DNA-Methylation Signatures of Tobacco Smoking in a High Cardiovascular Risk Population: Modulation by the Mediterranean Diet

Author:

Fernández-Carrión Rebeca12ORCID,Sorlí José V.12ORCID,Asensio Eva M.12ORCID,Pascual Eva C.1,Portolés Olga12,Alvarez-Sala Andrea1ORCID,Francès Francesc12,Ramírez-Sabio Judith B.3,Pérez-Fidalgo Alejandro456ORCID,Villamil Laura V.7,Tinahones Francisco J.28,Estruch Ramon29ORCID,Ordovas Jose M.21011,Coltell Oscar212ORCID,Corella Dolores12ORCID

Affiliation:

1. Department of Preventive Medicine and Public Health, School of Medicine, University of Valencia, 46010 Valencia, Spain

2. CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029 Madrid, Spain

3. Oncology Service, Sagunto Hospital, 46520 Valencia, Spain

4. Department of Medical Oncology, University Clinic Hospital of Valencia, 46010 Valencia, Spain

5. Biomedical Research Networking Centre on Cancer (CIBERONC), Health Institute Carlos III, 28029 Madrid, Spain

6. INCLIVA Biomedical Research Institute, 46010 Valencia, Spain

7. Department of Physiology, School of Medicine, University Antonio Nariño, Bogotá 111511, Colombia

8. Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Instituto de Investigación Biomédica de Málaga (IBIMA), University of Málaga, 29590 Málaga, Spain

9. Department of Internal Medicine, Institut d’Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Hospital Clinic, University of Barcelona, 08036 Barcelona, Spain

10. Nutrition and Genomics Laboratory, JM-USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, USA

11. Nutritional Control of the Epigenome Group, Precision Nutrition and Obesity Program, IMDEA Food, UAM + CSIC, 28049 Madrid, Spain

12. Department of Computer Languages and Systems, Universitat Jaume I, 12071 Castellón, Spain

Abstract

Biomarkers based on DNA methylation are relevant in the field of environmental health for precision health. Although tobacco smoking is one of the factors with a strong and consistent impact on DNA methylation, there are very few studies analyzing its methylation signature in southern European populations and none examining its modulation by the Mediterranean diet at the epigenome-wide level. We examined blood methylation smoking signatures on the EPIC 850 K array in this population (n = 414 high cardiovascular risk subjects). Epigenome-wide methylation studies (EWASs) were performed analyzing differential methylation CpG sites by smoking status (never, former, and current smokers) and the modulation by adherence to a Mediterranean diet score was explored. Gene-set enrichment analysis was performed for biological and functional interpretation. The predictive value of the top differentially methylated CpGs was analyzed using receiver operative curves. We characterized the DNA methylation signature of smoking in this Mediterranean population by identifying 46 differentially methylated CpGs at the EWAS level in the whole population. The strongest association was observed at the cg21566642 (p = 2.2 × 10−32) in the 2q37.1 region. We also detected other CpGs that have been consistently reported in prior research and discovered some novel differentially methylated CpG sites in subgroup analyses. In addition, we found distinct methylation profiles based on the adherence to the Mediterranean diet. Particularly, we obtained a significant interaction between smoking and diet modulating the cg5575921 methylation in the AHRR gene. In conclusion, we have characterized biomarkers of the methylation signature of tobacco smoking in this population, and suggest that the Mediterranean diet can increase methylation of certain hypomethylated sites.

Funder

The Conselleria de Innovación, Universidades, Ciencia y Sociedad Digital, Generalitat Valenciana

Publisher

MDPI AG

Subject

Health, Toxicology and Mutagenesis,Public Health, Environmental and Occupational Health

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