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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #368332

Research Project: Nutritional Epidemiology

Location: Jean Mayer Human Nutrition Research Center On Aging

Title: 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

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

Submitted to: 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.