Journal of Physiology and Biochemistry

, Volume 73, Issue 3, pp 445–455 | Cite as

Adherence to Mediterranean diet is associated with methylation changes in inflammation-related genes in peripheral blood cells

  • A. Arpón
  • J. I. Riezu-Boj
  • F. I. Milagro
  • A Marti
  • C. Razquin
  • M. A. Martínez-González
  • D. Corella
  • R. Estruch
  • R. Casas
  • M. Fitó
  • E. Ros
  • J. Salas-Salvadó
  • J. A. MartínezEmail author
Original Article


Epigenetic processes, including DNA methylation, might be modulated by environmental factors such as the diet, which in turn have been associated with the onset of several diseases such as obesity or cardiovascular events. Meanwhile, Mediterranean diet (MedDiet) has demonstrated favourable effects on cardiovascular risk, blood pressure, inflammation and other complications related to excessive adiposity. Some of these effects could be mediated by epigenetic modifications. Therefore, the objective of this study was to investigate whether the adherence to MedDiet is associated with changes in the methylation status from peripheral blood cells. A subset of 36 individuals was selected within the Prevención con Dieta Mediterránea (PREDIMED)-Navarra study, a randomised, controlled, parallel trial with three groups of intervention in high cardiovascular risk volunteers, two with a MedDiet and one low-fat control group. Changes in methylation between baseline and 5 years were studied. DNA methylation arrays were analysed by several robust statistical tests and functional classifications. Eight genes related to inflammation and immunocompetence (EEF2, COL18A1, IL4I1, LEPR, PLAGL1, IFRD1, MAPKAPK2, PPARGC1B) were finally selected as changes in their methylation levels correlated with adherence to MedDiet and because they presented sensitivity related to a high variability in methylation changes. Additionally, EEF2 methylation levels positively correlated with concentrations of TNF-α and CRP. This report is apparently the first showing that adherence to MedDiet is associated with the methylation of the reported genes related to inflammation with a potential regulatory impact.


Mediterranean Diet Adherence Methylation DNA Epigenetics 



Authors are very grateful to CIBERobn (CB12/03/30002 to J. A. M.) for the financial help and scientific support, as well as to the PREDIMED project (Red PREDIMED-RETIC RD06/0045).

A. A. was supported by a grant from Centro de Investigación en Nutrición (Universidad de Navarra) until August 2016 and from that day, by a “Formación de Profesorado Universitario” predoctoral fellowship from Ministerio de Educación, Cultura y Deporte (FPU15/02790). We specially thank Goñi-Echeverria E for his help in the statistical analysis.

Supplementary material

13105_2017_552_MOESM1_ESM.docx (55 kb)
Figure S1 (DOCX 55 kb)
13105_2017_552_MOESM2_ESM.docx (16 kb)
Table S1 (DOCX 15 kb)
13105_2017_552_MOESM3_ESM.docx (17 kb)
Table S2 (DOCX 16 kb)
13105_2017_552_MOESM4_ESM.docx (152 kb)
Table S3 (DOCX 151 kb)
13105_2017_552_MOESM5_ESM.docx (86 kb)
Table S4 (DOCX 85 kb)


  1. 1.
    Åberg UW, Saarinen N, Abrahamsson A et al (2011) Tamoxifen and flaxseed alter angiogenesis regulators in normal breast tissue in vivo. PLoS One 6(9):e25720CrossRefPubMedGoogle Scholar
  2. 2.
    Boulland ML, Marquet J, Molinier-Frenkel V et al (2007) Human IL4I1 is a secreted L-phenylalanine oxidase expressed by mature dendritic cells that inhibits T-lymphocyte proliferation. Blood 110(1):220–227CrossRefPubMedGoogle Scholar
  3. 3.
    Burdge GC, Hoile SP, Lillycrop KA (2012) Epigenetics: are there implications for personalised nutrition? Curr Opin Clin Nutr Metab Care 15(5):442–447CrossRefPubMedGoogle Scholar
  4. 4.
    Burdge GC, Lillycrop KA (2010) Bridging the gap between epigenetics research and nutritional public health interventions. Genome Medicine 2(11):80CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Burdge GC, Lillycrop KA, Phillips ES et al (2009) Folic acid supplementation during the juvenile-pubertal period in rats modifies the phenotype and epigenotype induced by prenatal nutrition. J Nutr 139(6):1054–1060CrossRefPubMedGoogle Scholar
  6. 6.
    Campión J, Milagro FI, Goyenechea E et al (2009) TNF-α promoter methylation as a predictive biomarker for weight-loss response. Obesity (Silver Spring) 17(6):1293–1297Google Scholar
  7. 7.
    Casas R, Sacanella E, Urpí-Sardà M et al (2010) The effects of the mediterranean diet on biomarkers of vascular wall inflammation and plaque vulnerability in subjects with high risk for cardiovascular disease. A randomized trial. PLoS One 9(6):e100084CrossRefGoogle Scholar
  8. 8.
    Ceccarelli V, Racanicchi S, Martelli MP et al (2011) Eicopentaenoic acid demethylates a single CpG that mediates expression of tumor suppressor CCAAT/enhancer-binding protein delta in U937 leukemia cells. J Biol Chem 286(31):27092–27102CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Chambers KF, Bacon JR, Kemsley EK et al (2009) Gene expression profile of primary prostate epithelial and stromal cells in response to sulforaphane or iberin exposure. Prostate 69(13):1411–1421CrossRefPubMedGoogle Scholar
  10. 10.
    Choi SW, Friso S (2010) Epigenetics: a new bridge between nutrition and health. Adv Nutr 1:8–16CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Cordero P, Campión J, Milagro FI et al (2011) Leptin and TNF-alpha promoter methylation levels measured by MSP could predict the response to a low-calorie diet. J Physiol Biochem 67(3):463–470CrossRefPubMedGoogle Scholar
  12. 12.
    Corella D, Ordovás JM, Sorlí JV et al. (2015) Effect of the Mediterranean diet on DNA methylation of selected genes in the PREDIMED-Valencia Intervention Trial. The FASEB Journal 29(1): Suppl LB242Google Scholar
  13. 13.
    Corella D, Ortega-Azorín C, Coltell O et al (2016) Diabetes and aging are associated with lower methylation levels of the irisin (FNDC5) gene, whereas higher adherence to the Mediterranean diet and physical activity increased methylation of these CpG sites in the PREDIMED-Valencia Study. Obesity Facts 9(Suppl 1):121Google Scholar
  14. 14.
    Do Amaral CL, Milagro FI, Curi R et al (2014) DNA methylation pattern in overweight women under an energy-restricted diet supplemented with fish oil. Biomed Res Int 2014:675021PubMedPubMedCentralGoogle Scholar
  15. 15.
    Estruch R, Martínez-González MA, Corella D et al (2006) Effects of a Mediterranean-style diet on cardiovascular risk factors: a randomized trial. Ann Intern Med 145(1):1–11CrossRefPubMedGoogle Scholar
  16. 16.
    Estruch R, Ros E, Salas-Salvadó J et al (2013) Primary prevention of cardiovascular disease with a Mediterranean diet. NEJM 368(14):1279–1290CrossRefPubMedGoogle Scholar
  17. 17.
    Ferguson LR, De Caterina R, Görman U et al (2016) Guide and position of the International Society of Nutrigenetics/Nutrigenomics on personalized nutrition: part 1—fields of precision nutrition. J Nutrigenet Nutrigenomics 9:12–27CrossRefPubMedGoogle Scholar
  18. 18.
    Fraga MF, Ballestar E, Paz MF et al (2005) Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A 102(30):10604–10609CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Goni L, Cuervo M, Milagro FI et al. (2016) Future perspectives of personalized weight loss interventions based on nutrigenetic, epigenetic and metagenomic data. J NutrGoogle Scholar
  20. 20.
    González-Terán B, Cortés JR, Manieri E et al (2013) Eukaryotic elongation factor 2 controls TNF-α translation in LPS-induced hepatitis. J Clin Invest 123(1):164–178CrossRefPubMedGoogle Scholar
  21. 21.
    Kiec-Wilk B, Sliwa A, Mikolajczyk M et al (2011) The CpG island methylation regulated expression of endothelial proangiogenic genes in response to β-carotene and arachidonic acid. Nutr Cancer 63(7):1053–1063CrossRefPubMedGoogle Scholar
  22. 22.
    Kohlmeier M, De Caterina R, Ferguson LR et al (2016) Guide and position of the International Society of Nutrigenetics/Nutrigenomics on personalized nutrition: part 2 - ethics, challenges and endeavors of precision nutrition. J Nutrigenet Nutrigenomics 9:28–46CrossRefPubMedGoogle Scholar
  23. 23.
    Kulkarni A, Dangat K, Kale A et al (2011) Effects of altered maternal folic acid, vitamin B12 and docosahexaenoic acid on placental global DNA methylation patterns in Wistar rats. PLoS One 6(3):e17706CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Li Q, Chen H (2011) Epigenetic modifications of metastasis suppressor genes in colon cancer metastasis. Epigenetics 6(7):849–852CrossRefPubMedGoogle Scholar
  25. 25.
    Mansego ML, Milagro FI, Zulet MA et al (2015) Differential DNA methylation in relation to age and health risks of obesity. Int J Mol Sci 16:16816–16832CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Martínez-González MA, Corella D, Salas-Salvadó J et al (2012) Cohort profile: design and methods of the PREDIMED study. Int J Epidemiol 41(2):377–385CrossRefPubMedGoogle Scholar
  27. 27.
    Martínez-González MA, Salas-Salvadó J, Estruch R et al (2015) Benefits of the Mediterranean diet: insights from the PREDIMED study. Prog Cardiovasc Dis 58(1):50–60CrossRefPubMedGoogle Scholar
  28. 28.
    Martino D, Saffery R (2015) Characteristics of DNA methylation and gene expression in regulatory features on the Infinium 450k Beadchip. bioRxiv 032862Google Scholar
  29. 29.
    Milagro FI, Campión J, García-Díaz DF et al (2009) High fat diet-induced obesity modifies the methylation pattern of leptin promoter in rats. J Physiol Biochem 65(1):1–10CrossRefPubMedGoogle Scholar
  30. 30.
    Milagro FI, Mansego ML, De Miguel C et al (2013) Dietary factors, epigenetic modifications and obesity outcomes: progresses and perspectives. Mol Asp Med 34(4):782–812CrossRefGoogle Scholar
  31. 31.
    Mitjavila MT, Fandos M, Salas-Salvadó J et al (2013) The Mediterranean diet improves the systemic lipid and DNA oxidative damage in metabolic syndrome individuals. A randomized, controlled trial. Clin Nutr 32(2):172–178CrossRefPubMedGoogle Scholar
  32. 32.
    Petro PD, Palou A, Bonet ML et al (2016) Cell-autonomous brown-like adipogenesis of preadipocytes from retinoblastoma haploinsufficient mice. J Cell Physiol 231(9):1941–1952CrossRefGoogle Scholar
  33. 33.
    Reis BS, Lee K, Fanok MH et al (2015) Leptin receptor signaling in T cells is required for Th17 differentiation. J Immunol 194(11):5253–5260CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    RStudio Team (2015) RStudio: integrated development for R. RStudio, Inc., Boston, MA Available: Google Scholar
  35. 35.
    Salas-Salvadó J, Garcia-Arellano A, Estruch R et al (2008) Components of the Mediterranean-type food pattern and serum inflammatory markers among patients at high risk for cardiovascular disease. Eur J Clin Nutr 62(5):651–659CrossRefPubMedGoogle Scholar
  36. 36.
    Schottelius AJ, Zügel U, Döcke WD et al (2010) The role of mitogen-activated protein kinase-activated protein kinase 2 in the p38/TNF-alpha pathway of systemic and cutaneous inflammation. J Invest Dermatol 130(2):481–491CrossRefPubMedGoogle Scholar
  37. 37.
    Schroder H, Fito M, Estruch R et al (2011) A short screener is valid for assessing Mediterranean diet adherence among older Spanish men and women. J Nutr 141:1140–1145CrossRefPubMedGoogle Scholar
  38. 38.
    Sharma S, Kelly TK, Jones PA (2010) Epigenetics in cancer. Carcinogenesis 31(1):27–36CrossRefPubMedGoogle Scholar
  39. 39.
    Sun Z, Cunningham J, Slager S et al (2015) Base resolution methylome profiling: considerations in platform selection, data preprocessing and analysis. Epigenomics 7(5):813–828CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Tammen SA, Friso S, Choi SW (2013) Epigenetics: the link between nature and nurture. Mol Asp Med 34(4):753–764CrossRefGoogle Scholar
  41. 41.
    Touleimat N, Tost J (2012) Complete pipeline for Infinium® Human Methylation 450K BeadChip data processing using subset quantile normalization for accurate DNA methylation estimation. Epigenomics 4(3):325–341CrossRefPubMedGoogle Scholar
  42. 42.
    Villegas R, Williams SM, Gao YT et al (2014) Genetic variation in the peroxisome proliferator-activated receptor (PPAR) and peroxisome proliferator-activated receptor gamma co-activator 1 (PGC1) gene families and type 2 diabetes. Ann Hum Genet 78(1):23–32CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Volkmar M, Dedeurwaerder S, Cunha DA et al (2012) DNA methylation profiling identifies epigenetic dysregulation in pancreatic islets from type 2 diabetic patients. EMBO J 31(6):1405–1426CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Wang Y, Iordanov H, Swietlicki EA et al (2005) Targeted intestinal overexpression of the immediate early gene tis7 in transgenic mice increases triglyceride absorption and adiposity. J Biol Chem 280(41):34764–34775CrossRefPubMedGoogle Scholar
  45. 45.
    Willett WC, Sacks F, Trichopoulou A et al (1995) Mediterranean diet pyramid: a cultural model for healthy eating. Am J Clin Nutr 61(6 Suppl):1402S–1406SPubMedGoogle Scholar
  46. 46.
    Yang X, Han H, De Carvalho DD et al (2014) Gene body methylation can alter gene expression and is a therapeutic target in cancer. Cancer Cell 26:577–590CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Yoshiko S, Hoyoku N (2007) Fucoxanthin, a natural carotenoid, induces G1 arrest and GADD45 gene expression in human cancer cells. In vivo 21(2):305–309PubMedGoogle Scholar
  48. 48.
    Yue Y, Huang W, Liang J et al (2015) IL4I1 is a novel regulator of M2 macrophage polarization that can inhibit T cell activation via L-tryptophan and arginine depletion and IL-10 production. PLoS One 10(11):e0142979CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Zhang Y, Hufnagel C, Eiden S et al (2001) Mechanisms for LEPR-mediated regulation of leptin expression in brown and white adipocytes in rat pups. Physiol Genomics 4(3):189–199PubMedGoogle Scholar

Copyright information

© University of Navarra 2017

Authors and Affiliations

  • A. Arpón
    • 1
    • 2
  • J. I. Riezu-Boj
    • 1
    • 2
    • 3
  • F. I. Milagro
    • 1
    • 2
    • 4
  • A Marti
    • 1
    • 3
    • 4
  • C. Razquin
    • 3
    • 4
    • 5
  • M. A. Martínez-González
    • 3
    • 4
    • 5
  • D. Corella
    • 4
    • 6
  • R. Estruch
    • 4
    • 7
  • R. Casas
    • 4
    • 7
  • M. Fitó
    • 4
    • 8
  • E. Ros
    • 4
    • 7
  • J. Salas-Salvadó
    • 4
    • 9
  • J. A. Martínez
    • 1
    • 2
    • 3
    • 4
    • 10
    Email author
  1. 1.Department of Nutrition, Food Sciences and PhysiologyUniversidad de NavarraPamplonaSpain
  2. 2.Centre for Nutrition ResearchUniversidad de NavarraPamplonaSpain
  3. 3.Navarra Institute for Health Research (IdiSNa)PamplonaSpain
  4. 4.Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBERobn)Institute of Health Carlos IIIMadridSpain
  5. 5.Department of Preventive Medicine and Public HealthUniversidad de NavarraPamplonaSpain
  6. 6.Department of Preventive Medicine and Public HealthUniversity of ValenciaValenciaSpain
  7. 7.Department of Endocrinology and Nutrition, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital ClinicUniversity of BarcelonaBarcelonaSpain
  8. 8.Cardiovascular and Nutrition Research GroupInstitut de Reçerca Hospital del MarBarcelonaSpain
  9. 9.Human Nutrition DepartmentHospital Universitari Sant Joan, Institut d’Investigació Sanitaria Pere Virgili, Universitat Rovira i VirgiliReusSpain
  10. 10.Madrid Institute of Advance Studies (IMDEA), IMDEA FoodMadridSpain

Personalised recommendations