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Fine-grained investigation of the relationship between human nutrition and global DNA methylation patterns

  • Original Contribution
  • Published:
European Journal of Nutrition Aims and scope Submit manuscript

Abstract

Purpose

Nutrition is an important, modifiable, environmental factor affecting human health by modulating epigenetic processes, including DNA methylation (5mC). Numerous studies investigated the association of nutrition with global and gene-specific DNA methylation and evidences on animal models highlighted a role in DNA hydroxymethylation (5hmC) regulation. However, a more comprehensive analysis of different layers of nutrition in association with global levels of 5mC and 5hmC is lacking. We investigated the association between global levels of 5mC and 5hmC and human nutrition, through the stratification and analysis of dietary patterns into different nutritional layers: adherence to Mediterranean diet (MD), main food groups, macronutrients and micronutrients intake.

Methods

ELISA technique was used to measure global 5mC and 5hmC levels in 1080 subjects from the Moli-sani cohort. Food intake during the 12 months before enrolment was assessed using the semi-quantitative EPIC food frequency questionnaire. Complementary approaches involving both classical statistics and supervised machine learning analyses were used to investigate the associations between global 5mC and 5hmC levels and adherence to Mediterranean diet, main food groups, macronutrients and micronutrients intake.

Results

We found that global DNA methylation, but not hydroxymethylation, was associated with daily intake of zinc and vitamin B3. Random Forests algorithms predicting 5mC and 5hmC through intakes of food groups, macronutrients and micronutrients revealed a significant contribution of zinc, while vitamin B3 was reported among the most influential features.

Conclusion

We found that nutrition may affect global DNA methylation, suggesting a contribution of micronutrients previously implicated as cofactors in methylation pathways.

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Availability of data and materials

The data underlying this article will be shared on reasonable request to the corresponding author. The data are stored in an institutional repository (https://repository.neuromed.it) and access is restricted by the ethical approvals and the legislation of the European Union.

Code availability

Not applicable.

Abbreviations

5mC:

5-Methylcytosine

5hmC:

5‑Hydroxymethylcytosine

CVD:

Cardiovascular disease

MD:

Mediterranean diet

MDS:

Mediterranean Diet Score

OD:

Optical density

SE:

Standard error

RF:

Random forest

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Acknowledgements

Moli-sani study investigators: the enrolment phase of the Moli-sani Study was conducted at the Research Laboratories of the Catholic University in Campobasso (Italy), the follow up of the Moli-sani cohort is being conducted at the Department of Epidemiology and Prevention of the IRCCS Neuromed, Pozzilli, Italy. Steering Committee: Licia Iacoviello*° (Chairperson), Giovanni de Gaetano* and Maria Benedetta Donati*. Scientific secretariat: Marialaura Bonaccio*, Americo Bonanni*, Chiara Cerletti*, Simona Costanzo*, Amalia De Curtis*, Augusto Di Castelnuovo§, Francesco Gianfagna°§, Mariarosaria Persichillo*, Teresa Di Prospero* (Secretary). Safety and Ethical Committee: Jos Vermylen (Catholic Univesity, Leuven, Belgio) (Chairperson), Ignacio De Paula Carrasco (Accademia Pontificia Pro Vita, Roma, Italy), Antonio Spagnuolo (Catholic University, Roma, Italy). External Event adjudicating Committee: Deodato Assanelli (Brescia, Italy), Vincenzo Centritto (Campobasso, Italy). Baseline and follow-up data management: Simona Costanzo* (Coordinator), Marco Olivieri (Associazione Cuore Sano, Campobasso, Italy), Teresa Panzera*. Data Analysis: Augusto Di Castelnuovo§ (Coordinator), Marialaura Bonaccio*, Simona Costanzo*, Simona Esposito*, Alessandro Gialluisi*, Francesco Gianfagna°§, Emilia Ruggiero*. Biobank and biochemical laboratory: Amalia De Curtis* (Coordinator), Sara Magnacca§. Genetic laboratory: Benedetta Izzi* (Coordinator), Annalisa Marotta*, Fabrizia Noro*, Roberta Parisi*, Alfonsina Tirozzi*. Recruitment staff: Mariarosaria Persichillo* (Coordinator), Francesca Bracone*, Francesca De Lucia (Associazione Cuore Sano, Campobasso, Italy), Cristiana Mignogna*, Teresa Panzera*, Livia Rago*. Communication and Press Office: Americo Bonanni*. Regional Health Institutions: Direzione Generale per la Salute—Regione Molise; Azienda Sanitaria Regionale del Molise (ASReM, Italy); Molise Dati Spa (Campobasso, Italy); Offices of vital statistics of the Molise region. Hospitals: Presidi Ospedalieri ASReM: Ospedale A. Cardarelli – Campobasso, Ospedale F. Veneziale – Isernia, Ospedale San Timoteo—Termoli (CB), Ospedale Ss. Rosario—Venafro (IS), Ospedale Vietri – Larino (CB), Ospedale San Francesco Caracciolo—Agnone (IS); Casa di Cura Villa Maria—Campobasso; Ospedale Gemelli Molise—Campobasso; IRCCS Neuromed—Pozzilli (IS). *Department of Epidemiology and Prevention, IRCCS Neuromed, Pozzilli, Italy, °Department of Medicine and Surgery, University of Insubria, Varese, Italy, §Mediterranea Cardiocentro, Napoli, Italy. Baseline Recruitment staff is available at https://www.moli-sani.org/?page_id=173.

Funding

The enrolment phase of the Moli-sani Study was supported by research grants from the Pfizer Foundation (Rome, Italy), the Italian Ministry of University and Research (MIUR, Rome, Italy)–Programma Triennale di Ricerca, Decreto no.1588 and Instrumentation Laboratory, Milan, Italy. This project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement no 798841 (BI). The present analyses were partially supported by the Italian Ministry of Health 2018 (Young Investigator number: GR-2018-12366528) (BI) and by Fondazione Umberto Veronesi (AG and FN).

Author information

Author notes

  1. Alessandro Gialluisi and Benedetta Izzi have equally contributed to the manuscript.

Authors and Affiliations

  1. Department of Epidemiology and Prevention, IRCCS NEUROMED, Via dell’Elettronica, 86077, Pozzilli, IS, Italy

    Fabrizia Noro, Annalisa Marotta, Marialaura Bonaccio, Simona Costanzo, Federica Santonastaso, Sabatino Orlandi, Alfonsina Tirozzi, Roberta Parisi, Amalia De Curtis, Mariarosaria Persichillo, Maria Benedetta Donati, Chiara Cerletti, Giovanni de Gaetano, Licia Iacoviello, Alessandro Gialluisi & Benedetta Izzi

  2. Mediterranea Cardiocentro, Naples, Italy

    Francesco Gianfagna & Augusto Di Castelnuovo

  3. Department of Medicine and Surgery, EPIMED Research Center, University of Insubria, Varese, Italy

    Francesco Gianfagna & Licia Iacoviello

Authors
  1. Fabrizia Noro
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  2. Annalisa Marotta
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  3. Marialaura Bonaccio
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  4. Simona Costanzo
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  5. Federica Santonastaso
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  6. Sabatino Orlandi
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  7. Alfonsina Tirozzi
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  8. Roberta Parisi
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  9. Amalia De Curtis
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  10. Mariarosaria Persichillo
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  11. Francesco Gianfagna
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  12. Augusto Di Castelnuovo
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  13. Maria Benedetta Donati
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  14. Chiara Cerletti
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  15. Giovanni de Gaetano
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  16. Licia Iacoviello
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  17. Alessandro Gialluisi
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  18. Benedetta Izzi
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Consortia

Moli-sani Study Investigators

  • Licia Iacoviello
  • , Giovanni de Gaetano
  • , Maria Benedetta Donati
  • , Marialaura Bonaccio
  • , Americo Bonanni
  • , Chiara Cerletti
  • , Simona Costanzo
  • , Amalia De Curtis
  • , Augusto Di Castelnuovo
  • , Francesco Gianfagna
  • , Mariarosaria Persichillo
  • , Teresa Di Prospero
  • , Jos Vermylen
  • , Ignacio De Paula Carrasco
  • , Antonio Spagnuolo
  • , Deodato Assanelli
  • , Vincenzo Centritto
  • , Marco Olivieri
  • , Teresa Panzera
  • , Simona Esposito
  • , Alessandro Gialluisi
  • , Emilia Ruggiero
  • , Sara Magnacca
  • , Benedetta Izzi
  • , Annalisa Marotta
  • , Fabrizia Noro
  • , Roberta Parisi
  • , Alfonsina Tirozzi
  • , Francesca Bracone
  • , Francesca De Lucia
  • , Cristiana Mignogna
  •  & Livia Rago

Contributions

BI, LI and AG designed the research; FN conducted the research; AM and FS contributed to the methylation experiments; MB, SC, AT, RP, ADeC and MP provided essential materials; AG, FS, FG and SO analysed data and performed statistical analysis; FN, BI and AG wrote the paper; BI, AG, and LI had primary responsibility for final content; CC, MBD, GdG, ADiC and LI conceived the Moli-sani study; All authors read and approved the final manuscript.

Corresponding author

Correspondence to Licia Iacoviello.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval and consent to participate

The Moli-sani study complies with the Declaration of Helsinki and was approved by the Ethical Committee of the Catholic University in Rome, Italy. All participants provided written informed consent.

Consent for publication

Not applicable.

Additional information

The members of the Moli-sani Study Investigators group are mentioned in the Acknowledgements section.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 119 kb)

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Noro, F., Marotta, A., Bonaccio, M. et al. Fine-grained investigation of the relationship between human nutrition and global DNA methylation patterns. Eur J Nutr 61, 1231–1243 (2022). https://doi.org/10.1007/s00394-021-02716-8

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  • DOI: https://doi.org/10.1007/s00394-021-02716-8

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