nutrition

THE TENETS OF NUTRITIONAL GENOMICS

How the mapping of the human genome will affect nutrition, health and chronic eye disease.

JEFFREY ANSHEL, O.D. Carlsbad, Calif.

With the recent mapping of the human genome, the worlds of genetics and medicine have changed forever. While geneticists are still deciphering the pieces of the genome puzzle, we already have a wealth of new information about the genesis of various chronic conditions, including eye diseases. As scientists continue to investigate the human genetic code, we'll see even more.

A primer

Genomics is the study of the global properties of genomes of related organisms. A genome is the sum of all genes we inherit from our parents and is encoded in our DNA. The interface between the nutritional environment and cellular/genetic processes is referred to as nutritional genomics or "nutrigenomics." Nutrigenomics seeks to provide a molecular genetic understanding of how common dietary chemicals (i.e., nutrition) affect health by altering the expression and/or structure of an individual's genetic makeup. Nutrigenomics postulates that changes in gene expression or differences in activities of proteins and enzymes cause the progression from a healthy phenotype to a chronic-disease phenotype. Nutritional genomics focuses on nutrients' affect on the genome, proteome and metabolome. (See, "Basic genetic terminology," page 52.)

The five tenets of Nutritional Genomics¹

1. Improper diet is a risk factor for diseases.

2. Dietary chemicals alter a patient's gene expression and/or genome structure.

3. An individual's genetic makeup influences how diet impacts health.

4. Diet-regulated genes play a role in chronic diseases.

5. Diets based on genotype, nutritional requirements and health status can prevent or mitigate chronic disease.

The two approaches to nutritional genomics are the "Reductionist Approach," which tries to identify the one gene that causes a particular disease, or the one dietary chemical or supplement that will prevent it.

The second approach, the "Systems Approach," uses methods from genetics, molecular biology, physiology and nutrition to study how diet affects an individual patient. So, rather than analyzing genes alone, it analyzes blood chemistries, enzymes, metabolites, etc. In addition, it looks at the interaction between genes to see how this affects their expression.

The cellular response

Our body's cellular response to Ribonucleic Acid (RNA)-decoded messages depends on our environmental status, including nutritional status. Nutritional deficiencies cause cells to respond to degenerative or toxic genetic messages.

Proper Deoxyribonucleic Acid (DNA) replication depends on a variety of nutritional elements; including folic acid, which contributes to guanine, thymine and adenine formation. For example, folic acid is a B-vitamin, and a deficiency causes uracil misincorporation into human DNA and chromosome breakage. Folate is also essential to maintain normal levels of homocysteine, an amino acid in the blood. Vitamin B6 contributes to thymine synthesis, and vitamin B3 contributes to thymine and cytosine synthesis.

Our cells respond to our nutritional status because free radical oxidation damages DNA, which requires sufficient amounts of vitamins A, D and zinc to convert to RNA. These are also necessary for proper RNA signaling (nuclear factor-kappa B-NFkB) to the protein messengers that control all body functions, including the development of vascular endothelial growth factor (VEGF) associated with angiogenesis.

We need nutritional antioxidants because free radical formation is a normal by-product of metabolism, and it is increased by infections, ultra-violet rays, smoke and pollutants but is reduced by antioxidants. A single cell's membrane has protein receptors that interact with the surrounding environment, and these receptors decide what enters the cell and what doesn't. The cell membrane depends on the full spectrum of minerals, particularly calcium, magnesium, sodium and potassium to channel nutrients into, and waste out of, the cells.

A theory called the "Primacy of DNA" (or "Genetic Determinacy") has been pervasive in our science community since the 1950s.² According to this theory, we are "victims" of our genes: They dictate who we are and what diseases we will inherit. This theory also says that one cannot alter or change genes. However, the cell's regulatory proteins act as gatekeepers of the environment. Thus, an environmental signal initiates the cellular response. This is called Primacy of the Environment, and it assumes that when our cells need a gene product, a signal from its environment activates expression of that gene.

Ocular disease

In looking at some of the more common chronic eye diseases, including age-related macular degeneration (AMD), cataracts, diabetic retinopathy and glaucoma, you'll find that they're not only genetically influenced, but also nutritionally influenced.

• HTRA1 and CFH. Recent studies in AMD genetics implicate a gene called HTRA1 as a major risk for AMD. This gene plays a critical role in the formation of blood-vessel development. A simple blood test can discover whether a patient is up to 700% more likely to develop AMD, giving them the chance to initiate early/preventative treatment.³

Basic genetic terminology

To fully understand how the nutritional genomics concept works, review some of the basic DNA biology. DNA: Deoxyribonucleic Acid (DNA) is made up of bases, which form nucleotides of the nucleic acids DNA and RNA. These bases are: Adenine (A), Thymine (T), Cytosine (C) and Guanine(G). These nucleotides combine in the familiar double-helix form to produce the strands of DNA that contain the genetic information. RNA: For DNA to duplicate, it transforms into Ribonucleic Acid (RNA), which is expressed in many forms. RNA is a nucleic acid polymer consisting of nucleotide monomers. RNA serves as the template for the translation of genes into proteins, transferring amino acids to the ribosome to form proteins and translating the transcript into proteins (transcriptomics). (See figure, page 54.) Transcriptomics: The transcription of genes to produce RNA is the first stage of gene expression. The transcriptome is the set of all messenger RNA (mRNA) molecules, or "transcripts," produced in one or a population of cells. Unlike the genome, which is roughly fixed for a given cell line (excluding mutations), the transcriptome can vary with external environmental conditions. Transcriptomics is therefore a global way of looking at gene expression patterns. A detailed view of a DNA strand's make-up and components. Proteonomics: The proteome is the complete set of proteins produced by the genome. The RNA is the messenger that delivers the DNA transcription to form the protein. The proteome is constantly changing via biochemical interactions with genes and the environment. Metabolomics: The systematic study of the unique chemical fingerprints that specific cellular processes leave behind, specifically, of their small-molecule metabolite profiles. The metabolome represents the collection of all metabolites in a biological organism — the end products of its gene expression. Metabolomic analysis allows us to directly see that the biochemical consequences of mutations changes in the environment and via drug treatment. Food can affect all areas of gene expression.

Four independent studies have also linked a single gene variation, complement factor H (CFH), to an increased risk for AMD. CFH might play a role in protecting blood vessels from inflammation and damage. It's also implicated in the development of soft drusen. To date, researchers believe about 10 different genes may be responsible for various aspects of AMD.⁴

• Vascular Endothelial Growth Factor (VEGF). This protein stimulates vascular edothelial cell growth. It binds to and activates two related receptors on the endothelial cell membrane, which initiate a signaling cascade that impacts the survival, proliferation and migration of endothelial cells, leading to angiogenesis.

The environmental and cellular triggers of VEGF include hypoxia, oncogenes, tumor suppressor genes, cellular receptor-induced VEGF expression and other growth factors and cytokines.

A patient's nutritional status influences DNA and RNA protein signaling or expression. Molecular nutrition protects our DNA and helps to control oxidized lipids (carboxyethylpyr-roles, CEPs), now linked with the development of wet AMD.⁵

• NFkB, inflammation and antioxidants. NFkB protein is found in many different cell types including B- and T-lymphocytes, macrophages and monocytes. Several autoimmune-mediated diseases are associated with over activity of NFkB. In resting cells, NFkB accumulates in the cytoplasm of the cell. The generation of reactive oxygen species (ROS) by phagocytic leukocytes is one of the most important hallmarks of the inflammatory process.

The common link between all aspects of gene expression is the food we eat.

In addition to promoting general cytotoxicity, ROS may also act to up-regulate pro-inflammatory gene expression by activating NFkB. A variety of antioxidant molecules, such as N-acetylcysteine, dithiocarbamates, vitamin E derivatives and glutathione peroxidase, can inhibit NFkB activation.⁶

Genes, nutrition & immunity

Our immune system is the "security patrol" of the body. Immunological surface barriers include the mechanical (skin); chemical (keratin) and biological (digestive).

The immune system is organized into two aspects: The Innate Immune System and the Adaptive Immune System. The Innate is made of three components: Humoral-inflammatory process; Chemical-compliment system; and Cellular-white blood cells. The Adaptive Immune System involves lymphocytes, which are involved in cell-mediated immune responses (T cells and B cells, among others). The pluripotential hematopoietic stem cells are derived from bone marrow, and a properly modulated immune system sends a clear message that protects the body against foreign invaders.

Studies have found that donor stem cells can integrate into the adult or degenerating retina if taken from the developing retina at a time coincident with the peak of rod genesis.⁷ These transplanted cells integrate, differentiate into rod photoreceptors, form synaptic connections and improve visual function.

The promise of nutritional genomics is personalized medicine and health based on an understanding of our nutritional needs, nutritional and health status and our genotype. Nutrigenomics will also have impacts on society, and its applications are likely to exceed that of even the Human Genome Project. Balanced, sensible diets may eventually prevent, or at least delay, chronic diseases, including chronic eye disease. The knowledge we gain from comparing diet/gene interactions will eventually find its way into the clinic, where we can affect the disease process by using appropriate nutritional therapy. OM

References furnished upon request.

Dr. Anshel is founder of Corporate Vision Consulting, a company that addresses vision demands related to computer work and nutrition. He also maintains a practice in Carlsbad, Calif.