A1 Refereed original research article in a scientific journal
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
Authors: Mandaviya PR, Joehanes R, Brody J, Castillo-Fernandez JE, Dekkers KF, Do AN, Graff M, Hanninen IK, Tanaka T, de Jonge EAL, Kiefte-de Jong JC, Absher DM, Aslibekyan S, de Rijke YB, Fornage M, Hernandez DG, Hurme MA, Ikram MA, Jacques PF, Justice AE, Kiel DP, Lemaitre RN, Mendelson MM, Mikkila V, Moore AZ, Pallister T, Raitakari OT, Schalkwijk CG, Sha J, Slagboom EPE, Smith CE, Stehouwer CDA, Tsai PC, Uitterlinden AG, van der Kallen CJH, van Heemst D, Arnett DK, Bandinelli S, Bell JT, Heijmans BT, Lehtimaki T, Levy D, North KE, Sotoodehnia N, van Greevenbroek MMJ, van Meurs JBJ, Heil SG
Publisher: OXFORD UNIV PRESS
Publication year: 2019
Journal: American Journal of Clinical Nutrition
Journal name in source: AMERICAN JOURNAL OF CLINICAL NUTRITION
Journal acronym: AM J CLIN NUTR
Volume: 110
Issue: 2
First page : 437
Last page: 450
Number of pages: 14
ISSN: 0002-9165
DOI: https://doi.org/10.1093/ajcn/nqz031
Self-archived copy’s web address: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669135/
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.
