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The Epigenetic Influence of the Mediterranean Diet

Unveiling the molecular basis of Mediterranean diet effects

In recent years, dietary guidelines have turned from emphasizing low fat consumption to embracing dietary patterns that are comprised of “whole” and unprocessed foods, such as the Mediterranean diet. The Mayo Clinic indicates that the Mediterranean diet emphasizes plant-based foods, healthy oils, fish and poultry, and red wine in moderation, with limited consumption of salt and red meat. It has been observed experimentally and in epidemiological studies that the Mediterranean Diet plays a beneficial role in health. For example, the PREDIMED study in Spain, in which participants were randomized to two types of Mediterranean diet or to a control diet that emphasized low-fat consumption found that the Mediterranean diets resulted in beneficial changes in metabolic syndrome, blood pressure, lipid profiles, lipoprotein particles, inflammation, oxidative stress, and carotid atherosclerosis, compared to the control diet.

Relatively little attention has been paid, however, to the genetic underpinnings and mechanisms that make the Mediterranean dietary pattern effective. Also termed nutrigenomics, the interaction of nutrient intake and individual genetic differences on genetic expression represents an opportunity for personalized medicine to expand beyond specialized medical fields like oncology into prevention and management of highly prevalent chronic diseases and preventable cancers that often present to primary care providers. Recent research shows that certain genes, including MTHFR, FTO, and TCF7L2 play a major role in determining whether and how the Mediterranean diet can influence health outcomes, particularly in cardiovascular health. Indeed, the PREDIMED study found that the Mediterranean diet interacts with gene polymorphisms known to play a role in inflammation and atherosclerosis, like COX-2, IL-6, CETP, and APOA2, and, thus, can alter the expression of these genes. Even in a population of high-risk cardiovascular participants, dietary intervention in the form of the Mediterranean diet can modulate the expression of genes tied to inflammation and atherosclerosis.

The gene MTHFR has been found to be closely associated with cardiovascular outcomes and its expression can be influenced by dietary intake. Polymorphisms of MTHFR are very common in the population and influence homocysteine concentrations in the blood. Elevated homocysteine is an independent risk factor for cardiovascular disease. The ATTICA study conducted in Greece found that adherence to a Mediterranean diet was associated with reduced homocysteine concentrations in nearly 60% of the population. This interaction provides insight into how the Mediterranean diet may influence cardiovascular risk in individuals with elevated homocysteine levels. Similarly, certain polymorphisms of the gene TCF7L2 are closely associated with type 2 diabetes, and potentially associated with elevated lipid levels and cardiovascular disease risk. When individuals with the highest risk TCF7L2 polymorphism, known as TT genotype, demonstrated high adherence to the Mediterranean diet, they had reduced fasting glucose and lipids, as well as reduced incidence of stroke.

Beyond influencing gene expression or association, dietary intervention can influence the methylation of certain genes. A pilot studyconducted within the PREDIMED cohort sought to analyze the influence of adherence to the Mediterranean diet on methylation of the TCF7L2 and FTO genes, which are known to be closely linked to stroke and diabetes. Polymorphisms of these genes were strongly associated with methylation levels, and an inverse association was found between adherence to the Mediterranean diet and methylation levels in the TCF7L2 gene. While the optimal level of methylation varies depending on the gene, CpG site, and polymorphism, this study illustrates that dietary intervention do influence methylation of gene sites that are involved in cardiovascular outcomes.

As the UC Davis Center of Excellence for Nutritional Genomics states, “Knowledge gained from comparing diet/gene interactions in different populations may provide information needed to address the larger problem of global malnutrition and disease.” Early studies on the role of the Mediterranean diet and cardiovascular health outcomes indicate that nutrigenomics is already providing data which can be used to address malnutrition and disease. For additional information on nutrigenomics and the role of nutrition as an epigenetic influence, visit and look up the “Gene Speak” series.


Corella D et al. Advances in understanding the molecular basis of the Mediterranean diet effect. Annu Rev Food Sci Technol. 2018;9:227-249.

Corella D et al. Effect of the Mediterranean diet on DNA methylation of selected genes in the PREDIMED-Valencia intervention trial. FASEB J. 2015;29(Suppl 1):LB242.

Corella D et al. Mediterranean diet reduces the adverse effect of the TCF7L2-rs7903146 polymorphism on cardiovascular risk factors and stroke incidence: a randomized controlled trial in a high-cardiovascular-risk population. Diabetes Care. 2013;36(11):3803-3811.

Dedoussis GV et al. Effect of interaction between adherence to a Mediterranean diet and the methylenetetrahydrofolate reductase 677C-T mutation on homocysteine concentrations in healthy adults: the ATTICA Study. Am J Clin Nutr. 2004;80(4):849-854.

Llorente-Cortes V et al. Effect of Mediterranean diet on the expression of pro-atherogenic genes in a population at high cardiovascular risk. Atherosclerosis. 2010;208(2):442-450.

Ros E et al. Mediterranean diet and cardiovascular health: teachings of the PREDIMED study. Adv Nutr. 2014;15(3):330S-336S.

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