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.
| Original language | English |
|---|---|
| Pages (from-to) | 437-450 |
| Number of pages | 14 |
| Journal | American Journal of Clinical Nutrition |
| Volume | 110 |
| Issue number | 2 |
| DOIs | |
| State | Published - Aug 1 2019 |
Bibliographical note
Publisher Copyright:© Copyright American Society for Nutrition 2019.
Funding
Leiden Longevity Study (LLS): We thank all participants of the LLS. This study received funding from the European Union’s Seventh Framework Programme (FP7/2007-2011) under grant agreement no. 259679, from the Innovation-Oriented Research Program on Genomics (SenterNovem IGE05007), the Centre for Medical Systems Biology, from the Netherlands Consortium for Healthy Ageing (grant 050-060-810), and from the Biobank-Based Integrative Omics Studies (BIOS) Consortium funded by Biobanking and Biomolecular Research Infrastructure Netherlands, a research infrastructure financed by the Dutch government (NWO 184.021.007), all in the framework of the Netherlands Genomics Initiative, the Netherlands Organization for Scientific Research (NWO). The RS is funded by the Erasmus Medical Center and Erasmus University, Rotterdam; the Netherlands Organization for Health Research and Development; the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture, and Science; the Ministry for Health, Welfare, and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. The authors are grateful to the study participants, the staff from the RS and the participating general practitioners and pharmacists. TwinsUK: TwinsUK was funded by the Wellcome Trust; the European Community’s Seventh Framework Programme (FP7/2007–2013) and also receives support from the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. PCT, JEC-F, and JTB were supported by the European Commission and the UK Economic and Social Research Council (ES/N000404/1). Atherosclerosis Risk in Communities (ARIC) Study: The ARIC Study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, NIH, Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, and HHSN268201700005I). We thank the staff and participants of the ARIC Study for their important contributions. Funding was also supported by 5RC2HL102419 and R01NS087541. AEJ was funded by NIH award K99/R00 HL130580. Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Lipidomics Study: Phenotype/participant characteristic data were collected under NIH NHLBI grant U01 HL072524; methylation data were collected under NIH NHLBI R01 HL104135. Rotterdam Study (RS): The generation and management of the Illumina 450 K methylation array data (EWAS data) for the RS were executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Netherlands. The EWAS data were funded by the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, and by the Netherlands Organization for Scientific Research (NWO; project number 184021007) and made available as a Rainbow Project (RP3; BIOS) of the Biobanking and Biomolecular Research Infrastructure Netherlands. We thank Michael Verbiest, Mila Jhamai, Sarah Higgins, and Marijn Verkerk for their help in creating the methylation database. Cohort study on Diabetes and Atherosclerosis Maastricht (CODAM): Part of this work was supported by grants of the Netherlands Organization for Scientific Research (940-35-034) and the Dutch Diabetes Research Foundation (98.901). Blood Institute, NIH and an NIH Director’s Challenge Award (DL, Principal Investigator). DPK was funded by NIH grant R01 AR041398. Invecchiare in Chianti (InCHIANTI) study: The InCHIANTI study baseline (1998–2000) was supported as a “targeted project” (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the US National Institute on Aging (Contracts: 263 MD 9164 and 263 MD 821336). Young Finns Study (YFS): The YFS has been financially supported by the Academy of Finland: grants 286284, 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi); the Social Insurance Institution of Finland; Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku University Hospitals (grant X51001); the Juho Vainio Foundation; the Paavo Nurmi Foundation; the Finnish Foundation for Cardiovascular Research; the Finnish Cultural Foundation; the Tampere Tuberculosis Foundation; the Emil Aaltonen Foundation; the Yrjö Jahnsson Foundation; the Signe and Ane Gyllenberg Foundation; and the Diabetes Research Foundation of the Finnish Diabetes Association. TwinsUK: TwinsUK was funded by the Wellcome Trust; the European Community's Seventh Framework Programme (FP7/2007-2013) and also receives support from the National Institute for Health Research (NIHR)- funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. PCT, JEC-F, and JTB were supported by the European Commission and the UK Economic and Social Research Council (ES/N000404/1). Cardiovascular Health Study (CHS): Infrastructure for the CHARGE Consortium is supported in part by the National Heart, Lung, and Blood Institute grant R01HL105756. The CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, K08HL116640, R01HL087652, R01HL092111, R01HL103612, R01HL105756, R01HL103612, R01HL111089, R01HL116747, and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided through R01AG023629 from the National Institute on Aging, the Merck Foundation/Society of Epidemiologic Research as well as Laughlin Family, the Alpha Phi Foundation, and the Locke Charitable Foundation. A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Framingham Heart Study (FHS): The Framingham Heart Study is funded by NIH contract N01-HC-25195. The laboratory work for this investigation was funded by the Division of Intramural Research, National Heart, Lung, and
| Funders | Funder number |
|---|---|
| Dutch government | |
| Erasmus University | |
| FP7/2007 | |
| Innovation-Oriented Research Program on Genomics | IGE05007 |
| Italian Ministry of Health | |
| Laughlin Family | |
| Locke Charitable Foundation | |
| Merck Foundation/Society of Epidemiologic Research | |
| DECA/NHLBI/NIH | R01 HL104135, U01 HL072524 |
| Netherlands Consortium for Healthy Ageing | 050-060-810 |
| Netherlands Organization for Health Research and Development | |
| Netherlands Organization for Scientific Research | 940-35-034 |
| Research Institute for Diseases in the Elderly | |
| Southern California Diabetes Endocrinology Research Center | |
| Turku University Hospitals | X51001 |
| US National Institute on Aging | 263 MD 821336, 263 MD 9164 |
| National Institutes of Health (NIH) | N01-HC-25195, R01 AR041398 |
| National Institutes of Health (NIH) | |
| U.S. Department of Health and Human Services | K99/R00 HL130580, HHSN268201700003I, HHSN268201700004I, HHSN268201700005I, HHSN268201700001I, 5RC2HL102419, HHSN268201700002I |
| U.S. Department of Health and Human Services | |
| National Institute on Aging | |
| National Heart, Lung, and Blood Institute (NHLBI) | R01HL111089, K08HL116640, HHSN268200800007C, R01HL116747, R01HL092111, N01HC55222, N01HC85081, U01HL080295, N01HC85082, R01HL105756, N01HC85080, HHSN268201200036C, N01HC85086, N01HC85083, R01HL120393, N01HC85079, R01HL103612, R01HL087652 |
| National Heart, Lung, and Blood Institute (NHLBI) | |
| National Institute of Diabetes and Digestive and Kidney Diseases | DK063491 |
| National Institute of Diabetes and Digestive and Kidney Diseases | |
| Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council | R01AG023629, R01NS087541 |
| Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council | |
| Alpha Phi Foundation | |
| National Center for Advancing Translational Sciences (NCATS) | |
| Yrjö Jahnssonin Säätiö | |
| Wellcome Trust | |
| Clinical and Translational Science Institute, University of California, San Francisco | UL1TR000124 |
| Clinical and Translational Science Institute, University of California, San Francisco | |
| Seventh Framework Programme | |
| University of Utah Gastroenterology Division in the Department of Internal Medicine | |
| Economic and Social Research Council | ES/N000404/1 |
| Economic and Social Research Council | |
| National Institute for Health Research | |
| European Commission | |
| Ministry of Education, Culture, Sports, Science and Technology | |
| Academy of Finland | 126925, 121584, 129378, 117787, 134309, 286284, 41071, 124282 |
| Academy of Finland | |
| Erasmus Medisch Centrum | |
| Diabetes Fonds | 98.901 |
| Diabetes Fonds | |
| Suomen Kulttuurirahasto | |
| Nederlandse Organisatie voor Wetenschappelijk Onderzoek | 184021007 |
| Nederlandse Organisatie voor Wetenschappelijk Onderzoek | |
| Ministry of Health, Labour and Welfare | |
| Juho Vainion Säätiö | |
| Signe ja Ane Gyllenbergin Säätiö | |
| Emil Aaltosen Säätiö | |
| Seventh Framework Programme | 259679 |
| Seventh Framework Programme | |
| Sydäntutkimussäätiö | |
| Tampereen Tuberkuloosisäätiö | |
| Diabetesliitto | |
| Paavo Nurmen Säätiö | |
| Centre for Medical Systems Biology |
Keywords
- DNA methylation
- Epigenome-wide Association Study
- FFQ
- Vitamin B-12
- diet
- epigenetics
- folate
- genome-wide
ASJC Scopus subject areas
- Medicine (miscellaneous)
- Nutrition and Dietetics