Nutritional genomics

Nutritional genomics is a science studying the relationship between human genome, nutrition and health. It can be divided into two disciplines:

• Nutrigenomics: studies the effect of nutrients on health through altering genome, proteome, metabolome and the resulting changes in physiology.
• Nutrigenetics: studies the effect of genetic variations on the interaction between diet and health with implications to susceptible subgroups.

Gene-Diet-Disease interaction

97% of the genes known to be associated with human diseases result in monogenic diseases, i.e. a mutation in one gene is sufficient to cause the disease. Modifying the dietary intake can prevent some monogenic diseases. One example is phenylketonuria, a genetic disease characterized by a defective phenylalanine hydroxylase enzyme, which is normally responsible for the metabolism of phenylalanine to tyrosine. This results in the accumulation of phenylalanine and its breakdown products in the blood and the decrease in tyrosine, which increases the risk of neurological damage and mental retardation. Phenylalanine-restricted tyrosine-supplemented diets are a means to nutritionally treat this monogenic disease.

In contrast, diseases currently in the world, e.g. obesity, cancer, diabetes, and cardiovascular diseases, are polygenic diseases, i.e. they arise from the dysfunction in a cascade of genes, and not from a single mutated gene. Dietary intervention to prevent the onset of such diseases is a complex and ambitious goal.

Recently, it was discovered that the health effects of food compounds are related mostly to specific interactions on molecular level, i.e. dietary constituents participate in the regulation of gene expression by modulating the activity of transcription factors, or through the secretion of hormones that in turn interfere with a transcription factor.

Nutrigenomics

Nutrigenomics refers to the prospective analysis of differences among nutrients in the regulation of gene expression i.e., it studies the effect of nutrients on the genome, proteome, and metabolome. It involves the application of high-throughput genomic tools such as DNA microarray technology in nutrition research. Nutrigenomics is a discovery science which aims at understanding how nutrition influences metabolic pathways and homeostatic control and how this regulation is disturbed in the early phase of a diet-related disease.

Biomics technologies

The recent advances in nutrigenomics studies are owed to the completion of human genome project and the new biomics technologies that provide means for the simultaneous determination of the expression of many thousands of genes at the mRNA (transcriptomics), metabolites (metabolomics) and protein (proteomics) levels. Genomic and transcriptomic studies are mostly conducted by DNA microarray technologies. Proteomics and metabolomics have no standardized procedures yet, but usually, proteome analysis is done by two-dimensional gel electrophoresis and Liquid chromatography-mass spectrometry, while metabolome analysis is conducted through gas chromatography-mass spectrometry, liquid chromatography-mass spectrometry and liquid chromatography-nuclear magnetic resonance. Usually, these technologies are applied in a “differential display” mode, i.e. by comparing two situations (e.g. diseased versus healthy) in order to reduce the complexity in data by examining only differences.

Example of applications

An example of the application of the nutrigenomic approach was a study that simultaneously identified a mechanism for the regulation of sterol uptake in the intestine and the basis for sitosterolemia (a genetic disorder characterized by hyperabsorption of dietary sterols leading to hypercholesterolemia with a high risk of developing atherosclerosis). In the study, a group of mice was treated with a lipid metabolism-altering drug and DNA microarray technology was used for mRNA expression profiling of various tissues. Differential display mode was used by comparing differences in expression levels with a control group of mice. This led to the discovery of an unknown gene. Through computer simulation techniques, it was found that two proteins produced by the newly discovered gene were responsible for the regulated reverse transport of animal and plant dietary sterols out of the apical surface of intestinal cells. By exploring human gene databases, a human homologue of the mouse gene was identified. This explained why dietary sterols, which are structurally similar to cholesterol, are not absorbed in normal individuals. By scanning sitosterolemic individuals for this gene, it was found that all of them had a mutation in this gene responsible for their uncontrolled hyperabsorption of dietary sterols.

Nutrigenetics

Nutrigenetics is the retrospective analysis of genetic variations among individuals with respect to the interaction between diet and disease. It is an applied science that studies how the genetic makeup of an individual affects the response to diet and the susceptibility to diet-related diseases. This necessitates the identification of gene variants associated with differential responses to nutrients and with higher susceptibility to diet-related diseases. The ultimate goal of nutrigenetics is to provide nutritional recommendations for individuals in what is known as personalized or individualized nutrition. A number of companies have sprung up to cash in on the current popularity of genetic testing. Independent analysis of the service these companies deliver show that at best the advice delivered is highly generic, and at worst may lull the recipient into a false sense of security. As these companies are not offering specific clinical advice, they do not qualify for regulation beyond the accuracy of the genetic test applied. Retail boycotts in the UK have led to the voluntary suspension of industry activity, and in the US severe criticisms have been leveled by the Government Accountability Office.

Applications

A number of genetic variations have been shown to increase the susceptibility to diet-related diseases. These include variants that have been associated with Type 2 diabetes mellitus, obesity, cardiovascular diseases, some autoimmune diseases and cancers. Nutrigenetics aims to study these susceptible genes and provide dietary interventions for individuals at risk of such diseases. Some examples are shown below.

Nutrigenetics and Type 2 Diabetes mellitus

A number of genes are involved in regulating lipid metabolism and insulin sensitivity, and thereby affecting the susceptibility to type 2 diabetes mellitus. Among them is the gene responsible for sterol response element binding protein-1c or SREBP-1c (a membrane-bound transcription factor which can directly activate the expression of several genes involved in the synthesis and uptake of cholesterol, fatty acids, triglycerides and phospholipids). In mice models, overexpression of SREBP-1c led to fatty livers, hypertriglyceridemia, severe insulin resistance and finally type 2 diabetes mellitus. Later, SREBP-1c was identified as a candidate gene in the regulation of human insulin resistance. Two missense mutations in exons coding the aminoterminal transcriptional activating domain of SREBP-1c were found in individuals displaying severe insulin resistance. Another association was found between an intronic single nucleotide polymorphism (C/T) between exons 18c and 19c and the onset of diabetes in men, but not in women. These studies suggest that mutations in SREBP-1c may increase the sensitivity to developing diabetes.

Furthermore, SREBP-1c appears to be susceptible to diet, and thus it can be a target for nutritional intervention. Studies in mice have shown that SREBP-1c mRNA expression was highly induced in mice having one polymorphism (–468 A/G) after the consumption of high fructose diets. This implies that a single nucleotide polymorphism can also modulate the sensitivity of a gene to dietary intervention.

Nutrigenetics and cardiovascular diseases

Hyperlipidemia is usually associated with atherosclerosis and coronary heart disease. Therapy includes lifestyle changes as alterations in the patient's diet, physical activity and treatment with pharmaceuticals such as statins. However, individuals respond differently to the treatment. This was attributed to genetic variations within the population. Genetic variations in genes encoding for apolipoproteins, some enzymes and hormones can alter individual sensitivity to developing cardiovascular diseases. Some of these variants are susceptible for dietary intervention, for example:

• Individuals with the E4 allele in the apolipoprotein E gene show higher low-density lipoprotein-cholesterol (bad cholesterol) levels with increased dietary fat intake compared with those with the other (E1, E2, E3) alleles receiving equivalent amounts of dietary fat.
• One single nucleotide polymorphism (-75 G/A) in the apolipoprotein A1 gene in women is associated with an increase in High density lipoprotein-cholesterol levels with the increase in the dietary intake of polyunsaturated fatty acids (PUFA). Individuals with the A variant showed an increase in the protective HDL (good cholesterol) levels following an increased consumption of PUFA compared with those with the G variant taking similar amounts of PUFA.
• One polymorphism (-514 CC) in the hepatic lipase gene is associated with an increase in protective HDL levels compared with the TT genotype (common in certain ethnic groups such as African-Americans) in response to high fat diet.

Nutrigenetics and cancer

Nutrients can contribute to the development of cancers especially colon, gastric and breast cancer. Several gene variants have been identified as susceptibility genes. One example is the N-Acetyltransferase (NAT) gene. NAT is a phase II metabolism enzyme that exists in two forms: NAT1 and NAT2. Several polymorphisms exist in NAT1 and NAT2, some of which have been associated with NAT capabilities of slow, intermediate or fast acetylations. NAT is involved in acetylation of heterocyclic aromatic amines found in heated products especially well cooked red meat. During cooking of muscle meat at high temperature, some amino acids may react with creatine to give heterocyclic aromatic amines (HAA). HAA can be activated through acetylation to reactive metabolites which bind DNA and cause cancers. Only NAT2 fast acetylators can perform this acetylation. Studies have shown that the NAT2 fast acetylator genotype had a higher risk of developing colon cancer in people who consumed relatively large quantities of red meat.