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Meets Learning Need Codes 2000, 2010, 2050, and 2100. To take the Continuing Professional Education quizfor this article, log in to ADA’s Online Business Center atwww.eatright.org/obc, click the “Journal ArticleQuiz” button, click “Additional Journal CPE Articles,” and select this article’s title from a list of availablequizzes.

utritional Genomics, Polyphenols, Diets, andheir Impact on Dietetics

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BSTRACTutritional genomics offers a way to optimize humanealth and the quality of life. It is an attractive endeavor,ut one with substantial challenges. It encompasses al-ost all known aspects of science, ranging from the ge-omes of humans, plants, and microorganisms, to theighest levels of food science, analytical science, comput-

ng, and statistics of large systems, as well as humanehavior. This paper describes the underlying biochem-stry that is targeted by the principal issues in nutritionalenomics, which entails genomics, transcriptomics, pro-eomics, and metabolomics. A major feature relevant toutritional genomics is the single nucleotide polymor-hisms in genes that interact with nutrients and otherioactive food components. These genetic changes mayead to alterations in absorption, metabolism, and func-ional responses to bioactive nutritional factors. Bioactiveood components may also regulate gene expression at theranscriptome, protein abundance, and/or protein turn-ver levels. Even if all of these variables are known,dditional variables to be considered include the nutri-ional variability of the food (unprocessed and processed),he amount that is actually eaten, and the eating-relatedehaviors of those consuming the food. These challengesre explored within the context of soy intake. Finally, the

. Barnes is with the Department of Pharmacology andoxicology, and Center for Nutrient-Gene Interaction inancer Prevention, University of Alabama at Birming-am, and the Purdue University-University of Alabamat Birmingham Botanicals Center for Age-Related Dis-ase, Birmingham.

Address correspondence to: Stephen Barnes, PhD,epartment of Pharmacology and Toxicology, 452cCallum Research Building, University of Alabama atirmingham, 1918 University Blvd, Birmingham, AL5294. E-mail: sbarnes@uab.eduManuscript accepted: May 6, 2008.Copyright © 2008 by the American Dietetic

ssociation.0002-8223/08/10811-0008$34.00/0

Tdoi: 10.1016/j.jada.2008.08.014

888 Journal of the AMERICAN DIETETIC ASSOCIATION

mportance of international cooperation in nutritionalenomics research is presented.Am Diet Assoc. 2008;108:1888-1895.

lthough many people have become familiar with theterm genomics, being the flagship of science at theNational Institutes of Heath at the transition into

he 21st century, other -omics have also been introducedn our vocabulary. Perhaps naively, it was assumed by

any in the 1980s and 1990s that if the human genesould be defined, then the causes of diseases and syn-romes could be understood sufficiently well to developtrategies (gene replacement/repair, optimal therapeu-ics, or lifestyle changes involving what we eat) thatould improve human health. When the sequencing ap-roaches adopted by the National Human Genome Re-earch Institute (1) and latterly Celera (2) only yielded0,000 to 24,000 genes instead of the 80,000 to 100,00hat were expected, many investigators reevaluated howhe cell really operates. Besides genomics, many otheromics— transcriptomics, metabolomics, physiologicalenomics, proteomics, epigenomics, and now nutritionalenomics—have emerged. Most recently, data from theNCODE (ENCyclopedia Of DNA Elements) project haveuggested that the concept of a gene and the resultingranscriptome may require substantial revision (3,4). Theoal of the ENCODE project is to identify all the func-ional elements in the human genome sequence. Resultseported in June 2007 revealed that the majority of theenome is transcribed, including non–protein-encodingegions, and that genes extensively overlap each other (3).

This review describes the underlying biochemistry, in-roduces the variation in the human genome and the rolef nutrition associated with nutritional genomics, andresents the role of timing of specific dietary componentsn which parts of the genome are expressed. As an exam-le, the role of dietary polyphenols in health is discussedrom a nutritional genomics and dietetics point of view.inally, the importance of the national and internationalfforts that are in progress in this new field are brieflyiscussed. For overviews of the impact of nutritionalenomics on dietetics, see Afman and Müller (5) and

rujillo and colleagues (6).

© 2008 by the American Dietetic Association

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HE FLOW OF BIOCHEMICAL INFORMATIONn the classical biochemical paradigm, genetic informa-ion encoded in genes in DNA (deoxyribonucleic acid) isranscribed by RNA (ribonucleic acid) polymerases toorm messenger RNAs (the transcriptome) (Figure 1). Re-ent research in the ENCODE project has revealed that,ather than information being drawn from one gene, theranscribed RNA may be a product of more than onedjacent gene (7). The mRNAs are exported from theucleus and form complexes with ribosomes; these ribo-uclear proteins synthesize polypeptides using theRNAs as templates (Figure 1). The triplet codon se-

uence of the mRNA is translated into amino acids one attime to form polypeptides (Figure 2). The polypeptides

old to form proteins with a wide variety of propertieshat are essential for life. These include cytoskeletaltructures (actin, tubulin, etc), membrane transporters,nd enzymes that utilize externally derived compoundsglucose, amino acids, fats) to generate energy to powerhe cell and to synthesize biochemically important inter-ediates (eg, amino acids, coenzyme A thioesters, deoxy-

ibonucleotides and ribonucleotides) needed for the syn-hesis of the materials required for cell division (thatnclude DNA and RNA) (Figure 1). Although for multicel-ular organisms the total available genes are the same forach cell, only a fraction of them is expressed to create theellular phenotype (the effective genome of that cell typever the life of the cell). Of these expressed genes, whileany are converted to proteins (structural proteins,

nzymes for intermediary metabolism) that are used

igure 1. Information flow between nucleic acids and proteins. Therincipal pathway is from DNA (deoxyribonucleic acid) to mRNA (mes-enger ribonucleic acid) to proteins (the bold lines) and is mediated bybevy of proteins including RNA polymerase and those of the trans-

ational apparatus. However, it is well-appreciated that enzymes controlhe synthesis of both DNA and RNA; their control is represented by theotted lines. Information flows from RNA to DNA by the action ofeverse transcriptase. Kinases regulate the phosphorylation status ofhe elongation-initiation factor 2-guanosine triphosphate (eIF2-GTP)omplex. Large-scale regulation of the genes that are expressed in aell at a particular time in our lifetime is determined by the posttrans-ational modification of histones, basic proteins that bind tightly to DNA.eacetylation of histones leads to the suppression of gene expression.

hroughout the lifetime of a cell, others that are needed to t

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ontrol the timing of the cell cycle are only present tran-iently. The set of proteins recovered at any moment inhe life of a cell is termed the proteome.

A complex set of small molecules in a cell representsts metabolome. The metabolome can be measured in aell, in tissues (eg, brain, heart, kidney, liver, muscle,vary, testis), or in biological fluids (eg, serum/plasma,rine, bile). It is a function of the genes available in theenome, the expressed genes in the transcriptome, theransporters that move extracellular and intracellularompounds across the cell membrane, and the catalyticctivity and organization of the enzymes within a cell.he metabolome is constantly changing. Maintaining thelements of the metabolome within certain ranges isalled homeostasis. For some compounds, such as intra-ellular ATP (adenosine triphosphate), the range that isormal is very narrow. For others, such as plasma glu-ose, the range is broader. However, for glucose there is aower limit at which point various mechanisms are in-oked to supply glucose and maintain homeostasis. Aslucose levels increase after a meal, signals from insulineleased from the pancreas serve to increase glucoseransport into cells and to store it as glycogen and fat.ersistent high levels of plasma glucose due to low levelsf insulin secretion or failure to respond to insulin lead tohe complications of diabetes mellitus.

Humans use food as the fuel to run their metabolicngines; food allows the metabolic system to create theieces that sustain a cell so that it can perform its nec-ssary functions, and so that undifferentiated cells canndergo division. Is there a particular set of foods needed

igure 2. Translation of DNA (deoxyribonucleic acid) sequence infor-ation via mRNA (messenger ribonucleic acid) to synthesis of a

pecific polypeptide. DNA is double-stranded, each strand being theirror image of the other. The image is created by matching cytosine

C) with guanosine (G) and adenosine (A) with thymidine (T) and viceersa. The information in the double-stranded DNA is transcribed usingNA polymerase to form a mRNA copy. (Note that while the C/G, G/Cnd T/A copies are upheld as in the DNA pairs, T is transcribed toridine [U].) The AUG codon on mRNA is the start codon; it also encodesethionine. The mRNA nucleotide sequence is converted to an amino

cid sequence by “reading” a series of contiguous triplet codons (threeuccessive nucleotides). Most, but not all, amino acids are encoded byore than one triplet codon.

o sustain metabolism? Fortunately, the answer is no.

ovember 2008 ● Journal of the AMERICAN DIETETIC ASSOCIATION 1889

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oods consist of many different polymers of carbohy-rates, fats, and proteins. These are broken down to theirugar, fatty acid, and amino acid monomeric unitshrough hydrolysis by saccharidases, lipases, and pro-eases released into the intestine from the pancreas. Thealue of a food can vary. Ideally, the food should generateufficient glucose and provide essential fatty acids andmino acids. It is unusual for one food to satisfy all ofhese requirements; thus, a diet including a variety ofood sources is usually necessary. For some foods, exter-al fermentation (pre-digestion by microorganisms) issed to make a food more bioavailable or palatable. Milk

s converted to cheese and yogurt, whereas soybeans areonverted to soy sauce, miso, tempeh, and soy paste. Andvantage of fermentation can be a shift of the amino acidontent toward a more optimal value because of the ad-ition of proteins from the microorganisms to the food.In addition to saccharides, fatty acids, and amino acids,

he human body requires other essential compounds inhe diet, including water, vitamins, and minerals. Otherioactive food components, many of which are phyto-hemicals (plant chemicals), are being identified as im-ortant to human health. Thus, the complete diet is aomplex matrix of food components, often supplementedith herbals, botanicals, and dietary supplements con-

aining bioactive components and vitamins/minerals. De-ivering that complex matrix is the challenge for theegistered dietitian, who not only determines the nutri-nts that need to be combined to make a healthful diet,ut also formulates methods based on knowledge of sev-ral sciences that ensure that the individual foods areafe and palatable (within the standards of the commu-ity in which they operate).

ENETIC VARIATION IN HUMAN BEINGSo, if humans have a given set of genes, why aren’t we allhe same? And if we all ate a healthful diet, would we alle all uniformly healthy? The answer to both questions ishat although Homo sapiens is a discrete species, therere differences in our individual genomes. In the case ofell-described single-gene disorders, there are distinctutations, deletions, and additions in certain genes that

ead to the absence or dysfunction of the proteins derivedrom them. Because each parent contributes one copy ofvery gene (an allele) to their children, in most cases (butot always) both alleles must be dysfunctional for thessociated condition to become manifest.In addition, there are other site-specific differences

hat occur throughout the genome, on average every 300ases. These are termed single nucleotide polymorphismsSNPs). Even if they are in the open-reading frame that isonverted to messenger RNA and translated into a pro-ein, the differences may be silent if they do not lead to ahange in the amino acid that is translated from eachodon. For instance, if the codon for glycine (GGU) shownn Figure 2 is mutated at the third nucleotide to formGA, GGC, or GGG, all of the mutations will still be

ranslated as glycine. However, for lysine (AAA in Figure), although mutation to AAG has no effect, mutation toAU or AAC results in a change in translation to aspar-gine. This amino acid remains hydrophilic, but it loseshe charge possible on the lysine residue. The outcome

ay be to alter rather than destroy the enzyme activity of a

890 November 2008 Volume 108 Number 11

he protein. Mutations of the first or second nucleotides intriplet codon almost always cause a change in the aminocid that is translated. Gene polymorphisms may alsoccur in noncoding DNA regions that regulate expressionf a gene. If the mutation stops gene expression, theutcome is severe and may result in classification as aenetic disease. However, a mutation that modulates (ie,ausing nonzero gene expression) the change in expres-ion of a gene may be much harder to detect because itsffects may fall within what is regarded as physiologicallyormal.Proteins have a wide range of sizes: from approxi-ately 50 amino acids (eg, insulin) to more than 2,500

eg, fatty acid synthase—accession number P49327 atttp://www.expasy.org). These proteins are encoded byenes having 150 to more than 7,500 nucleotides. Accord-ngly, some genes have no SNPs, whereas others haveeveral. For individuals with SNPs in multiple genes, theumber of SNP combinations is restricted; the observedlocks of SNPs are termed haplotypes, combinations oflleles at multiple linked loci that are transmitted to-ether. The pattern of SNPs is a reflection of geneticeritance, and certain haplotypes may be typical of those

ocated within a particular region. Because the Y chro-osome in males is present in only one copy, it is not

ubject to shuffling via recombination, and the pattern ofNPs therein establishes the paternal bloodline and theeographic origins of an individual’s patrilineal ances-ors.

As noted earlier, SNPs typically lead to altered func-ion of the protein product rather than severe impairmentr total loss of function. Therefore, the population of aountry may carry a high preponderance of a particularNP. Of course, with the intermixing of populations thatas occurred from migration, new SNPs may be intro-uced into a population.An example of a gene with a well-known SNP relevant

o nutrition and disease is the gene that encodes thenzyme methylenetetrahydrofolate reductase (MTHFR)accession number P42898 at http://www.expasy.org).his gene has a polymorphism at residue 677 (C or T)esulting in an alanine (677C) or valine (677T). Thus, anndividual may carry a CC, CT/TC, or TT genotype. TheT genotype is common in northern China (20%), south-rn Italy (26%), and Mexico (32%) (8). Its frequency is lown those of African ancestry (9). MTHFR is important inhe remethylation of homocysteine to methionine. It cat-lyzes the conversion of 5,10-methylenetetrahydrofolateo 5-methyltetrahydrofolate. Unlike many of the otherutations in MTHFR, the 677TT genotype reduces, but

oes not abolish, enzymatic activity. Thus, individualsith this genotype have a mild form of hyperhomocys-

einemia because they have less efficient conversion ofomocysteine to methionine than the common genotype.lcohol consumption also increases total plasma homo-ysteine. Both the MTHFR 677TT genotype and alcoholffects on plasma homocysteine can be offset by increas-ng the intake of folate (10). Interestingly, individualsith the 677TT genotype have a lower risk of colon cancer

f they consume a folate-supplemented diet (11). Thisolymorphism exemplifies how knowledge of the disad-antages of a specific genotype can be ameliorated by

djustment in nutrient intake. This association, and the

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ubsequent interventions, is described as nutrient-genenteraction and is part of the field of study of nutritionalenomics. It provides an explanation of why a nutritionecommendation that is optimal for a large group may notenefit an individual in the group.

HE NUTRIENT-DEPENDENT TRANSCRIPTOMEn the aforementioned scenario, the mutations in theoding regions of the gene of interest are the dominantssue. However, as noted in Figure 1, there are feedback

echanisms from the distal part of the gene-transcript-rotein pathway. A mutant protein may alter the regula-ion of the expression of genetic information. Similarly,mall molecules produced by concerted enzyme action inhe various pathways of the cell can feed back to regulatehe activity of the protein and also gene expression viaormonally sensitive receptors. For example, endog-nously produced steroids and eicosanoids interact with aariety of receptors that, once activated, alter the expres-ion of a large number of relevant genes. Receptor acti-ation is not restricted to endogenous compounds; someigands are derived directly from the diet. Plant-derivedstrogens (phytoestrogens), such as genistein, coumes-rol, and zearalenone bind to the estrogen receptor (12)nd may switch on a similar set of genes such as 17�-stradiol, the physiologic estrogen (13-15). Thus, the dietecomes an important regulator of gene expression withhe potential to offset the effects of the body of SNPs thatn individual may have. The matrix in which the phy-oestrogen is delivered may also have a role in genexpression. Su and colleagues (16) showed that the effectsf soy protein isolate (containing the isoflavones daidzein,enistein, and glycitein and their beta glycosides as wells other soy matrix components) and genistein on genexpression in rat mammary epithelial cells were essen-ially independent. Therefore, some of the benefits of ahytochemical may be lost if it is removed from its usualatrix.Microarray analysis is used to assess changes in the

ranscriptome. Although microarray technology has im-roved substantially over the past 10 years, it is tooxpensive to overcome the major limitation of its use: themall number of replicates vs the number of parametersgenes) being tested. Under the best analytical circum-tances, the number of expected differences between aontrol and treatment group under the null hypothesisie, there is no difference) with � set at .05 for an arrayhere there are 10,000 features (genes) is 500. This issue

s not limited to microarray analysis; it also applies toroteomic and metabolomic analyses. Early publicationsf DNA microarray data focused on genes whose expres-ion changed (up or down) twofold. These parametersay have led to selecting for genes whose expression

hanges considerably, but without biological importance17). The key issue is to have sufficient biological repli-ates that the variances can be calculated. Another way ofssessing microarray data is to determine whether ahole pathway is affected, which may help identify wherecritical gene or its gene product is located.Another way to sort out likely true-positives is to map

he observed changes onto the metabolic, synthetic, andignaling pathways in the cell. A group of similar changes

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ignificant. An important feature of microarray researchs the standardization and recording of every aspect of anxperiment (18). By following guidelines established foruch research (the MIAME [Minimum Information AboutMicroarray Experiment] standards) (19), investigators

an download publicly available microarray data (Na-ional Center for Biotechnology Information Gene Omni-us) (20) from experiments that are similar to the oneshey are planning to calculate the statistical powereeded for their experiment. Similarly, statistical tests ofhe genes and pathways changed by a nutrient can betrengthened by combining datasets. This approach hasot yet come into practice in proteomics and metabolom-

cs, but this presumably will occur just as it has foricroarray analysis.

IMING OF THE NUTRIENT–GENE INTERACTIONfeature of growth and development is the programmed

witching on and switching off of sets of genes that areeeded at different stages of life. Not all genes in a cellre “on” at any one time. When they are switched off, thentention is often that they stay that way. The on/offxpression of a gene is regulated by the extent to which its bound to chromatin in the nucleus. Nuclear DNA isackaged by histone proteins into a complex. The “open-ess” of the complex (to allow RNA polymerase to tran-cribe a gene) is regulated by acetylation (to relax chro-atin) and methylation (to bind the DNA more tightly).ecause there are several modification sites on histones,

he concept of a histone code to augment that of generanscription and translation has been proposed (21). Re-ent evidence suggests that nutrients/phytochemicals canlter the degree of histone acetylation. Administration ofhe sulphoraphane present in Brassica (broccoli) to hu-an embryonic kidney cells and to human colorectal tu-or cells inhibited histone deacetylase (22). Importantly,

ulphoraphane was not active itself; rather, its metabo-ites formed after reaction with glutathione. Sulphora-hane has also been shown to have histone deacetylasectivity in human subjects, albeit transiently (23,24).his type of modulation of gene expression is termedpigenetics (changing expression without altering theNA nucleotide sequence) and may be crucial in terms of

he benefit of the diet in preventing chronic disease.

IETARY POLYPHENOLS AND NUTRITIONAL GENOMICSolyphenols enter the diet from a wide variety of ediblelants. As part of the activities of the University of Ala-ama at Birmingham’s Center for Nutrient-Gene Inter-ction, three polyphenols (the isoflavone genistein fromoy, the stilbene trans-resveratrol from grapes, and epi-allocatechin-3-gallate from green tea) are being investi-ated for their roles in the prevention of breast cancer.vidence from rodent studies suggests that the chemo-reventive effects of genistein (25) and proanthocyanidin-ich grape seed extract (26) depend on the animals beingxposed to genistein or soy at the time of weaning anduberty. Epidemiological data suggest exposure to soy (inhe form of tofu) in adolescence is critical for beneficialffect of soy in reducing breast cancer risk (27,28). Simi-

ar to genistein, trans resveratrol administered in the diet

ovember 2008 ● Journal of the AMERICAN DIETETIC ASSOCIATION 1891

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1,000 ppm) from birth to weaning in rats and then from00 days of age caused a 50% reduction in the number ofammary tumors induced by carcinogens (29). In con-

rast, epigallocatechin-3-gallate administered in therinking water had no effect in this model.

OLYPHENOL VARIABILITY AND DISEASE PREVENTIONo polyphenolics have a significant effect in preventing

hronic diseases such as cancer? Many of the variablesentioned earlier that constitute nutritional genomics

ome into play and are not limited to the human subject.ven the soybean produces variable amounts of isoflavones.his has a genetic basis that is a function of the soybeantrain, the environment (temperature, humidity, altitude,nd sunlight) (30,31), and the time of harvesting (32). Thus,gram (or ounce) of a soybean or a soy food is not a unit of

mount of isoflavones and therefore food frequency ques-ionnaires should be augmented by analysis of what is beingaten by the subject group under study (33).Furthermore, the processing that occurs in the produc-

ion of a soy food alters the composition of the isoflavonesFigure 3). As examples, many of the Asian-style forms ofoy foods (eg, soy paste, miso, tempeh, soy sauce) areermented products (34). Fermentation removes the gly-osidic moiety that is chemically bound to isoflavones inoybeans. The unconjugated isoflavone is rapidly ab-orbed in the upper gut (35). In addition, fermentationeads to altered chemistry of the isoflavone, typically hy-

igure 3. Effect of processing of soybeans into different soy foo�-O-malonylglucosides of daidzein, genistein, and glycitein. (Genisteinlucose moiety as well as hydroxylation at the 6 and 8 positions. Extrahe isoflavone composition. However, heating to toast the soy flour ca

6�-O-acetylglucoside. This also occurs for soy products formed by hoasted products (SoyLife, Frutarom, Haifa, Israel). Hot pressurized extalonyl group, converting the isoflavones to simple glucosides. Produ

re designed to be very bland and are made from soy flour that has beo these products are essentially isoflavone-free.

roxylation of the A-ring. Soy sauce can also be prepared d

892 November 2008 Volume 108 Number 11

y chemical treatment of soybeans. However, this leads tolmost total loss of isoflavones. Most American-styleorms of soy involve recovery of the soy protein fractionrom soybeans without fermentation and tend to preservehe glycosidic conjugates; indeed, heating (toasting) of theoy protein can convert the isoflavone-6�-O-malonylglu-oside to the 6�-O-acetylglucoside (36,37). This form mustnter the colon before it can be hydrolyzed to unconju-ated isoflavones, which leads to a more rapid conversiono secondary bacterial metabolites of isoflavones (dihy-rodaidzein, O-desmethylangolensin and S-equol). Evenhe colonic bacteria are a variable because these are aunction of what we eat and drink. Approximately one inhree individuals is an equol producer. Some have sug-ested that equol production is tightly linked to the ben-ficial effects of a soy-rich diet (38-41). This is believed toe due to the interaction of S-equol with the estrogeneceptor beta (42). Perimenopausal women who are equolroducers retain bone better than non–equol producers38). In a recent randomized, controlled, parallel studyesign of 62 adults with hypercholesterolemia on a step 2iet containing 80 g of pasta with or without soy germsoflavones, equol producers had improved in serum lipidnd other cardiovascular parameters compared with non-roducers (43).

OLYPHENOLS AND DIETETICSpolyphenol-rich diet is consistent with the recommen-

ducts on the isoflavone composition. Soybeans consist mostly ofown in this example.) Fermentation leads to the cleavage of the entireof crushed soybeans with n-hexane to recover the oils does not altera loss of CO2 from the malonyl group that converts the isoflavone totrusion methods such as those for textured vegetable protein (TVP) orn of soybeans with water to make soy milk leads to hydrolysis of theade from full-fat soy milk have this composition. Some soy productseated with hot aqueous ethanol. This solvent extracts the isoflavones,

d prois shctionusesot exractiocts men tr

ations for eight to 10 servings per day of fruits and

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egetables, as recommended by both the Centers for Dis-ase Control and Prevention (44) and the National Heart,ung and Blood Institute (45). Isoflavones are the majorolyphenols in soybeans and soy foods; proanthocyani-ins are prominent in apples, grapes, and many berries;atechins (flavanols) are in teas, particularly green tea;esveratrol is in peanuts and grape skin. Integratinghese foods into a healthful and tasty diet is attainable. In007 fast-food outlets and schools began to provide fruitnd salad alternatives to the ubiquitous french fry. Thisay be in response to increasing awareness of obesity

nd changes in eating-related behaviors.

ONCLUSIONS AND CHALLENGES IN NUTRITIONAL GENOMICShat becomes clear as the description of nutritional

enomics unfolds is that it consists of numerous dimen-ions: the genome, the complement of genes and theirutations that are available to be expressed, the tran-

criptome (both protein-encoding and non–protein-encod-ng RNAs), the proteome (primary polypeptides, theirosttranslational modifications, and protein complexes),he epigenome (methylated DNA and methylated andcetylated histones), the metabolome (the small endoge-ous molecules that create energy and are used for theynthesis of complex bioactive intermediates includingipids, complex carbohydrates, proteins, and nucleic ac-ds), the nutribiome (food-derived xenobiotics), and theenobiome (other compounds derived from sources out-ide of the body, including pollutants). Analyzing all ofhese variables is a substantial challenge to the investi-ator.As for all studies of populations, their genes, and the

actors from the diet that interact with them, a majorhallenge is the need to have sufficient statistical powero make firm conclusions. Researchers need a largenough study group to satisfy the statistical require-ents and adequate grant support to conduct such large

tudies. The ability to conduct suitably powered clinicaltudies is a problem even in the United States and at theost prestigious institutions. Koushik and colleagues

46), using data gathered from the Nurses’ Health Studynd the Health Professionals Follow-up Study cohorts,ere able to show (in a study of 376 men and women with

olorectal cancer and 849 control subjects) that patientsith the MTHFR 677TT genotype had a reduced risk of

olorectal cancer (odds ratio 0.66; 95% confidence inter-al, 0.43 to 1.00), but could not discern a relationshipith dietary methyl status. They concluded that theirork lacked the requisite statistical power.Nutrient–gene interaction is becoming an important

art of public health policy throughout the world as eachountry strives to most efficiently ensure the health androductivity of its peoples through prevention strategies.ccordingly, a group of investigators with expertise inutritional genomics from 21 different countries and fiveontinents called for an international alliance to addresshe most important questions (47). Coordination of re-earch in nutritional genomics is provided by the Euro-ean Nutritional Genomics Organization (48) and theutritional Genomics Society (49). These groups envisage

ooperative, multinational studies of the major questionsn nutritional genomics. This was discussed in depth at a

007 conference entitled, “Who We Are and What We Eat:

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he Role of Metabolomics and Nutritional Genomics inreating Healthful Foods and Healthy Lives” (50). Thisooperation is analogous to the advantages provided byinocular vision or large array radio telescopes. However,ow nutritional genomics projects are to be conceived,xecuted, and analyzed depends on international stan-ards. For now, it is work in progress.

upport for the UAB Center for Nutrient-Gene Interac-ion in Cancer Prevention is provided by a grant-in-aidU54 CA100949, Stephen Barnes, principal investigator)rom the National Cancer Institute. Support for researchn botanicals and dietary supplements at the Purdueniversity-University of Alabama at Birmingham Botan-

cal Center for Age-related Disease is provided by a grantP50 AT00477, Connie M. Weaver, principal investigator)rom the National Center for Complementary and Alter-ative Medicine and the National Institutes of Healthffice of Dietary Supplements.The authors thank Ruth DeBusk for editorial advice

rovided by during the writing of the manuscript.

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