Nutritional Influence on Epigenetics and Disease

  

    
Disease 
    
Nutrition 
    
Effect 
    
Reference 
  
  

    
Autoimmune
  
  

    
MS
    
Vitamins, fish oil
    
slow-down of    disease
    
[42]
  
  

    
ALS
    
Balanced diet
    
prevention of    malnutrition
    
[43]
  
  

    
Cancer
  
  

    
Breast 
    
Adolescent red meat
    
increased risk on pre-menopausal    breast cancer
    
[57]
  
  

    

    
Dietary fiber
    
meta-analysis on    reduced cancer risk
    
[142]
  
  

    

    
Dairy products (not    milk)
    
meta-analysis on    reduced cancer risk
    
[143]
  
  

    

    
Soy isoflavones
    
reduced cancer risk    in Asian women
    
[144]
  
  

    
Colon
    
Vegetables, fruits
    
reduced risk of    cancer
    
[145]
  
  

    

    
Green tea
    
anticancer activity
    
[51]
  
  

    

    
Myrosinase    hydrolysate
    
reduced risk of    colon cancer
    
[99]
  
  

    
Colorectal
    
Vitamin D
    
lower cancer risk,    improved survival
    
[56]
  
  

    
Esophageal
    
Vegetables, fruits
    
decreased risk of    esophageal carcinoma
    
[146]
  
  

    

    
Vegetables, fruits
    
prevention of    cancer
    
[145]
  
  

    
Gastric
    
Vegetables, fruits
    
prevention of    cancer
    
[145]
  
  

    
Head & neck
    
Zinc
    
beneficial effects    in cancer patients
    
[93]
  
  

    
Liver
    
Coffee, tea
    
inverse correlation    with risk of HCC
    
[58]
  
  

    
Lung
    
Tea
    
reduced risk of    lung cancer
    
[59]
  
  

    
Ovarian
    
Green tea
    
Anticancer activity
    
[51]
  
  

    
Prostate
    
fruits, vegetables
    
change in    cancer-related gene expression
    
[54]
  
  

    

    
Urolithin A & B
    
reduced    proliferation and growth of cancer cells
    
[55]
  
  

    

    
Polyphenols, green    tea
    
inhibition of tumor    xenograft growth in mice
    
[147]
  
  

    

    
Nigerian diet
    
chemoprevention of    prostate cancer
    
[148]
  
  

    

    
Sulforaphane, tea
    
prevention of    prostate cancer
    
[90]
  
  

    
Skin
    
Folate
    
protection of    sun-exposed skin to cancer
    
[149]
  
  

    

    
Epicatechins, green    tea
    
chemoprevention of carcinogenesis
    
[47]
  
  

    

    
Proanthocyanid,    grape
    
chemoprevention of    carcinogenesis
    
[47]
  
  

    

    
Vitamin D
    
reduced mortality
    
[150]
  
  

    
Stomach
    
Green tea
    
anticancer activity
    
[51]
  
  

    
Cardiovascular
  
  

    
CHD
    
Mediterranean diet
    
reduced risk of    disease
    
[14]
  
  

    

    
Low CH, high prot    & fat
    
inverse association    with cardiovascular disease
    
[26]
  
  

    

    
Vitamin A
    
deficiency and    excess: increased CHD mortality
    
[28]
  
  

    

    
Vitamin D
    
association between    CHD and vitamin-deficiency
    
[27]
  
  

    
Myocardial    infarction
    
Mediterranean diet
    
72% reduction in    cardiac deaths
    
[15]
  
  

    

    
PPolysaturated    fatty acid
    
PPARG polymorphism enhances infarction risk
    
[20]
  
  

    

    
Saturated fat intake
    
APOE SNPs linked to myocardial infarction risk
    
[25]
  
  

    

    
Alcohol consumption
    
ADH3 SNPs linked to    myocardial infarction risk
    
[22]
  
  

    

    
Coffee
    
CYP1A2 polymorphism    linked to infarction
    
[24]
  
  

    
AMI
    
Moderate wine    drinking
    
reduced risk of CHD    complications
    
[16]
  
  

    
Stroke
    
Folate
    
MHFR SNPs linked to    ischemic stroke risk
    
[23]
  
  

    
Arterial disease
    
Low-fat vegetarian    diet
    
coronary arterial    disease stopped
    
[49]
  
  

    
Liver diseases
  
  

    
Fatty liver disease
    
Polyphenols
    
miR-103/107,    miR-122 prevents disease
    
[127]
  
  

    
NAFLD
    
High-fat diet
    
miRNAs linked to    disease
    
[132]
  
  

    
Metabolic
  
  

    
Obesity
    
Calorie intake
    
FTO SNPs increase    disease risk
    
[7, 8]
  
  

    

    
Calorie-controlled    diet
    
weight loss and weight    management
    
[141]
  
  

    
Insulin-resistance
    
Saturated fat
    
PLIN polymorphism    increases disease risk
    
[12]
  
  

    

    
High saturated    fatty acid
    
induced insulin    secretion
    
[13]
  
  

    
Coeliac
    
Gluten-free diet
    
successful    treatment of disease
    
[134]
  
  

    
Examples of Epigenetic Drugs 
  
  

    
Disease 
    
Nutrition
    
Epigenetics
    
Reference
  
  

    
Neurological disorders
  
  

    
Alzheimer’s disease
    
Phytonutrient    suppl.
    
potential disease    protection
    
[33]
  
  

    

    
Antioxidants
    
protection against    oxidative stress, disease
    
[35]
  
  

    

    
Fruits, nuts,    vegetables
    
reduces disease    risk in the elderly
    
[36]
  
  

    
Parkinson’s disease
    
Phytonutrient    suppl.
    
potential disease    protection
    
[34]
  
  

    

    
Low vitamin B6
    
increased disease    risk
    
[37]
  
  

    
Cognition
    
Clorogenic acid
    
improved cognition
    
[39]
  
  

    
Traumatic brain    injury
    
Omega-3 fatty acids
    
protection at neuronal    level
    
[40]
  
  

    
Neurodegeneration
    
PC (spices, herbs)
    
prevention against    neurodegeneration
    
[41]
  
  

    

    
PC, Curcumin (in    curry)
    
neuronal protection
    
[41]
  
  

    

    
PC, tea catechin
    
neuronal protection
    
[41]
  
  

    
ALS
    
Balanced diet
    
improved quality of    life
    
[43]
  
  

    
ASD
    
Gluten-,    casein-free diet
    
therapeutic effect
    
[45]
  
  

    
ADH3: Alcohol    Dehydrogenase type 2; ALS: Amyotropic Lateral Sclerosis; AMI: Acute    Myocardial Infraction; ASD: Autism Spectrum Disorder; CHD: Coronary Heart    Disease; CYP1A2: Cytochrome P450 1A2; FTO: Fat Mass and Obesity Associated;    HCC: Hepatocellular Carcinoma; MS: Multiple Sclerosis; MHFR:    Metethylentetrahydrofolate; 
    
NAFLD: Non-Alcoholic Fatty Liver Disease; PC:    Phenolic Compounds; PLIN: Storage of Lipids in Adipose Tissue; PPRAG:    Peroxisome Proliferator�Activated Receptor Gamma 
  

Table 1:  Examples of Nutrition and Disease.

Metabolic disease

Studies on food intake have revealed that children with the genetic variant rs9939609 SNP in the first intron of the fat mass- and obesity associated (FTO) gene is associated with increased risk of obesity and type 2 diabetes [7]. Furthermore, children with the FTO variant showed increased calorie intake compared to a control group when subjected to unlimited food intake suggesting that the enhanced energy consumption was rather related to the energy density of the nutrition than the weight of the consumed food [8]. Additional studies have revealed a relationship between the FTO variant and physical activity [9,10], which suggested an increased susceptibility to obesity for the FTO variant when physical activity was not encouraged. Obesity has been linked to insulin resistance with over-nutrition a potential cause, although other factors might be involved [11]. For instance, the relationship between insulin-resistance and the intake of saturated fat is associated with polymorphism at the perilipin (PLIN) (storage of lipids in adipose tissue) locus and not related to obesity [12]. Another study showed that high saturated fatty acid intake induced insulin secretion in healthy volunteers via increased gastric inhibitory polypeptide levels [13].

Cardiovascular disease

The influence of diet on cardiovascular diseases has received much attention particularly through studies such as the Seven Countries’ Study linking coronary heart disease (CHD) mortality to lifestyle factors [14]. Application of the Mediterranean diet rich in vegetables and fruits and low intake of meat and dairy products resulted in significant differences in CHD deaths compared to a control group. Similarly, 605 patients who had experienced a first myocardial infarction were assigned to a Mediterranean diet and compared to individuals receiving a diet recommended by the American Heart Association (AHA) in the Lyon Diet Heart Study [15]. A remarkable 72% reduction in cardiac deaths and non-fatal acute myocardial infarction was observed after 46 months in individuals subjected to the Mediterranean diet in comparison to the control group. Furthermore, a 65% and a 55% reduction in CHD mortality and in all-cause mortality, respectively, were observed. Similarly, in patients with a recent history of acute myocardial infarction (AMI) moderate wine drinking was associated with a reduced risk of CHD complications [16]. In another study, a rigorous lifestyle regimen including low-fat vegetarian food, smoking cessation and regular exercise reduced the progression of coronary arterial disease and even showed disease reversion by effective reduction of sclerotic plaques [17].

Genetic factors also play an important role in the relationship between nutrition and cardiovascular disease [18]. For instance, the complex interaction of genetic and environmental factors in cardiovascular disease is illustrated by polymorphism at the peroxisome proliferator-activated receptor alpha (PPARA) and PLIN loci [19]. Likewise, polyunsaturated fatty acid intake by individuals with polymorphism of the Pro12Ala peroxisome proliferatoractivated receptor gamma (PPARG) gene showed enhanced risk of myocardial infarction [20]. Moreover, individuals with the CETPTaqIB SNP showed sensitivity to alcohol consumption triggering myocardial infarction [21]. Similarly, alcohol consumption showed correlation with the alcohol dehydrogenase type 3 (ADH3) SNP in relation to myocardial infarction [22]. In this context, moderate drinkers homozygous for the ADH3 gamma-2 allele accumulate higher HDL levels and therefore present a substantially lower risk of myocardial infarction. Also, serum folate intake plays a role in determining the risk of ischemic stroke in individuals with the C677T SNP in the methylenetetrahydrofolate reductase (MTHFR) gene [23]. Moreover, polymorphism at the cytochrome P450 1A2 (CYP1A2) influenced the metabolism after coffee drinking, where homozygotes for the CYP1A2*1A showed a “rapid” caffeine metabolism while carriers of the CYP1A2*1F allele provided “slow” caffeine metabolism [24]. For this reason, individuals with the CYP1A2*1F allele have been associated with an increased risk of non-fatal myocardial infarction. Likewise, increased risk of myocardial infarction has been associated with intake of saturated fat in carriers of the APOE SNP E2 and E4 gene variants [25].

In a recent 29-year follow-up study in Japan it was observed that moderate diets lower in carbohydrates and higher in protein and fat were inversely associated with cardiovascular disease and total mortality in women [26]. In association with the Heart and Soul Study, the effect of vitamin D deficiency on cardiovascular events in CHD patients was evaluated [27]. Adjustment for socio-demographic factors showed an association between vitamin deficiency (<20 ng/L) and cardiovascular events. However, there was no longer association after further adjustment for potential biological mediators, which highlighted the needs for controlled trials to establish the role of vitamin D supplementation in prevention of cardiovascular disease. As vitamin A has also been associated with cardiovascular events, a study on serum levels of vitamin A and the harmful effects on the cardiovascular system were investigated in older adults in the US [28]. The results indicated that both vitamin A deficiency and excessive vitamin A serum levels presented increased death from all-cause and cause-specific mortality and coronary artery diseaserelated mortality.

Neurologic disorders

The increase in neurological disorders has often been linked to the ageing population, but also genetics and nutrition has been demonstrated to play an important role. For instance, gene variants involved in lipid metabolism have been linked to the development of Alzheimer’s disease and Parkinson’s disease [29]. In this context, the APOE e4 allele presents a significant risk factor for Alzheimer’s disease [30]. Similarly, the cytochrome P450 mono-oxygenase CYP2D6 polymorphism has been linked to Alzheimer’s disease and Parkinson’s disease [31]. Moreover, the leucine-rich repeat kinase 2 (LRRK2, PARK8) gene has been indicated as the most common cause of Parkinson’s disease [32]. Meta-analysis revealed that G2019S, G2385R, R1628P and A419V gene variations present risk factors associated with increased susceptibility to Parkinson’s disease. Furthermore, dietary phytonutrient supplements have provided potential protection against Alzheimer’s disease [33] and Parkinson’s disease [34]. Related to Alzheimer’s disease, antioxidants have demonstrated protection against amyloid �-peptide induced oxidative stress thereby slowing down disease development [35]. Various polyphenols like quercetin and resveratrol have been suggested to promote treatment of Alzheimer’s disease. Moreover, a higher intake of fruits, vegetables, fish, nuts and legumes combined with reduced consumption of meats, high fat dairy and sweets was associated with reduced risk of Alzheimer’s disease in the elderly [36]. Another study in Parkinson’s patients in Japan indicated that low intake of vitamin B6, but not folate, vitamin B12 or riboflavin showed an increase in disease risk [37]. Furthermore, higher intake of vitamin E and �-carotene might be associated with a decreased risk of Parkinson’s disease [38]. A number of studies have linked Clorogenic Acid (CGA) consumption to a wide range of benefits on cognition and neurological health [39]. Mounting evidence suggests that intake of polyphenols including CGAs can reduce the risk of developing neurodegenerative conditions.

Related to traumatic brain injury, omega-3 fatty acids (ω-3 FAs) provide protective mechanisms at the cellular and neuronal levels including the modulation of inflammatory cascades [40]. Moreover, beneficial effects of ?-3 FAs such as eicosapetaenoic acid and docosahexaenoic acid should be considered for preventive general health, particularly for athletes and soldiers exposed to risk of high exposure to brain impacts. Also some phenolic compounds present in spices and herbs have been demonstrated to provide prevention against various age-related pathologic conditions in neurodegenerative disease [41]. For instance, heme-oxygenase-1 (HO- 1) expression provides strong protection against, oxidative damage and cell death in astrocytes, plays a crucial role in the pathogenesis of neurodegenerative disorders and is induced by curcumin present in curry. Furthermore, HO-1 induction by epigallocatechin-3-gallate, the major green tea catechin, can enable protection of neurons. Other phenolics such as caffeic acid phenethyl ester and ethyl ferulate show neuron protection by HO-1 induction.

In the context of Multiple Sclerosis (MS), nutrition has been shown to play an important role [42]. Dietary interventions can provide a pleiotropic role by changing cell metabolism from anabolism to catabolism and down-regulation of inflammation through interaction with nuclear receptors and transcriptional factors. Therefore, low fat diets including specific vitamins, oligoelements and dietary integrators such as fish oil and polyphenols might slow down disease progression and improve the quality of life of MS patients. Similarly, changes in nutritional state, energy intake and energy expenditure are important factors to prevent malnutrition in patients with Amyotropic Lateral Sclerosis (ALS) [43].

Nutrition has also been linked to learning, behavioral and mood disorders [44]. As is well recognized, modern lifestyle and social factors has strongly contributed to the limited consummation of fruits and vegetables, whole grains and oily fish while intake of refined carbohydrates, altered fats, meat and dairy products has increased. Nutritional factors can therefore generate physiological responses, which influence mood and promote anti-social behavior. Dietary interventions and identification of potential food intolerance, hormone imbalances, blood sugar levels, enzyme deficiencies and other factors therefore play important roles in mood and behavioral disorders. Interestingly, the majority of children with Autism Spectrum Disorder (ASD) display gastrointestinal symptoms and increased intestinal permeability [45]. Furthermore, the micro biotic composition in ASD patients and control individuals show large differences. Abnormalities in carbohydrate digestion and absorption could explain some of the gastrointestinal problems in ASD patients. When ASD patients were subjected to gluten-free diets, caseinfree diets, and pre- and probiotic, and multivitamin supplements contradictive but promising results were obtained. Nutrition and other environmental factors might therefore lead to the development of autism at least in a subset pf ASD patients.

Although nutritional interventions have provided some encouraging results in both disease prevention and treatment, failures have also been encountered. For instance, the combination of vitamin E, vitamin C and alpha-lipoic acid (ALA) supplements did not show a significant effect on Cerebrospinal Fluid (CSF) biomarkers for Alzheimer’s disease in relation to amyloid or tau pathology in a randomized controlled trial [46]. Despite the reduction of oxidative stress in the brain due to lower CSF F2-isoprostane levels, the treatment raised the concern of an accelerated decline in cognitive performance.

Cancer

The impact of dietary intake on cancer has received significant attention as it was suggested already in 1981 that nutrition accounted for approximately a third of the risk of developing cancer in the US [47]. However, the many parameters such as individual variation in the amount of food consumed, digestion, metabolism and other factors has complicated the identification of those specific food components most important for human health [48,49]. In this context, a diet rich in vegetables and fruits could significantly inverse the association with the risk for development of gastric and esophageal cancer [50]. Furthermore, tea and particularly green tea has demonstrated benefits in relation to anticancer properties as it prevented stomach, ovarian and colon cancers [51].

Bioactive food compounds such as folate, polyphenols, selenium and retinoids have been demonstrated to influence epigenetic function through DNA methylation and histone modifications affecting early carcinogenesis [52]. Furthermore, nutritional modifications can result in aberrant epigenetic mechanisms through gene silencing by micro- RNA (miRNA), which may contribute to enhanced risk of cancer development [53]. It was also recently discovered that bioactive food compounds are capable of modifying miRNA expression resulting in protection against cancer.

Remarkably, drastic nutritional changes and lifestyle modifications showed a strong impact in low-risk prostate cancer patients [54]. These patients demonstrated substantial improvement in treatment of obesity, blood pressure and lipid profiles. Monitoring of gene expression profiles from RNA samples before and three months after the intervention revealed up- or down-regulation of 501 genes. Interestingly, significant changes were observed in pathways for protein metabolism, intracellular protein traffic and phosphorylation related to cancer development. Moreover, walnut polyphenol metabolites such as urolithins A and B were demonstrated to slow the proliferation and growth of different types of cancer cells [55]. Urolithins showed down-regulation of mRNA and protein levels of prostate specific antigen (PSA) and androgen receptor in human LNCaP prostate cancer cells. Therefore, a diet rich in polyphenols such as walnuts may contribute to prostate cancer prevention. In another aspect of nutrition, vitamin D deficiency has been associated with health issues. In this context, higher vitamin D levels have been linked to lower risk of colorectal cancer and improved survival in colorectal cancer patients [56].

In the recent Nurses’ Health Study II cohort adolescent consumption of red meat was evaluated for breast cancer risk [57]. Greater intake of adolescent total red meat showed a significant correlation with higher pre-menopausal breast cancer risk, but not post-menopausal breast cancer risk. Moreover, the risk was lower in case of poultry consumption. When one serving/day of red meat was replaced with a combination of poultry, fish, legumes and nuts, the overall breast cancer risk decreased by 16% and the pre-menopausal risk was 24% lower. In another multicenter, prospective cohort study, the inverse association of coffee and tea in relation to Hepatocellular Carcinoma (HCC) risk was confirmed [58]. Increased coffee and tea consumption was consistently associated with a lower risk of HCC. Tea consumption has also been associated with a reduced risk of lung cancer [59]. In a meta-analysis of 26 case-control and 12 cohort studies overall tea consumption was significantly associated with decreased risk of lung cancer. Both green tea and black tea intake reduced the risk of lung cancer [59].

Nutritional interventions have also demonstrated an impact on quality of life in cancer patients. When patients with malnutrition disorders received ice cream as an adapted nutrition supplement significant differences in anxiety and depression was observed in comparison to the control group [60]. In conclusion, administration of ice cream presented in part the social aspect of food provision and could improve the quality of life in malnourished cancer patients.

Nutrigenomics

The impact of nutrigenomics in disease prevention and treatment by targeting food intake can be compared to how genomics information has influenced drug development. Obviously, the emerging area of personalized medicine and individually designed diets will play an important part in future disease prevention and improved health. Moreover, to establish a more complete picture of nutrigenomics, a metagenomic approach covering the interaction of the genomes of food, gut microbes and the human host needs to be addressed [61]. In this context, food proteomes of both animal and plant origin have been characterized [62,63]. Plants provide a variety of bioactive food compounds, which function as growth factors, anti-hypertensive agents, anti-microbials and immune regulators. Bioactive food compounds containing soy, rice, cereals and sunflower can provide protection against oxidative stress and different types of cancer and are released through proteolysis by host or microbial gut enzymes during food processing and ripening [64].

Milk is an important food source, which has been demonstrated to present significant differences dependent on whether of human or bovine origin [65]. For instance, the protein/peptide, lipid and carbohydrate contents are different with human milk containing caseins and whey proteins at a 50:50 weight/weight ratio in comparison to 80% caseins and 20% whey proteins in bovine milk [66]. Human milk also presents a strong impact on the host defense system as it contains various immunoglobulins and the iron-binding protein lactoferrin [67]. Milk provides protection against bacterial pathogens supports the growth of protective colonic microbes, reduces gastro-intestinal infections, inflammation, and allergic disorders [68]. Furthermore, food-derived peptides have demonstrated reduced cardiovascular disease risk by affecting blood pressure, oxidative stress, appetite, and lipid metabolism [69]. In this context, lactotripeptides were shown to inhibit angiotensin-converting enzyme (ACE) resulting in reduced blood pressure in rats [70]. Soybean can also provide significant health benefits as they contain high amounts of all essential amino acids, isoflavones and saponins [71]. Moreover, phytochemicals, lunasin Bowman-Birk inhibitor, lectin and beta-conglycinin have been associated with prevention of cancer cell division and histone acetylation [72,73].

A bioinformatics-based strategy called “reverse-genome engineering” was applied for in silico discovery and evaluation of bioactive food compounds [74]. In this approach, public domains are searched for known bioactive peptides and mapped onto suitable animal or plant food genomes for identification of their location in parent protein sequences. Moreover, human digestive or food processing-related conditions can be mimicked to reveal the proteolytic release of bioactive peptides by in silico analysis. Currently, bioactivity prediction based on only amino acid sequences is not possible, but in the future the technology might be expanded to peptide sequences in general.

Obviously, human health is strongly affected by the complex composition of the gut microbiota, which consists of a huge biomass of more than 100,000 billion bacteria representing more than 400 species [75]. The gut microflora is involved in an intense metabolic activity, degradation of otherwise non-digestible substances and providing resistance to colonization by external bacterial strains. When germ free (GF) mice were colonized by a human baby flora (HBF) resistance to obesity was observed in animals fed on a highfat and high carbohydrate diet, which indicated that GF mice consumed fewer calories, excreted more fecal lipids and weight significantly less than control mice [76]. In addition, GF mice showed higher sensitivity to insulin and glucose tolerance. Human obesity has also been linked to the microbiota. For instance, the beneficial gut bacteria group Bacteroidetes was found in obese individuals compared to lean people in reduced proportion and it increased with weight loss [77]. When GF mice were colonized with Bacteroides thertaiotaomicron the outcome was intestinal cellular differentiation and gene expression, which resulted in benefits to both the host and the microbe [78]. Further studies of the gut microbial system has also revealed how age-related changes affect the gastro-intestinal tract, the lifestyle, nutritional behavior and the host immune system [79]. In ageing individuals the changes in gut microbiota balance has resulted in “inflamm-ageing” and “immunosenescence” [61]. Also, studies on the relationship between the gut microbiota and human intestinal dendritic cells revealed enhanced IL-6 production in patients with Crohn’s disease, which correlated with disease progression [80]. Related to inflammatory bowels disease, bacterialdriven metalloproteases caused degradation of extracellular matrix components [81].

The gut microbiota has recently been shown to contribute to the etiology of colorectal cancer (CRC) [82]. For instance, the shortchain fatty acid acetate, propionate and butyrate are linked to the suppression of inflammation and cancer. Moreover, other microbial metabolites like secondary bile acids promote carcinogenesis. Furthermore stool profiling identified intestinal bacteria and metabolites, which are differentially expressed in patients with CRC compared to healthy controls [83]. Particularly, butyrate-producing species were under-represented in CRC patients, while the mucindegrading Akkermansia muciniphilia showed 4-fold higher levels. When the combined datasets were subjected to correlative analysis some potential relationships between stool metabolites and certain bacterial species was discovered.

Food intake in humans is also strongly influenced by a number of factors such as age, physical activity and special conditions like pregnancy. Additionally cultural and ethnic aspects as well as lifestyle have a great impact. Obviously genetic factors should not be neglected. In this context, the most prominent genetic individual differences are SNPs, but also deletions, insertions and copy number variations play important roles. G proteins, which act as central signal translation mediators for G protein-coupled receptors (GPCRs) have shown relevant responses on the gene level to nutritional interventions [84]. For instance, the C825T polymorphism in the G�3 subunit and the G659C in the Ga11 subunit have been associated with weight loss after sibutramine treatment [85]. Likewise, carriers of the 825T allele in the GNB3 subunit indicated an enhanced hypertension risk [86]. The first signs of metabolic syndrome with increased total cholesterol and uric acid were observed in lean mice carrying the C825T mutation [87]. In older hypertensive subjects insulin resistance was more prominent for the 825TT and 825TC genotypes than the 825CC genotype. In another study, the C to T substitution in the methylene-tetrahydropholate-reductase (MTHFR) gene resulted in elevated plasma homocysteine and a different response to folic acid supplements [88], which affected the risk for such chronic diseases as vascular disease, cancer and neural tube defects.

Epigenetics

Epigenetics has received plenty of attention recently because of mechanisms leading to modifications outside the scope of conventional genetics and does not involve any modifications of the primary DNA sequence [89]. The reversibility of epigenetic functions has also made their application as targets for therapeutic interventions attractive. The three main mechanisms for epigenetic functions are DNA methylations, histone modifications and RNA interference. DNA methylation involves covalent addition of methyl groups to the 5’-position of cytosines upstream of guanosines, which affects regulation of gene expression, genomic imprinting and DNA repair mechanisms [90]. Methylated CpG dinucleotides affect mRNA transcription resulting in reduced or terminated transcription but also in its up-regulation, which has been linked to cancer [91, 92]. In this context, hypermethylation in promoter regions has been linked to the inactivation of HIC1, INK4b and TIMP3 tumor suppressor genes [93]. Histone modifications such as acetylation, methylation, ubiquitination and phosphorylation can modify histones H3 and H4 and thereby provide essential epigenetic mechanisms resulting in either repression or activation of transcription [94,95]. Similarly, RNA interference (RNAi) strongly contributes to the regulation of gene expression [96]. In this context, 21-23 nucleotide singlestranded microRNAs (miRNAs) interfere with mRNA leading to down-regulation of gene expression [97]. Alternatively, miRNAs can increase transcription and gene expression [98]. Currently, more than 1000 human miRNAs have been isolated and it is believed that up to a third of all human mRNAs are regulated by miRNAs [99].

Nutrition and epigenetics

There are numerous indications of how nutrition affects epigenetic functions (Table 2). The classic example of how nutrition causes epigenetic modification is from the Agouti mouse model where the fur color is linked to the methylation of the Agouti gene [100]. When pregnant black mice carrying the eumelanin (a) gene are fed on a methyl-supplemented diet a shift in offspring color occurred. However, when the food intake of pregnant yellow mice contained methyl donors (folic acid, vitamin B12, choline and betaine) the color of the offspring changed [101]. In the presence of a complete unmethylated Agouti gene, the coat color is yellow and the mice become obese and show a high risk for diabetes and cancer. Another approach relates to feeding mice with a choline-methionine deficient (CMD) diet, which resulted in elevated expression of Igf2 and H19 in prostate tissue compared to control mice [102]. Shorter exposure to the CMD diet demonstrated the reversibility of the epigenetic regulation of gene expression. The lack of change in DNA methylation in the promoter regions and H19 and Igf2 imprinting was a strong indication of epigenetic plasticity and suggested that methyl deficient diets have a stronger effect on chromatin modifications than DNA methylation. In humans, overfeeding with a high-fat diet induced DNA methylation in men with low birth weight leading to peripheral insulin resistance and decrease in peroxisome proliferator-activated receptor gamma-1 alpha (PPARGC1A) and oxidative phosphorylation (OXPHOS)-related gene expression in five days [103].

  

    
Nutrition 
    
Epigenetic effect 
    
Reference 
  
  

    
Polyphenols
  
  

    
Fatty liver disease
    
miR-103/107, 122    dysregulation
    
[127]
  
  

    
ApoE mutant mice
    
miR-30c, 291, 296,    374, 476b dysregulation
    
[128]
  
  

    
Polanthocyanidines    in HepG2 cells
    
miR-30b, 197,    532-3p, 1224-3p dysregulation
    
[129]
  
  

    
High-fat diet
  
  

    
Obesity
    
up-regulation of    miR-21, 142, 146
    
[130]
  
  

    
C57BLJ6 mice
    
down-regulation of    miR-1, 30, 122
    
[130]
  
  

    
Diabetes
    
up-regulation of 8 miRNAs
    
[131]
  
  

    
Skeletal muscle
    
down-regulation of    22 miRNAs
    
[131]
  
  

    
NAFLD
    
miR-467b    dysregulation
    
[132]
  
  

    
Insulin resistance
    
DNA methylation    decreased PPARGC1A, OXPHOS levels
    
[103]
  
  

    
Circadian Npas2    gene in primates
    
histone    modification affected Npas2 promoter activity
    
[104]
  
  

    
Alcohol
  
  

    
Alcohol-induced    fetal alcohol-syndrome
    
induced methylation    in sperm embryo, developing brain
    
[107]
  
  

    
Maternal smoking
  
  

    
Fetal growth,    long-term health
    
aberrant DNA    methylation, reduced miR16, 21, 146a levels
    
[112]
  
  

    
Link to disease    pathogenesis
    
lower DNA    methylation in transposable element AluYb8
    
[113]
  
  

    
Maternal drug use
  
  

    
Premature birth,    cardiac defects
    
aberrant DNA    methylation after maternal cocaine use
    
[114]
  
  

    
Impaired memory,    hyperactivity
    
histone    modifications after parental cocaine use
    
[117]
  
  

    
Impaired fetal    cardiac development
    
aberrant DNA    methylation after maternal cocaine use
    
[118]
  
  

    
Impaired fetal    growth
    
epigenetic    modifications after cannabis use
    
[121]
  
  

    
Special diet
  
  

    
Agouti mouse fur color
    
aberrant DNA    methylation after methyl-supplemented diet
    
[100]
  
  

    
Choline-methionine    deficient diet
    
DNA methylation led    to increased Igf2 and H19 expression
    
[102]
  
  

    
Plant intake
  
  

    
Gene expression    regulation in mammals
    
decrease of LDLRAP1    by miR-168a after rice consumption
    
[124]
  
  

    
Differential gene    expression
    
miR-92 differences    in vegans, vegetarians, omnivores
    
[126]
  
  

    
Carcinogens
  
  

    
2-acetylaminofluorene
    
miR-34, 200b, 200c    dysregulation
    
[151]
  
  

    
Diethylhexylphthlate
    
miR-429    dysregulation
    
[151]
  
  

    
Metapyrilene
    
miR-429    dysregulation
    
[151]
  
  

    
LDLRAP1: Low-Density Lipoprotein    Receptor Adapter Protein 1; NAFLD: Non-Alcoholic Fatty Liver Disease; OXPHOS: Oxidative Phospohorylation; PPARGC1A: Peroxisome    Proliferator-Activated Receptor Gamma-1 alpha
  

Table 2:  Examples of Association of Nutrition with Epigenetics.