Physiol Genomics 16: 161–165, 2004;

10.1152/physiolgenomics.00204.2003. Invited Review

Nutritional genomics
Patrick J. Stover
Cornell University, Division of Nutritional Sciences, 315 Savage Hall, Ithaca, New York 14853
Submitted 5 December 2003; accepted in final form 8 December 2003

Stover, Patrick J. Nutritional genomics. Physiol Genomics 16: 161–165, 2004;

10.1152/physiolgenomics.00204.2003.—The integration of genomics into nutri-
tional sciences has illuminated the complexity of genome responses to nutritional
exposures while offering opportunities to increase the effectiveness of nutritional
interventions, both clinical and population based. Nutrients elicit multiple physio-
logical responses that affect genome stability, imprinting, expression, and viability.
These effects confer both health benefits and risks, some of which may not become
apparent until later in life. Nutritional genomics challenges us to understand the
reciprocal and complex interactions among the human genome and dietary com-
ponents in normal physiology and pathophysiology. Understanding these interac-
tions will refine current definitions of benefit and risk and lead to the establishment
of dietary recommendations that have a high predictive value, minimize the risk of
unintended consequences, and account for the modifying effects of human genetic
variation. Furthermore, nutritional genomics will enable the design of effective
dietary regimens for the prevention and management of complex chronic disease.
This review focuses on new perspectives that have been presented to the nutritional
sciences by the advent of genomics, and new challenges that demand attention
because of their potential impact on, and immediate translation into, current public
health nutrition recommendations and interventions.
nutrition; genetic variation; recommended daily allowance; single-nucleotide poly-
morphism; haplotype; mutation; selection

GENOMICS ENCOMPASSES KNOWLEDGE related to “the study of the
functions and interactions of all the genes in the genome,
including their interactions with environmental factors” (27,
43). The acquisition of whole genome sequences is the foun-
dation from which this new discipline emerged, which seeks to
understand fundamentally the origin and molecular basis of all
life processes that are encoded by DNA sequence, processes
that are hardwired and those that are modifiable by environ-
ment. “Nutritional genomics,” sometimes referred to as “nu-
trigenomics,” is a widely recognized term that has renewed
interest in the benefits of nutrition research but has suffered
from a lack of meaningful scientific identity. Definitions of
nutritional genomics range from the application of high-
throughput genomic technologies to nutrition research (13, 34,
50) to the genetic enhancement of plants for higher nutritional
quality (8). Technological and theoretical advances in nano-
biotechnology, robotics, genetics, mathematics, and computa-
tional biology, among others, unquestionably facilitate and in
some cases enable research and discovery in genomics and all
of the life sciences. However, definitions of nutritional genom-
ics that exclusively accentuate the application of high-through-
put and/or genomic technologies to accelerate the pace of
traditional nutrition research and its applications fail to recog-
nize the new science that has evolved at the interface of the
disciplines of nutrition and genomics and the new opportunities
for research, discovery, and application that it offers. This
Article published online before print. See web site for date of publication
(http://physiolgenomics.physiology.org).
Address for reprint requests and other correspondence: P. J. Stover, Cornell
Univ., Division of Nutritional Sciences, 315 Savage Hall, Ithaca, NY 14853
(E-mail: pjs13@cornell.edu).
1094-8341/04 $5.00 Copyright © 2004 the American Physiological Society
Downloaded from journals.physiology.org/journal/physiolgenomics (103.255.007.034) on January 8, 2022.
mini-review focuses on new perspectives that have been of-
fered to the nutritional sciences by the advent of genomics, and
new challenges that demand attention because of their potential
impact on, and immediate translation into, current public health
nutrition recommendations and interventions.
Nutrition is an integrative discipline. From its inception,
nutritional science has been distinguished by its integration of
knowledge and technology derived from the biological and
physical sciences to understand the role of nutrients and other
dietary components in human health and disease throughout
the life cycle, and the translation of that information for the
improvement of public health (1, 14). Basic nutrition knowl-
edge is built upon research from many diverse disciplines
including analytical chemistry for isolation and structural char-
acterization of essential nutrients, biochemistry and physiology
for elucidation of nutrient metabolic and signaling pathways
and their role in homeostasis, and human genetics for the initial
discovery of gene-nutrient interactions through the study of
inborn errors of metabolism. However, these approaches are
not sufficient to predict and quantify interactions among di-
etary components and human polymorphic alleles. This limi-
tation has hindered efforts to achieve scientifically based di-
etary recommendations and effective nutrient interventions that
faithfully maximize health benefit and minimize the risk of
unintended consequences for all human populations. Nutri-
tional genomics challenges us to understand, in molecular
detail, the reciprocal and complex interactions within the
human genome, including all genetic variation therein, and
dietary components in normal physiology and pathophysiology
(Fig. 1). These interactions, including the modifying influence
of genetic variation on nutritional requirements, have been
161
Invited Review
162 NUTRITIONAL GENOMICS
Fig. 1. Nutritional genomics. Research and discovery in nutritional genomics
elucidate the reciprocal interactions among nutrients, metabolic intermediates,
and the mammalian genome. Understanding the interrelationships among
human genetic diversity, genome function, and dietary components will enable
precise manipulation of genome function and stability throughout the life cycle
for optimal human health and disease prevention.
appreciated for decades but not developed sufficiently to in-
fluence dietary recommendations or nutrition policy.
The primary goals of nutritional genomics research are: 1) to
establish dietary recommendations that have a high predictive
value with respect to disease prevention, minimize the risk of
unintended consequences, and account for the modifying ef-
fects of human genetic variation; and 2) to design effective
dietary regimens for the management of complex chronic
disease (Fig. 1). The identification of alleles that contribute to
polygenetic chronic diseases such as obesity, diabetes, and
hypertension is expected to catalyze organism-based research
that will support the rational design of targeted dietary regi-
mens for the prevention and/or management of disease pheno-
types (48). Such expectations for achieving therapeutic nutri-
tion through the application of genomics to nutrition research
and practice are warranted. There exists a scant yet persuasive
literature that demonstrates the potential for modifying the
penetrance of deleterious genetic alleles by optimizing gene-
nutrient interactions through dietary interventions. The preven-
tion of severe cognitive dysfunction associated with phenyl-
ketonuria by dietary phenylalanine restriction is the classic
example (3, 32). Yet, enthusiasm is tempered by an inability to
identify low-penetrant contributing alleles in multigenic disor-
ders (48), insufficient knowledge to accurately modify genome
function and cell physiology through diet, and an inability to
address and minimize the potential for unintended conse-
quences resulting from the administration of nutrients at intake
levels that cannot normally be achieved with a healthy and
natural food-based diet (21).
Reciprocal interactions between nutrition and the mamma-
lian genome. The primary sequence of the human genome and
the genetic variation that exists within the human species are
the result of molecular adaptation to evolutionary pressures
that have been exerted through the processes of gene mutation
and purifying selection as well as random drift (10). Through-
out this process, nutrition has been perhaps the most persistent
and variable of the environmental exposures that have chal-
lenged and thereby shaped the human genome and contributed
to its variation (Fig. 1). Individual dietary components mark-
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edly affect gene mutation rates (15), and nutrients are one of
several environmental factors that can influence fetal viability
and modify the penetrance of deleterious genetic lesions;
nutrition is in utero selective pressure that can contribute to the
fixation of new mutations in human populations (Fig. 1) (4, 30,
45). Likewise, past decades of nutrition research have estab-
lished that the function of the modern human genome, which is
made manifest through its expression, is modified continuously
in response to dietary exposures. Homeostatic mechanisms
have evolved to permit adaptive genomic responses to nutri-
tional milieu at the level of DNA transcription, mRNA trans-
lation, as well as protein and mRNA stability. These mecha-
nisms permit cells to regulate rates of nutrient transport and
nutrient status, alter nutrient storage capacity, fine-tune the flux
of intermediates through metabolic branch points, dramatically
restructure the cellular transcriptome and proteome, and trigger
the cellular programs of differentiation, cell cycle, and apop-
tosis. A comprehensive understanding of the mechanisms that
underlie the reciprocal interactions of dietary components with
the genome, which is not attainable by genomic profiling
approaches alone, will enable the manipulation of genome
expression and stability for benefit through diet with high
predictive value (Fig. 1).
Genetic variation influences nutritional requirements. The
term “nutrient” has been most recently defined as a “fully
characterized (physical, chemical, physiological) constituent of
a diet, natural or designed, that serves as a significant energy
yielding substrate or a precursor for the synthesis of macro-
molecules or of other components needed for normal cell
differentiation, growth, renewal, repair, defense, and/or main-
tenance or a required signaling molecule, cofactor, or determi-
nant of normal molecular structure/function and/or promoter of
cell and organ integrity” (23, 54). A primary goal of the
nutritional sciences is to establish scientifically based “recom-
mended dietary allowance” (RDA) for each nutrient, which is
defined as the level of dietary intake that is sufficient to meet
the requirement of 97% of healthy individuals in a particular
life stage and gender group (29). In the absence of sufficient
data to calculate an RDA for a nutrient, an “adequate intake”
(AI), which is an estimated recommended intake value, is
established (Fig. 2). Some nutrients are toxic at elevated intake
levels, and therefore a “tolerable upper intake level” (UL) may
be established for an individual nutrient. A UL represents the
highest level of nutrient intake that can be achieved without
incurring risk for adverse health effects for most individuals in
the general population (29).
Even prior to the sequencing of the human genome and
initiation of haplotype mapping efforts (20), nutritional re-
quirements were recognized to be complex traits that are
subject to modification by both genetic background and by
nutrient-nutrient interactions. Genetic background can alter
both minimal nutrient requirements and tolerable upper intake
levels. Single-nucleotide polymorphisms (SNPs) have been
identified in genes that encode proteins that function in nutrient
metabolism or storage and alter optimal nutritional require-
ments. A common polymorphism in the methylenetetrahydro-
folate reductase (MTHFR) gene (A222V) generates an amino
substitution in the protein that alters its stability and affinity for
its riboflavin cofactor (24, 26). The MTHFR polymorphic
allele encodes an enzyme with decreased enzymatic activity
compared with the enzyme encoded by the normal allele and
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NUTRITIONAL GENOMICS
impairs both folate accumulation and homocysteine remethy-
lation (2, 18, 19). This polymorphism is a risk factor for neural
tube defects and cardiovascular disease but decreases risk for
colon cancer (2). The penetrance of this polymorphic allele is
modified by dietary folate. Carriers of the A222V MTHFR
polymorphism require higher intakes of folic acid to lower
serum homocysteine and reduce their risk for folate-related
pathologies (2).
Genetic variation can also influence ULs. An SNP in the
hereditary haemochromatosis linked gene (HFE) increases risk
for haemochromatosis, an iron storage disease, which can
result in up to 50-fold increases in storage deposits (25). These
examples have questioned the concept of generalized nutri-
tional requirements and fueled a movement to personalize
these recommendations. The degree to which common poly-
morphisms lower the UL or increase the RDA for a given
nutrient and thereby narrow the window of optimal nutrient
intake has not been established and depends on the criteria that
are used to establish requirement and toxicity. The few SNPs
that have been demonstrated to be penetrant with respect to
their impact on metabolism and nutrient requirements were
identified because of their obvious association with disease.
However, highly penetrant monogenic alleles are expected to
be the exception, because of the recognition that individual
nutrient requirements are polygenic traits and modifiable by
intake levels of other nutrients.
The impact of genetic variation on public health nutrition
policy remains uncertain. Haplotype mapping efforts offer the
possibility of “classifying humans” for personalized preventa-
tive and therapeutic medicine (6) and enable initiatives in
pharmacogenomics that seek to optimize the efficacy of phar-
maceutical agents to genetic background (47). Similar benefits
have been anticipated for nutritional genomics, but may not be
realized. Nutrition, unlike pharmaceuticals, is a lifelong expo-
sure and a selective pressure during mammalian development.
Nutrient availability selects against embryonic genotypes that
confer nutritional requirements that cannot be met by the
placenta. Mammalian genomes encode developmental termi-
nation programs, including embryo resorption in rodents and
spontaneous abortion in primates, which can be activated by
malnutrition and/or deleterious genetic lesions (33). Polymor-
phisms that escape this selection can be masked or buffered by
compensatory alterations in genome expression that are set and
memorized during early development (7). This phenomenon,
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Invited Review
163
Fig. 2. Establishing dietary requirements. Estimated average
requirement (EAR) represents the intake at which the risk of
inadequacy is 0.5 (50%) to an individual. Recommended di-
etary allowance (RDA) represents a level of nutrient intake at
which the risk of inadequacy is ⬍3%. Adequate intake (AI) is
not based on an EAR but is assumed to be near or above the
RDA if one could be calculated. The tolerable upper intake
level (UL) represents risk of excess that is set close to 0. This
is adapted from a figure in Ref. 29.
referred to as canalization, has been observed in studies of
mice with induced gene deletions (22, 31, 46). Therefore, it is
not unreasonable to assume that RDAs and ULs can be gen-
eralized, with few exceptions, to entire populations because
genomes that confer extreme nutrient requirements fail to
develop or undergo adaptation. Screening for genetic minori-
ties with exceptional nutrient requirements may prove to be
advantageous, but this is not currently common practice.
Nutrient intakes influencing genome stability and genetic
variation. The impact of dietary components on genome integ-
rity and viability may provide new criteria for establishing both
RDAs and ULs. Nutritional requirements have been defined
historically as the level of intake required to prevent severe
deficiency and the associated clinical symptoms (29). Because
genomic mutation is the antecedent of certain developmental
anomalies, degenerative diseases, and cancers and is a physi-
ological event that can be quantified in a controlled experimen-
tal setting, it has been suggested that the effects of key minerals
and vitamins on DNA mutation rates should be considered
when establishing RDAs (15). Studies in cell cultures and
animal models have established that marginal deficiencies in
folate, vitamin B12, niacin, and zinc can influence genome
stability, and antioxidants including carotenoids, vitamin C,
and vitamin E may prevent the oxidation of macromolecules in
vivo. Validation of these protective effects in controlled human
trials may indicate benefits and lead to increased recommended
intake levels for these nutrients for certain populations (Fig. 2),
perhaps at levels not normally achievable from a natural
food-based diet.
Other genomic outcomes, including embryo rescue, are
emerging as criteria for establishing tolerable upper limits
during reproductive ages. The concept of nutritional rescue of
genetic mutations, or “good diet hides genetic mutations,” was
recently publicized (44). Individual nutrients, when adminis-
tered in supra-physiological levels during critical developmen-
tal windows, can rescue severe genetic lesions in mice. Mater-
nal retinoic acid administration between 7.5 and 9.5 days
postconception rescued deafness and inner ear development in
Hoxa1⫺/⫺ mice (42). Folic acid has also been demonstrated to
rescue skeletal defects associated with deletion of a Hox gene,
as well as neural tube defects in mice that have no evidence of
disrupted folate metabolism (49). The prevalence of this rescue
phenomenon is not established, but animal studies indicate that
nutrients can modify the viability of genomes, including ge-
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164 NUTRITIONAL GENOMICS
nomes that confer atypical nutrient requirements to the surviv-
ing fetus (16).
However, to be relevant, the rescue of more subtle yet
deleterious genetic mutations (i.e., SNPs) by less extreme
ranges of nutrient intakes must be demonstrated rigorously,
and the mechanisms whereby nutrients override developmental
termination programs must be established. Nutritional rescue
of deleterious genomes is suggested but has not been demon-
strated conclusively in human populations. SNPs in the
MTHFR (A222V) and MTHFD1 (R653Q) genes, which en-
code folate-dependent enzymes, are associated with increased
risk for neural tube defects. These polymorphisms are not in
Hardy-Weinberg equilibrium (5, 35, 45), consistent with evi-
dence that the MTHFR A222V polymorphism is a risk factor
for spontaneous miscarriage and decreased fetal viability (36–
41). A recent study (45) indicated that maternal folate supple-
mentation has increased the prevalence of the normally under-
represented A222V allele in a Spanish population, suggesting
that folate may be rescuing human embryos as observed in
animal studies, although such findings have been challenged
(53). The percentage of fetal loss that can be prevented by
optimizing maternal nutrition is unknown. However, nearly
62% of all human conceptuses are lost before the 12th week of
gestation (11, 12), and therefore rapid genotypic shifts may be
enabled through maternal vitamin supplementation as indi-
cated (45). Although the long-term health consequences, if
any, for embryos that result from nutritional rescue are un-
known, confirmation of this effect in both human populations
and experimental animal studies is warranted.
Maternal nutritional status can also alter the epigenetic state
of the fetal genome and imprint gene expression levels with
lifelong consequences (51). Epigenetic alterations of the fetal
genome do not affect the primary sequence of DNA, but rather
alter gene expression, and may explain subtle phenotypic
differences observed in identical twins (9). DNA methylation
of cytosine nucleotides is the best-established mechanism for
nutrient imprinting of fetal gene expression, because methyl-
ation regulates gene expression. Methylation patterns are es-
tablished very early in development and can remain metastable
throughout life. The methyl groups that modify DNA are
derived from one-carbon metabolism, a metabolic pathway that
is dependent on B vitamins as enzymatic cofactors including
folate, vitamin B12, and vitamin B6. Cytosine methylation is
highly sensitive to cellular folate status, and DNA methylation
density varies proportionately with folate status (17). Maternal
supplementation with folate and other methyl donors alters the
methylation status of targeted alleles in the embryo, and these
methylation patterns are retained into adulthood (52). Genes
that neighbor retroviral elements have been indicated to be
preferred targets for epigenetic regulation by B vitamins (52),
and such epigenetic genomic alterations are associated with
and may underlie common diseases (9). Other studies have
demonstrated culture-induced alterations in the methylation
and expression of selected genetically imprinted genes in
pre-implantation embryos (28, 30), indicating that permanent
genomic alterations can result from in vitro fertilization pro-
cedures. Nutrient modification of epigenetic programs may
begin to provide a mechanistic foundation for observational
studies that associate risk for adult chronic disease with ma-
ternal malnutrition (51) and provide a sound scientific justifi-
cation for investigating the long-term consequences of mater-
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nal undernutrition and overnutrition on fetal viability and
lifelong disease risk.
Conclusions. The integration of genomics into nutritional
sciences has illuminated the complexity of genomic responses
to nutritional exposures while offering opportunities to in-
crease the effectiveness of nutritional interventions, both clin-
ical and population based. Basic research, facilitated by high-
throughput technologies, will continue to elucidate mecha-
nisms that underlie the effects of nutrients on genome stability,
imprinting, expression, and viability. Quantifying the magni-
tude of these effects and their relevance and application to
nutrition policy will prove to be more challenging. Definitions
of benefit and risk associated with dietary exposures are likely
to include effects on genome function, stability, and/or viabil-
ity. However, nutrients elicit multiple genomic effects that
confer both health benefits and risks that may not become
apparent until later in life. Therefore, recommendations that
encourage elevated intakes of individual nutrients at levels not
normally achievable in healthy food-based diets, as present in
common dietary supplements, may be justified, but will require
rigorous validation so that their safety is established. Further-
more, nutritional interventions that target entire populations
must consider adverse consequences to genetic minorities that
may accrue risk while others benefit. The considerations raised
in this review, which are not intended to be exhaustive,
illustrate that the new science of nutritional genomics presents
many more opportunities and challenges to the field of nutri-
tion than it provides solutions.
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