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-Reference-Cited by-同舟云学术

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

Published:2019-06-05 Issue:2 Volume:110 Page:437-450
ISSN:0002-9165
Container-title:The American Journal of Clinical Nutrition
language:en
Short-container-title:

Author:

Mandaviya Pooja R¹²^ORCID,Joehanes Roby³⁴⁵,Brody Jennifer⁶^ORCID,Castillo-Fernandez Juan E⁷^ORCID,Dekkers Koen F⁸^ORCID,Do Anh N⁹,Graff Mariaelisa¹⁰,Hänninen Ismo K¹¹^ORCID,Tanaka Toshiko¹²,de Jonge Ester A L¹¹³,Kiefte-de Jong Jessica C¹³¹⁴^ORCID,Absher Devin M¹⁵,Aslibekyan Stella¹⁶,de Rijke Yolanda B²,Fornage Myriam¹⁷,Hernandez Dena G¹⁸,Hurme Mikko A¹⁹^ORCID,Ikram M Arfan¹³,Jacques Paul F²⁰²¹^ORCID,Justice Anne E²²,Kiel Douglas P³⁴^ORCID,Lemaitre Rozenn N⁶,Mendelson Michael M⁵²³,Mikkilä Vera²⁴,Moore Ann Z¹²,Pallister Tess⁷,Raitakari Olli T²⁵,Schalkwijk Casper G²⁶,Sha Jin²⁷,Slagboom Eline P E⁸,Smith Caren E²⁰,Stehouwer Coen D A²⁶,Tsai Pei-Chien⁷²⁸²⁹^ORCID,Uitterlinden André G¹^ORCID,van der Kallen Carla J H²⁶,van Heemst Diana³⁰,Arnett Donna K³¹,Bandinelli Stefania³²,Bell Jordana T⁷,Heijmans Bastiaan T⁸,Lehtimäki Terho¹¹,Levy Daniel⁵,North Kari E¹⁰,Sotoodehnia Nona⁶,van Greevenbroek Marleen M J²⁶,van Meurs Joyce B J¹,Heil Sandra G²

Affiliation:

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

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.

Funder

Erasmus Medical Center

Erasmus Universiteit Rotterdam

Ministry of Education, Culture, and Science

Seventh Framework Programme

Netherlands Consortium for Healthy Ageing

Biobanking and Biomolecular Research Infrastructure Netherlands

National Institute on Aging

Academy of Finland

Turku University Hospitals

Juho Vainio Foundation

Paavo Nurmi Foundation