TY - JOUR
T1 - Association of dietary folate and Vitamin B-12 intake with genome-wide DNA methylation in blood
T2 - A large-scale epigenome-wide association analysis in 5841 individuals
AU - Mandaviya, Pooja R.
AU - Joehanes, Roby
AU - Brody, Jennifer
AU - Castillo-Fernandez, Juan E.
AU - Dekkers, Koen F.
AU - Do, Anh N.
AU - Graff, Mariaelisa
AU - Hänninen, Ismo K.
AU - Tanaka, Toshiko
AU - De Jonge, Ester A.L.
AU - Kiefte-De Jong, Jessica C.
AU - Absher, Devin M.
AU - Aslibekyan, Stella
AU - De Rijke, Yolanda B.
AU - Fornage, Myriam
AU - Hernandez, Dena G.
AU - Hurme, Mikko A.
AU - Ikram, M. Arfan
AU - Jacques, Paul F.
AU - Justice, Anne E.
AU - Kiel, Douglas P.
AU - Lemaitre, Rozenn N.
AU - Mendelson, Michael M.
AU - Mikkilä, Vera
AU - Moore, Ann Z.
AU - Pallister, Tess
AU - Raitakari, Olli T.
AU - Schalkwijk, Casper G.
AU - Sha, Jin
AU - Slagboom, Eline P.E.
AU - Smith, Caren E.
AU - Stehouwer, Coen D.A.
AU - Tsai, Pei Chien
AU - Uitterlinden, André G.
AU - Van Der Kallen, Carla J.H.
AU - Van Heemst, Diana
AU - Arnett, Donna K.
AU - Bandinelli, Stefania
AU - Bell, Jordana T.
AU - Heijmans, Bastiaan T.
AU - Lehtimäki, Terho
AU - Levy, Daniel
AU - North, Kari E.
AU - Sotoodehnia, Nona
AU - Van Greevenbroek, Marleen M.J.
AU - Van Meurs, Joyce B.J.
AU - Heil, Sandra G.
N1 - Publisher Copyright:
© Copyright American Society for Nutrition 2019.
PY - 2019/8/1
Y1 - 2019/8/1
N2 - 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.
AB - 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.
KW - DNA methylation
KW - Epigenome-wide Association Study
KW - FFQ
KW - Vitamin B-12
KW - diet
KW - epigenetics
KW - folate
KW - genome-wide
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U2 - 10.1093/ajcn/nqz031
DO - 10.1093/ajcn/nqz031
M3 - Article
C2 - 31165884
AN - SCOPUS:85070851213
SN - 0002-9165
VL - 110
SP - 437
EP - 450
JO - American Journal of Clinical Nutrition
JF - American Journal of Clinical Nutrition
IS - 2
ER -