Nutrigenomics

Definition

Origins

Description

Function

Benefits

Precautions

Risks

Research and general acceptance

Resources

Definition

Nutrigenomics can be defined as the study of the relationships between dietary factors and individual genes. Nutrigenomics is sometimes referred to as:

• nutritional genomics
• nutrigenetics
• nutritional genetics
• the DNA die

Definitions of nutrigenomics often include the determination of individual nutritional requirements based on the genetic makeup of the person, as well as the association between diet and chronic disease. Nutrigenomics is part of a broader movement toward personalized medicine, focusing on a personalized diet.

Some scientists distinguish between nutrigenomics and nutrigenetics. They define nutrigenomics as the identification of genes that are involved in physiological responses to diet and the genes in which small changes, called polymorphisms, may have significant nutritional consequences. Nutrigenetics is then defined as the study of these individual genetic variations or polymorphisms, their interaction with nutritional factors, and their association with health and disease. Others define nutrigenetics as the study of the functional interactions between food and the genome at the molecular, cellular, and organismic levels, and the ways in which individuals respond differently to diets depending on their genetic makeup.

Known interactions between food and inherited genes

(Illustration by GGS Information Services/Thomson Gale.)

Jose M. Ordovas, a pioneer researcher in the field, uses the following definition: ‘Nutritional genomics covers nutrigenomics, which explores the effects of nutrients on the genome, proteome and metabolome, and nutrigenetics, the major goal of which is to elucidate the effect of genetic variation on the interaction between diet and disease.’ The genome is the DNA that makes up an individual’s genes. The proteome consists of all of the proteins—the products of gene expression—that are produced under specific conditions. The metabolome is comprised of all of the metabolites in the body under specific dietary and physiological conditions. However many authors do not distinguish between the terms nutritional genomics, nutrigenomics, and nutrigenetics.

Origins

The concept that diet influences health is an ancient one. In 400 B.C. Hippocrates advised physicians: ‘Leave your drugs in the chemist’s pot if you can heal your patient with food.’ Likewise it has long been known that individuals can differ in their requirements for a given nutrient.

Nutrigenomics includes known interactions between food and inherited genes, called ‘inborn errors of metabolism,’ that have long been treated by manipulating the diet:

• Phenylketonuria (PKU) is caused by a change (mutation) in a single gene. Affected individuals must avoid food containing the amino acid phenylalanine.
• Many Asians have a defective aldehyde dehydrogenase enzyme, which is involved in ethanol metabolism. Alcohol consumption has unpleasant effects on these individuals.
• Galactosemia—caused by an inherited defect in one of three enzymes involved in the metabolism of the sugar galactose—is controlled with a milk-free diet, since galactose is a metabolite or breakdown product of lactose or milk sugar.
• The majority of adults in the world are lactose intolerant, meaning that they cannot digest milk products, because the gene encoding lactase, the enzyme that breaks down lactose, is normally ‘turned off after weaning. However some 10,000-12,000 years ago a polymorphism in a single DNA nucleotide appeared among northern Europeans. This single nucleotide polymorphism—a SNP—resulted in the continued expression of the lactase gene into adulthood. This was advantageous because people with this SNP could utilize nutritionally-rich dairy products in regions with short growing seasons.

With the revolution in molecular genetics in the late twentieth century, scientists set out to identify other genes that interact with dietary components. By the 1980s companies were commercializing nutrigenomics. The Human Genome Project of the 1990s, which sequenced all of the DNA in the human genome, jump-started the science of nutrigenomics. By 2007 scientists were discovering numerous interrelationships between genes, nutrition, and disease.

Description

Principles of nutrigenomics

Nutrigenomics draws from various scientific disciplines including:

• genetics
• molecular biology
• bioinformatics
• biocomputation
• physiology
• pathology
• nutrition
• sociology
• ethics.

There are five principles of nutrigenomics:

• Diet can be a serious risk factor for a number of diseases for some individuals under certain circumstances.
• Substances in the diet can act on the human genome, either directly or indirectly, to alter gene structure or expression.
• Individual genetic makeup or genotype can influence the balance between health and disease.
• Genes that are regulated by dietary factors can play a role in the onset, incidence, progression, and/or severity of chronic diseases.

KEY TERMS

APO —Apolipoprotein; proteins that combine with lipids to form lipoproteins; APOA1 is one of the class A apoliproteins; APOE is a class E apolipoprotein.

DNA methylation —The enzymatically controlled addition of a methyl group (CH3) to the nucleotide base cytosine in DNA; methylation is involved in suppressing gene expression or turning off genes.

Epigenetic —A modification of gene expression that is independent of the DNA sequence of the gene.

Folic acid —Folate; a B-complex vitamin that is required for normal production of red blood cells and other physiological processes; abundant in green, leafy vegetables, liver, kidney, dried beans, and mushrooms.

Galactosemia —An inherited metabolic disorder in which galactose accumulates in the blood due to a deficiency in an enzyme that catalyzes its conversion to glucose.

Genome —A single haploid set of chromosomes and their genes.

Genotype —All or part of the genetic constitution of an individual or group

HDL cholesterol —High-density lipoprotein; ‘good’ cholesterol that helps protect against heart disease.

Homocysteine —An amino-acid product of animal metabolism that at high blood levels is associated with an increased risk of cardiovascular disease (CVD).

Kinase —An enzyme that catalyzes the transfer of phosphate groups from high-energy phosphate containing molecules, such as ATP, to another molecule.

Lactose —Milk sugar; a disaccharide sugar present in milk that is made up of one glucose molecule and one galactose molecule.

LDL cholesterol —Low-density lipoprotein; ‘bad’ cholesterol that can clog arteries.

Metabolome —All of the metabolites found in the cells and fluids of the body under specific dietary and physiological conditions.

MTHFR —Methylene tetrahydrofolate reductase; an enzyme that regulates folic acid and maintains blood levels of homocysteine.

Phenylketonuria —PKU; an inherited metabolic disorder caused by an enzyme deficiency that results in the accumulation of the amino acid phenylalanine and its metabolites in the blood.

Polymorphism —A gene that exists in variant or allelic forms.

Polyunsaturated fatty acid —PUFA; fats that usually help to lower blood cholesterol; found in fish, saf-flower, sunflower, corn, and soybean oils.

Proteome —All of the proteins expressed in a cell, tissue, or organism.

SNP —Single nucleotide polymorphism; a variant DNA sequence in which the base of a single nucleo-tide has been replaced by a different base.

Triglycerides —Neutral fat; lipids formed from one glycerol molecule and three fatty acids that are widespread in adipose tissue and circulate in the blood as lipoproteins.

• Dietary intervention based on individual nutritional status and requirements and genotype can prevent, mitigate, or cure chronic disease.

Nutrigenomics is in sharp contrast to the traditional food pyramid and recommended daily allowances (RDAs) that are intended to prevent nutritional deficiencies in the general population. Nutrigenomics also contrasts with foods and supplements that are claimed to be beneficial for everyone. Rather genetic variations among individuals can result in very different responses to general diets and specific foods. Nutrigenomics can be applied to populations, sub-populations, and ethnic groups that share genetic similarities, as well as to individuals.

Nutrigenomic diseases

Diseases and conditions that are known to have genetic and/or nutritional components are candidates for nutrigenomic studies to determine whether dietary intervention can affect the outcome. Differences in genetic makeup or genotype are factors in:

• gastrointestinal cancers
• other gastrointestinal conditions or digestive diseases
• inflammatory diseases
• osteoporosis.

Nutrient imbalances are factors in:

• aging
• alcoholism/substance abuse
• behavioral disorders
• cancer
• cardiovascular disease (CVD)
• chronic fatigue
• deafness
• diabetes
• immune disorders
• macular degeneration
• multiple sclerosis
• neurological disorders
• osteoporosis
• Parkinson’s disease
• stroke.

Diseases that are known to involve interactions between multiple genetic and environmental factors such as diet include:

• many cancers
• diabetes
• heart disease
• obesity
• some psychiatric disorders.

Inherited mutations in genes can increase one’s susceptibility for cancer . The risk of developing cancer can be markedly increased if there is a gene-diet interaction. Studies of twins show that the likelihood of identical twins developing the same cancer is less than 10%, indicating that the environment plays an important role in cancer susceptibility. There are various examples of the effects of diet on cancer risk:

• High consumption of red meat has been shown to increase the risk of colorectal cancer.
• The incidence of colon cancer among Japanese increased dramatically after the 1960s as the Japanese diet became westernized.
• Dietary fiber has a protective effect against bowel cancer.
• Some studies have shown a relationship between dietary fat and breast cancer

Among people with high blood pressure only about 15% have sodium-sensitive hypertension . For the other 85%, eliminating salt from the diet has no effect on their blood pressure. Nutrigenomics is addressing why some people can control their hypertension with diet, whereas others require drugs.

SNPs

The DNA sequence of the human genome varies by only 0.1% between individuals. However that small variation is very important for disease susceptibility. These variations in the DNA sequences of genes are called polymorphisms. Some polymorphisms affect the functioning of the proteins encoded by the genes. The most common type of variation is a change in just one nucleotide or unit of the DNA sequence, called a single nucleotide polymorphism or SNP. Some of the differences in individual responses to components of food are due to SNPs, which may change the way a protein interacts with metabolites in the body.

MTHFR One of the best-known examples of a gene-nutrient interaction is the MTHFR gene that encodes the enzyme methylene tetrahydrofolate reductase. MTHFR regulates folic acid and maintains blood levels of homocysteine. A specific SNP in the MTHFR gene is found in 10% of northern Europeans and 15% of southern Europeans. People with this SNP in both copies of their MTHFR gene have elevated levels of homocysteine in their blood, particularly if their intake of folic acid is low. This condition is associated with CVD. However it is not yet known whether folic-acid supplementation will prevent CVD in these individuals a recent study in the British Medical Journal supported the use of folic acid supplements for those with elevated homocysteine levels. This SNP in MTHFR is also associated with a reduced risk for colon cancer, but only if folic-acid intake is normal. However there is no evidence that treatment with folic acid, or eating foods such as beans, peas, green leafy vegetables, and fortified grains that provide folic acid, will prevent colon cancer. There are numerous genes associated with the development of CVD and a multitude of dietary nutrients that interact with these genes. Researchers have also found genetic differences in folic-acid metabolism among black American and Mexican women and MTHFR SNPs have been associated with other disorders including severe migraines and depression.

LIPID METABOLISM One of the first applications of nutrigenomics was to examine the differences among individuals and populations in the blood levels of lipids—triglycerides and HDL (‘good’) and LDL (‘bad’) cholesterol—and the effect of high-fat diets on these levels. High levels of HDL cholesterol are associated with a reduced risk for CVD. Dietary changes have a modest beneficial effect on blood-lipid levels in the majority of people. However some people experience no effect and others experience the opposite effect from the same dietary modifications. SNPs in genes that are directly or indirectly involved in lipoprotein metabolism may be responsible for these differences. Therefore typical healthy diet recommendations may actually harm people who have a specific genotype.

In women who have a particular SNP in the gene encoding apolipoproteinA-1 (APOA1), an enzyme involved in lipid metabolism, high levels of HDL cholesterol are correlated with high consumption of poly-unsaturated fatty acids (PUFA). In contrast women who have the more common form of APOA1 have low levels of HDL cholesterol with high consumption of PUFA. Thus this SNP may be associated with a large change in the risk for CVD. The relationship between HDL cholesterol and PUFA is not seen in men. Thus increased PUFA consumption—from foods such as fish, vegetable oils, and nuts—would be expected to benefit one group of women, harm another group of women, and have little effect on men, although this has not yet been scientifically demonstrated.

Similarly people carrying a particular SNP in the gene encoding hepatic lipase respond to high-fat diets with increased HDL cholesterol. People with variations in a gene called APOE, which is involved in cholesterol balance, respond differently to low-fat diets. One variant of the APOE gene is associated with an increased risk for Alzheimer’s disease, but only in Caucasians and Japanese. Black Africans with the same variant do not have an increased risk.

Alterations in gene expression

SNPs can cause changes in gene-food interactions by changing the way a protein encoded by the SNP-containing gene interacts with a metabolite. SNPs can also change the expression of a gene, causing the gene to produce more or less protein. Chemicals in foods can also directly or indirectly affect the expression of a gene. Plant chemicals called phytonutrients can alter the cell-signaling pathways that regulate gene expression. Small plant proteins called peptides can also alter the regulation of gene expression. Lunasin is a substance in soy that has been associated with reduced risks for heart disease and several cancers including prostate cancer. Lunasin appears to increase the expression of genes that monitor damage to DNA and suppress the proliferation of tumor cells.

Nutritional factors can act as signaling molecules that interact with a complex system of more than 540 enzymes called kinases. Kinases transmit signals from the environment, including food, to the genome, turning on and off the expression of genes that produce the proteins involved in metabolism. Two kinase pathways are known to be involved in:

• satiety
• insulin signaling
• muscle energy reserves
• lipid metabolism
• inflammation.

These processes are associated with obesity , type 2 diabetes, and atherosclerosis. There are specific phytonutrients that are known to affect these two kinase pathways.

Epigenetic modifications are changes in gene expression that do not affect the DNA sequence of the gene. One of these modifications is DNA methyl-ation, which attaches small molecules to the DNA. During early development DNA methylation is highly susceptible to nutritional and other environmental influences.

Dietary components such as retinoic acid and zinc can bind to DNA and affect gene expression. Zinc, which is abundant in red meat and some seafoods, turns on some genes and turns off others. For example zinc activates genes associated with the production of white blood cells that fight infection. Dietary fatty acids can also directly modify gene expression.

Commercial nutrigenomics

A number of companies offer genetic profiling or genotyping of DNA that is obtained from a swab of the inside of the cheek. The DNA analysis, along with a detailed nutritional and lifestyle questionnaire, is used to recommend individualized nutritional changes for improving health and preventing disease. However as of 2007 less than 20 genes were being tested for variations that have nutrigenomic implications. These include:

• MTHFR
• genes affecting cholesterol levels
• genes affecting insulin sensitivity
• a specific genetic variation that makes it more difficult to absorb calcium in the presence of caffeine.

The report, which costs $250-$1,500, may include an estimate of folate levels in the body based on the questionnaire. Some companies then sell the client supplements or products that are claimed to be nutrigenomic.

For the majority of people a nutrigenomic diet will not differ significantly from a standard diet that includes plenty of fruits and vegetables. The client may be told to get more exercise and to avoid:

• alcohol
• processed bread

  preservatives

• bacon and sausage
• dairy
• junk food.

Nutrigenomics is almost certainly the wave of the future. As more gene-diet associations are discovered, genetic profiling and nutritional prescriptions are expected to become commonplace. For this reason major food corporations are investing large amounts of money in nutrigenomics and in the development of new products to meet the demands of personalized diets. Nutrigenomics is also being applied to the development of pet foods and animal feed stocks.

Function

Although it is widely believed that nutrigenomics will have a tremendous impact on diets in the not-too-distant future, as of 2007 it was not particularly relevant to the average consumer. Most people who buy commercial nutrigenomic products:

• are middle-to-upper class
• have a family history of chronic disease or weight problems
• are worried about aging and age-related diseases
• have a strong commitment maintaining good health.

Nutrigenomics may be most relevant for the approximately 20% of the population for whom diet has little affect on health and for the approximately 20% for whom a conventional diet is unhealthy. The former group may want to feel free to eat whatever they choose and the latter group may need professional advice in designing an appropriate diet. However some experts believe that the future of nutrigenomics is as a population—rather than an individual—nutritional program, with the development of foods that meet the nutritional requirements for the majority of genotypes, thus maximizing the benefits.

Benefits

The mission of the National Center for Minority Health and Health Disparities (NCMHD) Center of Excellence for Nutritional Genomics, a major nutrigenomics initiative at the University of California at Davis, is: ‘to reduce and ultimately eliminate racial and ethnic health disparities‘ that result from interactions between genes and the environment, particularly dietary factors. Its goal is to devise ‘genome-based nutritional interventions to prevent, delay, and treat diseases such asthma, obesity, Type 2 diabetes, cardiovascular disease, and prostate cancer.’

However current benefits from nutrigenomics are limited:

• Obtaining a personalized dietary regimen may encourage people to become more health conscious.
• People are more likely to heed advice that they pay for.
• Discovering genetic susceptibilities can be a strong motivator for making dietary and lifestyle changes.

The potential future benefits from nutrigenomics are tremendous:

• The safe upper and lower limits for essential macro-nutrients—proteins, carbohydrates, and fats—and micronutrients such as vitamins and minerals will be better defined and understood.
• Diseases may be avoided or ameliorated.
• Unnecessary vitamins and other dietary supplements can be avoided.
• People whose health is relatively unaffected by diet can continue to eat foods that they enjoy.
• Lifespan may be extended.

Precautions

Far more research is needed before nutrigenomic diets become a reality. There are very few diet-gene interactions for which there is enough information to yield specific useful advice and even fewer genetic variants that can be screened for. Nutrigenomic prescriptions will probably differ depending on age and other physiological conditions including pregnancy.

At present there is no evidence that nutritional changes made on the recommendations of commercial analysis will reduce an individual’s risk of developing a particular disease. John Erdman, professor of food sciences and human nutrition at the University of Illinois at Urbana-Champaign, told U.S. News & World Report in 2006: ‘Identifying a handful of genes from a snippet of hair or a mouth swab and returning with a diet plan and a bill for several hundred dollars is a waste of money and is way premature.’

Nutrigenomics companies have been accused of making false claims. The U.S. Government Accounting Office concluded in 2006 that nutrigenomic tests lacked scientific accountability and could be misleading to consumers. As of 2007 many of the products marketed by these companies were supplements that had no basis in nutrigenomics.

Nutrigenomic testing raises numerous ethical questions, such as whether genetic profiling should remain restricted to wealthy clients or whether it should be available as standard healthcare coverage.

QUESTIONS TO ASK YOUR DOCTOR

• Are you familiar with nutrigenomicsand genetic profiling?
• Do I have symptoms that might be explained by interactions between genes and food?
• Am I a candidate for genetic testing?
• Would you be able to make nutritional and lifestyle recommendations based on the results of my tests?
• Are there other types of medical tests that would give me the same or better information?

Risks

Nutrigenomics risks include:

• The knowledge of a disease susceptibility may cause high levels of anxiety and stress.
• Genetic testing raises privacy concerns—some companies already sell the results of their genetic profiling to other companies.
• Those with known genetic susceptibilities may be discriminated against in employment or health insurance.
• Physicians may not be qualified to interpret nutrige-nomic reports and make appropriate decisions based on them.
• The demand for nutrigenomic evaluations may eventually overtax the healthcare system. As with any new technology, nutrigenomics also may pose as-yet-unrecognized risks.

The nutrigenomics industry remains unregulated. It is unclear whether any future regulation will treat nutrigenomics as medicine or as nutrition.

Research and general acceptance

Research

Nutrigenomics is a very active field of research in both the United States and Europe and clinical studies are ongoing. Evidence is accumulating that the nutrients in food and supplements may affect the expression and even the structure of specific genes. However the science of nutrigenomics is extremely complex. The elucidation of the APOA1 gene variants was possible only because of a very large decades-long epidemiological study called the Framingham Heart Study. Although most experts believe that any clinical applications of nutrigenomics are premature, some scientists believe that reliable diet recommendations based on individual genetic profiles may be available as early as 2010.

Many scientists believe that nutrigenomics has tremendous potential for improving public health. In the future it will probably be possible to analyze DNA to precisely determine individual nutritional guidelines, with diets designed to fit a specific genetic profile. Specific products may be available to meet the health requirements of individuals. Technological developments may enable doctors to perform nutrigenomic tests in their offices. Children may be tested at a young age so that diet can be used as preventative medicine. The development of nutrigenomics is expected to revolutionize the dietetics profession.

General acceptance

Very few consumers have as yet made use of nutrigenomics. However the food industry, healthcare providers, and consumers have vested interests in the development of the science. Studies have shown that 85–93% of people believe that diet is an important part of health and of the management of aging and conditions such as arthritis. However it is also possible that nutrigenomics will suffer a consumer backlash, similar to the European backlash against genetically-modified foods.

Resources

BOOKS

Brigelius-Flohe, Regina and Hans-Georg Joost, editors. Nutritional Genomics: Impact on Health and Disease. Weinheim: Wiley-VCH, 2006.

Castle, David. Science, Society, and the Supermarket: The Opportunities and Challenges of Nutrigenomics. Hobo-ken, NJ: Wiley-Interscience, 2007.

DeBusk, R. M. Genetics: The Nutrition Connection. Chicago: American Dietetic Association, 2003.

Kaput, J. and R. Rodriguez, editors. Nutritional Genomics: Discovering the Path to Personalized Nutrition. New York: Wiley & Sons, 2006.

Meskin, Mark S., and Wayne R. Bidlack, editors. Phyto-chemicals: Nutrient-Gene Interactions. Boca Raton, FL: CRC, 2006.

PERIODICALS

Check, Erika. ‘Consumers Warned That Time Is Not Yet Ripe for Nutrition Profiling.’ Nature 426 (November 13, 2003): 107.

DeBusk, Ruth M. ‘Nutrigenomics and the Future of Dietetics.’ Nutrition & Dietetics: The Journal of the Dieticians Association of Australia 62 (June-September 2005): 63-65.

Goodman, Brenda. ‘The Do-It-Your-Way Diet.’ Health 20 (July-August 2006): 136-142.

Gorman, Christine. ‘Does My Diet Fit My Genes?’ Time 167 (June 12, 2006): 69.

Grierson, Bruce. ‘What Your Genes Want You to Eat.’ New York Times Magazine (May 4, 2003): 76-77.

Hawkinson, Ani K. ‘Nutrigenomics and Nutrigenetics in Whole Food Nutritional Medicine.’ Townsend Letter for Doctors and Patients 282 (February-March 2007): 102-103.

Healy, Bernadine, ‘Food With a Purpose.’ U.S. News & World Report 140 (February 13, 2006): 60.

Kummer, Corby. ‘Your Genomic Diet.’ Technology Review 108 (August 2005): 54-58.

Ordovas, J. M., et al. ‘Polyunsaturated Fatty Acids Modulate the Effects of the APOA1 G-A Polymorphism on HDL-Cholesterol Concentrations in a Sex-Specific Manner: The Framingham Study.’ American Journal of Clinical Nutrition 75 (2002): 38-46.

Pray, Leslie A. ‘Dieting for the Genome Generation: Nutrigenomics Has Yet to Prove its Worth. So Why Is It Selling?’ The Scientist 19 (January 17, 2005): 14-16.

Trivedi, Bijal. ‘Feeding Hungry Genes’ New Scientist 2587 (January 20, 2007).

Trujillo, E., D. Davis, and J. Milner. ‘Nutrigenomics, Pro-teomics, Metabolomics, and the Practice of Dietetics.’ Journal of the American Dietetic Association 106 (March 2006): 403-413.

OTHER

Burton, Hilary, and Alison Stewart. ‘Nutrigenomics.’ The Nuffield Trust February 5, 2004. <http://www.nuffieldtrust.org.uk/ecomm/files/Nutrigenomics.pdf> (March 23, 2007).

Mosing, Lisa. ‘Nutrigenomics: The DNA Diet Approach.’ Lifescript March 29, 2006. <http://www.lifescript.com/channels/food_nutrition/> (March 23, 2007).

‘Nutrigenomics.’ Talk of the Nation December 26, 2003. <http://www.npr.org/templates/story/story.php?storyId=1571846> (April 16, 2007).

ORGANIZATIONS

American Dietetic Association. 120 South Riverside Plaza, Suite 2000, Chicago, IL 60606-6995. Telephone: (800) 877-1600. <http://www.eatright.org>.

Center for Emerging Issues in Science. Life Sciences Research Office, Inc. 9650 Rockville Pike, Bethesda, MD 20814. (301) 634-7030. <http://www.LSRO.org>.

European Nutrigenomics Organisation (NuGO). Nutrigenomics Society. <http://www.nugo.org>.

Institute for the Future. 124 University Avenue, 2nd Floor, Palo Alto, CA 94301. (650) 854-6322. <http://www.iftf.org/>.

National Center for Minority Health and Health Disparities (NCMHD) Center of Excellence for Nutrigenomics. Section of Molecular and Cellular Biology, University of California, 1 Shields Avenue, Davis, CA 95616. (530) 752-3263. <http://nutrigenomics.ucdavis.edu>.

National Human Genome Research Institute. National Institutes of Health. Building 31, Room 4B09, 31 Center Drive, MSC 2152, 9000 Rockville Pike, Bethesda, MD 20892-2152. (301) 402-0911. <http://www.genome.gov>.

Margaret Alic, PhD