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, POOJA - Erasmus Medical Center; JOEHANES, ROBY - National Institutes Of Health (NIH); BRODY, JENNIFER - University Of Washington; CASTILLO-FERNANDEZ, JUAN - King'S College; DEKKERS, KOEN - Leiden University Medical Center; DO, ANH - The Icahn School Of Medicine At Mount Sinai; GRAFF, MARIAELISA - University Of North Carolina; HANNINEN, ISMO - University Of Tampere; TANAKA, TOSHIKO - National Institute On Aging (NIA, NIH); DE JONGE, ESTER - Erasmus Medical Center; KIEFTE-DE JONG, JESSICA - Erasmus Medical Center; ABSHER, DEVIN - Hudsonalpha Institute For Biotechnology; ASLIBEKYAN, STELLA - University Of Alabama; DE RIJKE, YOLANDA - Erasmus Medical Center; FORNAGE, MYRIAM - University Of Texas; HERNANDEZ, DENA - National Institute On Aging (NIA, NIH); HURME, MIKKO - University Of Tampere; IKRAM, MOHAMMED - Erasmus Medical Center; JACQUES, PAUL - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; JUSTICE, ANNE - Geisinger Medical Center; KIEL, DOUGLAS - Harvard University; LEMAITRE, ROZENN - University Of Washington; MENDELSON, MICHAEL - Harvard University; MIKKILA, VERA - University Of Helsinki; MOORE, ANN - National Institute On Aging (NIA, NIH); PALLISTER, TESS - King'S College; RAITAKARI, OLLI - University Of Turku; SCHALKWIJK, CASPER - Maastricht University; SHA, JIN - University Of Pennsylvania; SLAGBOOM, ELINE - Leiden University; SMITH, CAREN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; STEHOUWER, COEN - Maastricht University; TSAI, PEI-CHIEN - King'S College; UITTERLINDEN, ANDRE - Erasmus Medical Center; VAN DER KALLEN, CARLA - Maastricht University; VAN HEEMST, DIANA - Leiden University Medical Center; ARNETT, DONNA - University Of Kentucky; BANDINELLI, STEFANIA - Azienda Sanitaria Di Firenze; BELL, JORDANA - King'S College; HEIJMANS, BASTIAAN - Leiden University; LEHTIMAKI, TERHO - University Of Tampere; LEVY, DANIEL - National Institutes Of Health (NIH); NORTH, KARI - University Of North Carolina; SOTOODEHNIA, NONA - University Of Washington; VAN GREVENBROEK, MARLEEN - Maastricht University; VAN MEURS, JOYCE - Erasmus Medical Center; HEIL, SANDRA - Erasmus Medical Center

Submitted to: The American Journal of Clinical Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/12/2018
Publication Date: 6/5/2019
Citation: Mandaviya, P.R., Joehanes, R., Brody, J., Castillo-Fernandez, J., Dekkers, K.F., Do, A.N., Graff, M., Hanninen, I.K., Tanaka, T., De Jonge, E.A., Kiefte-De Jong, J.C., Absher, D.M., Aslibekyan, S., De Rijke, Y.B., Fornage, M., Hernandez, D.G., Hurme, M.A., Ikram, M.A., Jacques, P.F., Justice, A.E., Kiel, D.P., Lemaitre, R.N., Mendelson, M.M., Mikkila, V., Moore, A.Z., Pallister, T., Raitakari, O.T., Schalkwijk, C.G., Sha, J., Slagboom, E.P., Smith, C.E., Stehouwer, C.D., Tsai, P., Uitterlinden, A.G., Van Der Kallen, C.J., Van Heemst, D., Arnett, D.K., Bandinelli, S., Bell, J.T., Heijmans, B.T., Lehtimaki, T., Levy, D., North, K.E., Sotoodehnia, N., Van Grevenbroek, M.M., Van Meurs, J.B., Heil, S.G. 2019. 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. American Journal of Clinical Nutrition. 110(2):437-450. https://doi.org/10.1093/ajcn/nqz031.
DOI: https://doi.org/10.1093/ajcn/nqz031

Interpretive Summary: Folate and vitamin B-12 are essential micronutrients connected to a diverse array of diseases. One way by which vitamin B-12 and folate may alter disease risk is through an epigenetic (i.e., non-genetic) modification of DNA by means of a process called DNA methylation. DNA methylation is critical to healthy development, and abnormal DNA methylation is linked to several disease outcomes. We undertook a large-scale study of the relationship between folate and vitamin B-12 intake and DNA methylation using an epigenome-wide association study (EWAS). An EWAS is a study examining epigenetic markers, in this case DNA methylation, to look at the association between the marker and a trait of interest, such as vitamin intake. This study analyzed the association between folate and vitamin B-12 intake among 5,841 individuals enrolled in 10 different cohorts from Europe and North America. Our results identified novel epigenetic loci (ie. a position on a chromosome where a methylation site is located) that are associated with folate and vitamin B-12 intake. However, no association was found between B-12, folate, and DNA methylation.

Technical Abstract: 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 genomewide 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.