Dietary and supplemental intake of vitamins C and E is associated with altered DNA methylation in an epigenome-wide association study meta-analysis

ABSTRACT

Background: Dietary intake of antioxidants such as vitamins C and E protect against oxidative stress, and may also be associated with altered DNA methylation patterns.

Methods: We meta-analysed epigenome-wide association study (EWAS) results from 11,866 participants across eight population-based cohorts to evaluate the association between self-reported dietary and supplemental intake of vitamins C and E with DNA methylation. EWAS were adjusted for age, sex, BMI, caloric intake, blood cell type proportion, smoking status, alcohol consumption, and technical covariates. Significant results of the meta-analysis were subsequently evaluated in gene set enrichment analysis (GSEA) and expression quantitative trait methylation (eQTM) analysis.

Results: In meta-analysis, methylation at 4,656 CpG sites was significantly associated with vitamin C intake at FDR ≤ 0.05. The most significant CpG sites associated with vitamin C (at FDR ≤ 0.01) were enriched for pathways associated with systems development and cell signalling in GSEA, and were associated with downstream expression of genes enriched in the immune response in eQTM analysis. Furthermore, methylation at 160 CpG sites was significantly associated with vitamin E intake at FDR ≤ 0.05, but GSEA and eQTM analysis of the top most significant CpG sites associated with vitamin E did not identify significant enrichment of any biological pathways investigated.

Conclusions: We identified significant associations of many CpG sites with vitamin C and E intake, and our results suggest that vitamin C intake may be associated with systems development and the immune response.

KEYWORDS:

• Epigenetics
• Vitamin C
• Vitamin E
• diet
• epidemiology

Disclosure statement

No potential conflict of interest was reported by the authors.

Disclaimer

The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services.

Data availability

FHS: Data from the FHS Offspring and Third-Generation cohorts are available at the Database of Genotypes and Phenotypes (dbGaP) at https://www.ncbi.nlm.nih.gov/gap/, reference number phs000007.v29.p10.

TwinsUK: Many of the data analysed in the current study is available through GEO GSE62992 and GSE121633. Additional individual-level data are not permitted to be shared or deposited due to the original consent given at the time of data collection. However, access to these data can be applied for through the TwinsUK data access committee. For information on access and how to apply http://twinsuk.ac.uk/resources-for-researchers/access-our-data/.

KORA: The informed consents given by KORA study participants do not cover data posting in public databases. However, data are available upon request from KORA Project Application Self-Service Tool (https://helmholtz-muenchen.managed-otrs.com/external) Data requests can be submitted online and are subject to approval by the KORA Board.

Young Finns Study: The dataset supporting the conclusions of this article were obtained from the Cardiovascular Risk In Young Finns study which comprises health-related participant data. The use of data is restricted under the regulations on professional secrecy (Act on the Openness of Government Activities, 612/1999) and on sensitive personal data (Personal Data Act, 523/1999, implementing the EU data protection directive 95/46/EC). Due to these restrictions, the data can not be stored in public repositories or otherwise made publicly available. Data access may be permitted on a case by case basis upon request only. Data sharing outside the group is done in collaboration with YFS group and requires a data-sharing agreement. Investigators can submit an expression of interest to the chairman of the publication committee (Prof Mika Kähönen, Tampere University, Finland) or Professor Terho Lehtimäki (Tampere University, Finland) concerning the epigenetic and genetic data.

Raine Study: The Raine Study holds a rich and detailed collection of data gathered over 30 years for the purpose of health and well-being research. The informed consent provided by each participant does not permit individual-level data to be made available in the public domain (i.e., a public data repository). However, de-identified analytic data sets are available to all researchers for original research or auditing of published findings. All data access is managed through established Raine Study procedures which require data handlers to agree to a code of conduct that includes safeguards to protect the identity of participants. Details of the data access processes, and code of conduct are available on the Raine Study website https://rainestudy.org.au/. The governance process for accessing the Raine Study data can be accessed here: https://rainestudy.org.au/information-for-researchers/information-for-new-researchers/.

Rotterdam Study: The Rotterdam Study data can be made available to interested researchers upon reasonable request. Requests can be directed to data manager Frank J.A. van Rooij ([email protected]). We are unable to place data in a public repository due to legal and ethical restraints. Sharing of individual participant data was not included in the informed consent of the study, and there is potential risk of revealing participants’ identities as it is not possible to completely anonymize the data. This is of particular concern given the sensitive personal nature of much of the data collected as part of the Rotterdam Study.

ARIC Study: The DNA methylation dataset from ARIC is available upon request at https://sites.cscc.unc.edu/aric/distribution-agreements.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/15592294.2023.2211361

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

The Framingham Heart Study laboratory work for this project was funded by the National Institutes of Health contract N01-HC-25195. The analytical component of this project was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (D. Levy, Principal Investigator).The KORA study was initiated and financed by the Helmholtz Zentrum München –German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. The work was further supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the EU Joint Programming Initiative ‘A Healthy Diet for a Healthy Life’ (DIMENSION grant number 01EA1902A).The TwinsUK methylation study received support from the UK Biotechnology and Biological Sciences Research Council (BBSRC BB/T019980/1 to J.T.B.) and from the JPI HDHL DIMENSION project (administered by the BBSRC UK, BB/S020845/1 to J.T.B.). TwinsUK is funded by the Wellcome Trust, Medical Research Council, Versus Arthritis, European Union Horizon 2020, Chronic Disease Research Foundation (CDRF), Zoe Ltd and the National Institute for Health Research (NIHR) Clinical Research Network (CRN) and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London.The Young Finns Study has been financially supported by the Academy of Finland: grants 322098, 286284, 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), 41071 (Skidi), 330809 and 338395; the Social Insurance Institution of Finland; Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku University Hospitals (grant X51001); Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation for Cardiovascular Research; Finnish Cultural Foundation; Sigrid Jusélius Foundation; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Yrjö Jahnsson Foundation; Signe and Ane Gyllenberg Foundation; Diabetes Research Foundation of Finnish Diabetes Association; This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreements No 848146 (To Aition) and No 755320 (TAXINOMISIS); This project has received funding from the European Research Council (ERC) advanced grants under grant agreement No 742927 (MULTIEPIGEN project); Tampere University Hospital Supporting Foundation and Finnish Society of Clinical Chemistry.The Raine Study was supported by the National Health and Medical Research Council of Australia [grant numbers 572613, 403981, and 1059711] and the Canadian Institutes of Health Research [grant number MOP-82893]. The authors gratefully acknowledge the NHMRC for their long-term funding to the study over the last 30 years and also the following institutes for providing funding for Core Management of the Raine Study: The University of Western Australia (UWA), Curtin University, Women and Infants Research Foundation, Telethon Kids Institute, Edith Cowan University, Murdoch University, The University of Notre Dame Australia and The Raine Medical Research Foundation. Generation of DNA methylation data was supported by NHMRC grant 1059711. R-CH is supported by NHMRC Fellowships 1053384 and PEM by NHMRC grant 2001203.The core management of the Raine Study is funded by the University of Western Australia, Curtin University, Telethon Kids Institute, Women and Infants Research Foundation, Edith Cowan University, Murdoch University, the University of Notre Dame Australia and the Raine Medical Research Foundation. The Pawsey Supercomputing Centre provided computation resources to carry out analyses required with funding from the Australian Government and the Government of Western Australia. Specific funding for the 17-year follow-up was provided by the National Health and Medical Research Council (NHMRC) (Program Grant Stanley et al., ID 353514, Beilin et al., ID 403981, Palmer et al., ID 572613, Huang et al., ID 1059711) and the Canadian Institutes of Health Research (Lye et al., MOP-82893).We would like to acknowledge the Raine Study participants and their families for their ongoing participation in the study and the Raine Study team for study co-ordination and data collection.The Rotterdam Study is supported by the Erasmus MC University Medical Center and Erasmus University Rotterdam; The Netherlands Organisation for Scientific Research (NWO); The Netherlands Organisation for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); The Netherlands Genomics Initiative (NGI); the Ministry of Education, Culture and Science; the Ministry of Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam.The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-C-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. The project described was supported by Grant Number UL1 RR 025005 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) and NIH Roadmap for Medical Research, and its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. KLY was supported by NHLBI R21 HL140419. The authors thank the staff and participants of the ARIC Study for their important contributions.