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FROM THE ACADEMY

Position Paper

Position of the Academy of Nutrition and Dietetics:Nutritional Genomics

ABSTRACTIt is the position of the Academy of Nutrition and Dietetics that nutritional genomicsprovides insight into how diet and genotype interactions affect phenotype. The practicalapplication of nutritional genomics for complex chronic disease is an emerging scienceand the use of nutrigenetic testing to provide dietary advice is not ready for routinedietetics practice. Registered dietitian nutritionists need basic competency in geneticsas a foundation for understanding nutritional genomics; proficiency requires advancedknowledge and skills. Unlike single-gene defects in which a mutation in a single generesults in a specific disorder, most chronic diseases, such as cardiovascular disease,diabetes, and cancer are multigenetic and multifactorial and therefore genetic muta-tions are only partially predictive of disease risk. Family history, biochemical parame-ters, and the presence of risk factors in individuals are relevant tools for personalizingdietary interventions. Direct-to-consumer genetic testing is not closely regulated in theUnited States and may not be accompanied by access to health care practitioners.Applying nutritional genomics in clinical practice through the use of genetic testingrequires that registered dietitian nutritionists understand, interpret, and communicatecomplex test results in which the actual risk of developing a disease may not be known.The practical application of nutritional genomics in dietetics practice will require anevidence-based approach to validate that personalized recommendations result inhealth benefits to individuals and do not cause harm.J Acad Nutr Diet. 2014;114:299-312.

POSITION STATEMENT

It is the position of the Academy of Nutritionand Dietetics that nutritional genomics pro-vides insight into how diet and genotypeinteractions affect phenotype. The practicalapplication of nutritional genomics for com-plex chronic disease is an emerging scienceand the use of nutrigenetic testing to pro-vide dietary advice is not ready for routinedietetics practice. Registered dietitian nutri-tionists need basic competency in geneticsas a foundation for understanding nutritionalgenomics; proficiency requires advancedknowledge and skills.

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HE SCIENCE OF GENETICS AND happened, both abnormal and normal. published in 2003.2 Perhaps the most

Tgenomics is moving at anaccelerated pace. New tech-nologies and scientific discov-

eries are deepening our understandingof how nutrients and dietary patternsaffect health maintenance and diseasedevelopment. Advances in epigeneticsand the influence of the microbiomeon health and disease also arecontributing to the understanding ofnutrition and health. Many omicapproaches—transcriptomics, proteomics,and metabolomics—will help usunderstand nutrientegenome in-teractions. Genotyping alone will not besufficient to personalize diet forimproved health.1 Understanding andmanipulating how diet affects thephenotype of an individual will requiretechnologies that can reveal the pro-cesses of what happens from the geneticblueprint through transcription and syn-thesis of proteins to identification of me-tabolites that will tell us what has

Whereas new scientific discoveries andtechnologies continually inform the sci-ence of nutritional genomics, translatingthese scientific discoveries into practicalclinical application requires obtainingthe same rigorous evidence that is thebackbone of dietetics practice.

SEQUENCING THE HUMANGENOMEThe first draft of the human genomewas published in 2001 through an in-ternational effort called the HumanGenome Project that took 20 yearsfrom inception to completion and cost$3 billion. This incredible accomplish-ment was a mere 150 years afterMendel manipulated the colors ofpeas leading to his discovery of auto-somal recessive inheritance, 100 yearsafter chromosomes were identified asbearing inherited traits, 50 years afterWatson and Crick described the mo-lecular structure of genetic materialas the double helix, and 30 years afterthe first DNA sequencing technologywas invented. The full sequence ofthe human genomewas completed and

AD

startling discovery was that the num-ber of human genes was estimated tobe significantly fewer than early esti-mates. Since the completion of theHuman Genome Project, hundreds ofgenomes have been sequenced fromthe tiniest bacteria to the largestmammal.3 Technological advanceshave dramatically dropped the cost ofsequencing a human genome from $95million in 2001 to <$6,000 in 2013.4

However, these costs do not reflectthe costs associated with the devel-opment of bioinformatics, computa-tional tools, equipment, and theanalysis and interpretation of thedata.5 As the time and cost to sequencea human genome continues to drop,the expectation that it will become anintegrated part of medical practicebecomes more of a reality. However,translating whole genome sequencinginto therapies that will benefit an in-dividual will require strategies tohandle large amounts of biological andmedical data and the ability to identifysignificant and clinically meaningfulresults.6

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GENETICSGenes contain all of the biological in-formation needed to build and main-tain a living organism (see Figure 1).Genes are responsible for protein

Figure 1. Within the nucleus of cells throughmaterial organized into sequences known astranscription, the information stored in a genmessage from the DNA out of the nucleus inof mRNA bases. Each sequence of three babrought to the ribosome by transfer RNA (tRNcodons along the mRNA.

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formation and, ultimately, metabolicfunction. Genes are turned on and offin response to metabolic signals thatthe nucleus receives from internal fac-tors, such as hormones and enzymes,

out our body are 23 pairs of chromosomes;genes. During the processes of transcriptione’s DNA is transferred to RNA in the cell nucto the cytoplasm. In translation, mRNA interases, called a codon, usually codes for one pA). These tRNAs are specific for the particular

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and external/environmental factors,such as diet.

Genes vary in size from a few hun-dred DNA bases to >2 million bases.Human beings have between 20,000

within each chromosome is the geneticand translation, proteins are formed. Inleus. Messenger RNA (mRNA) carries thects with ribosomes to read the sequencearticular amino acid. Each amino acid isamino acid they carry and recognize the

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FROM THE ACADEMY

and 25,000 genes. Most genes are thesame from person to person, but <1%of genes are slightly different betweenpeople, which translates to a differ-ence of 3 million bases. Natural varia-tions in a gene, DNA sequence, orchromosome that occur with fairlyhigh frequency in the general popula-tion are known as polymorphisms.7

The most common type of poly-morphism involves variation at a sin-gle base pair and are known as singlenucleotide polymorphisms (SNPs), alsoreferred to simply as polymorphisms(see Figure 2).SNPs are the most common type of

genetic variation in human beings.Each SNP represents a difference in anucleotide. For example, an SNP mayreplace cytosine with thymine in aspecific stretch of DNA. SNPs areconsidered a normal variation in theDNA; they account for the differencesin human eye color, hair color, andblood type. Some SNPs may influencethe risk of developing certain diseasesor disorders.7 A glossary that defines

Figure 2. Single nucleotide polymorphismsmany individuals vary by a single base; nhave a chromosome with an A at a particupopulation.

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some terms used in this article is foundin Figure 3.

Gene ExpressionThe central dogma of molecularbiology is the flow of information fromDNA to RNA. In a tightly controlledprocess of transcription and trans-lation, proteins are formed. The firststep, transcription, occurs when theinformation stored in a gene’s DNA istransferred to RNA in the cell nucleus.Messenger RNA (mRNA) carries themessage from the DNA out of the nu-cleus into the cytoplasm. The secondstep, translation, occurs when mRNAinteracts with ribosomes, which readthe sequence of mRNA bases. Eachsequence of three bases, called a codon,usually codes for one particular aminoacid. Proteins are formed in a processof gene expression (see Figure 1).8

Nutritional GenomicsThe genome is the entire DNAsequence of an organism; the genome

(SNPs) are small sequence differences withot all SNPs result in structural protein chalar site where others have a chromosome w

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contains all of the biological informa-tion needed to build and maintain aliving organism. Omics refers to theentire complement of a given categoryof biological molecules and informa-tion being studied, measured, ordescribed.9

Nutritional genomics is the broadterm encompassing nutrigenetics,nutrigenomics, and nutritional epi-genomics, all of which involve hownutrients and genes interact and areexpressed to reveal phenotypic out-comes, including disease risk. Nutrige-netics is the influence of geneticvariability between individuals ac-counting for the variations in healthstatus and disease risk despite similar-ities in dietary intake.10 Nutrigenomicsencompasses the interactions betweendietary components and the genomeand the resulting changes in proteinsand other metabolites that affect geneexpression.11 Despite these de-lineations, nutrigenomics is often usedsynonymously with nutritional geno-mics. Nutritional epigenomics refers to

in genes where the DNA sequences ofnges. For example, some people mayith a G. SNPs occur in about 1% of the

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Term Definition

Allele An allele is one of two or more versions of a gene. An individual inherits two alleles for eachgene, one from each parent. If the two alleles are the same, the individual is homozygous forthat gene. If the alleles are different, the individual is heterozygous.82

Chromosomes Structure found in the nucleus of a cell, which contains the genes. Chromosomes come inpairs, and a normal human cell contains 46 chromosomes.82

Codon In DNA or RNA, a sequence of three nucleotides that codes for a certain amino acid or signalsthe termination of translation (stop or termination codon).82

DNA Deoxyribonucleic acid. The molecules inside cells that carry genetic information and pass itfrom one generation to the next.

DNA methylation The degree to which methyl groups are present or absent from certain regions of genes.35

Epigenetics Changes in the regulation of the expression of gene activity without alteration of geneticstructure.82

Gene silencing Interruption or suppression of the expression of a gene at transcriptional or translationallevels.82

Genome The entire set of genetic instructions found in a cell. In human beings, the genome consists of23 pairs of chromosomes found in the nucleus, as well as a small chromosome found in thecells’ mitochondria. These chromosomes, taken together, contain approximately 3.1 billionbases of DNA sequence.82

Genome wideassociationstudies (GWAS)

GWAS searches the genome for small variations or SNPs that occur more frequently in peoplewith a particular disease than in people without the disease. Each study can look at hundredsor thousands of SNPs at the same time. These studies identify genes that may contribute therisk of developing a certain disease.82

Genotyping Testing that reveals the specific alleles inherited by an individual; particularly useful whenmore than one genotypic combination can produce the same clinical presentation, as in theABO blood group, where both the AO and AA genotypes yield type A blood.82

Histone A protein that provides structural support to a chromosome. For very long DNA molecules tofit into the cell nucleus, they wrap around complexes of histone proteins, giving thechromosome a more compact shape. Some variants of histones are associated with theregulation of gene expression.82

Human Genome Project An international research effort to determine the sequence of the human genome andidentify the genes that it contains.83

messenger RNA (mRNA) A single-stranded RNA molecule that is complementary to one of the DNA strands of a gene.The mRNA is an RNA version of the gene that leaves the cell nucleus and moves to thecytoplasm where proteins are made. During protein synthesis, the ribosome moves along themRNA, reads its base sequence, and uses the genetic code to translate each three-base triplet,or codon, into its corresponding amino acid.82

Methylenetetrahydrofolatereductase (MTHFR)

This enzyme converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. Thisreaction is required for the multistep process that converts homocysteine to methionine.84

Microbiome The collective genomes of the microbes (composed of bacteria, bacteriophage, fungi,protozoa and viruses) that live inside and on the human body.85

Multigenetic The combined contribution of one or more often unspecified genes and environmentalfactors, often also unknown, which cause a particular trait or disease.82

(continued on next page)

Figure 3. Glossary of terms used in the Academy of Nutrition and Dietetics position paper on nutritional genomics. The terms in thisglossary are related to genetics, genomics, and epigenetics.

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Term Definition

Nutrigenetics Impact of genetic differences between individuals on the response to dietary intake and theultimate influence on health status and disease risk.10

Nutrigenomics The interactions between dietary components and the genome and the resulting changes inproteins and other metabolites that affect gene expression.11

Phenotype Observable characteristics of an organism produced by the organism’s genotype interactingwith the environment.82

Polygenic Genetic disorder resulting from the combined action of alleles of more than one gene (eg,heart disease, diabetes, and some cancers). Although such disorders are inherited, theydepend on the simultaneous presence of several alleles; thus, the hereditary patterns usuallyare more complex than those of single-gene disorders.82

Proteomics The study of protein expression and function.82

Ribonucleicacid (RNA)

A single-stranded molecule similar to DNA. An RNA strand has a backbone made of alternatingsugar (ribose) and phosphate groups. Attached to each sugar is one of four bases: adenine (A),uracil (U), cytosine (C), or guanine (G). Different types of RNA exist in the cell: mRNA, ribosomalRNA, and transfer RNA. Some small RNAs have been found to be involved in regulating geneexpression.82

Ribosome A cellular particle made of RNA and protein that serves as the site for protein synthesis in thecell.82

Ribosomal RNA (rRNA) The most abundant form of RNA. Together with proteins, rRNA form the ribosomes and play astructural role and also a role in ribosomal binding of mRNA and tRNAs.82

Single nucleotidepolymorphisms (SNPs)

A type of polymorphism involving variation of a single base pair.82

transferRNA (tRNA) A class of RNA that recognizes the triplet nucleotide coding sequences of mRNA and carriesthe appropriate amino acid to the ribosomes, where proteins are assembled according to thegenetic code carried by mRNA.82

Figure 3. (continued) Glossary of terms used in the Academy of Nutrition and Dietetics position paper on nutritional genomics. Theterms in this glossary are related to genetics, genomics, and epigenetics.

FROM THE ACADEMY

the influence of diet on changes ingene expression without changing theDNA sequence. Other omic areas aremodified in response to diet. Theseinclude transcriptomics (the study ofthe transcriptome, the complete set ofRNA transcripts produced by thegenome at any one time), proteomics(the study of protein expression andfunction), and metabolomics (the studyof lowemolecular-weight moleculesfound within cells and biologicalsystems).

NutrigeneticsThe best-known example of nutrige-netics is classic phenylketonuria (PKU)caused by mutations in the phenylala-nine hydroxylase gene. The primarytreatment is a low phenylalaninediet. PKU is among a small groupof rare, autosomal recessive metabolic

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disorders of nutrient metabolism inwhich dietary treatment that is imple-mented shortly after birth amelioratesthe phenotype of severe cognitiveimpairment and a host of medicalproblems. Unlike PKU, most chronicdisorders, such as cardiovascular dis-ease (CVD), hypertension, diabetes, andcancer, are multigenetic and multifac-torial.12 In these chronic diseases, agenetic variant, or SNP, does notnecessarily translate into a greater riskof developing disease. Environmentalfactors, such as smoking, physical ac-tivity, and diet modify genetic expres-sion and influence disease outcome.13

A nutritionally relevant SNP orpolymorphism involves folate and ho-mocysteine status, and potentiallyCVD, neural tube defects, and otherdisease risks. The C677T polymorphismis a common SNP of the methylenete-trahydrofolate reductase (MTHFR) gene,

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which encodes the 5,10-MTHFR enzymeand uses folate to metabolize andthereby remove homocysteine. TheC677T polymorphism in the MTHFRgene reduces enzyme efficiency, so inmany populations without folic acidfortification, individuals with TT geno-type havea lower blood folate levels andabout a 20% higher homocysteine levelthan those with the more common CCgenotype.14 The C677T polymorphismin the MTHFR gene has been associatedwith a moderately increased risk ofCVD occurrence in some genotypingstudies in countries that do not fortifyfoods with folic acid, but overall theCVD risk of individuals with the TTgenotype is unclear. Interestingly, folicacid fortification, which occurred in theUnited States in 1998, may be lesseningthe CVD risk in individuals with thisgenotype. An inverse relationship ofthe TT variant and CVD mortality was

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found in a cohort in the periodfollowing folic acid fortification.15 It ispossible that the additional folic acid inthe diet is protecting those susceptibleindividuals, although multiple path-ways are involved in folate metabolism,which makes interpretation of folicacid status complex. There is insuffi-cient evidence regarding C677T poly-morphism in the MTHFR gene tomodify current folate recommenda-tions from those provided in the Di-etary Reference Intakes.Folate, methionine, and choline are

intricately involved in the methylationof DNA, RNA, and proteins; disturbingthe metabolism of one results incompensatory changes in the others.16

The importance of their interactionsis evident in the example of cholinestatus in premenopausal women. Pro-viding a choline-deficient diet to hu-man beings results in reversible fattyliver with liver and muscle damage.17

Premenopausal women are somewhatresistant to these deleterious outcomesbecause they have an estrogen-enhanced capacity for producingcholine through the phosphatidyletha-nolamine N-methyltransferase (PEMT)gene.17 The PEMT gene is induced byestrogen and codes for an enzyme thatcatalyzes the endogenous synthesis ofcholine. However, premenopausalwomen who have an SNP in PEMT mayhave an increased risk for developingliver and muscle dysfunction when feda low-choline diet. In addition, pre-menopausal womenwith an SNP in themethylenetetrahydrofolate dehydroge-nase 1 (MTHFD1) gene, which codes foranother folate enzyme, were 15 timesmore likely to develop signs of cholinedeficiency on the low-choline diet thanthose without the SNP.17 These SNPsmay provide insight as to the interin-dividual variation in choline and folaterequirements. However, more researchis needed before clinical application ofgenetic testing of the PEMT gene isavailable and adequate intake valuesfor choline are adjusted.The most widely investigated com-

mon SNPedisease association is therelationship between the apolipoproteinE (apoE) genotype and coronary heartdisease (CHD) risk. ApoE is a proteininvolved in cholesterol and triglyceridemetabolism and clearance. ApoE hasthree isoforms (E2, E3, and E4) thatequate to three gene alleles; E3 is normalwhereas E2 and E4 are dysfunctional.

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Generally, individuals with the E4 allelehave higher low-density lipoprotein(LDL) cholesterol levels and those withthe E2 allele have lower LDL cholesterollevels than individualswith the commonE3/E3 genotype.18 However, the consis-tency in phenotypic outcome from genevariants is not always what is expected.In the case of apoE, numerous studieshave investigated the effect of the apoEgenetic variant on CHD risk, includingthree meta-analyses.18-20 Two of the an-alyses found that individuals with the E4allele had an increased risk of CHD andthose with the E2 allele showed no dif-ference in CHD compared with thecommon allele19,20; the third analysisshowed less of an effect in individualswith the E4 allele and a stronger pro-tective effect of the E2 allele.18 Theseanalyses did not consider dietary influ-ence, whichmay have contributed to theinconsistent results. Other potentialvariables contributing to the in-consistencies are the lack of statisticalpower, confusion by other gene variants,dietary interactions, and the lack of ac-curate measurements of dietary fat.13

Early studies indicate that the apoE ge-notype interacts with dietary saturatedfat, increasing LDL cholesterol concen-trations andCHDrisk,more inE4carriersthan the other alleles.13 Insufficient evi-dence, study limitations, and other riskfactors for CHD preclude making dietaryfat recommendations based on apoEgenotype testing.A similar scenario exists with the

cholesteryl ester transfer protein ge-notype. Initial research indicates aninteraction between cholesteryl estertransfer protein SNP and alcohol con-sumption in determining high-densitylipoprotein cholesterol concentrationsand CVD risk. However, it has beendifficult to replicate these results.13

Another CVD risk-related gene variantis the apolipoprotein A5. In this case,the SNP is associated with higher tri-glyceride concentrations and n-6 poly-unsaturated fatty acid dietary intakeincreases triglyceride levels.21 Althoughthis finding is promising, more studiesare required before practitioners canprovide dietary guidance based onapolipoprotien A5 genotype.Genetic variations that predispose

individuals to obesity, inflammation,dyslipidemia, and oxidative stress mayinteract with environmental exposures,including diet, to alter an individual’srisk for developing these conditions.22

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Several single gene mutations havebeen linked to severe obesity; however,they represent only a small fraction ofpopulation-level obesity. Like mostchronic disease, obesity is polygenic,involving complex geneegene andgeneeenvironment interactions.23

More than 20 genes are associatedwith obesity-related anthropometricmeasures, including body mass index(BMI), waist circumference, and waist-to-hip ratio.24 Gene variants relatingto the regulation of energy intake andexpenditure include the adrenergicreceptors, uncoupling proteins, perox-isome proliferator-activated receptor,proopiomelanocortin, melanocortin 4receptor, and fat mass and obesityassociated (FTO) genes.23

Variation in the FTO gene has beenassociated with obesity in genome-wide association studies. Adults withthe FTO SNP genotype are likely to bemore obese than thosewho do not carrythe risk allele.25 Energy intake is higherin children with the FTO risk allele, in-dependent of body weight.26 Carryingthe A allele of the FTO gene increases therisk of obesity but the risk can bemodified by either physical activity orby reducing energy intake.23 The ge-netic vulnerability to obesity may beexpressed in specific eating and activitypatterns that are heritable, but onlyexpressed when the environmental ex-posures permit them to be expressed.

The established obesity-associatedgenes together explain <2% of theinterindividual BMI variation, whichfalls well below the estimated herita-bility for obesity. The heritability ofBMI and waist circumference of 40% to70% indicates there may be much moregenetic variation left to uncover.24,27

Additional genetic factors, such as rareand low-frequency variants, copynumber variants, noncoding RNA (ie,microRNAs that regulate gene expres-sion after transcription), and epigeneticmodifications may be involved.24

When additional functional geneticvariants and further molecular andphysiologic characterizations of thegenes and pathways are uncovered,therapeutic guidelines for obesityintervention based on genotype vari-ance may become a viable approach.

NutrigenomicsEnergy restriction and dietary modifi-cation in obese individuals are

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providing insights into how nutrientsaffect gene expression. Studies arefinding that when overweight andobese individuals modify their diet,genes related to metabolism andinsulin-like growth factor are decreasedor down-regulated.28,29

Future nutrigenomic studies, whichexamine how diet and dietary patternsaffect gene expression, may help guideclinicians in classifying obese patientsinto subtypes and identify differentphases of weight loss, such as acute orlong-term weight loss.30 Althoughnutrigenomic and gene profiling testsare not validated for clinical practice,future testing may allow for more tar-geted therapy to subclasses of obesepatients and aid in the development ofobesity treatment strategies.The effects of diet intervention on

gene expression is beginning to emergein other diseases, including cancer.Nutrigenomic testing was used in apilot study of low-risk prostate cancerpatients who declined traditionaltreatment and participated in anintensive nutrition and lifestyle inter-vention.31 After 3 months, the menwere consuming about 12% energyfrom fat, exercising >3.6 hours perweek, and practicing stress manage-ment for 4.5 hours per week. CVD riskfactors were improved, including re-ductions in BMI, waist circumference,blood pressure, and lipid levels. Geneexpression analysis detected 48 up-regulated and 453 down-regulatedtranscripts after the intervention. Inparticular, a set of RAS family onco-genes were down-regulated, whichmay function as an androgen receptorcoactivator, and for which expression isincreased in tumor tissues.31 A double-blind placebo-controlled randomizedclinical trial, the Molecular Effects ofNutrition Supplements, also looked atnutrient intervention and gene ex-pression in low-risk cancer patientsand found no effects of diet on geneexpression. Men with low-risk prostatecancer were stratified based on self-reported dietary consumption of fishand tomatoes and then randomized toreceive supplemental lycopene, fish oil,or placebo. After 3 months, gene ex-pression analysis revealed no signifi-cant individual genes that wereassociated with high intake of fish ortomato.32 Limitations of this studyinclude not controlling the patients’dietary intake and the multiple lifestyle

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variables that could confound theresults.

EPIGENOMICSEpigenetics are the heritable changesnot encoded in the DNA sequence it-self, but that play an important role inthe control of gene expression.33 Epi-genetics is the process that regulateshow and when genes are silenced andactivated; epigenomics refers to theanalysis of epigenetic changes in acell.34 Diet can cause epigeneticchanges that may turn certain genes onor off, ultimately affecting cellularfunction and metabolism.34 Oneepigenetic mechanism is DNA methyl-ation, which refers to the degree towhich methyl groups are present orabsent from certain regions of genes.Generally, hypomethylation allowsgene expression to be activated;hypermethylation interferes with geneexpression. Both hypomethylation orhypermethylation describe an aberrantscenario and the influence on a genewill depend on the specific genes, thetime point, and the tissues.35

Nutritional EpigenomicsThe nutrients folate, methionine,choline, vitamin B-12, and vitamin B-6are involved in one-carbon metabolismand play a critical role in maintainingDNA methylation. The intake of toomuch or too little of any of these nu-trients affects one-carbon metabolismand has the potential to disrupt DNAand histone methylation patterns.36 Inanimal studies, diets deficient inmethionine, choline, vitamin B-12, orfolate induce global hypomethylationand site-specific hypermethylation andhave been linked to increased cancerdevelopment.36

Some of the strongest evidence thatdiet plays a role in epigenetics, throughmethylation, was done in the agoutimouse model. The wild type agoutimice have a yellow coat color and aregenetically prone to obesity. The addi-tion of folic acid, vitamin B-12, choline,and betaine to the maternal diet ofpregnant mice altered the wild typephenotype of yellow coat and obesity toa phenotype characterized by a lessyellow coat color; pseudo-agouti; andlower prevalence of cancer, diabetes,and obesity.37 Adding genistein atlevels comparable with human beings

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consuming high-soy diets to thematernal diet led to similar outcomes.38

Dietary factors can act via epigeneticmechanisms throughout the lifespan,and also may extend across genera-tions. Individuals exposed to famineprovide evidence that early-life envi-ronmental conditions can cause epige-netic changes in human beings thatpersist through generations. Six de-cades after individuals were prenatallyexposed to famine during the DutchHunger Winter in 1944-1945, they hadless DNA methylation of the maternallyimprinted insulin-like growth factor 2gene, which is a key factor in humangrowth and development, comparedwith their unexposed, same-sex sib-lings.39 The association occurred in thepericonceptional period, reinforcingthat very early mammalian develop-ment is a crucial period for establishingand maintaining epigenetic marks.39

The individuals exposed to faminepericonceptionally have had a higherincidence of chronic diseases, includinga doubling in the incidence of schizo-phrenia, type 2 diabetes, CHD, hyper-cholesterolemia, and some cancers.40

This concept of early programmingmechanisms in human adaptation tothe social environment can havegenerational effects.

The chronic low-grade inflamma-tory state that is associated withobesity, insulin resistance, CVD, andmetabolic syndrome may also be un-der epigenetic regulation.41 Humantrials are looking at DNA methylationpatterns before and after dietary in-terventions. In a small study of obesemen on a weight loss regimen, hypo-caloric diets induced changes in theDNA methylation pattern. There werenoted differences in methylation be-tween those men considered to behigh responders (lost >5% bodyweight) compared with the low re-sponders (lost �5% body weight). Af-ter the weight loss intervention,methylation changes from baselinewere apparent, leading to the premisethat some of the markers affectedcould be used as early indicators ofresponse to the metabolic effects of aweight-loss program.42 Future epige-netic research will likely focus onquantifying the importance of epige-netic regulation in the etiology anddevelopment of obesity and the char-acterization of the genes involved inthe processes.41

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Other epigenetic mechanismsinclude histone modifications, genesilencing by microRNA, and chromo-some stability. DNA is tightly coiledaround proteins known as histones;histone modification refers to howtightly the DNA strand is wrappedaround the histones. Histone modifi-cations are known to influence proteintranscription, DNA repair processes,DNA replication, and chromatincondensation. Promising evidence inhuman beings suggests that diet andenvironmental factors directly influ-ence these epigenetic mechanisms.33

Genomic imprinting, which canoccur through DNA methylation orhistone modification, is another mech-anism that allows for gene expression.In genomic imprinting, only the pater-nally or maternally inherited allele isexpressed. For example, Prader-Willisyndrome that leads to severe obesityarises from imprinted gene muta-tions.35 Interestingly, loss of expressionon the paternally inherited allelecauses Prader-Willi syndrome, whereasabsence of expression of the maternalallele results in Angelman syndrome,43

a neurodevelopmental disorder char-acterized by severe mental retardationand not associated with obesity.44

Although there is promising evi-dence that diet can influence epige-netic mechanisms, there are still manyunanswered questions that need tobe addressed. Such questions includewhether the nutritional influences onepigenetic modifications observed inanimal and cell models correlate withmanifestations in human beings, andfurther, what is the optimal type, dose,duration, and timing of the nutritionalintervention and the potential trans-generational influence.35

APPLICATION OF NUTRITIONALGENOMICS TO DIETETICSPRACTICEThe practical application of nutritionalgenomics on a personalized level re-quires knowledge of an individual’spotential susceptibility to disease. Thisinformation may be obtained in severaldifferent ways. Family history; bio-chemical parameters; the presence ofrisk factors for disease such as obesity,hypertension, or hyperlipidemia; andresults from genetic testing may pro-vide useful information about an

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individual’s risk of developing diseaseor maintaining health.

Family HistoryFamily history is an importantscreening tool to determine risk ofinherited diseases. Family history pro-vides information on the genes, be-haviors, and environmental exposuresthat relatives share in common. How-ever, a state-of-the science conferenceconvened by the National Institutes ofHealth found that the usefulness offamily history in assessing the risk andtargeting interventions for chronicdisease is limited.45 A complete familyhistory can take 15 to 20 minutes torecord, and its accuracy is influencedby factors such as patient uncertaintiesregarding the details of their relatives’health or a poor understanding of themedical terms. Generally, health carepractitioners are not obtaining familyhistories and, if they are, the familyhistory is not being done thoroughly.46

The utility of the family history is stillrelevant. In the case of type 2 diabetesmellitus, in which more than 40 locihave been associated with the disease,a positive family history of diabetespredicts risk and genetic variation.46

People with a family history of colo-rectal cancer are at increased risk ofdeveloping this disease.47 Family his-tory also may help guide decisionsregarding the use of genetic testing inat-risk individuals. For example, theEvaluation of Genomic Applications inPractice and Prevention WorkingGroup recommends that all individualswith a new diagnosis of colorectalcancer be offered genetic testing forhereditary nonpolyposis colorectalcancer or Lynch syndrome, to helpprevent cancer in their close rela-tives.48 For CVD, traditional risk factors,such as lipid levels, blood pressure, andthe use of family history, are beneficialfor assessing disease risk. However, forpersons with CVD, there is insufficientevidence to recommend genomicprofiling testing because the healthbenefit from the testing is negligible.49

Genetic TestingDuring the past decade, the availabilityof genetic tests has increased markedly.Historically, genetic tests were usedwithin a traditional medical setting toconfirm a suspected diagnosis, screen

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for heritable disorders in at-risk pop-ulations, and conduct population-widenewborn screening. Currently, thereare about 2,000 genetic tests availablefor use in clinical settings,50 most ofwhich test for rare single-gene disor-ders. In single-gene disorders, a defec-tive gene may confer as high as 100%probability of the disorder, such as inHuntington’s disease. In regard tobreast cancer genes—BRCA1 and BRCA2—there is a significant increase in proba-bility of developing breast cancerassociated with these genes. Testingfor single-gene disorders occurs pri-marily within the traditional medicaltesting.51

Complex disorders, such as cancer,CVD, and diabetes, are caused by ge-netic and environmental factors andgenetic mutations are only partiallypredictive of risk. Because of the largenumber of possible geneeenvironmentinteractions, the interplay amongenvironment, genes, and disease ispoorly understood.6 Tests for somecomplex disorders are commerciallyavailable to the public primarilythrough direct-to-consumer (DTC) ge-netic testing companies. Unlike genetictests for single-gene disorders, tests forcomplex disorders, which look formutations in SNPs, are only predictiveof an altered risk associated with dis-ease development. Because not all SNPassociations and other factors thatcontribute to the development of aparticular disease are known, the ab-solute risks from SNP association testsare low and they are not of significantutility to alter the standard of care atthis time.51

The need to define the validity andusefulness of genetic tests offered inmedical settings and directly to con-sumers in predicting disease and todetermine whether identifying muta-tions improve patient outcomes promp-ted the Centers for Disease Controland Prevention (CDC) Office of PublicHealth Genomics to develop the ACCEmodel. The ACCE model defines analyt-ical validity, clinical validity, and clinicalutility and ethical considerations of ge-netic tests as follows:

� Analytic validity refers to howaccurately and reliably the testdetects whether a specific ge-netic variant is present or absent.For example, a test that mightbe used in the diagnosis of

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FROM THE ACADEMY

familial hypercholesterolemia(FH) would accurately andconsistently determine thepresence of mutations in theLDLR, APOB, or PCSK9 genes.52

� Clinical validity refers towhether the test accurately de-tects or predicts the presence ofa disorder or disease. Using theFH example, if specific mutationsare present in the LDLR, APOB, orPCSK9 genes, the test wouldconfirm a diagnosis of FH.

� Clinical utility refers to howlikely it is that the test willimprove patient outcomes. Inthe FH example, the test resultsallow for meaningful clinicaldecision making for theindividual.

� Ethical, legal, and social impli-cations that may be associatedwith use of the test.

The CDC categorized genetic testsand their application in practice bylevel of evidence.53 This categorizationassists clinicians in the application ofgenomic tests.49 Currently, the CDCOffice of Public Health Genomics pro-vides evidence-based recommenda-tions for the following genomic teststhat can be recommended for clinicaluse, having achieved analytic validity,clinical validity, and clinical utility:

� newborn screening panel of 31core conditions for all newborns;

� BRCA1/2 analysis for womenwith specific history of breast orovarian cancer;

� Lynch syndrome screening;� FH among relatives of persons

with FH;� human leukocyte antigen testing

for abacavir sensitivity for pa-tients with human immunodefi-ciency virus; and

� human epidermal growth factorreceptor 2 mutation testing inbreast cancer in patients withinvasive breast cancer.

According to the CDC, the genomicapplications that have demonstratedanalytic and clinical validity but haveinsufficient evidence for clinical utilityinclude:

� breast cancer gene expressionprofiles to estimate risk ofrecurrence and target therapy;

� family history for commondiseases;

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� pharmacogenomic testing toinform safety and effectivenessof medications; and

� single-gene disorders and chro-mosomal abnormalities for diag-nosis, management, and carriertesting for these disorders.

The CDC determined the followinggenomic applications are not ready forroutine practice because they lack an-alytic validity, clinical validity, andclinical utility:

� genetic risk factors for commondiseases;

� >400 emerging genomic testsfor various intended uses; and

� next-generation sequencing/whole genome sequencing toassess risk for common diseases.

Genetic tests are added or re-categorized as their status changes,depending on the outcome of severalevidence-based evaluation mecha-nisms, including from the Evaluation ofGenomic Applications in Practice andPrevention Working Group and the USPreventive Services Taskforce54; theCDC website is periodically updated.

Regulation and Oversight ofGenetic TestsMultiple federal and state govern-mental entities share responsibilityfor the oversight of genetic tests. Acomprehensive review is available in USSystem of Oversight of Genetic Testing: AResponse to the Charge of the Secretary ofHealth and Human Services.55

There are two categories of genetictests used in clinical practice. In vitrodiagnostic tests are manufactured to bedistributed to multiple laboratories.Laboratory-developed tests are solelyused in the test developer’s laboratory.New technologies and testing plat-forms, such as gene panels and whole-genome tests that analyze manyvariants and DTC genomic testing, arechallenging conventional regulatoryparadigms. DTC genetic tests areconsidered laboratory-developed testsbut their classification is unclearbecause they often use a gene chip, atool that identifies variations in genes,bought from a third party.56

DTC Genetic Testing andNutrigenetic TestingDTC genetic testing refers to genetictests that are marketed directly to

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consumers; DTC genetic testing hasbecome increasingly available onlineduring the past 10 years due todeclining costs, improved testing tech-nologies,57 and lack of regulation.58

Typically, a customer sends a DNAsample, such as a cheek swab, throughthe mail and results are returned bymail, over the telephone, or postedonline.59 A health care provider istypically not involved in either orderingthe test or interpreting the results,60

although some DTC genetic testingcompanies do provide access to a healthcare practitioner.

Currently available DTC genetic testsinclude >100 disease susceptibilitymarkers, a number of traits (eg, eyecolor), carrier and diagnostic testing,drug response, and ancestry andkinship testing.51 Despite claims byDTC testing companies that the infor-mation provided allows consumers tomake more informed health care de-cisions, the health value of this testingremains questionable.57 Moreover, theresults that are returned to consumersis an interpretation of risk, and theaccuracy of the interpretation isdependent on many factors, includingthe particular panel of risk SNPs usedby the company and the other envi-ronmental factors that contribute tothe risk of developing disease.61

DTC nutrigenetic testing companiesthat offer tailored diets and adviceregarding the use of dietary supple-ments based on SNP analysis prolifer-ated during the early 2000s. Theconcern about the lack of regulation ofDTC nutrigenetic tests was brought towide attention during 2006 with thepublication of a US GovernmentAccountability Office report62 thatfound selected tests misled consumersand provided nutrition advice basedprimarily on medical and family his-tory. The Federal Trade Commissionnotified several companies that theiradvertising claims mislead consumersbecause their tests had not demon-strated clinical validity or utility. Mostof these companies went out of busi-ness or changed their businessmodel.63 Other DTC companies markettheir tests as lifestyle behavior ap-proaches rather than disease diag-nosis59 and have been able to avoid theregulatory red flags of selling medicaldevices. Regulatory agencies, such asthe Federal Trade Commission andthe Food and Drug Administration,

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Agency Genetic testing activities Comments Website

Food and DrugAdministration(FDA)

� Regulates genetic tests asmedical devices if theyprovide medical informa-tion used to diagnose,treat, or prevent disease61

� Regulates IVDa genetictests that are made byone company then sold asa kit to a laboratory

� Regulates genetic testsbased on risk/degree ofharm of inaccurate testresults, not dependent ontype of test or who makesthe test

� FDA has authority overLDTsb, but has limited itsregulation becausehistorically LDTs were low-risk diagnostic toolsinterpreted by experts intest developer’s laboratory

� FDA has exercised its reg-ulatory authority over IVDsand approved severaltests for specific geneticfactors

� LDTs have been increas-ingly used to assess high-risk common conditionsoften with minimal or nofindings to support theirclinical usefulness

www.fda.gov/MedicalDevices/default.htmwww.fda.gov/NewsEvents/Testimony/ucm219925.htm

Centers forMedicare &MedicaidServices(CMS)

� Regulates clinical labora-tory testing in the UnitedStates through CLIAc

� Ensures analytical validityof genetic tests

� Does not address theclinical validity or utility oftests64

www.cms.gov/Regulations-and-Guidance/Legislation/CLIA/index.html?redirect¼/clia/

Federal TradeCommission(FTC)

� Administers consumerprotection laws, especiallyrelated to unfair ordeceptive trade practices,such as misleading adver-tising claims

� Relevant for DTCd genetictesting becausecompanies marketproducts directly toconsumers rather than tophysicians or health carecompanies

� FTC can enforce action toprohibit DTC companies’claims of clinical validity ifthere is inadequate scien-tific evidence for suchclaims

www.consumer.ftc.gov/articles/0166-home-genetic-tests

NationalInstitutesof Health (NIH)Genetic TestingRegistry (GTR)

� Central location forvoluntary submission ofgenetic test informationby CLIA-certifiedlaboratories

� Does not independentlyverify informationsubmitted

� Does not endorse tests orlaboratories listed

www.ncbi.nlm.nih.gov/gtr/docs/code/

(continued on next page)

Figure 4. Regulation and oversight of genetic tests and personal genetic information.

FROM THE ACADEMY

308 JOURNAL OF THE ACADEMY OF NUTRITION AND DIETETICS February 2014 Volume 114 Number 2

Agency Genetic testing activities Comments Website

� Information included isthe test’s purpose, meth-odology, validity, evidenceof test usefulness, andlaboratory contacts andcredentials

� Submitters must abide byCode of Conduct that for-bids them to make claimsthat NIH approves or en-dorses tests or informa-tion submitted

ConsumerProtection Description Comments Website

GeneticInformationNondiscriminationAct of 2008(GINA)

� Prohibits discriminationby health insurance com-panies and employers onthe basis of geneticinformation

� Genetic information isdefined as informationabout an individual’s ge-netic tests, genetic tests offamily members, andmanifestation of a diseaseor disorder in familymembers

� Does not cover life,disability, and long-termcare insurance

www.genome.gov/24519851

aIVD¼in vitro diagnostic.bLDT¼laboratory-developed tests.cCLIA¼Clinical Laboratory Improvement Amendment.dDTC¼direct to consumers.

Figure 4. (continued) Regulation and oversight of genetic tests and personal genetic information.

FROM THE ACADEMY

monitor the industry (see Figure 4).61,64

A recent Food and Drug Administrationpanel recommended that some DTCgenetic tests sold online no longer bereadily available to consumers and thatpre-symptomatic, high predictor teststhat are available for at-home usewithout a prescription should not beused without the involvement of aphysician or genetic specialist.65

Ethical, Legal, and Social IssuesEthical issues associated with nutri-tional genomics relate to research, ge-netic testing, and clinical practice. Thesame regulations that apply to usinghuman subjects in research66 apply tonutritional genomic research. Nutri-tional genomics research ethics chal-lenges traditional human researchethics because genetic information isoften generated through large-scalepopulation studies.67 The generationof genetic information raises issues ofwhether or not genetic data per seshould be treated differently from

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other health-related information andgenetic exceptionalism. Genetic ex-ceptionalism refers to information thatidentifies family relationships, can pre-dict future health events, may be ofinterest to third parties such as insurersand employers, and can be recoveredfrom stored biological specimens in thefuture.68 There are protections in placearising from the Genetic InformationNondiscrimination Act of 2008, whichprohibits discrimination by health in-surance companies and employers onthe basis of genetic information (seeFigure 4). Ethical questions ariseregarding the obligation of informingnutrigenomic study participants of re-sults of genotypic tests in which theconsequences of particular genotypesmay be unknown.67

Whether or not registered dietitiannutritionists (RDNs) inform clientsabout genetic test results is an ethicalissue and the course of action is notwell defined. Although it has beensuggested that RDNs inform clients ofgenetic test results that might include

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unrelated or incidental findings,69

informing clients about results thatare not in their purview may haveserious ramifications depending on thespecific findings. Disclosure of thepresence of a gene variant from SNPanalysis to a relative may pose undueburden and should also be handled bygeneticists or genetic counselors. In thecase of genetic variants, it is difficult topredict disease risk in an individual; toextrapolate results to family memberswould be questionable. As an integralpart of a team approach to patient care,an RDN may collaborate with a primarycare physician and/or genetics profes-sional in the interpretation of genetictesting results and development of acare plan. However, disclosure of ge-netic test results should be the re-sponsibility of primary care physiciansin conjunction with geneticists or ge-netics counselors. As genetic testingexpands to genome sequencing and thepotential to detect the presence of ge-netic mutations of unknown signifi-cance, recessive disease carrier status,

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FROM THE ACADEMY

and genes that predict adult-onsetconditions in children, interpretationand decisions regarding disclosure ofresults to clients and patients shouldbe handled by genetics professionals.

RDNs’ Knowledge of Geneticsand Nutritional GenomicsThe application of nutritional genomicsin clinical practice requires that healthcare professionals understand, inter-pret, and communicate complex testresults in which the actual risk ofdeveloping a disease may or may notbe known.70 Yet most health care pro-viders are not trained in clinical ge-netics and molecular testing and havelimited ability to discuss probabilityand risk.70

For more than a decade, surveys ofRDNs in the United States, Canada, andthe United Kingdom have found lowknowledge of nutritional genomicsand poor confidence in incorporatingthis science into practice.71-74 Geneticscourse content is required in under-graduate dietetics programs andinternships; however, stand-alone ge-netics courses are not required andthe degree of proficiency in geneticknowledge has not been delineated. Aswould be expected, those who hadexposure to genetics through universityeducation and continuing professionaleducation reported greater knowledgeabout the relationship between ge-netics and diet.74 A plan to introducenutritional genomics education in un-dergraduate dietetics curricula hasbeen reported.75

The Future of NutritionalGenomicsModels being developed for personal-ized medicine may be applicable tonutritional genomics in the future. Arecently described model, the Integra-tive Personal Omics Profile, combinesgenomic data with transcriptomic,proteomic, and metabolomic profilesand other biochemical data to under-stand healthy states and monitor theonset and progression of diseasestates.76 In a case that used this inte-grative model, Chen and colleagues76

sequenced the genome of a normalweight, healthy man and discoveredrisk alleles for type 2 diabetes. During a14-month period, blood tests weredrawn every 2 months and the manwas monitored. Based on increasing

310 JOURNAL OF THE ACADEMY OF NUTRIT

blood glucose and glycosylated hemo-globin levels, the man was diagnosedwith type 2 diabetes triggered by aviral infection. The implementation ofdietary changes and increased exercisenormalized this man’s biochemicalparameters without the use of medi-cations. Although this was a singlesubject, the case highlights severalimportant aspects of the application ofnutritional genomics to dietary prac-tice. The use of multiple technologiescombined in ways that identify medicalrisk and monitor physiologic statesis a model that will link associateddisease risk alleles with the develop-ment of actual disease or maintenanceof health. This model provides an op-portunity to positively change out-comes and influence standards of care.In addition, RDNs as integral membersof health care teams will have theadvantage of intervening early inchronic disease progression with theaim of prevention.The 2012-2022 Dietetics Workforce

Supply and Demand Future Scan iden-tified the evolution of personalizednutrition as a “change driver.”77

Whereas “new personal health testingandmonitoring technologieswill createopportunities for dietetics practi-tioners,” specialized knowledge and/orexperience will be required.77 Accord-ing to the scan, RDNs with expertise inmanaging genetic metabolic disordersthrough nutrition intervention andcounseling will lead the way.77 Stan-dardsof Professional Practice for geneticmetabolic dietitians were published in200878 and their role as advancedpractitioners in genetics and nutritionalgenomics has been characterized.79

Although these RDNs have focusedtheir clinical and academic expertiseprimarily on single-gene disorders, theyare well trained for complex, multifac-torial disorders. RDNs in integrative andfunctional medicine have developedstandards of practice that include theuse of genetics and genomics in clinicalcare.80 RDN researchers, academicians,and clinical practitioners with expertisein systems biology, outcomes research,and those with academic coursework ingenetics and genomics are needed tomove the discipline of nutritional ge-nomics forward in the future.Food consumption is driven by cul-

ture, economics, availability, andknowledge. Some people eat for plea-sure, some eat what is available, others

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eat with concern for specific healtheffects, and many fall somewhere be-tween those. Current public healthmessages provide important nutritionguidance for the general population.Nutritional genomics may help RDNsbridge the gap from overarching publichealth messages to more individualizeddietary guidance. Although the disci-pline of nutritional genomics holdspromise for tailoring diet to a person’sgenotype and influencing chronic dis-ease development, the science is stilldeveloping. The knowledge gainedfrom nutritional genomics requires anevidence-based approach to validatethat personalized recommendationsresult in health benefits to individuals34

and do not cause harm.79 Whether ornot the knowledge gained from nutri-tional genomics can be integrated intothe everyday lives of consumers is yetunknown.81

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This Academy of Nutrition and Dietetics position was adopted by the House of Delegates Leadership Team on September 17, 2013. This positionis in effect until December 31, 2016. Requests to use portions of the position must be directed to the Academy at journal@eatright.org.

Authors: Kathryn M. Camp, MS, RD, CSP, Kelly Government Solutions, Rockville, MD (Consultant to the Office of Dietary Supplements, NationalInstitutes of Health, Bethesda, MD); Elaine Trujillo, MS, RD, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health,Bethesda, MD.

Reviewers: Sharon Denny, MS, RD (Academy Knowledge Center, Chicago, IL); Oncology dietetic practice group (DPG) (Suzanne Dixon, MPH, MS,RD, The Health Geek, LLC, Portland, OR); Dietitians in Integrative and Functional Medicine DPG (Colleen Fogarty Draper, MS, LDN, Nestlé Instituteof Health Sciences, EPFL Campus, Lausanne Switzerland); Johanna T. Dwyer, DSc, RD (Tufts University, Boston, MA); Lynnette R. Ferguson, DPhil(Oxon), DSc, FNZIFST (The University of Auckland, Auckland, New Zealand); Donna A. Israel, PhD, RD, LPC, FADA (Baylor University, Waco, TX);Quality Management Committee (Barbara Kamp, MS, RD, Johnson & Wales University, Miami, FL); Mary Pat Raimondi, MS, RD (Academy PolicyInitiatives & Advocacy, Washington, DC); Research DPG (Colleen Spees, PhD, MEd, RD, LD, Ohio State University, Columbus, OH); Alison Steiber,PhD, RD (Academy Research & Strategic Business Development, Chicago, IL).

Academy Positions Committee Workgroup: Linda B. Godfrey, MS, RD, SNS, LD (chair); Christine A. Rosenbloom, PhD, RD, LD, CSSD; and Tanya Agurs-Collins, PhD, RD (content advisor).

The findings and conclusions of this report do not necessarily represent the views of the National Institutes of Health or the US Department ofHealth and Human Services.

February 2014 Volume 114 Number 2