 2026
$40.4M
Building on GWAS for NHLBI-disease: the CHARGE consortiumRC2HL102419 · NHLBI · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · PI BOERWINKLE, ERIC A. · 2009 to 2010
$27.6M
RISK FACTORS FOR VERTEBRAL FRACTURE AND BONE LOSSR01AR041398 · NIAMS · RHODE ISLAND HOSPITAL (PROVIDENCE, RI) · PI KIEL, DOUGLAS P. · 1991 to 2025
$16.1M
Genetic and Environmental Determinants of TriglyceridesU01HL072524 · NHLBI · UNIVERSITY OF MINNESOTA TWIN CITIES · PI ARNETT, DONNA K · 2002 to 2008
$11.9M
Exceptional Survival: Trajectories to Functional Aging (CHS All Stars)R01AG023629 · NIA · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI NEWMAN, ANNE B. · 2004 to 2016
$9.5M
CHARGE Consortium: Omics Discovery for CVD and Aging PhenotypesR01HL105756 · NHLBI · UNIVERSITY OF WASHINGTON · PI Bruce M Psaty, NICHOLAS L SMITH · 2011 to 2026
$9.5M
Rare variants and NHLBI traits in deeply phenotyped cohortsR01HL120393 · NHLBI · UNIVERSITY OF WASHINGTON · PI PSATY, BRUCE M, RICE, KENNETH M. · 2014 to 2016
$8.9M
CHS research resources for the cardiovascular health of older adultsU01HL130114 · NHLBI · UNIVERSITY OF WASHINGTON · PI BURKE, GREGORY L, KRONMAL, RICHARD A · 2016 to 2019
$6.6M
Epigenetic Determinants of Lipid Response to Dietary Fat and FenofibrateR01HL104135 · NHLBI · UNIVERSITY OF KENTUCKY · PI ARNETT, DONNA K · 2010 to 2015
$5.5M
Prospective meta-analyses of drug-gene interactions: CHARGE GWAS consortiumR01HL103612 · NHLBI · UNIVERSITY OF WASHINGTON · PI PSATY, BRUCE M · 2011 to 2014
$5.4M
NCATS NIH HHS UL1 TR000124NHLBI NIH HHS HHSN268200800007CNHLBI NIH HHS HHSN268201200036CNHLBI NIH HHS HHSN268201700001CNHLBI NIH HHS HHSN268201700001INHLBI NIH HHS HHSN268201700002CNHLBI NIH HHS HHSN268201700002INHLBI NIH HHS HHSN268201700003CNHLBI NIH HHS HHSN268201700003INHLBI NIH HHS HHSN268201700004CNHLBI NIH HHS HHSN268201700004INHLBI NIH HHS HHSN268201700005CNHLBI NIH HHS HHSN268201700005INHLBI NIH HHS K08 HL116640NHLBI NIH HHS K99 HL130580NHLBI NIH HHS K99 HL136875NHLBI NIH HHS N01 HC025195NHLBI NIH HHS N01 HC055222NHLBI NIH HHS N01 HC085079NHLBI NIH HHS N01 HC085080NHLBI NIH HHS N01 HC085081NHLBI NIH HHS N01 HC085082NHLBI NIH HHS N01 HC085083NHLBI NIH HHS N01 HC085086NHLBI NIH HHS R00 HL130580NHLBI NIH HHS R01 HL087652NHLBI NIH HHS R01 HL092111NHLBI NIH HHS R01 HL103612NHLBI NIH HHS R01 HL104135NHLBI NIH HHS R01 HL105756NHLBI NIH HHS R01 HL111089NHLBI NIH HHS R01 HL116747NHLBI NIH HHS R01 HL120393NHLBI NIH HHS RC2 HL102419NHLBI NIH HHS U01 HL072524NHLBI NIH HHS U01 HL080295NHLBI NIH HHS U01 HL130114NIAMS NIH HHS R01 AR041398NIA NIH HHS R01 AG023629NIDDK NIH HHS P30 DK063491NINDS NIH HHS R01 NS087541Wellcome Trust
6 · The paper itself

Abstract

backgroundFolate and vitamin B-12 are essential micronutrients involved in the donation of methyl groups in cellular metabolism. However, associations between intake of these nutrients and genome-wide DNA methylation levels have not been studied comprehensively in humans.

objectiveThe aim of this study was to assess whether folate and/or vitamin B-12 intake are asssociated with genome-wide changes in DNA methylation in leukocytes.

methodsA large-scale epigenome-wide association study of folate and vitamin B-12 intake was performed on DNA from 5841 participants from 10 cohorts using Illumina 450k arrays. Folate and vitamin B-12 intakes were calculated from food-frequency questionnaires (FFQs). Continuous and categorical (low compared with high intake) linear regression mixed models were applied per cohort, controlling for confounders. A meta-analysis was performed to identify significant differentially methylated positions (DMPs) and regions (DMRs), and a pathway analysis was performed on the DMR annotated genes.

resultsThe categorical model resulted in 6 DMPs, which are all negatively associated with folate intake, annotated to FAM64A, WRAP73, FRMD8, CUX1, and LCN8 genes, which have a role in cellular processes including centrosome localization, cell proliferation, and tumorigenesis. Regional analysis showed 74 folate-associated DMRs, of which 73 were negatively associated with folate intake. The most significant folate-associated DMR was a 400-base pair (bp) spanning region annotated to the LGALS3BP gene. In the categorical model, vitamin B-12 intake was associated with 29 DMRs annotated to 48 genes, of which the most significant was a 1100-bp spanning region annotated to the calcium-binding tyrosine phosphorylation-regulated gene (CABYR). Vitamin B-12 intake was not associated with DMPs.

conclusionsWe identified novel epigenetic loci that are associated with folate and vitamin B-12 intake. Interestingly, we found a negative association between folate and DNA methylation. Replication of these methylation loci is necessary in future studies.

Indexed as

DietEpigenomicsGenome-Wide Association StudyAdultAgedDNA MethylationFemaleFolic AcidGene Expression RegulationHumansMaleMiddle AgedVitamin B 12Folic AcidVitamin B 12dietDNA methylationepigeneticsEpigenome-wide Association StudyFFQfolategenome-widevitamin B-12

Identifiers

PMID31165884
PMCPMC6669135
OpenAlexW2948181444

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.