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
Creators: name: Tsai, P.-C.
name: De Rijke, Y.B.
name: Mikkilä, V.
name: Absher, D.M.
name: Sha, J.
name: Schalkwijk, C.G.
name: Smith, C.E.
name: Slagboom, E.P.E.
name: Van Heemst, D.
name: Dekkers, K.F.
name: Mendelson, M.M.
name: Bell, J.T.
name: Lehtimäki, T.
name: Lemaitre, R.N.
name: Castillo-Fernandez, J.E.
name: Joehanes, R.
name: Sotoodehnia, N.
name: Kiefte-De Jong, J.C.
name: Van Meurs, J.B.J.
name: De Jonge, E.A.L.
name: Hänninen, I.K.
name: Brody, J.
name: Heijmans, B.T.
name: Heil, S.G.
name: Fornage, M.
name: Do, A.N.
name: North, K.E.
name: Levy, D.
name: Tanaka, T.
name: Graff, M.
name: Van Greevenbroek, M.M.J.
name: Jacques, P.F.
name: Stehouwer, C.D.A.
name: Mandaviya, P.R.
name: Raitakari, O.T.
name: Hernandez, D.G.
name: Van Der Kallen, C.J.H.
name: Aslibekyan, S.
name: Hurme, M.A.
name: Ikram, M.A.
name: Pallister, T.
name: Bandinelli, S.
name: Arnett, D.K.
name: Moore, A.Z.
name: Justice, A.E.
name: Kiel, D.P.
name: Uitterlinden, A.G.
Publisher: name: Oxford University Press
Year: 2019

description: 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.