In this article we will discuss about the Nutrigenomics:- 1. Meaning of Nutrigenomics 2. Micronutrients, Macronutrients: Effects on Gene 3. Genotype and Environment Interactions 4. Role of Folic Acid in Nutri-genomics 5. Direct Biochemical Effects 6. Nucleotide Biosynthesis 7. Polymorphism in Gene for MTHFR 8. Biological Methylation 9. Homocysteine Metabolism 10. Conclusion.
Contents:
- Meaning of Nutrigenomics
- Micronutrients, Macronutrients: Effects on Gene
- Genotype and Environment Interactions
- Role of Folic Acid in Nutri-genomics
- Direct Biochemical Effects of Nutrigenomics
- Nucleotide Biosynthesis
- Polymorphism in Gene for MTHFR
- Biological Methylation
- Homocysteine Metabolism
- Conclusion to Nutrigenomics
1. Meaning of Nutrigenomics:
Nutrigenomics may be defined as the application of genomic tools to study the integrated effects of nutrients on gene regulation. However, it holds great promise in increasing the understanding of how nutrients affect molecular events in an organism for development and progression of various diseases.
The working definition of Nutrigenomic is that it provides a genetic and molecular understanding for how common dietary chemicals (i.e., nutrients) affect the balance between health and disease by altering the expression and/or structure of an individual’s genetic make-up.
The new branch of genomic and nutritional research can finely be summarized with the following five points:
a. Common dietary chemicals and nutrients directly or indirectly act on the human genome to alter gene expression or structure.
b. Under certain circumstances and in some individuals, diet can be a serious risk factor for a number of diseases.
c. Some diet-regulated genes are susceptible genes and likely to play a role in the onset, incidence, progression, and/or severity of chronic diseases.
d. The degree to which diet influences the balance between healthy and disease states may depend on an individual’s genetic make-up (e.g., efficient genetic polymorphism and nutrient metabolism).
e. Dietary process based on knowledge of nutritional requirements, nutrition states, and genotype (i.e., “individualized nutrition”) can be used to prevent, mitigate, or cure chronic disease.
Many chemicals in foods are nutrients, i.e., these are metabolized to energy or involved in key metabolic reactions (e.g., vitamins). But some naturally occurring chemicals in foods are ligands for transcription factors and directly alter gene expression. Other dietary chemicals alter signal transduction pathways and chromatin structure to indirectly affect gene expression.
Studies have shown that intake of different diets are associated with the incidence and severity of chronic diseases. Overconsumption of proteins, fat or carbohydrates, or lack of key micronutrients are associated with obesity, cardiovascular diseases, certain cancers, developmental defects, and neurological diseases such as Alzheimer’s.
At the cellular level nutrient may:
a. Act as a ligand for transcription factor receptor.
b. Be metabolized by primary, secondary pathways, thereby altering concentration of substrate or intermediates.
c. Positively or negatively affects signal pathway.
Dietary chemical may interact with one or more variants to increase or decrease disease risk.
2. Micronutrients, Macronutrients: Effects on Gene:
Human diets almost require 40 micronutrients. The specific micronutrients are associated with CVD (B Vitamin, carotinoids, Vitamin E), cancer (folate, carotinoids), neural tube defect (folate) and bone mass.
The deficiency of vitamin B12/B6/folic acid/niacin/, vitamin C and E or iron and zinc appear to mimic radiation in damaging DNA by causing single and double strand breaks, oxidative lesion or both. A good number of other degenerative diseases of aging are also being associated with low fruits and vegetables intake.
The specific mechanisms are being determined for the role of certain minerals (calcium, magnesium, manganese, copper, and selenium) and vitamins in heart disease from work in humans in cell culture systems.
Unbalanced intake of any of the three major macronutrients, carbohydrates, fats, proteins causes the initiation, progression, and severity of chronic disease.
The single macronutrient or micronutrient is unable to prevent chronic diseases. Dietary imbalances and dietary supplements from micronutrients deficiencies to overconsumption of macronutrients of dietary supplements are the modifiers of metabolism and potentiates of chronic diseases.
Specific subgroups are already targeted with “subgroup nutrition” (e.g., cholesterol-lowering margarines) without stressing the genetic background of variation of nutritional response.
A big challenge is in front of us in validating the combined action of these minor-impact polymorphisms and their practical effect on the relation between nutrition and health on the basis of scientific point of view (Fig. 56.1).
3. Genotype and Environment Interactions:
It is defined as a different effect of an environmental exposure on disease risk in persons with different genotypes or a different effect of a genotype on disease risk in persons with different environmental exposures.
In humans, many diseases are related to deficits of essential nutrients, imbalance of macronutrients, micronutrients, even toxic concentrations of certain food compounds. It is finally realised that the nutrition and health relationship is perfectly anchored in interactions on the levels of DNA, RNA, protein, and metabolites (Fig. 56.2).
Our diet is a complex mixture of many possible bioactive chemical compounds, chronically administered in different compositions, and with a multitude of biological effects.
The majority of these biological responses are mediated through effector genes, effects on enzyme concentration or activity, and changes in metabolite concentration.
Each of our genes contains ten deviations in its code from the “standard gene”. But not all of these polymorphisms have a functional impact.
A small number of these polymorphism have serious health implications and may even be lethal. This is the domain of clinical genetics. Many polymorphisms have only a mild effect on the functionality of the resulting protein.
A large variety in response to nutrition have been observed within certain limits of “health”. Many examples have been set up in which nutritional compounds directly cause DNA damage or modulate susceptibility against DNA damage through regulation of specific pathways in many processes involved in these events.
4. Role of Folic Acid in Nutri-genomics:
Up to this date 1,000 human diseases gene are being identified. 97 per cent of which cause monogenic diseases.
Most of the chronic diseases (obesity, diabetes, cardiovascular diseases, cancer) are due to complex interaction between several genes and environmental factors.
More complete single nucleotide polymorphism (SNP) and halo type maps are helpful in identifying the genes involved in the disease.
Deficiency of folic acid and other macro and micronutrients appear to mimic radiation in damaging DNA by causing single and double strand breaks, oxidative lesion or both.
Nutrient deficiencies are orders of magnitude more important than radiation because of constancy of exposure to milieu promoting DNA damage. Folate deficiency breaks chromosome due to substantial incorporation of uracil in human DNA.
Single strand break in DNA are formed during base excision repair, with two nearby single-strand breaks on opposite DNA strands leading to chromosomal fragmentation.
In humans, folate level and variation of different genes that code the folate-dependent enzymes are linked to many diseases like cancer, vascular diseases, birth defects and complications of pregnancy.
The genomic machinery is very much sensitive to folate and vitamin B status and responsible to interaction between folate nutrition and folate-dependent enzyme polymorphism (folate Nutri-genomics).
Mechanisms that may affect:
a. Maintenance of genomic CpG methylation pattern (which regulate gene expression).
b. Synthesis of nucleotide to prevent DNA damage.
c. Influence plasma homocysteine status, thus risk of vascular diseases.
This complex relationship is shown in Fig. 56.3.
Currently, worldwide interest on folate research is due to discovery of several single nucleotide polymorphisms (SNP) which modulate risk of several diseases (Table 56.2).
Dietary folate interacts with proteins that are encoded by various genes and reduces the risk to development of various diseases and gives protection over the diseases.
5. Direct Biochemical Effects:
Folate stabilizes the polymorphic enzyme encoded by C677T variant gene by preventing it from relinquishing its flavin cofactors.
Since 5, 10 methylene-tetrahydrofolate reductase is a flavin protein people with TT recessive genotype may respond more rapidly to riboflavin supplements as well as folate to lower homocysteine.
6. Nucleotide Biosynthesis:
dTMP synthesized by the thymidylate synthetase from dUMP and requires the one carbon unit of 5, 10 methylene-tetrahydrofolate. dTMP is used by DNA. If there is low level of folate, uracil misincorporation occurs leading to breakage of DNA strand which predisposes to cancer.
The polymorphic enzyme coded by C677T variant genes can enhance the synthesis of dTMP nucleotide if folate status is good, and this is thought to afford protection against colon cancer and leukaemia.
7. Polymorphism in Gene for MTHFR:
A common functional polymorphism in the gene of methylene-tetrahydrofolate reductase (MTHFR, a major enzyme involved in folate metabolism) is associated with an increased risk of colorectal cancer. Dietary folate and methionine intake modify colorectal cancer risk in people with MTHFR polymorphism.
Nurses’ health study showed that folate in women who used alcohol had a 25 per cent reduction in breast cancer risk. Recently a team of American and Chinese researchers showed that folic acid have protective effect against breast cancer. The effect of it had been pronounced when taken with other vitamins especially B6, B12, and methionine.
Researchers believed that folic acid exerts its protective effect by preventing errors in DNA replication and by helping to regenerate methionine, a vital component of DNA synthesis, vitamin B6, B12 and act as cofactors required for folic acid to “do its job”.
If folate status is poor, single nucleotide polymorphism may confer risk rather than protection.
8. Biological Methylation:
Since dietary methionine cannot provide all methyl groups for cellular methylation reaction there is requirement of de novo synthesis of methionine from folate one carbon pool. S-adenosylmethionine regulates protein, biogenic amine, lipid, and DNA methylation. The S-adenosylmethionine dependent DNA methylation of specific CpG site regulates gene expression and play a critical role in the developmental process.
Methylation of cluster of CpG sites associated with promoter regions tends to silence gene expression. A deficiency of methyl group may alter the normal control of proto-oncogene expression. The polymorphic enzyme encoded C677T variant gene may reduce availability of de novo methyl groups for this important reaction.
Since folate is necessary in embryogenesis its supplementation reduces the risk of neural tube defects. Various studies show that folate supplementation decreases the risk of first occurrence of neural tube defect and recurrent defects in women with previously affected pregnancy.
9. Homocysteine Metabolism:
Polymorphic 5, 10 methylene-tetrahydrofolate reductase reduces one carbon flux to methyl-folate, the donor molecule for conversion of homocysteine into methionine. This single nucleotide polymorphism may thus elevate homocysteine which is the independent risk factor for the cardiovascular diseases.
Homocysteine is atherogenic and undergoes redox cycling in the presence of transition metal ions, forming radical that causes oxidative damage to low density lipoprotein. It also reacts with cysteine SH groups and modifies apolipoprotein.
It is also a hypertensive compound. It also reacts with endothelium—derived relaxation factor to form S-nitrosohomocysteine and superoxide. This leads to loss of vasodilatation action.
Since homocysteines promote atherosclerosis through oxidative stress hyperhomocysteinemia is being associated with coronary artery diseases. Recent researchers have studied that folic acid supplementations reduce the risk of CAD (coronary artery diseases).
It also inhibits and down regulates anticoagulants including prostacycline synthesis, activation Protein C, thrombomodulin expression, heparin sulphate expression and fibrinolysis. People with inflammatory bowel diseases (ulcerative colitis, Crohn’s disease) have high risk of thromboembolic events, such as stroke and peripheral venous thrombosis.
It is also observed that patients with Crohn’s disease may be benefited from supplementation of folic acid. It also activates factor V and tissue clotting factor. The final effects of it are to chelate copper and inhibit lysyl oxidase which impairs crosslinking of collagen and elastin and leads to connective tissue abnormalities.
10. Conclusion Nutrigenomics:
The new science of nutritional systems biology is emerging, taking up the challenge of exploiting all available data generated by genomics technology in a complete description of a biological system.
This new method is ideally fit for the evaluation of many vital changes in biological activity as propagated by nutrition. A good number of bioactive compounds act simultaneously and chronically in constantly changing combinations.
The recent unrevealing of human genomic and the coinciding technological developments, genotyping, transcriptomics, proteomics, and metabolomics are now available to nutritional research. In future we are likely to see new screening tools for the selection of bioactive nutrients, new biomarkers for the in vivo efficacy of nutrients, and better insight into the influence of genetic polymorphisms on nutrient metabolism.