Public health nutrition continues to be challenged by increasing expectations from the food supply on one hand, and fundamental gaps in nutrition knowledge on the other, which can constrain the development and implementation of nutrition and food policy (1). Current demands on the food supply are no longer limited to ensuring general safety and preventing micronutrient deficiences. Increasingly, there is interest in engineering medicinal qualities into the food supply to enable diets that promote health and “nurture” a sense of well-being that transcends the mere absence of disease by improving biological functions and even increasing lifespans. Unquestionably, nutrition is one of the primary environmental exposures that determines health. Common human chronic diseases, including type 2 diabetes, metabolic syndrome, cardiovascular and neurological disease, and many cancers are initiated and/or accelerated by nutrient/food exposures. However, it is also recognized that chronic diseases are complex in their etiology and include a substantial genetic component; individuals respond differently to foods and even individual nutrients. Investigation in this new field of nutrition research, often referred to as nutritional genomics, focuses on deciphering the biological mechanisms that underlie both the acute and persistent genome-nutrient interactions that influences health.
Nutritional genomics, while centered on the biology of individuals, distinguishes itself from other “omics” fields by its unique focus on disease prevention and healthy aging through the manipulation of gene–diet interactions. Nutritional genomics promises to revolutionize both clinical and public health nutrition practice and facilitate the establishment of (a) genome-informed nutrient and food-based dietary guidelines for disease prevention and healthful aging, (b) individualized medical nutrition therapy for disease management, and (c) better targeted public health nutrition interventions, including micronutrient fortification and supplementation, that maximize benefit and minimize adverse outcomes within genetically diverse human populations. Research dietitians are among the leading scientists pioneering this field, and food and nutrition professionals will be primarily responsible for its implementation. In 2006, the Institute of Medicine convened a workshop to review the state of the various domains of nutritional genomics research and policy and to provide guidance for further development and translation of this knowledge into nutrition practice and policy (2). Three scientific domains of nutritional genomics were discussed: (a) nutritional genetics or nutrigenetics, which involves the identification, classification, and characterization of human genetic variation that modifies nutrient metabolism/ utilization and food tolerances (Figure 1); (b) nutritional epigenetics, which refers to the effect of nutrients on deoxyribonucleic acid (DNA)/chromatin (and hence gene expression), which programs or reprograms biological networks with multigenerational consequences; and (c) systems biology and nutritional engineering, which is the application of nutrigenomics information to manipulate biological pathways and networks for benefit through nutrition, including the use of food-based diets, dietary restriction, or nutritional supplements to affect genome expression, stability, and/or direct dietary compensation for metabolic deficiencies (2). This Institute of Medicine report provides background for this review, which is restricted in scope to highlighting the interactions of the B vitamin folate with the human genome and the current gaps in knowledge that must be overcome to achieve genomically driven nutrition practice and policies.
ORIGIN OF GENE–NUTRIENT INTERACTIONS
The human genome, and the genetic variation present within human populations, is in part a product of adaptive evolution to an often scant and unpredictable food supply (3,4). Single nucleotide polymorphisms (SNPs), which are common, single base-pair differences in DNA sequence, represent a primary form of human genetic variation. Of the approximately 10 million SNPs in the human genome, many are believed to have functional consequences (eg, alter the activity/function of the protein product) (5,6). SNPs arise through the sequential process of DNA mutation and subsequent expansion of the mutation within a population. Food and nutrient exposures affect both of these processes. For example, B-vitamin deficiencies impair DNA synthesis/stability and increase DNA mutation rates (germ line and somatic DNA mutations) as do excesses of pro-oxidants, including iron. Likewise, the nutritional environment can accelerate the expansion of fortuitous germ line DNA mutations within a population such that they accumulate and contribute to human genetic variation.
Indeed, many SNPs that affect nutrient utilization display genomic “signatures” of such positive selection (3). For example, a SNP located near the gene that encodes lactase enables carriers of this SNP to produce this enzyme throughout adulthood and thus continue to tolerate milk (7). This SNP penetrated populations whose ancestors came from places where dairy herds could be raised safely and economically, such as in Europe (8,9). However, several gene variants that arose through positive selection are modern-day candidates for disease alleles; gene variants that permit adaptation to one environment can be deleterious when the environmental conditions change (eg, the nature and abundance of the food supply). For example, the HFE gene variant that is associated with risk for hemochromatosis may have conferred advantage in iron-poor regions but confers risk for iron overload in iron-rich environments (10,11). Expansion of a SNP also requires that the associated changes in biochemistry permit embryonic survival in the interuterine environment. Both malnutrition and some gene variants that impair nutrient metabolism and/or utilization are risk factors for spontaneous abortion (12). Nutrients and other bioactive food components can also regulate gene expression (Figure 1). All organisms have acquired the ability to sense and adapt to their nutrient environment by altering the expression of proteins that function in metabolic and signaling pathways. Salient examples include, but are not limited to, the regulation of gene transcription by vitamin A or vitamin D through interaction with their respective nuclear receptors. This ability of nutrients to communicate with the genome is an essential feature of organismal evolution. Nutrients can elicit transient alterations in gene expression and/or influence more permanent whole genome reprogramming events that can be inherited (ie, passed onto offspring). The term epigenetics refers to the inheritance of traits through mechanisms that are independent of DNA primary sequence and includes the inheritance of gene expression patterns and/or expression levels that contribute to phenotypic differences among individuals, including monozygotic twins (13). The embryo seems to be especially susceptible to nutrient- induced adaptations in gene expression, a phenomenon referred to as metabolic imprinting or metabolic programming (14). These adaptations occur within critical windows during embryonic development and can persist into adulthood. The associated changes in metabolism resulting from these reprogramming events are believed to enable in utero survival in suboptimal nutrient environments, but predispose the individual to metabolic disease in adulthood (14). This relationship among maternal nutrition, fetal epigenetic programming, and adult-onset chronic disease is the basis of the fetal origins of adult disease hypothesis, which proposes that nutrition acts very early in life to program risk for adverse outcomes in adult life (15). This theory, which was originally supported only by epidemiological associations, has now been validated in whole-animal studies. These studies demonstrate that early nutrition exposures increased risk in adulthood for obesity, hypertension, and insulin resistance, which are the antecedents of adult chronic disease including cardiovascular disease and diabetes (15). The genome, in turn, can constrain diet (Figure 1). Genetic variation and/or variations in epigenetic programming can affect nutrient absorption and utilization (eg, hemochromatosis) and thereby confer differences in food/nutrient tolerances (eg, iron) and may contribute to the variation in human nutrient requirements (3).
Excerpt from: Patrick J. Stover, PhD, Marie A. Caudill, PhD, RD. "Genetic and Epigenetic Contributions to Human Nutrition and Health: Managing Genome–Diet Interactions."
1. Garza C, Stover PJ. The role of science in identifying common ground in the GMO debate. Trend Food Tech. 2003;14:182-190.
2. IOM. Nutrigenomics and beyond: Informing the future. Washington, DC: The National Academies Press; 2007.
3. Stover PJ. Human nutrition and genetic variation. Food Nutr Bull. 2007;28(Suppl International 1):S101-S115.
4. Tishkoff SA, Verrelli BC. Role of evolutionary history on haplotype block structure in the human genome: Implications for disease mapping. Curr Opin Genet Dev. 2003;13:569-575.
5. Cargill M, Altshuler D, Ireland J, Sklar P, Ardlie K, Patil N, Shaw N, Lane CR, Lim EP, Kalyanaraman N, Nemesh J, Ziaugra L, Friedland L, Rolfe A, Warrington J, Lipshutz R, Daley GQ, Lander ES. Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nat Genet. 1999;22:231-238.
6. Tishkoff SA, Kidd KK. Implications of biogeography of human populations for ’race’ and medicine. Nat Genet. 2004;36(Suppl 11):S21-S27.
7. Enattah NS, Sahi T, Savilahti E, Terwilliger JD, Peltonen L, Jarvela I. Identification of a variant associated with adult-type hypolactasia. Nat Genet. 2002;30:233-237.
8. Bersaglieri T, Sabeti PC, Patterson N, Vanderploeg T, Schaffner SF, Drake JA, Rhodes M, Reich DE, Hirschhorn JN. Genetic signatures of strong recent positive selection at the lactase gene. Am J Hum Genet. 2004;74:1111-1120.
9. Bloom G, Sherman PW. Dairying barriers and the distribution of lactose malabsorption. Evolution and Human Behavior. 2005;26:301- 312.
10. Toomajian C, Ajioka RS, Jorde LB, Kushner JP, Kreitman M. A method for detecting recent selection in the human genome from allele age estimates. Genetics. 2003;165:287-297.
11. Toomajian C, Kreitman M. Sequence variation and haplotype structure at the human HFE locus. Genetics. 2002;161:1609-1623.
12. Stover PJ, Garza C. Bringing individuality to public health recommendations. J Nutr. 2002;132(8 Suppl):S2476-S2480.
13. Dennis C. Epigenetics and disease: Altered states. Nature. 2003;421: 686-688.
14. Waterland RA, Garza C. Potential mechanisms of metabolic imprinting that lead to chronic disease. Am J Clin Nutr. 1999;69:179-197.
15. Barker DJ. Intrauterine programming of coronary heart disease and stroke. Acta Paediatr Suppl. 1997;423:178-182; discussion 183.
16. Stover PJ. Physiology of folate and vitamin B12 in health and disease. Nutr Rev. 2004;62(6 Pt 2):S3-S12; discussion S13.
17. Henikoff S, McKittrick E, Ahmad K. Epigenetics, histone H3 variants, and the inheritance of chromatin states. Cold Spring Harb Symp Quant Biol. 2004;69:235-243.