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James Kaput, Department of Surgery, University of Illinois, Chicago, Section of Cellular and Molecular Biology, Center of Excellence in Nutritional Genomics, University of California at Davis, and Scientific Advisor, European Nutrigenomics Organisation (NuGO), summarizes the conceptual basis of nutrigenomics with five tenets: (i) improper diets are risk factors for disease; (ii) dietary chemicals alter gene expression and/or genome structure; (iii) the influence of diet depends on an individual's genetic makeup; (iv) genes regulated by diet play a role in chronic disease; and (v) personalized nutrition based on genotype, nutritional requirements, and status prevents and mitigates chronic disease.
New NutritionHelen Kim, Department of Pharmacology and Toxicology and Co-Director, University of Alabama at Birmingham (UAB) Comprehensive Cancer Center Mass Spectrometry/Proteomics Shared Facility, uses proteomic approaches to study the effects of antioxidant polyphenol-rich dietary supplements on in vivo models of neurodegeneration and other chronic diseases, a field she refers to as “new (nontraditional) nutrition.” Her lab is looking at the effects on the brain subproteome of expressed proteins that are affected by dietary agents. “A major point of this research is that proteomics detects proteins directly affected by stimuli, whereas the genomics may be unchanged, the messenger RNA (mRNA) may be the same, but the protein is modified, so we are looking at the epigenetic effect on the function of interest.”
Polyphenolic antioxidants [e.g., resveratrol (from grapes), catechin (tea and grapes), and genistein (soy)] have been shown to have beneficial effects on learning and memory capacity in animals and people. Kim has compared brain proteins from rats whose diet included grape seed extract for 6 weeks with rats fed a control diet. The brain proteins show differences by two-dimensional (2-D) gel electrophoresis. Although differences can be due to increased expression, she has found differences that would not be detected by examining mRNA levels. Using mass spectrometry, she has confirmed that spots in different locations in the grape seed diet versus control diet are the same protein, migrating differently due to changes in charge or acidity. She has also seen two isoforms of the same protein both reduced to the same extent by the grape seed diet, which would have been impossible to discern by examining mRNA differences alone. Other effects include changes in molecular weight due to differential processing. “The value of proteomics,” Kim observes, “is that proteins are the functional readout of genes, they are the molecules that do things. These functions can be directly affected by dietary compounds like antioxidants.”
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Joe Vinson, Department of Chemistry, University of Scranton, PA, believes that along with various vitamins, glutathione, and enzymes, phytochemicals contribute to the body's defense against oxidative stress, e.g., in the form of free radicals that are created by many disease processes, including hyperlipidemia and diabetes. Vinson's group sampled common foods, determined the total amount of phenols and antioxidant activity, and estimated the per capita intake of polyphenolic antioxidants in the United States based on the 2003 U.S. Department of Agriculture database of consumption. In the U.S., beverages, including coffee, tea, red wine, fruit juice, and beer, contribute to 49% of total per capita intake of phenolic antioxidants. Nuts contribute 20%, fruits 12%, vegetables 10%, and grains 9%.
“We don't know if phytochemicals effective in one disease will be good for another,” Vinson notes. “We need a wide variety in our diet. Although cranberries, red grapes, and cherries are higher in antioxidants, in the U.S., bananas contribute more antioxidants than do other fruit, whereas in other countries apples are the number one fruit source. It depends on the ability to buy fresh fruit.”
Stephen Barnes, Departments of Pharmacology and Toxicology, Biochemistry and Molecular Genetics, Environmental Health Sciences, Center for Nutrient-Gene Interaction, Purdue-UAB Botanicals Centers for Age-Related Disease, Comprehensive Center at UAB, notes that in addition to individual differences in the expression of genes involved in metabolism, we need to understand differences in what we are eating. “The nutrient content of food is affected by farming practices and manufacturing, e.g., the omega 3 fatty acids in fish come from plankton, and if there are no plankton available to farmed fish, these fish may not have the omega 3 fatty acid content of wild fish,” he says. Further, he observes that “we are the minor organism in our bodies. There are more bacteria in the gut than human cells, so the genetic variation of our bacterial flora should be considered, too.”
A Matter of TasteAhmed El-Sohemy, Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Canada, is identifying genetic determinants of individual food preferences. Taste, says El-Sohemy, is probably the most important determinant. At least one taste receptor gene for each of the five tastes, sweet, salty, umami (glutamine), sour, and bitter, has been identified. Many, but not all, people perceive members of the Brassicaceae (Cruciferae) family, which includes cabbage, broccoli, and cauliflower, as bitter. El-Sohemy speculates that although toxic chemicals in plants tend to be bitter, some bitter nontoxic foods may have helped nontasters survive in some populations.
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Phenylthiocarbamide (PTC), a synthetic chemical similar to bittertasting vegetables, has been used for decades to classify people as supertasters, tasters, and nontasters. In a study of 638 people, the ability to taste PTC was correlated with allelic frequencies of the bitter taste gene TAS2R38. Individuals who self-reported Asian ethnicity were more likely to have the supertaster genotype, yet all had a preference for green tea, which other ethic groups with the supertaster genotype perceived as bitter and did not prefer. An allele of a second bitter receptor gene, TAS2R50, is associated with a preference for grapefruit juice, but not other citrus or bitter foods, by both whites and Asians, and to a greater degree by women than men. “There are over two dozen other genes in this family that have not been studied,” says El-Sohemy. This has led to what he calls “genetic confounding” of epidemiologic observational studies in people. “Are broccoli lovers the same genetically as broccoli haters? If not, what does the lower colon cancer rate in broccoli eaters mean? If grapefruit avoiders are at risk for some diseases, are they also avoiding something else that has not yet been identified?” he asks.
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No Simple Solution
Jose M. Ordovas, Nutrition and Genetics, School of Nutrition Science and Policy, Director, Nutrition and Genomics Laboratory and Lipid Metabolism Laboratory, Jean Mayer-USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, has been working in the field of nutrigenomics for over 20 years. “The network of players in this game is quite amazing. For diseases like obesity, cardiovascular disease, and osteoporosis, there are hundreds of genes involved. All we can do is place each piece by piece in place like a puzzle,” he says. “The technology is not an issue. The problem we are all confronting is the statistical analysis. The tools we have are not optimal to deal with gene-nutrient interactions, to allow us to connect the dots with large populations of people with lots of phenotypes.” Still, he believes the promise is great. “We have been looking at the low hanging fruit, but new approaches, including genomics, should help define new ways genes interact with nutrients, physical activity, and the environment.”
His group focuses on lipoprotein metabolism and genetic predisposition to obesity. They would like to be able to predict who will and will not respond to different types of diets, because it is clear that not all diets are successful for all people. Some subpopulations, which are “wired for starvation,” have not been able to cope with a wealth of calories. “There is no simple solution, no silver bullet,” Ordovas says. “Our biology has a backup system, it's redundant. We can sequence everybody, but the question is to understand the data.”
Future DirectionsOrdovas sees progress in the future coming from a critical mass of statisticians, geneticists, physiologists, and behaviorists forming a large network to study large populations. Barnes asks, “Can we motivate individuals at risk to change their dietary habits?” Kaput says it remains to be determined how to produce foods that are nutritional, edible, stable, shippable, and will allow us to feed all the hungry in the world. “It does no good,” he observes, “to tell people in inner cities to eat well if no fresh fruits and vegetables are available.”
