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Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095 and * Department of Pediatrics, Harbor-UCLA Medical Center, Los Angeles, CA 90025
4To whom correspondence should be addressed. E-mail: vlwgo{at}ucla.edu.
ABSTRACT
The U.S. Department of Health and Human Services (DHHS)/USDA Dietary Guidelines for Americans is a science and population evidence-based guide on diet and physical activity, providing advice and recommendations to promote a healthier lifestyle and reduce the risk of chronic diseases, including cancer. These recommendations are supported by the comprehensive evidence-based review on diet and cancer prevention conducted by the American Institute for Cancer Research, National Cancer Institute, World Health Organization/International Agency for Research on Cancer, and others. However, influencing dietary effects are the individual genetic predispositions that are the basis for considerable interindividual variations in cancer risk within the population and in nutrient homeostasis, which is maintained by genomic-nutrient and metabolic-phenotype interactions. Although genetics is an important component, it accounts for only a portion of this variation. An individual’s overall phenotype, including health status, is achieved and maintained by the sum of metabolic activities functioning under differing circumstances within the life cycle and the complex interactions among genotype, metabolic phenotype, and the environment. In this postgenomic era, high-throughput groups of technologies in genomics, proteomics, and metabolomics measure and analyze DNA sequences, RNA transcripts, proteins, and nutrient-metabolic fluxes in a single experiment. These advances have transformed biomarker studies on nutrient-gene interactions from a reductionist concept into a holistic practice in which many regulated genes involved in metabolism, along with its metabolic phenotypes, can be measured through functional genomics and metabolic profiling. The overall integration of data and information from the building blocks of metabolism-based nutrient-gene interaction can lead to future individualized dietary recommendations to diminish cancer risk.
KEY WORDS: • nutrient-gene interaction • genotype-phenotype continuum • Dietary Guidelines for Americans 2005
Good nutrition is vital to good health, optimal growth and development, and prevention of diseases. Through untold millennia, people have come to appreciate the food-health connection and different civilizations have incorporated this concept into their approach to healing. With the advent of nutritional sciences, we now understand that nutrients and other food substances obtained when eating a wide variety of foods promote health, maintain metabolic homeostasis, and fulfill our energy requirements. After World War II, various governments began to establish dietary guidelines for their populations to address the state of nutrient deficiencies and to conquer deficiency-related diseases through public health policy recommendations. The current U.S. dietary guidelines are population- and evidence-based advice on diet. However, humans differ in many ways in their response to diet because of interindividual variations in genetic, epigenetic, and metabolic phenotype status. Therefore, to transform current population-based dietary guidelines into future personalized dietary recommendations, we will need tools and knowledge to investigate the molecular basis of genetic variation. These tools will provide an overview of the metabolic status and biochemical events associated with cellular and biological organ systems as well as nutrient-specific responses, including genotype expression, which determines the metabolic phenotype that leads to the various predispositions to diet-related diseases (1).
Although genetics is an important component, it accounts for only a portion of this variation. An individual’s overall phenotype, including health status, is achieved and maintained by the sum of metabolic activities functioning under different circumstances within the life cycle and the complex interactions among genotype, metabolic phenotype, diet, lifestyle, and the environment. Metabolic regulation, from genes to metabolites, dictates biochemical functions as well as the nutritional and dietary needs of an individual. Therefore, genetic disposition and metabolic needs are important in determining the optimal diet for an individual. In this postgenomic era, high-throughput technologies in genomics, proteomics, and metabolomics can now measure and analyze DNA sequences, RNA transcripts, proteins, and nutrient-metabolic fluxes in a single experiment (2,3). The overall integration of information obtained through such high-throughput technologies will lead to individual metabolic genotype and phenotype analysis and can give rise to personalized nutrition and dietary recommendations to help individuals maintain a healthier nutritional status and prevent chronic diseases. This manuscript will review the current population-evidence-based Dietary Guidelines for Americans 2005 (4), the technological advances investigating the metabolic genotype-phenotype continuum, and the relationship and application of nutrigenomic concepts to individual diet and cancer prevention.
Dietary Guidelines for Americans 2005
The Dietary Guidelines for Americans was first published in 1980. The guidelines are reviewed, updated if necessary, and published every 5 years as required by public law (5). The Dietary Guidelines for Americans, which targets the general population over 2 y of age, established the direction for all U.S. government nutrition programs, including research, education, food assistance, labeling, and nutrition promotion as well as other programs focused on health promotion and risk reduction.
The process of developing of the 2005 Dietary Guidelines for Americans involved 3 stages (Fig. 1). In the first stage the U.S. Department of Health and Human Services (DHHS) and USDA jointly appointed a 13-member Dietary Guidelines Advisory Committee to review new scientific information. The committee conducted an evidence-based review of the literature on diet and health, primarily reports related to evidence obtained from randomized controlled trials, cohort and case-control studies, and occasionally ecological studies—by analyzing national data sets such as those used in the Institute of Medicine’s reports and comprehensive evidence-based reviews on diet and cancer prevention conducted by the American Institute for Cancer Research, National Cancer Institute, World Health Organization/International Agency for Research on Cancer, and others. In August 2004 the committee submitted its report, which was made available to the general public and government agencies for comment (6).
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During the second stage, DHHS and USDA jointly developed key recommendations based on the advisory committee’s report along with public and federal agency comment and then published the Dietary Guidelines for Americans 2005 in January 2005 (4). Finally, in the third stage, DHHS and USDA staff revised the one-size-fits-all food guideline pyramid system to the new MyPyramid Steps to a Healthier You. This new food guideline system is Web-based and can provide recommendations that take into account an individual’s age, sex, and physical activity level. In addition, a few special nutrient recommendations were included for specific populations including the elderly, women, and women of childbearing age (7).
The 2005 edition of the Guidelines encourages most Americans to consume fewer calories, be more active, and make wiser food choices. The key recommendations are grouped under 9 interrelated focuses. These include: 1) consuming a variety of foods within and among the basic food groups while staying within energy needs; 2) controlling calorie intake to manage body weight; 3) being physically active every day; 4) increasing daily intake of fruits and vegetables, whole grains, and nonfat or low-fat milk and milk products; 5) selecting fats wisely for good health; 6) choosing carbohydrates wisely for good health; 7) choosing and preparing foods with little salt; 8) drinking alcoholic beverages in moderation if at all; and 9) keeping food safe to eat.
These recommendations are formulated using population-based evidence science for individual health promotion and disease prevention. However, as our knowledge of genetic information progresses and our understanding increases on the specific influence of certain food components on metabolic pathways and phenotype during an individual’s life cycle, we will gain the ability to tailor nutritional advice based on a person’s specific metabolic profile. Assessment of the long-term risk for disease and personalized dietary recommendations can be made based on an individual’s genotype and metabolic phenotype resulting from the complex interaction of the genotype-phenotype continuum under differing circumstances in the context of an individual’s life cycle, lifestyle, and environment. Undoubtedly, these factors will be considered in future revisions of the Guidelines (1).
Metabolic genotype-phenotype relationship
One of the key achievements in biological science research over the past 100 y was the elucidation of the biochemical pathways in human metabolism. The relationship of enzymes, cofactors, substrates, metabolites, and enzyme kinetics influencing metabolic pathway fluxes has been partially or fully characterized. The assembled biochemical and cellular physiological knowledge of the role of nutrients on human metabolism has transformed the practice of medicine and public health policy in mitigating nutrient deficiency. This biochemical-metabolism knowledge base has also had a major impact on our food supplies and the development of pharmaceutical and biotechnology industries (2). As Carpenter (8) pointed out in his short history of nutritional science series, the developments made in the early to mid 20th century are now seen as the "golden age of nutrition."
In the later half of the past century, after the discovery of the structure of DNA by Watson and Crick, and the beginning of this century with the decoding of the human genome, a massive advance has been made in technological development in genomics, proteomics, and metabolomics and the bioinformatic processing of the massive data sets generated (9) (Fig. 2). Functional analysis at the level of the genome (large-scale DNA sequencing that provided insight to the heterogeneity in coding regions of genes that leads to polymorphisms), of gene expansion (transcriptomics), of protein translation (proteomics), and of metabolite network and fluxes (metabolomics) is now fully developed. These new "omic" technologies permit the investigation of the multistep molecular pathway from genome to phenotype in nutrient metabolism as a continuum, and interrelated complex metabolic network, or both (2) (Fig. 3).
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Cancer is now considered a chronic disease of the genome that may be influenced at many stages in its natural history by nutritional and metabolic factors that affect not only the prevention but also the progression and treatment of this devastating disease. The cancer phenotype is the result of the interaction of both genetic and environmental influences and most of the evidence for this is drawn on studies of human populations as well as from animal experiments that model the process of carcinogenesis (19). Perhaps the strongest evidence environmental influence is that of diet. It is estimated that up to 80% of colon, breast, and prostate cancer cases and one third of all cancer cases may be influenced by diet and associated lifestyle factors. All classical nutrient categories consist of bioactive dietary compounds, including carbohydrates, amino acids, fatty acids and structural lipids, minerals, and vitamins. In addition, there is an extensive list of non-nutrient components, particularly phytochemicals, which can have anticancer activity. Phytochemicals are components of plant-based diet that possess substantial anticarcinogenic and antimutagenic properties (19). An estimated 25,000 different chemical compounds occur in fruits, vegetables, and other plants eaten by humans. They can encompass such diverse chemical classes as carotenoids, flavonoids, organosulfur compounds, isothiocyanates, indoles, monoterpenes, phenolic acids, and chlorophyll (20). Most of these nutrients can influence gene expression of steps along the genotype-phenotype continuum (20) (Fig. 3).
Dietary habits continue to surface as significant factors that may influence cancer incidence and tumor behavior (20). Alan Jackson pointed out during the 2005 AICR/WCRF International Research Conference that nutritional programming in utero has a major impact on the development of chronic illnesses in later life (21) (Fig. 4). Therefore, it is essential to measure new biomarkers of nutrient-gene interaction in the genotype-phenotype continuum at different stages of our life cycle. Expanding knowledge based on "omic" responses across tissues and integrated through systems biology potentially will provide the specificity and sensitivity of responses to bioactive food constituencies, identify biomarkers, and identify responders and nonresponders to a particular diet (20). Therefore, nutritional genomics has far-reaching potential in the prevention of diet-related diseases and provides a new frontier, challenges, and opportunities in moving nutrition towards individualized health (22,23).
With the advent of the postgenomic era, biological and medical research and clinical practice has witnessed an explosion in strategies and goals (24–26). This eventually will revolutionize the classical practice of nutrition from the current evidence-based medicine towards genomic-based medicine (1). To accomplish this goal we need appropriate bioinformatics to analyze data obtained by each "omic" technology and need to be able to integrate the findings obtained from genomic, proteomic, and metabolic measurements into a coherent application database to address the genotype-phenotype relationship. Information stored in a database can only serve the needs of science once they are coordinated with other clinical variables such as personal and family history, physical examinations, and laboratory and functional imaging information of the individual. This is the great challenge ahead of us but this is also a great opportunity in the dawn of nutritional genomics.
ACKNOWLEDGMENTS
We are grateful to Raymond Gonzales for the artwork and to Ms. Yu Wang at the Pancreas Editorial Office for providing editorial support.
FOOTNOTES
1 Published in a supplement to The Journal of Nutrition. Presented as part of the International Research Conference on Food, Nutrition, and Cancer held in Washington, DC, July 14–15, 2005. This conference was organized by the American Institute for Cancer Research and the World Cancer Research Fund International and sponsored by (in alphabetical order) California Avocado Commission; California Walnut Commission; Campbell Soup Company; The Cranberry Institute; Danisco USA, Inc.; The Hormel Institute; National Fisheries Institute; The Solae Company; and United Soybean Board. Guest editors for this symposium were Vay Liang W. Go, Ritva R. Butrum, and Helen A. Norman. Guest Editor Disclosure: R. R. Butrum and H. Norman are employed by conference sponsor American Institute for Cancer Research; V.L.W. Go, no relationships to disclose. 
2 Author Disclosure: No relationships to disclose.
3 Funded in part by the National Cancer Institute/UCLA Clinical Nutrition Research Unit Grant CA42710, NCI grant R25 CA96975 and NCI/NCCAM R21 AT1535.
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