Diet rich in DNA methylation and heart diseases

By Sandeep Grover

Dietary factors are one of the major environmental components that are considered as risk factor for cardiovascular diseases (CVD). Specifically, fatty acids in our diet are known to increase HDL-cholesterol and lower triglycerides (TG). In addition, fatty acids have also been known to play a crucial role in altering inflammatory pathways, considered to be central in the pathogenesis of blockage of arteries that carry oxygenated blood to the heart. Furthermore, the role of genetic factors in differential response to dietary fatty acids has been well-documented. The connection of CVD with DNA methylation as one of the genetic factors in influencing circulation of various atherogenic risk factors (promoting deposition of fatty acids in the arteries) has also been widely studied in recent years. Specifically, epigenetic changes have been implicated in influencing internal walls of bloods vessels, contraction and dilation of blood vessels, cytokine signaling and plaque formation. Besides dietary fatty acids, several other dietary components including those in maternal diet during preconception period, which are known to influence DNA methylation patterns, have been shown to affect cardiovascular health.

Pathways influencing Cardiovascular risk factors

High fat and high glucose diet have been shown to influencing methylation pattern of genes long known to be correlated with heart diseases. Several study designs have been investigated to dissect the role of epigenetics in the intricate causal relationship between diet and CVD:

A. Effect of fasting blood lipids

The association between DNA methylation, altered gene expression, and fasting blood lipids namely very low density lipoprotein (VLDL) cholesterol, and triglyceride (TG) was recently replicated in two independent epigenome-wide large scale studies (Genetics of lipid-lowering drugs and diet network study and Framingham heart study)1. Specifically, methylation within the gene encoding carnitine palmitoyltransferafe 1A was observed to be associated with its expression.

B. Effect of high-fat diet

Another study showed that overfeeding by high-fat diet increased DNA methylation in promoter regions of genes affecting adipocyte differentiation, and lipid metabolism, specifically in the adipose tissues.2 A differential effect of different profiles of fatty acids was observed on site specific methylation with saturated-fatty acids inducing altered methylation in genes influencing pro-inflammatory pathways e.g. FTO, IL6, and POMC. An increased methylation of genes encoding proteins that regulate lipogenesis and lipoprotein metabolism was also observed by another independent report. The same study also reported hypomethylation of CPT1A gene which is involved in hepatic fatty acid β metabolism3.

C. Effect of obesity

In addition, promoters of several other genes such as PLIN1, PPARG, HAND2, HOXC6, SORBS2, CD36, and CLDN1 known to be involved in adipogenesis, impaired triglyceride uptake, and insulin sensitivity4,5.

D. Effect of ω-3 fatty acid (n-3 PUFA) supplementation

Circulating fatty acids mainly α-linoleic acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been shown to influence changes in methylation of genes such as APOE, IL6 and ABCA1, all of which are known to increase the risk for CVD6. While APOE and ABCA1 are regulators of cholesterol transport and homeostasis, IL6 on the other hand is a key protein involved in inflammation.

Effect of Mediterranean diet

A Mediterranean diet refers to dietary patterns prevalent among inhabitants of olive-growing areas of Mediterranean region. Although several variants of Mediterranean diet have been identified in the past, few dietary factors that unify them together are high monounsaturated/ saturated fat ratio; moderate ethanol consumption in the form of wine, high consumption of fruits and vegetables, high consumption of legumes and grains, moderate consumption of milk and milk products, and low consumption of meat and meat products. A Mediterranean diet has also been reported to be associated with a low levels of inflammation biomarkers and with a protective role in predisposition to CVD. Adherence to Mediterranean diet has been long been known to be associated with a lower risk of CVD incidence and mortality7. A recent study epigenetic study further showed that individuals consuming Mediterranean diets showed hypermethylation and suppression of several genes related to inflammation and immunocompetence (EEF2, COL18A1, IL4I1, LEPR, PLAGL1, IFRD1, MAPKAPK2, and PPARGC1B)8.

E. Effect of Diet during embryonic development

Data from Dutch Famine birth cohort has shown that individuals with prenatal famine exposure had a higher risk of CAD and hypertension in later life9 (See section on Role of diet during embryonic development: Genomic). The high risk group individuals further showed altered DNA methylation within INSR and CPT1A genes, known to be involved in prenatal growth and fatty acid oxidation10.
F. Effect of diet rich in methyl donors
Another recent study investigating role of maternal nutrition during pregnancy showed that supplemental intake of methyl-group donors namely folate, betaine, and folic acid was associated with DNA methylation in genes involved in growth (IGF2), metabolism (RXRA) and appetite control (LEP)11.Several dietary compounds have been long believed to extend lifespan mainly polyphenols (flavanols, anthocyanins, lignins) and inforganic nitrates12. The polyphenols have been shown to influence DNA methylation and are likely to reduce cardiovascular damage in old age by reduction of blood pressure, glucose and cholesterol or enhance capacity of circulatory system to repair damage. Dietary intervention with tea and cocoa flavanols (catechins and their gallate deriavatives) containing food has been shown to be associated with cardiovascular benefits, possibly by modulating blood pressure, and vascular stiffness. Anthocyanins present mainly in blueberries have been observed in several epidemiological studies for association with a lower incidence of coronary artery disease. In summary, methylation studies in the field of heart diseases has focused more on traditionally known risk factors and long term prospective cohort studies exploring dietary role of methyl donors are relatively scarce.

 

 

References

1. Irvin MR, Zhi D, Joehanes R, et al. Epigenome-wide association study of fasting blood lipids in the Genetics of Lipid-lowering Drugs and Diet Network study. Circulation 2014;130:565-72.

2. Perfilyev A, Dahlman I, Gillberg L, et al. Impact of polyunsaturated and saturated fat overfeeding on the DNA-methylation pattern in human adipose tissue: a randomized controlled trial. Am J Clin Nutr 2017;105:991-1000.

3. Lai CQ, Wojczynski MK, Parnell LD, et al. Epigenome-wide association study of triglyceride postprandial responses to a high-fat dietary challenge. J Lipid Res 2016;57:2200-7.

4. Bialesova L, Kulyte A, Petrus P, et al. Epigenetic Regulation of PLIN 1 in Obese Women and its Relation to Lipolysis. Sci Rep 2017;7:10152.

5. Keller M, Hopp L, Liu X, et al. Genome-wide DNA promoter methylation and transcriptome analysis in human adipose tissue unravels novel candidate genes for obesity. Mol Metab 2017;6:86-100.

6. Ma Y, Ordovas JM. The integration of epigenetics and genetics in nutrition research for CVD risk factors. Proc Nutr Soc 2017;76:333-46.

7. Rosato V, Temple NJ, La Vecchia C, Castellan G, Tavani A, Guercio V. Mediterranean diet and cardiovascular disease: a systematic review and meta-analysis of observational studies. Eur J Nutr 2019;58:173-91.

8. Arpon A, Riezu-Boj JI, Milagro FI, et al. Adherence to Mediterranean diet is associated with methylation changes in inflammation-related genes in peripheral blood cells. J Physiol Biochem 2016;73:445-55.

9. Painter RC, de Rooij SR, Bossuyt PM, et al. Early onset of coronary artery disease after prenatal exposure to the Dutch famine. Am J Clin Nutr 2006;84:322-7; quiz 466-7.

10. Tobi EW, Goeman JJ, Monajemi R, et al. DNA methylation signatures link prenatal famine exposure to growth and metabolism. Nat Commun 2014;5:5592.

11. Pauwels S, Ghosh M, Duca RC, et al. Maternal intake of methyl-group donors affects DNA methylation of metabolic genes in infants. Clin Epigenetics 2017;9:16.

12. Heiss C, Spyridopoulos I, Haendeler J. Interventions to slow cardiovascular aging: Dietary restriction, drugs and novel molecules. Exp Gerontol 2018;109:108-18.

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