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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

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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, Jessica C. Kiefte-de Jong, Devin M. Absher, Stella Aslibekyan, Yolanda B. de Rijke, Myriam Fornage, Dena G. Hernandez, Mikko A. Hurme, M. Arfan Ikram, Paul F. Jacques, Anne E. Justice & 27 more Douglas P. Kiel, Rozenn N. Lemaitre, Michael M. Mendelson, Vera Mikkilä, Ann Z. Moore, Tess Pallister, Olli T. Raitakari, Casper G. Schalkwijk, Jin Sha, Eline P.E. Slagboom, Caren E. Smith, Coen D.A. Stehouwer, Pei Chien Tsai, André G. Uitterlinden, Carla J.H. van der Kallen, Diana van Heemst, Donna K. Arnett, Stefania Bandinelli, Jordana T. Bell, Bastiaan T. Heijmans, Terho Lehtimäki, Daniel Levy, Kari E. North, Nona Sotoodehnia, Marleen M.J. van Greevenbroek, Joyce B.J. van Meurs, Sandra G. Heil

Original languageEnglish
Pages (from-to)437-450
Number of pages14
JournalThe American journal of clinical nutrition
Issue number2
Publication statusPublished - 1 Aug 2019

King's Authors


BACKGROUND: Folate 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. OBJECTIVE: The 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. METHODS: A 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. RESULTS: The 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. CONCLUSIONS: We 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.

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