Pooja R Mandaviya1,2, Roby Joehanes3,4,5, Jennifer Brody6, Juan E Castillo-Fernandez7, Koen F Dekkers8, Anh N Do9, Mariaelisa Graff10, Ismo K Hänninen11, Toshiko Tanaka12, Ester A L de Jonge1,13, Jessica C Kiefte-de Jong13,14, Devin M Absher15, Stella Aslibekyan16, Yolanda B de Rijke2, Myriam Fornage17, Dena G Hernandez18, Mikko A Hurme19, M Arfan Ikram13, Paul F Jacques20,21, Anne E Justice22, Douglas P Kiel3,4, Rozenn N Lemaitre6, Michael M Mendelson5,23, Vera Mikkilä24, Ann Z Moore12, Tess Pallister7, Olli T Raitakari25, Casper G Schalkwijk26, Jin Sha27, Eline P E Slagboom8, Caren E Smith20, Coen D A Stehouwer26, Pei-Chien Tsai7,28,29, André G Uitterlinden1, Carla J H van der Kallen26, Diana van Heemst30, Donna K Arnett31, Stefania Bandinelli32, Jordana T Bell7, Bastiaan T Heijmans8, Terho Lehtimäki11, Daniel Levy5, Kari E North10, Nona Sotoodehnia6, Marleen M J van Greevenbroek26, Joyce B J van Meurs1, Sandra G Heil2. 1. Department of Internal Medicine. 2. Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands. 3. Institute for Aging Research, Hebrew SeniorLife, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. 4. Broad Institute of MIT & Harvard, Cambridge, MA. 5. Framingham Heart Study, National Heart, Lung, and Blood Institute, NIH, Framingham, MA. 6. Department of Medicine, University of Washington, Seattle, WA. 7. Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom. 8. Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands. 9. Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY. 10. Department of Epidemiology, University of North Carolina, Chapel Hill, NC. 11. Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Pirkanmaa, Finland. 12. Translational Gerontology Branch, National Institute on Aging, Baltimore, MD. 13. Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands. 14. Faculty of Governance and Global Affairs, Leiden University College, The Hague, The Netherlands. 15. HudsonAlpha Institute of Biotechnology, Huntsville, AL. 16. Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL. 17. Brown Foundation Institute of Molecular Medicine and Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX. 18. Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD. 19. Department of Microbiology and Immunology, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Pirkanmaa, Finland. 20. USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA. 21. Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA. 22. Biomedical and Translational Informatics, Geisinger Health, Danville, PA. 23. Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA. 24. Division of Nutrition, Department of Food and Environmental Sciences, Helsinki, Uusimaa, Finland. 25. Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, and Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Southwest Finland, Finland. 26. Department of Internal Medicine, Maastricht University Medical Centre and CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands. 27. Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. 28. Department of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan. 29. Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, Linkou, Taiwan. 30. Department of Internal Medicine, Section Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands. 31. College of Public Health, University of Kentucky, Lexington, KY. 32. Geriatric Unit, Azienda Sanitaria di Firenze, Florence, Tuscany, Italy.
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 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.
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.
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