Cardiovascular disease (CVD) is a leading cause of mortality and is projected to hold its grim record as developing countries increase their wealth. Since specific nutritional habits are important risk factors for CVD, it is imperative to understand how ingredients of risk-associated diets convert a healthy cellular transcriptional program into a pathological one. Epigenetics has enriched our view of the genome by showing that DNA-associated regulatory proteins and RNAs, together with chemical modifications of the DNA itself, determine which parts of the DNA chain are transcribed or silent in a given phase of a cell’s life. This complex biological entity – the epigenome – accounts for the enormous phenotypic diversity within a multicellular organism despite its unicellular origin. Crucially, the epigenome can be modified by diet and other exogenous factors, thus suggesting that epigenetic mechanisms might underlie pathological responses to CVD risk factors. Here, we will review the current knowledge of epigenetic mechanisms in diet-gene interactions and propose ways in which epigenetics might clarify the impact of genetic variants on CVD risk.

Keywords:
Atherosclerosis, Cardiovascular disease, Chromatin, Diet, DNA methylation, Epigenetics
1.
Libby P: Fat fuels the flame: triglyceride-rich lipoproteins and arterial inflammation. Circ Res 2007;100:299–301.
2.
Ohlstein EH, Douglas SA, Sung CP, Yue TL, Louden C, Arleth A, Poste G, Ruffolo RR Jr, Feuerstein GZ: Carvedilol, a cardiovascular drug, prevents vascular smooth muscle cell proliferation, migration, and neointimal formation following vascular injury. Proc Natl Acad Sci USA 1993;90:6189–6193.
3.
Loh HS: Mortality from atherosclerosis and vitamin-C intake. Lancet 1973;ii:153.
4.
Geng YJ, Libby P: Progression of atheroma: a struggle between death and procreation. Arterioscler Thromb Vasc Biol 2002;22:1370–1380.
5.
Balagopal PB, de Ferranti SD, Cook S, Daniels SR, Gidding SS, Hayman LL, McCrindle BW, Mietus-Snyder ML, Steinberger J, American Heart Association Committee on Atherosclerosis, Hypertension and Obesity in Youth of the Council on Cardiovascular Disease in the Young, Council on Nutrition, Physical Activity and Metabolism, Council on Epidemiology and Prevention: Nontraditional risk factors and biomarkers for cardiovascular disease: mechanistic, research, and clinical considerations for youth: a scientific statement from the American Heart Association. Circulation 201114;123:2749–2769.
6.
Murray CJ, Lopez AD: Alternative projections of mortality and disability by cause 1990–2020: Global Burden of Disease Study. Lancet 1997;349:1498–504.
7.
Mathers CD, Loncar D: Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 2006;3:e442.
8.
Sabatti C, Service SK, Hartikainen AL, Pouta A, Ripatti S, Brodsky J, Jones CG, Zaitlen NA, Varilo T, Kaakinen M, Sovio U, Ruokonen A, Laitinen J, Jakkula E, Coin L, Hoggart C, Collins A, Turunen H, Gabriel S, Elliot P, McCarthy MI, Daly MJ, Järvelin MR, Freimer NB, Peltonen L: Genome-wide association analysis of metabolic traits in a birth cohort from a founder population. Nat Genet 2009;41:35–46.
9.
Berger SL: The complex language of chromatin regulation during transcription. Nature 2007;447:407–412.
10.
Guil S, Esteller M: DNA methylomes, histone codes and miRNAs: tying it all together. Int J Biochem Cell Biol 2009;41:87–95.
11.
Gefter M, Hausmann R, Gold M, Hurwitz J: The enzymatic methylation of ribonucleic acid and deoxyribonucleic acid. X. Bacteriophage T3-induced S-adenosylmethionine cleavage. J Biol Chem 1966;241:1995–2006.
12.
Grandjean V, Yaman R, Cuzin F, Rassoulzadegan M: Inheritance of an epigenetic mark: the CpG DNA methyltransferase 1 is required for de novo establishment of a complex pattern of non-CpG methylation. PLoS One 2007;2:e1136.
13.
Laurent L, Wong E, Li G, Huynh T, Tsirigos A, Ong CT, Low HM, Kin Sung KW, Rigoutsos I, Loring J, Wei CL: Dynamic changes in the human methylome during differentiation. Genome Res 2010;20:320–331.
14.
Barrès R, Osler ME, Yan J, Rune A, Fritz T, Caidahl K, Krook A, Zierath JR: Non-CpG methylation of the PGC-1 α promoter through DNMT3B controls mitochondrial density. Cell Metab 2009;10:189–198.
15.
Zilberman D, Gehring M, Tran RK, Ballinger T, Henikoff S: Genome-wide analysis of Arabidopsis thaliana DNA methylation uncovers an interdependence between methylation and transcription. Nat Genet 2007;39:61–69.
16.
Monk M, Boubelik M, Lehnert S: Temporal and regional changes in DNA methylation in the embryonic, extraembryonic and germ cell lineages during mouse embryo development. Development 1987;99:371–382.
17.
Ng RK, Gurdon JB: Epigenetic inheritance of cell differentiation status. Cell Cycle 2008;7:1173–1177.
18.
Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A: An operational definition of epigenetics. Genes Dev 2009;23:781–773.
19.
Murgatroyd C, Wu Y, Bockmühl Y, Spengler D: Genes learn from stress. How infantile trauma programs us for depression. Epigenetics 2010;5:194–199.
20.
Weaver IC, Cervoni N, Champagne FA, D’Alessio AC, Sharma S, Seckl JR, Dymov S, Szyf M, Meaney MJ: Epigenetic programming by maternal behavior. Nat Neurosci 2004;7:847–854.
21.
Krause B, Sobrevia L, Casanello P: Epigenetics: new concepts of old phenomena in vascular physiology. Curr Vasc Pharmacol 2009;7:513–520.
22.
Schorderet DF, Gartler SM: Analysis of CpG suppression in methylated and nonmethylated species. Proc Natl Acad Sci USA 1992;89:957–961.
23.
Kerkel K, Spadola A, Yuan E, Kosek J, Jiang L, Hod E, Li K, Murty VV, Schupf N, Vilain E, Morris M, Haghighi F, Tycko B: Genomic surveys by methylation-sensitive SNP analysis identify sequence-dependent allele-specific DNA methylation. Nat Genet 2008;40:904–908.
24.
Waterland RA, Jirtle RL: Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol 2003;23:5293–5300.
25.
Feinberg AP: Phenotypic plasticity and the epigenetics of human disease. Nature 2007;447:433–440.
26.
Duthie SJ: Epigenetic modifications and human pathologies: cancer and CVD. Proc Nutr Soc 2011;70:47–56.
27.
Ordovás JM, Smith CE: Epigenetics and cardiovascular disease. Nat Rev Cardiol 2010;7:510–519.
28.
Rodríguez-Paredes M, Esteller M: Cancer epigenetics reaches mainstream oncology. Nat Med 2011;17:330–339.
29.
Newman PE: Can reduced folic acid and vitamin B12 cause deficient DNA methylation producing mutations which initiate atherosclerosis? Med Hypotheses 1999;53:421–424.
30.
Laukkanen MO, Mannermaa S, Hiltunen MO, Aittomäki S, Airenne K, Jänne J, Ylä-Herttuala S: Local hypomethylation in atherosclerosis found in rabbit ec-sod gene. Arterioscler Thromb Vasc Biol 1999;19:2171–2178.
31.
Shirodkar AV, Marsden PA: Epigenetics in cardiovascular disease. Curr Opin Cardiol 2011;26:209–215.
32.
Chen KC, Wang YS, Hu CY, Chang WC, Liao YC, Dai CY, Juo SH: OxLDL up-regulates microRNA-29b, leading to epigenetic modifications of MMP-2/MMP-9 genes: a novel mechanism for cardiovascular diseases. FASEB J 2011;25:1718–1728.
33.
Zawadzki C, Chatelain N, Delestre M, Susen S, Quesnel B, Juthier F, Jeanpierre E, Azzaoui R, Corseaux D, Breyne J, Torpier G, Staels B, Van Belle E, Jude B: Tissue factor pathway inhibitor-2 gene methylation is associated with low expression in carotid atherosclerotic plaques. Atherosclerosis 2009;204:e4–e14.
34.
Bird A, Taggart M, Frommer M, Miller OJ, Macleod D: A fraction of the mouse genome that is derived from islands of nonmethylated, CpG-rich DNA. Cell 1985;40:91–99.
35.
Castillo-Díaz SA, Garay-Sevilla ME, Hernández-González MA, Solís-Martínez MO, Zaina S: Extensive demethylation of normally hypermethylated CpG islands occurs in human atherosclerotic arteries. Int J Mol Med 2010;26:691–700.
36.
Lund G, Andersson L, Lauria M, Lindholm M, Fraga MF, Villar-Garea A, Ballestar E, Esteller M, Zaina S: DNA methylation polymorphisms precede any histological sign of atherosclerosis in mice lacking apolipoprotein E. J Biol Chem 2004;279:29147–29154.
37.
Baccarelli A, Wright RO, Bollati V, Tarantini L, Litonjua AA, Suh HH, Zanobetti A, Sparrow D, Vokonas PS, Schwartz J: Rapid DNA methylation changes after exposure to traffic particles. Am J Respir Crit Care Med 2009;179:572–578.
38.
Gallou-Kabani C, Junien C: Nutritional epigenomics of metabolic syndrome: new perspective against the epidemic. Diabetes 2005;54:1899–1906.
39.
Muiesan G: Risk factors in hypertension and ischaemic heart disease. Postgrad Med J 1979;55(suppl 3):15–20.
40.
Lawlor DA, Smith GD, O’Callaghan M, Alati R, Mamun AA, Williams GM, Najman JM: Epidemiologic evidence for the fetal overnutrition hypothesis: findings from the Mater-University Study of Pregnancy and Its Outcomes. Am J Epidemiol 2007;165:418–424.
41.
Waterland RA, Travisano M, Tahiliani KG, Rached MT, Mirza S: Methyl donor supplementation prevents transgenerational amplification of obesity. Int J Obes (Lond) 2008;32:1373–1379.
42.
Ikenasio-Thorpe BA, Breier BH, Vickers MH, Fraser M: Prenatal influences on susceptibility to diet-induced obesity are mediated by altered neuroendocrine gene expression. J Endocrinol 2007;193:31–37.
43.
Massiera F, Barbry P, Guesnet P, Joly A, Luquet S, Moreilhon-Brest C, Mohsen-Kanson T, Amri EZ, Ailhaud G: A Western-like fat diet is sufficient to induce a gradual enhancement in fat mass over generations. J Lipid Res 2010;51:2352–2361.
44.
Kaati G, Bygren LO, Edvinsson S: Cardiovascular and diabetes mortality determined by nutrition during parents’ and grandparents’ slow growth period. Eur J Hum Genet 2002;10:682–688.
45.
Pembrey ME, Bygren LO, Kaati G, Edvinsson S, Northstone K, Sjöström M, Golding J, ALSPAC Study Team: Sex-specific, male-line transgenerational responses in humans. Eur J Hum Genet 2006;14:159–166.
46.
Kuzawa CW, Sweet E: Epigenetics and the embodiment of race: developmental origins of US racial disparities in cardiovascular health. Am J Hum Biol 2009;21:2–15.
47.
Kucharski R, Maleszka J, Foret S, Maleszka R: Nutritional control of reproductive status in honeybees via DNA methylation. Science 2008;319:1827–1830.
48.
Dunn GA, Bale TL: Maternal high-fat diet effects on third-generation female body size via the paternal lineage. Endocrinology 2011;152:2228–2236.
49.
Carone BR, Fauquier L, Habib N, Shea JM, Hart CE, Li R, Bock C, Li C, Gu H, Zamore PD, Meissner A, Weng Z, Hofmann HA, Friedman N, Rando OJ: Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell 2010;143:1084–1096.
50.
Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, Perry JR, Elliott KS, Lango H, Rayner NW, Shields B, Harries LW, Barrett JC, Ellard S, Groves CJ, Knight B, Patch AM, Ness AR, Ebrahim S, Lawlor DA, Ring SM, Ben-Shlomo Y, Jarvelin MR, Sovio U, Bennett AJ, Melzer D, Ferrucci L, Loos RJ, Barroso I, Wareham NJ, Karpe F, Owen KR, Cardon LR, Walker M, Hitman GA, Palmer CN, Doney AS, Morris AD, Smith GD, Hattersley AT, McCarthy MI: A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 2007;316:889–894.
51.
Stumvoll M, Tschritter O, Fritsche A, Staiger H, Renn W, Weisser M, Machicao F, Häring H: Association of the T-G polymorphism in adiponectin (exon 2) with obesity and insulin sensitivity: interaction with family history of type 2 diabetes. Diabetes 2002;51:37–41.
52.
Yang WS, Tsou PL, Lee WJ, Tseng DL, Chen CL, Peng CC, Lee KC, Chen MJ, Huang CJ, Tai TY, Chuang LM: Allele-specific differential expression of a common adiponectin gene polymorphism related to obesity. J Mol Med 2003;18:428–434.
53.
Yang WS, Hsiung CA, Ho LT, Chen YT, He CT, Curb JD, Grove J, Quertermous T, Chen YD, Kuo SS, Chuang LM, Sapphire Study Group: Genetic epistasis of adiponectin and PPARγ2 genotypes in modulation of insulin sensitivity: a family-based association study. Diabetologia 2003;46:977–983.
54.
Zaina S, Pérez-Luque EL, Lund G: Genetics talks to epigenetics? The interplay between sequence variants and chromatin structure. Curr Genomics 2010;11:359–367.
55.
Shoemaker R, Deng J, Wang W, Zhang K: Allele-specific methylation is prevalent and is contributed by CpG-SNPs in the human genome. Genome Res 2010;20:883–889.
56.
Schalkwyk LC, Meaburn EL, Smith R, Dempster EL, Jeffries AR, Davies MN, Plomin R, Mill J: Allelic skewing of DNA methylation is widespread across the genome. Am J Hum Genet 2010;86:196–212.
57.
Choi JK: Contrasting chromatin organization of CpG islands and exons in the human genome. Genome Biol 2010;11:R70.
58.
Prokopenko I, Morison IM, Mill J, Pidsley R, International Type 2 Diabetes 1q Consortium, Deloukas P, Frayling TM, Hattersley AT, McCarthy MI, Beck S, Hitman GA: Integrated genetic and epigenetic analysis identifies haplotype-specific methylation in the FTO type 2 diabetes and obesity susceptibility locus. PLoS One 2010;5:e14040.
59.
Bell CG, Teschendorff AE, Rakyan VK, Maxwell AP, Beck S, Savage DA: Genome-wide DNA methylation analysis for diabetic nephropathy in type 1 diabetes mellitus. BMC Med Genomics 2010;3:33.
60.
vel Szic KS, Ndlovu MN, Haegeman G, Vanden Berghe W: Nature or nurture: let food be your epigenetic medicine in chronic inflammatory disorders. Biochem Pharmacol 2010;80:1816–1832.
61.
Kulkarni A, Dangat K, Kale A, Sable P, Chavan-Gautam P, Joshi S: Effects of altered maternal folic acid, vitamin B12 and docosahexaenoic acid on placental global DNA methylation patterns in Wistar rats. PLoS One 2011;6:e17706.
62.
Roy S, Kale A, Dangat K, Sable P, Kulkarni A, Joshi S: Maternal micronutrients (folic acid and vitamin B12) and omega 3 fatty acids: implications for neurodevelopmental risk in the rat offspring. Brain Dev 2011, E-pub ahead of print.
63.
Blasbalg TL, Hibbeln JR, Ramsden CE, Majchrzak SF, Rawlings RR: Changes in consumption of omega-3 and omega-6 fatty acids in the United States during the 20th century. Am J Clin Nutr 2011;93:950–962.
64.
Ly A, Lee H, Chen J, Sie KK, Renlund R, Medline A, Sohn KJ, Croxford R, Thompson LU, Kim YI: Effect of maternal and postweaning folic acid supplementation on mammary tumor risk in the offspring. Cancer Res 2011;71:988–997.
65.
Schaible TD, Harris RA, Dowd SE, Smith CW, Kellermayer R: Maternal methyl-donor supplementation induces prolonged murine offspring colitis susceptibility in association with mucosal epigenetic and microbiomic changes. Hum Mol Genet 2011;20:1687–1696.
66.
De-Regil LM, Fernández-Gaxiola AC, Dowswell T, Peña-Rosas JP: Effects and safety of periconceptional folate supplementation for preventing birth defects. Cochrane Database Syst Rev 2010;10:CD007950.
67.
Lichtenstein AH: Nutrient supplements and cardiovascular disease: a heartbreaking story. J Lipid Res 2009;50:S429–S433.
68.
Bhupathiraju S, Tucker KL: Coronary heart disease prevention: nutrients, foods, and dietary patterns. Clin Chim Acta 2011;412:1493–1514.
69.
Chung TL, Brena RM, Kolle G, Grimmond SM, Berman BP, Laird PW, Pera MF, Wolvetang EJ: Vitamin C promotes widespread yet specific DNA demethylation of the epigenome in human embryonic stem cells. Stem Cells 2010;28:1848–1855.
70.
Chung TL, Turner JP, Thaker NY, Kolle G, Cooper-White JJ, Grimmond SM, Pera MF, Wolvetang EJ: Ascorbate promotes epigenetic activation of CD30 in human embryonic stem cells. Stem Cells 2010;28:1782–1793.
71.
Kim MS, Fujiki R, Kitagawa H, Kato S: 1α,25(OH)2D3-induced DNA methylation suppresses the human CYP27B1 gene. Mol Cell Endocrinol 2007;265–266:168–173.
72.
Chonchol M, Cigolini M, Targher G: Association between 25-hydroxyvitamin D deficiency and cardiovascular disease in type 2 diabetic patients with mild kidney dysfunction. Nephrol Dial Transplant 2008;23:269–274.
73.
Messenger W, Nielson CM, Li H, Beer T, Barrett-Connor E, Stone K, Shannon J: Serum and dietary vitamin D and cardiovascular disease risk in elderly men: a prospective cohort study. Nutr Metab Cardiovasc Dis 2011, E-pub ahead of print.
74.
Razzaque MS: The dualistic role of vitamin D in vascular calcifications. Kidney Int 2011;79:708–714.
75.
Li D: Chemistry behind vegetarianism. J Agric Food Chem 2011;59:777–784.
76.
Massy ZA, Chadefaux-Vekemans B, Chevalier A, Bader CA, Drüeke TB, Legendre C, Lacour B, Kamoun P, Kreis H: Hyperhomocysteinaemia: a significant risk factor for cardiovascular disease in renal transplant recipients. Nephrol Dial Transplant 1994;9:1103–1108.
77.
Hollis BW, Wagner CL: Assessment of dietary vitamin D requirements during pregnancy and lactation. Am J Clin Nutr 2004;79:717–726.
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