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The FASEB Journal Review

Nutrigenomics and nutrigenetics: the emerging faces of


nutrition
David M. Mutch,*,,1 Walter Wahli, and Gary Williamson*
*Nestle Research Center, Vers-chez-les-Blanc, Lausanne, Switzerland; and Center for Integrative
Genomics, University of Lausanne, Lausanne, Switzerland
The recognition that nutrients have the
ability to interact and modulate molecular mechanisms
underlying an organisms physiological functions has
prompted a revolution in the field of nutrition. Performing population-scaled epidemiological studies in
the absence of genetic knowledge may result in erroneous scientific conclusions and misinformed nutritional
recommendations. To circumvent such issues and more
comprehensively probe the relationship between genes
and diet, the field of nutrition has begun to capitalize
on both the technologies and supporting analytical
software brought forth in the post-genomic era. The
creation of nutrigenomics and nutrigenetics, two fields
with distinct approaches to elucidate the interaction
between diet and genes but with a common ultimate
goal to optimize health through the personalization of
diet, provide powerful approaches to unravel the complex relationship between nutritional molecules, genetic polymorphisms, and the biological system as a
whole. Reluctance to embrace these new fields exists
primarily due to the fear that producing overwhelming
quantities of biological data within the confines of a
single study will submerge the original query; however,
the current review aims to position nutrigenomics and
nutrigenetics as the emerging faces of nutrition that,
when considered with more classical approaches, will
provide the necessary stepping stones to achieve the
ambitious goal of optimizing an individuals health via
nutritional intervention.Mutch, D. M., Wahli, W.,
Williamson, G. Nutrigenomics and nutrigenetics: the
emerging faces of nutrition. FASEB J. 19, 16021616
(2005)
ABSTRACT

Key Words: coronary heart disease diabetes integrative metabolism metabolomics nutrient-gene interaction polymorphism systems biology
Since the times of the renowned Greek physician
Hippocrates, nutrition has clearly had a predominant
and recognizable role in health management. However, with time our understanding of diet and its effects
on health has evolved from crude associations to conclusive facts. The advent of modern science led to the
realization that not only are certain nutrients essential,
but also that specific quantities of each were necessary
for optimal health, thereby leading to such notions as
dietary recommendations, nutritional epidemiology,
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and the realization that food can directly contribute to


disease onset. In this regard, human development is
clearly defined by both environmental influences (e.g.,
diet, smoking, education, physical activity, etc.) and
heredity, indicating that both aspects must be considered if one aims to optimize health. However, despite
this acceptance, experimental designs are often specific
to one factor, i.e., either genes or environment are
analyzed but not both simultaneously (1). This issue
can now be eloquently resolved with modern technologies that permit both factors to be considered concurrently, as demonstrated by profound and recent advances in our understanding of health and disease.
These modern technologies have capitalized on the
completion of the sequenced human (2, 3), mouse (4,
5), and rat (6) genomes. The vast quantity of information stemming from these achievements has not only
prompted the active development of comprehensive
analytical platforms and their appropriate data mining
software, but have also revolutionized our approach to
understanding health and disease. Gone are the days
when one is constrained to study only a single gene or
gene product in a biologically out-of-context situation;
rather, emerging technologies for investigating all
genes, proteins, and metabolites provide the means to
scrutinize this information in relation with all other
biological elements present in a given sample. As a
result, this has led to the creation of popular terms,
ending with the Greek suffix ome, meaning complete or all, describing the global analysis of genes
(genomics), mRNA (transcriptomics), proteins (proteomics), and metabolites (metabolomics). Although
50 omic terms have been described in the literature,
it is the 4 aforementioned terms that are widely established and accepted (7). Genomics can be simply
defined as the approach describing the mapping, sequencing, and analysis of all genes present in the
genome of a given species. The awesome quantity of
information comprised within a given genome has led
to genomic offspring, each with a specific goal. The
1

Correspondence: The Scripps Research Institute, 10550


North Torrey Pines Rd., MEM 275, La Jolla, CA 92037. E-mail:
dmmutch_sci@hotmail.com
2
http://www.mged.org/Workgroups/MIAME/miame.html
3
http://www.ncbi.nlm.nih.gov/geo/
doi: 10.1096/fj.05-3911rev
0892-6638/05/0019-1602 FASEB

predominant genomic derivative has been coined functional genomics, which aims to uncover both the functional roles of different genes and how these genes
interact with, and/or influence, each other in the
functional network underlying health and disease.
However, other extensions such as structural genomics
and comparative genomics are rapidly becoming popular methods to further annotate the genome. Transcriptomics, using either cDNA or oligonucleotide microarray technology, describes the approach in which
gene expression (mRNA) is analyzed in a biological
sample at a given time under specific conditions. This
field is certainly the most widely used of the omic
technologies, in part due to the intense activity of such
initiatives as the minimum information about microarray experiments (MIAME)2 (8, 9) and the gene
expression omnibus (GEO)3 (10, 11) to standardize
experimental procedures and the storage of data, respectively.
Studying the other facets of biological complexity,
such as proteins and metabolites, is especially important with the realization that the principle of one gene
leads to one protein leads to one metabolite is a
simplistic and often incorrect notion, as experimentally
demonstrated (12). Therefore, proteomics aims to
characterize all proteins in a biological sample, including their relative abundance, distribution, post-translational modifications, functions, and interactions with
other biological molecules (7). Metabolomics, or metabonomics, can be simply defined as the quantitative
analysis of all metabolites in an isolated cell system,
tissue, or biological fluid. Although these two terms
tend to be used interchangeably, metabonomics is
generally associated with drug discovery and refers to a
systems approach to metabolite profiling, whereas the
more widely used term metabolomics refers more specifically to cell-based metabolite profiling. For the purpose of this review, metabolite profiling will be referred
to as metabolomics from here on. In contrast with
transcriptomics, proteomics and metabolomics are not
yet routine and standardized procedures, and continue
to face challenges such as sample preparation, technological sensitivity, lack of standardized statistical methods and public databases (1318). Nevertheless, their
potential benefits for health management are undisputed and have fuelled current efforts to assess, utilize,
interpret, and ultimately integrate these global technologies in order to define a phenotype characterizing
health status.
These analytical platforms are now widely used by
both the pharmaceutical and nutritional communities
alike; however, whereas pharmaceuticals have a targeted approach aimed at restoring health, diet is a
multi-parametric approach to preserve and/or optimize health. Indeed, the diet is comprised of a multitude of nutritional and chemical molecules each capable of regulating disparate biological processes, and
thus cannot use an approach similar to the pharmaceutical industry, i.e., the one drug one target paradigm
(19). Hence, nutrition is a true integrative science that
NUTRITION IN THE POSTGENOMIC ERA

is well positioned to benefit from the exploitation of


novel technologies capable of assessing biological networks rather than single endpoints (20). Despite the
powerful analytical platforms available for the analysis
of genes, proteins, and metabolites, few examples have
used a comprehensive and integrative approach to
understand the influences of nutritional factors on
metabolism (2124). Rather, the great majority of
intervention studies performed to date are platformspecific. Inasmuch as each of these analytical platforms,
from genomics to proteomics to metabolomics, provides increasingly accurate information describing a
given phenotype, it is the integration of these technologies that provides the optimal means to unravel the
effects of a biological challenge on an organism; thus,
the concept of systems biology (or integrated metabolism) (20, 25, 26). Indeed, an integrated metabolism
approach yields an attractive and exciting future for
both pharmaceutical and nutritional communities, and
their quest to ameliorate health and prevent disease.
Considering multiple facets of biological complexity
within the confines of a single analysis provides a means
to consider how specific genetic profiles respond to
environmental challenges.
For the field of nutrition, this would encompass the
ongoing efforts to understand the relationships between the genome and diet, currently termed nutrigenomics and nutrigenetics (27). Although these two
concepts are intimately associated, they take a fundamentally different approach to understanding the relationship between genes and diet (Fig. 1). Nutrigenomics aims to determine the influence of common dietary
ingredients on the genome, and attempts to relate the
resulting different phenotypes to differences in the

Figure 1. Nutrigenomics and nutrigenetics: two sides of a


coin. For the target goal of personalized nutrition to be
realized, the effects of diet on whole-body metabolism (i.e.,
genes, proteins, and metabolites) and the influence of genotype on nutritionally related disease must be considered.
Food pyramid image obtained from: http://www.shb.ie/
content454667358_1.cfm.
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cellular and/or genetic response of the biological


system (28). More practically, nutrigenomics describes
the use of functional genomic tools to probe a biological system following a nutritional stimulus that will
permit an increased understanding of how nutritional
molecules affect metabolic pathways and homeostatic
control (29). Nutrigenetics, on the other hand, aims to
understand how the genetic makeup of an individual
coordinates their response to diet (28), and thus considers underlying genetic polymorphisms. In other
words, nutrigenetics embodies the science of identifying and characterizing gene variants associated with
differential responses to nutrients, and relating this
variation to disease states (30). Therefore, both disciplines aim to unravel diet / genome interactions;
however, their approaches and immediate goals are
distinct. Nutrigenomics will unravel the optimal diet
from within a series of nutritional alternatives, whereas
nutrigenetics will yield critically important information
that will assist clinicians in identifying the optimal diet
for a given individual, i.e., personalized nutrition (28).
Despite the immediate goals differing, the long-term
goal of improving health and preventing disease with
nutrition requires the amalgamation of both disciplines.

A COMPLEX PARTNERSHIP: DISEASE AND


NUTRITION
Since the sequencing of several eukaryotic genomes,
our understanding of human disease has progressed at
an accelerated rate (31). Indeed, of the nearly 1000
genes that have so far been associated with human
disease, 97% result in monogenic diseases, i.e., a
single dysfunctional gene is responsible for disease
(32). Modifying the consumption of certain dietary
compounds can prevent some monogenic diseases,
such as galactosemia and phenylketonuria. Galactosemia arises from a rare recessive trait in galactose-1phosphate uridyltransferase (GALT), leading to the
accumulation of galactose in the blood and increasing
the risk of mental retardation (33). Phenylketonuria is
characterized by the defective phenylalanine hydroxylase (PAH) enzyme, resulting in the accumulation of
phenylalanine in the blood that drastically increases the
risk of neurological damage (34). Galactose-free and
phenylalanine-restricted tyrosine-supplemented diets
are a means to nutritionally treat these monogenic
diseases, respectively (35).
In contrast, those diseases reaching epidemic proportions in the Western world, such as cancer, obesity,
diabetes and cardiovascular disease, often arise from
dysfunctional biological networks, and not a single
mutated gene (i.e., polygenic diseases). For example,
the recent meta-analysis by Segal et al. of nearly 2000
microarray studies spanning 22 different tumor types
demonstrated that no single common gene mutation is
responsible for the onset of these tumors, but that
shared functional modules exist between various can1604

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cer types (36). Thus, dietary intervention to prevent the


onset of such diseases is a complex and ambitious goal
that requires not only knowledge of how a single
nutrient may affect a biological system, but also how a
complex mixture (i.e., diet) of nutrients will interact to
modulate biological functions (15).

NUTRIGENOMICS
As previously mentioned, nutrigenomics offers a powerful and exciting approach to unravel the effects of
diet on health. The potential of such an approach for
nutrition and its role in health management is enormous; however, for this to be successfully accomplished, it requires a radical addition to the current
conception of nutrition. Nutrition can no longer be
viewed as simply epidemiological studies whose aims
are to identify relationships between nutrition and
chronic disease in genetically uncharacterized populations; rather, complex cell and molecular biology coupled with biochemistry and genetics are required if the
ambitious goals of nutrigenomics are to be realized.
Prior to the complete sequencing of genomes, the
research community was unable to take an integrative
metabolism approach to explore the role of diet on
disease onset. Thus, the majority of experimental designs, including epidemiological studies, were obliged
to use common and well-characterized biomarkers to
advance our understanding of various disease states.
For example, studies aimed at elucidating the molecular mechanisms promoting cardiovascular disease
(CVD) and other CVD-related diseases have often used
classical biomarkers, such as plasma cholesterol, triglycerides, or C-reactive protein (37). Inasmuch as these
studies are constantly improving the validity and accuracy of our knowledge of these disease states, they all
suffer from a similar inherent quandary; namely, that
these studies have been designed using current dogma.
Thus, the ability to identify novel mechanisms of action
and/or biomarkers that may more accurately depict
health status is greatly diminished, as only accepted and
characterized endpoints are examined. As demonstrated in the following sections, nutrigenomic technologies resolve this tunnel vision by providing a means to
identify previously unrecognized and unanticipated
molecular endpoints (7).
Plant sterols and sitosterolemia
The power of omic protocols to compare gene expression profiles to understand spontaneous differences in
phenotype due to disease was creatively extended by
inducing differences in phenotype through molecular
intervention. This was eloquently executed in a study
that simultaneously identified a mechanism for the
regulation of sterol uptake in the intestine and the
molecular basis for a genetic disease: sitosterolemia
(38). Until this study, no mechanism could explain why
plant sterols, which are structurally similar to choles-

The FASEB Journal

MUTCH ET AL.

terol, are normally absorbed in negligible amounts, nor


why sitosterolemic individuals absorb phytosterols to
high concentrations. In the study reported by Berge et
al. (38), mice were treated with a lipid metabolismaltering drug and the global mRNA expression profiles
of various tissues were compared with that of normal
mice. Differentially expressed genes were evaluated
and an unknown gene was found by bioinformatic tools
to be homologous to the ATP binding cassette (ABC)
family of genes, which include genes coding cellular
lipid transport proteins. Indeed, defects in another
member of this family (ABCA1) are the basis of the
poor cholesterol delivery to HDL that underlies
Tangiers disease (39). Through the use of a variety of in
silico techniques, Berge et al. concluded that the proteins produced from these newly discovered genes,
ABCG5 and ABCG8, were responsible for the regulated
reverse transport of newly absorbed animal and plant
sterols out of the apical surface of intestinal cells.
Exploring public gene databases, a human homologue
of the putative mouse transporter was identified,
cloned and used to screen sitosterolemic humans. In all
cases, individuals diagnosed with this disease were
found to contain mutations in these genes and thus
lack the machinery responsible for the selective and
controlled transport of cholesterol, and therefore hyper absorb various sterols (including plant sterols).
This study illustrated many of the strengths of a nutrigenomic approach, from identifying phenotypically important genes using microarray technology, to database
polling, to deducing structure function from sequence
comparison, to characterizing individual variation
(polymorphism) linked to health.
Long-chain polyunsaturated fatty acids and
carcinogenesis
Currently, no human in vivo data exists in which
nutrigenomic technologies were used to elucidate
those molecular mechanisms modulated after the consumption of long chain polyunsaturated fatty acids
(LC-PUFA); however, several animal and in vitro microarray studies have demonstrated that these dietary
compounds clearly regulate the cellular machinery in a
variety of healthy and carcinomic tissues. Indeed, there
is an active interest to comprehensively unravel the
biological functions of this class of dietary compounds,
as epidemiological studies have demonstrated that the
consumption of LC-PUFA beneficially affect physiological processes including growth, neurological development, lean and fat mass accretion, reproduction, innate
and acquired immunity, infectious pathologies of viruses, bacteria and parasites; and the incidence and
severity of virtually all chronic and degenerative diseases including cancer, atherosclerosis, stroke, arthritis,
diabetes, osteoporosis, and neurodegenerative, inflammatory, and skin diseases (40 47). Their disparate
roles on health can be associated with their ability to
serve as or be processed to ligands for a number of
critically important transcription factors, including perNUTRITION IN THE POSTGENOMIC ERA

oxisome proliferator activated receptors, hepatic nuclear factor-4, sterol regulatory expressed binding proteins, liver-X-receptor , and nuclear factor , which
are able to disseminate the biological activity of LCPUFA throughout the various tissues of the body (48,
49). Additionally, fatty acids have been found to modulate protein activity (50) and localization (51). Furthermore, LC-PUFA are associated with alterations in
lipid metabolism and the remodeling of several lipid
species, such as phospholipids (PLs), triglycerides
(TGs), and cholesterol esters (CEs) (5255). Indeed,
the extensive influence of dietary LC-PUFA on metabolism, in addition to the many epidemiological studies
demonstrating their beneficial health effects, renders
this class of nutrients ideal for study by a nutrigenomics
approach.
Carcinogenesis is a process composed of multiple
stages in which gene expression, and protein and
metabolite function begin to operate aberrantly (56).
In the post-genomic era, the cellular events mediating
the onset of carcinogenesis, in addition to their modulation by dietary factors, has yielded important information in our understanding of this disease. The most
commonly studied dietary lipids, with respect to their
effects on cancer, are LC-PUFA (57). Previous findings
have found that fish oil, rich in omega-3 fatty acids,
inhibit the growth of colonic tumors in both in vitro
and in vivo systems (58 60). Modern nutrigenomic
technologies, coupled with bioinformatics, have begun
to reveal the complexity of LC-PUFA signaling (Fig. 2);
however, current lipid metabolic pathways have proven
to be relatively underdeveloped (57). Thus, the deluge
of information derived from microarray technology
provides a potential method to further annotate the
biological functions of these common dietary compounds and complete the poorly defined pathways.
Preliminary microarray work has found that LC-PUFA
mediate the functions of several transcription factors,
cell-cycle regulatory genes, RNA transcription processes, prostaglandin synthesis, and inducible nitric
oxide synthase and related proinflammatory genes (61
63); however, it remains unclear to what extent LCPUFA are directly and indirectly involved in modulating these biological processes. Further work, in which
specific inhibitors, small inhibiting RNA technology
and alternate analytical (proteins, metabolites) platforms are incorporated, can clarify the biological functions mediated by dietary lipids. Although clearly at the
beginning, nutrigenomics offers an attractive means to
decipher the molecular networks regulated by LCPUFA, and promises an exciting future for nutritionists
and biochemists alike.
Rosiglitazone and type 2 diabetes mellitus
More recently, metabolomic technologies have established their ability to identify novel and potential
biomarkers characterizing unseen tissue toxicity. Currently, no concrete examples exist in the field of
nutrition; thus the following demonstrates the power of
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synthesis, suggesting that the use of these fatty acids as


potential biomarkers for hepatic lipotoxicity should be
further explored.
Likewise, metabolomic profiling after the consumption of food compounds promises to identify biomarkers capable of predicting nutrition-related diseases; yet,
the multidimensionality of diet-induced metabolic
changes suggests that identifying these biomarkers may
prove challenging. In contrast to medicinal compounds, such as rosiglitazone, nutrients will have subtle
effects on the metabolome; however, well-controlled
experimental designs coupled with the appropriate
statistical models may prove sufficiently robust for the
identification of biomarkers indicative of nutritionrelated diseases.

NUTRIGENETICS

Figure 2. Biological network triggered after the consumption


of LC-PUFA. As reported, LC-PUFA actions are mediated by
transcription factors, such as PPAR and SREBP. These transcription factors may be both differentially expressed themselves and/or directly activated to instigate the functional
consequences of consuming LC-PUFA. Highlighted in blue
are known functional and/or physical interactions between
PPAR- and other genes. Network created using Ingenuity
Systems, Inc. software (www.ingenuity.com), where green is
indicative of a down-regulation, red of an up-regulation and
clear of no regulation for a given gene.

these modern technologies to identify subtle metabolic


changes in response to a drug compound. As diabetes is
characterized by metabolic changes, the goal is to
address these changes while minimizing undesirable
side effects. Using an appropriate mouse model, it was
shown that lipid metabolism in the liver, adipose and
heart tissues was altered after treatment with rosiglitazone, a drug commonly used by type 2 diabetic patients
(64). The authors revealed that fatty acid synthesis was
markedly increased in the aforementioned tissues, leading to lipotoxicity; however, this increased synthesis was
not reflected in the plasma lipid profile, where cholesterol esters and triglycerides were decreased. Therefore, examining standard biomarkers would have falsely
indicated that rosiglitazone decreases de novo lipid
synthesis. In reality, lipid synthesis was increased locally
and the processes regulating lipid import/export into
tissues were apparently modified, concealing the side
effects stemming from chronic rosiglitazone therapy.
The acyl composition (namely 16:1n7 and 18:1n7) of
plasma lipids reflected the increased hepatic lipid
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Nutrigenetics, as previously defined, aims to understand how the genetic makeup of an individual coordinates the response to diet. Indeed, if the human
population were genetically identical and lived in a
constant environment, then our response to diet and
drugs would be equivalent; however, this is clearly not
the case. Since the complete sequencing of the human
genome, the Single Nucleotide Polymorphisms (SNP)
Consortium is mapping important polymorphic sites
within the genome that dictate individual phenotypic
differences among the population (http://ncbi.nih
.gov/SNP). The largest public repository for SNP data
is the dbSNP, containing 7.7 million SNPs for which
4.8 million can be linked to discrete locations on the
whole human genome map (65). The importance of
genetic variation in the need for, and physiological
response to, particular nutrients is already well described in principle, and examples continue to emerge.
Furthermore, it is already apparent that there are many
polymorphisms that influence risk in cardiovascular
disease and diabetes. SNP analysis provides a powerful
molecular tool for investigating the role of nutrition in
human health and disease, and their consideration in
clinical, metabolic and epidemiological studies can
contribute enormously to the definition of optimal
diets (66).
Clearly, the potential influence of nutrients on the
genome cannot be underestimated; however, there will
be certain genes (often referred to as candidate or
susceptibility genes) that will have a heightened sensitivity to diet (67 69). The identification of these
candidate genes often meets one or more of the
following conditions:
1. Genes that are chronically activated during a
disease state and have been previously demonstrated to
be sensitive to dietary intervention.
2. Genes with functionally important variations.
3. Genes that have an important hierarchical role in
biological cascades.

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MUTCH ET AL.

4. Polymorphisms that are highly prevalent in the


population.
5. Genes with associated biomarkers, rendering clinical trials facile.
Using such criteria, several studies have correlated a
small number of important SNPs to particular phenotypes, and many new trials are being planned to examine the correlation between subsets of the millions of
newly discovered sites of genetic variation (66). It is
important to note that uniform standards for running
nutritional epidemiological studies do not exist, thus
the biological correlations made between diet and
genes in the following sections stem from a multitude
of studies differing in both cohort size and the severity
of background genotyping. Nevertheless, these important studies linking genetic variation and dietary intervention to insulin resistance, type 2 diabetes mellitus
(T2DM) and CVD demonstrate how individual genotyping will assist with managing diets for disease prevention.
Coronary heart disease
Coronary heart disease (CHD) is one of the most
prevalent diseases in Western society, and has been
attributed the cause of one in every five deaths in
America each year (70). Epidemiological studies and
long-term outcome trials have established a clear link
between lipids and the development of CHD (71),
leading The National Cholesterol Education Program to
specify two lipoproteins as primary targets in combating
CHD: low density lipoproteins (LDL) and high-density
lipoproteins (HDL). Lipoproteins are macromolecular
complexes comprised of a lipid-rich core surrounded
by a surface monolayer containing phospholipids, unesterified cholesterol, and specific proteins. Various
complexes exist and are defined based on their composition, which ultimately affects their density: chylomicron (high lipid to protein ratio, highest in TG as %
of weight), VLDL (very low density lipoprotein, 2nd
highest in TG as % of weight), IDL (intermediate
density lipoprotein), LDL (highest in CE as % of
weight), and HDL (high protein to lipid ratio). Clinical
data have demonstrated the efficacy of lipid-lowering
modes of therapy for the prevention of CHD. The first
line of therapy, termed therapeutic lifestyle changes, is
composed of alterations in the individuals diet and
physical activity, coupled with reductions in smoking
and weight if applicable. The second line of therapy
involves pharmaceutical compounds, such as statins,
which have been found to efficaciously inhibit the
activity of hepatic 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoA reductase) and ultimately decrease
the levels of circulating cholesterol (72, 73). However,
it is well known that individuals respond differently to
the aforementioned therapeutic interventions and that
subsets of the population, in response to a given
therapy, are unable to achieve the recommended levels
of lipids (71). These varying degrees of response have
NUTRITION IN THE POSTGENOMIC ERA

been accredited to genetic differences in the population, thereby emphasizing the importance of identifying those genes that play a critical role in the onset or
protection from CHD, and unravel their interactions
with common dietary compounds (74). To date, several
candidate genes, and their common SNPs, have been
identified and preliminary evidence supports the notion that genetic variations in such genes as cholesterol
ester transfer protein (CETP), lipoprotein lipase
(LPL), hepatic triglyceride lipase (HL), LDL-receptor,
apolipoprotein E (APOE), apolipoprotein A1
(APOA1), ATP binding cassette transporter A1
(ABCA1), and lecithin-cholesterol acyltransferase
(LCAT) will alter individual sensitivity to developing
CHD (75 82). Additionally, a nutrigenetic approach
has begun to reveal that several of the aforementioned
genes and their polymorphisms, such as APOA1 and
LPL, are susceptible to dietary intervention and may
modulate the onset of CHD.
Apolipoprotein A1 (APOA1)
HDL plays a critically important role in the prevention
of CHD, predominantly through the transport of cholesterol from peripheral tissues to the liver for excretion in bile. APOA1 is a major component of plasma
HDL (83) and is thought to contribute to the transport
of cholesterol from ABCA1 to HDL particles (84).
Recently, it has been found that HDL levels are sensitive to dietary factors, such as PUFA. In the context of
the Framingham Heart Study (85), individuals with a
polymorphism in the APOA1 gene promoter region
(75 G/A) were found to differentially respond to
dietary PUFA (86). In brief, the authors found that
individuals with the A allele showed an increase in HDL
levels following an increased consumption of PUFA. In
contrast, those with the more common G allele showed
an inverse relationship between HDL levels and PUFA
consumption. Furthermore, the authors revealed that
differences in sex also mediate the response. Indeed,
men did not show a relationship between HDL and
PUFA consumption, irrespective of their APOA1 polymorphism. However, women with the A allele and a
high intake of PUFA (8% of energy derived from
PUFA) were found to have high levels of HDL. In
comparison, women with the common G allele were
found to have high HDL levels when fed low quantities
of PUFA (4% of energy derived from PUFA). This
example highlights the complex interactions that arise
between dietary molecules and genotype, and the additional influence that gender may have.
Lipoprotein lipase (LPL)
LPL is responsible for catalyzing the hydrolysis of TGs
present in circulating chylomicrons and VLDL particles, providing nonesterified fatty acids and 2-monoacylglycerol for tissue utilization. Dysfunctional LPL has
been associated with various disease states, such as
atherosclerosis, chylomicronaemia, obesity, Alzhei1607

mers disease, and the dyslipidemia related with diabetes and insulin resistance (87). Furthermore, several
polymorphisms have been described that disrupt normal LPL function and contribute to the premature
development of CHD, primarily through the increased
levels of circulating TGs (88). Indeed, several of the
common LPL polymorphisms described by Merkel et
al. have recently been established to influence circulating lipid levels in pregnant women, whom are often
characterized with high levels of circulating TGs and
increased total cholesterol. Although TG levels were
unaffected, certain LPL SNPs modulated HDL levels
and may alter the susceptibility of pregnant women to
developing CHD (89); however, further studies are
required to definitively define a relationship between
lipid levels, CHD, and pregnant women. Therefore, the
importance of LPL in the whole-body regulation of
lipid metabolism has been avidly demonstrated and
merits further exploration.
One common LPL polymorphism, known as T495G
HindIII, has been extensively examined and demonstrates the complexity of disease prediction associated
with a single SNP. Indeed, preliminary indications
suggest that this polymorphism may play a role in the
onset of several important diseases, such as CHD,
diabetes and obesity. This SNP has been associated with
the higher plasma TG and lower HDL levels characteristic with the early onset of diabetes (90). Preliminary
results have also suggested a positive association between the HindIII polymorphism and a predisposition
to developing obesity (91). Finally, this polymorphism
has been associated with variations in lipid levels and
heart disease, and that these alterations were attenuated by such environmental factors as physical exercise
(92) and low calorie diets (93), reiterating the important interactions arising between lifestyle, nutrition,
and disease. Although these associations are not conclusive, they do suggest that LPL variants play a critically important role in the regulation of whole-body
lipid metabolism that may predispose an individual to
the onset of several metabolic diseases.
A relationship was established between a low calorie
diet and the circulating lipid profile in obese individuals with the HindIII polymorphism (93). Homozygotes
(H2H2) were found to have significantly higher levels
of plasma VLDL-TG and APOB than heterozygotes
(H1). Caloric restriction reduced lipid levels in both
H2H2 and H1 individuals to a point where no difference was observed between the groups. Although
H2H2 individuals responded more strongly (larger
decreases in plasma lipids) to the low calorie diet, these
preliminary results identify an important relationship
between LPL polymorphisms, function, and diet.
Insulin resistance and type 2 diabetes mellitus
T2DM is a metabolic disorder, stemming from either
an insufficient secretion or impaired action of insulin,
characterized by hyperglycemia, dyslipidemia, and associated with impaired carbohydrate, protein and lipid
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metabolism (94, 95). The importance of lifestyle has


been linked to the high incidence of T2DM in Westernized societies through several observational studies,
which identified a higher rate of incidence in individuals leading inactive lives and/or with high levels of
food consumption (94). Furthermore, since the initial
study by West and Kalbfleish (96), diets high in fat and
energy have been repeatedly shown to play a fundamental role in the onset of T2DM. However, evidence
exists that both environmental and genetic factors are
important in the etiology of T2DM. Recent mechanistic
work using mouse models with various genetic modifications affecting lipid metabolism have conclusively
demonstrated a relationship between lipids and disease
state (97). Furthermore, the genetic manipulation of
genes involved in fatty acid and TG synthesis have
demonstrated that neither T2DM nor insulin resistance
are monogenic diseases; rather, a myriad of susceptibility genes involved in regulating lipid metabolism and
insulin sensitivity have been demonstrated to modulate
the risk of disease onset and novel targets continue to
be discovered (98). The following examples do not
comprise the inclusive list of genes associated with
T2DM (e.g., recent findings have identified adiponectin (99) and resistin (100) as possible susceptibility
genes for T2DM); however, preliminary evidence suggests that those genes discussed below are responsive to
diet, and thereby demonstrate important interactions
between genotype and nutrition in an individuals
predisposition to T2DM.
Sterol response element binding protein (SREBP)
SREBP-1a and 1c, splice variants arising from alternate
start sites, have been repeatedly shown to have an
important role in fatty acid synthesis. Using transgenic
and knockout mouse models, these membrane-bound
transcription factors were found to directly activate the
expression of more than 30 genes involved in the
synthesis and uptake of cholesterol, fatty acids, TGs,
and PLs (101, 102). Two transgenic models leading to
the overexpression of SREBP-1c in either the liver or
adipose tissue have demonstrated that this transcription factor plays an important role on the development
of diabetes (97). When hepatic SREBP-1c was overexpressed, mice developed a fatty liver, associated with
increases in TGs and CEs (103). In comparison, overexpressing SREBP-1c in adipose tissue had far more
drastic effects. These mice were characterized with
abnormal white adipose tissue development, fatty livers,
hypertriglyceridemia, and severe insulin resistance and
T2DM (104). Hence, perturbations in fatty acid synthesis, coupled with observations that dysfunctional
SREBP-1c expression initiates the onset of T2DM, suggest SREBP-1c is a suitable target for the management
of disease progression through dietary intervention.
Recently, SREBP-1c was identified as a candidate
gene in the regulation of human insulin resistance
(105). Maudes and colleagues identified two missense
mutations (P87L and P416A) in exons coding the

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MUTCH ET AL.

aminoterminal transcriptional activating domain and


found a correlation with individuals displaying severe
insulin resistance; however, their preliminary findings
revealed that the DNA binding ability of normal
SREBP-1c and the two mutants were equivalent. Furthermore, data mining the Cambridgeshire Case Control
Population cohort database identified a significant association between an intronic SNP (C/T) between exons
18c and 19c and the onset of diabetes in men, but not
in women. Although only a preliminary study, these
findings suggest that mutations in SREBP-1c may render a heightened sensitivity to developing diabetes;
however, as no differences were observed in DNA
binding between the various mutants, conclusive evidence concerning the role of SREBP-1c polymorphisms
on the manifestation of disease remains to be demonstrated (105).
Nevertheless, SREBP-1c appears to be susceptible to
diet, thus rendering this candidate gene a target for
nutritional intervention. Examining two mouse models
(CBA/JN and DBA/2N), Nagata and colleagues found
that SREBP-1c hepatic gene expression differed between the models after the consumption of high fructose diets (106). Whereas hepatic SREBP-1c mRNA was
significantly induced in CBA/JN mice, no response was
observed in DBA/2N mice. Comparing the nucleotide
sequences between the two mouse strains revealed a
polymorphism ( 468 A/G) that altered the binding
potential of an unidentified nuclear protein. These
findings demonstrate that a single polymorphism cannot only regulate a molecular event, but also ultimately
modulate the sensitivity of a gene to dietary intervention.
Peroxisome proliferator-activated receptors (PPARs)
PPARs are an important group of ligand-activated transcription factors that mediate the cellular response to
synthetic and biological compounds, such as fibrates,
thiazolidinediones (TZDs), and fatty acids and their
derivatives (107, 108). Three PPAR isotypes with tissuespecific expression, termed , /, and , play critical
roles in mediating fatty acid catabolism, adipocyte
differentiation, and wound healing (109 111). The
pharmaceutical industry has focused much attention to
PPAR-, as its activation promotes adipogenesis and the
storage of TGs by regulating an important subset of
adipose genes, including those involved in fatty acid
transport, assembly into TGs, and glyceroneogenesis
(97). Thus, activating PPAR- with TZDs reduces circulating fatty acid levels by promoting their uptake in
adipocytes, and ultimately increasing insulin sensitivity.
The creation of several PPAR transgenic and knockout
animal models have additionally demonstrated their
potential as targets for therapeutic intervention (112).
Initial work with PPAR- demonstrated that a homozygous null mouse was not viable, whereas the
heterozygous animal is viable and has since been used
in several studies (113116). Curiously, studies using
PPAR- / mice have demonstrated that the tissueNUTRITION IN THE POSTGENOMIC ERA

specific molecular functions of this transcription factor


are not yet fully understood. For example, it was
unexpectedly found PPAR- / mice are more sensitive to insulin, in contrast to what the authors expected (115, 116). However, a liver-specific PPAR-
deficient mouse with an obese-phenotype stemming
from leptin deficiency was found to lack the ability to
store lipids in the liver, resulting in the aggravated
development of T2DM and insulin resistance (117).
Although discrepant results exist regarding our understanding for the mechanistic actions of PPAR-, the
efficacy of TZDs to alleviate symptoms associated with
T2DM remains undisputed.
The functionally important role of PPAR- has led to
it being considered as a candidate gene that may have
a fundamental role in the onset of T2DM (118).
Preliminary work has demonstrated that a missense
mutation (proline 3 alanine) in PPAR-2 is associated
with improved insulin sensitivity and a decreased risk of
developing T2DM (119). Indeed, both the Bogalusa
Heart study (119) and the Go-DARTS study (120) have
found that Pro12Ala polymorphism in the PPAR-2
gene beneficially affects insulin resistance and the risk
of myocardial infarction associated with T2DM, respectively. However, a number of earlier studies found the
Pro12Ala polymorphism to be associated with an increased body mass index (a predisposing factor for
T2DM) (121, 122). Although recent work would suggest that the Pro12Ala has an overall modest protective
effect against T2DM, this effect has not considered the
influence of diet. For example, preliminary indications
suggest that the Pro12Ala polymorphism responds differently to changes in the dietary polyunsaturated/
saturated fatty acid ratio. More specifically, when this
ratio is low, individuals with the Ala allele had a greater
BMI than individuals with the Pro allele. The opposite
was seen when the dietary ratio was increased (123).
Thus, it is clear that PPAR-2, and its associated polymorphisms, play an important role in mediating the
onset of insulin resistance and T2DM. Furthermore, it
is imperative that a continued nutrigenetic approach
be considered if we are to ultimately unravel the
influence of PPAR-2 polymorphisms on the individuals response to dietary intervention.
Intestinal fatty acid binding protein (IFABP)
The gastrointestinal tract (GIT) is the bodys first tissue
boundary to interact with dietary compounds. The
importance of unraveling the molecular mechanisms
regulating the bioavailability (i.e., the degree or rate at
which a substance is absorbed or becomes available at
the site of physiological activity) of a given nutritional
molecule are fundamentally important if we are to
understand their bioactive roles throughout the body;
however, this remains a difficult goal to achieve primarily due to the lack of well-characterized in vitro model
systems and the in vivo complexity of this organ.
Indeed, factors such as gastric motility, pH, disease
status and the enzymatic contribution of the diverse
1609

microbial community will play a critical role in defining


the bioavailability of a substance (124, 125). Associations between the various aforementioned factors of
the GIT and physiological states suggest that understanding the interactions between diet and disease
states should begin in the GIT. For example, recent
work has revealed that the presence of a gut microbiota
mediates energy storage by increasing fat reserves and
insulin resistance, and thus may have an influence on
the development of T2DM and obesity (126). In another example, certain fibers increased the viscosity of
the GIT luminal contents and resulted in decreased
plasma cholesterol levels, demonstrating that GIT motility modulates cholesterol absorption and plays an
important role in defining nutrient bioavailability
(127). To date, little work has explored the role of
genetic polymorphisms in the intestine on nutrient
bioavailability; however, examining the role of polymorphisms in transporter genes regulating drug bioavailability suggests that this line of research will reveal
important information explaining the inter-individual
and inter-ethnical variability in drug/nutrient disposition and response (128 130).
As previously stated, little work has concentrated on
intestinal gene polymorphisms; however, preliminary
work aimed at unraveling the genetics behind T2DM in
Pima Indians have suggested an association between
insulin action, plasmatic nonesterified fatty acids
(NEFA), and polymorphisms in the intestinal fatty acid
binding protein (IFABP) (131), suggesting that SNPs
have the ability to modulate intestinal transport function. The FABP family is comprised of nearly 20 soluble
proteins capable of binding long chain fatty acids
(LCFA), bile acids or retinoids with a high affinity
(132). One member, IFABP, is exclusively expressed in
the small intestine along with the liver-FABP and ileal
bile acid binding protein (IBABP). Although the precise physiological functions of these proteins have not
been elucidated, IFABP is believed to bind and transport LCFA in the cytoplasm of columnar absorptive
epithelial cells of the small intestine (131, 133). A
polymorphism at codon 54 of the IFABP gene
(Ala54Thr), resulting in a change from alanine to
threonine, has been associated with a heightened affinity to bind LCFA (134) and increase TG secretion
(135). Although these findings have been reported
using in vitro model systems, the Thr54 allele has been
associated with impaired insulin action and increased
fat oxidation in several populations (134, 136). Pratley
and colleagues demonstrated that healthy Pima Indians
homozygous for the Thr54 form have higher plasmatic
concentrations of NEFA and an increased insulin response after the consumption of a high fat meal;
however, such findings have not been observed in all
studies (136). Nevertheless, these preliminary findings
suggest that elucidating the role of IFABP polymorphisms on dietary LCFA transport, and, ultimately on
insulin action, merit further investigation. In conclusion, both IFABP and the previously discussed ABCG5/
ABCG8 highlight that polymorphisms in genes coding
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Vol. 19

October 2005

for intestinal transporters may compromise health by


modulating the bioavailability of dietary components.

OUTLOOK
Our dependence on food for survival is evident. Furthermore, the ability of foods to contribute to health
management has long been recognized. Yet despite this
recognition, the prevalence of food-related diseases
such as obesity, T2DM, and CHD, are on the rise in
Westernized nations. A primary influence on the onset
of these diseases is thought to arise from changes in our
lifestyle, i.e., an abundance of food coupled with low
levels of physical activity. Even with clear correlations
between disease states and nutrition, the precise mechanisms by which these lifestyle changes modulate
health remain enigmatic. Indeed, this enigma is exemplified by the all too common situation of two individuals with an equivalent level of physical activity eating
an identical diet, and only one gains weight. Although
dietary recommendations have been implemented to
improve health and diminish the risk of CVD, cancer,
hypertension, T2DM, and obesity, these recommendations have been established based on populations and
not the individual. The drastically different responses
between individuals to a given diet clearly highlights
the limitations of population-based nutritional recommendations and suggest that our understanding of the
mechanisms responsible for inter-individual differences are far from being understood. Therefore, an
intense interest has developed in understanding the
biological mechanisms triggered by our environmental
surroundings. Although smoking, physical activity and
toxins are clearly capable of modulating health, it is our
continuous exposure to foods throughout our lifetime
that renders diet the most important environmental
factor challenging our biological system (30).
The observed differences in an individuals response
to diet have been attributed to differences in the
underlying genetic makeup, prompting exploration
into the role of nutrient-gene interactions in the determination of a healthy phenotype. This avenue of research has been facilitated by our recent entrance into
the post-genomic era, which has witnessed the development of analytical platforms and complementary data
mining algorithms capable of comprehensively studying and interpreting a biological system. However,
unlike the pharmaceutical industry, which aims to
target a specific dysfunctional gene or gene product to
improve health, the nutritional industry must manage
health through a complex mixture of nutritional molecules (i.e., diet), each with their own influences on the
biological system. Thus, in comparison with a medicinal
compound, consuming a diet drastically increases the
number of molecular endpoints that are capable of
influencing phenotype, and thereby places the field of
nutrition in a prime position to benefit from the
technological innovations brought forth by the postgenomic era. Indeed, the one drug one target para-

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MUTCH ET AL.

Figure 3. Integrated metabolism offers a


reductionist approach to unraveling the
metabolic functions of nutrients and drugs.
To minimize the analytical limitations of
each technique, combining at least two of
the three principle platforms and focusing
on common changes, as identified using the
appropriate platform-specific statistical models, proffers a reductionist approach for unraveling the roles of nutrients in the biological system.

digm of the pharmaceutical industry is simply not an


appropriate or feasible goal for nutrition. Hence, the
advent of nutrigenomics and nutrigenetics: two approaches with distinct immediate goals for unraveling
the relationship between diet and genes, but a common
ultimate objective to optimize health (28, 29). Although both of these approaches individually will begin
to unravel nutrient-gene interactions, it is critical that
these approaches are amalgamated if we are to achieve
the ambitious goal of a personalized nutrition. Furthermore, the diverse genetic-makeup of humans implies
that the clear distinction of these two approaches is
difficult to achieve. Using genetically identical animal
models permits gene-diet interactions to be explored
by either approach; however, this is nearly impossible to
achieve in humans and suggests that these approaches
could fall under the more general label of nutritional
genomics. Irrespective of the terminology used, understanding nutrient-gene interactions will benefit from
the concept of systems biology (or integrative metabolism), which aims to understand physiology and disease
by integrating and considering molecular pathways,
regulatory networks, cells, tissues, organs, and ultimately the whole organism (26, 137); however, such an
approach is not routinely used in nutrition and is
conceptually challenging due to the large quantities of
data generated. Currently, few examples exist in which
an integrated approach has been used to examine the
influences of exogenous factors on metabolism (2224,
138, 139); yet, even these eloquent examples have only
provided the genomic and metabolomic profiles of a
single organ. Nevertheless, an underlying theme begins
to emerge with these studies. Indeed, there is an
inherent, albeit counterintuitive, advantage with such
an approach that is able to minimize the known limitations associated with these analytical platforms (e.g.,
such as those observed with microarray data analysis
(140)). The integration of various platforms has the
ability to reduce the quantity of distracting noisy data
associated with each individual technology and diminish the number of molecular endpoints to be interpreted by focusing on only those endpoints common
NUTRITION IN THE POSTGENOMIC ERA

between the various experimental platforms (Fig. 3).


Although at first glance this may seem contradictory, as
the use of multiple platforms will yield large quantities
of data, the appropriate statistical models can filter
through this data and highlight only those important
changes. Indeed, this reductionist concept has been
previously demonstrated, where a combined lipidmetabolomics and transcriptomics approach identified
a single hepatic gene target responsible for changes in
lipid-metabolites after the consumption of arachidonic
acid, despite nearly 300 genes being identified as
differentially expressed after the consumption of this
diet (24, 62).
Although such results demonstrate the advantage of
an integrated approach for the study of exogenous
compounds, it is important to note that these studies
used genetically identical mice; therefore the role of
genetic polymorphisms has not been considered. Furthermore, while the targeted study of single organs
produce invaluable information concerning the metabolism of these compounds, the influence of the remaining biological system is often not considered. Not only
do exogenous factors have differential responses both
within and between various tissues, but underlying
differences between the distinct regions of an organ
(e.g., the gastrointestinal tract) may also mediate metabolism. Therefore, the presence of genetic polymorphisms that can influence nutrient absorption, metabolism and transport throughout the body must be
acknowledged prior to making dietary recommendations to ameliorate health. For example, using margarines enriched with plant sterols to assist in reducing
circulating cholesterol levels could be counterproductive in individuals with mutations inhibiting the proper
function of ABCG5 or ABCG8 transporters.
If the goal of a personalized nutrition is to be
realized, we must begin to think of the biological system
as a physiological network that is intricately connected
rather than composed of individual and unrelated
elements. Comparable to the reverberations felt by a
spider when an insect crashes into its web, nutritional
molecules have the ability to trigger inter-connected
1611

molecular mechanisms in various tissues throughout


the body. Although it is experimentally feasible to use a
systems biology approach in humans (similar to that
recently performed with the ApoE* Leiden transgenic
mouse (138)), it is ethically impossible to even conceptualize that such an analysis will be performed in
humans in the foreseeable future. Therefore, alternate
methods to assess nutrient-gene interactions must be
envisioned.
Profiling metabolites, which best depict an organisms acute cellular function, offers an attractive platform to identify disease biomarkers (141143). Furthermore, defining the metabolite profile associated with
disease and health states will offer an ideal starting
point to decipher how nutritional molecules can modulate these phenotypes. It is enticing indeed to imagine
that a drop of blood could be rapidly analyzed for its
comprehensive metabolite profile, uploaded into software capable of comparing this profile with those
present in a massive database, and return information
enabling a physician to make dietary recommendations
to optimize health; however, several important points
must be resolved if we are to achieve such an attractive
aspiration. First, there is currently no single technology
capable of comprehensively assessing all of the metabolites in a biological sample. Nuclear magnetic resonance, chromatography and mass spectrometry are
powerful analytical platforms; however, the complete
spectrum of metabolites is currently assessable only
through the integration of these technologies (144).
Thus, the creation of a unique platform that is capable
of noninvasively assessing the complete metabolome
will become a valuable tool in both a clinical and
research environment. Second, in order to characterize
the metabolic profile underlying a healthy phenotype,
one must characterize the variability existing in metabolites across healthy individuals. Indeed, this prompts
the question, What metabolic profile characterizes
healthiness? The influence of such factors as asthma
(145), smoking (146) and physical activity (147) have
been reported to affect metabolism; however, are these
differences significant when considering all metabolites
simultaneously? A comprehensive approach to metabolite profiling, coupled with robust statistical algorithms, may reveal that these perturbations have a
minimal effect on the overall metabolite profile. For
this to be assessed objectively, it becomes critically
important that individuals participating in such epidemiological studies are genotyped prior to their inclusion in a cohort and that cohorts are of a sufficient size
to permit statistical algorithms to function optimally.
Only then can we determine whether metabolomics
can identify a healthy phenotype. Third, the metabolite profile associated with various disease states must
be characterized. A suitable and feasible starting point
would define the metabolite profile of monogenic
diseases, which stem from a single dysfunctional gene.
In contrast, the metabolite profiles of diseases such as
CHD, cancers, and T2DM are difficult to correlate with
single genes, as dysfunctional networks characterize
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Vol. 19

October 2005

these conditions. Rather, the use of annotated microarray results to identify common biological functions,
such as that used by Segal and colleagues to classify
different tumor types (36), suggests that these polygenic diseases may have similar metabolite profiles
despite varied gene expression profiles. For the moment, the metabolite profiles of polygenic diseases have
not been comprehensively explored; however, it insinuates that associating a candidate disease gene with a
metabolite profile may not be an appropriate endpoint.
However, relating perturbed functional networks with
metabolite profiles may have more relevance from a
clinical perspective. Finally, it is vital that this information be stored in publicly available databases that have
stringent and universally accepted criteria for accepting
data (144). The vast quantity of metabolite data produced by profiling diseased and healthy individuals will
be difficult to interpret by a human; however, such
databases will empower supervised biomathematical
algorithms to compare a given metabolomic profile
with those referenced in the database. Although there
is currently no existing database empowering the scrutinization of metabolite profiles and permitting nutritional recommendations to be proposed, the initiatives
of groups such as the American Society for Nutritional
Sciences Long Range Planning Committee will manifest
itself into a database with precisely this objective.
In this regard, the future lies not with the technologies, but with the storage, management, and interpretation of the vast quantity of metabolomic data. No
single lab will be able to achieve the concept of a
personalized nutrition alone; rather, a collective effort
by the scientific community to adhere to guidelines put
forth regarding experimental designs, analysis, and
data storage will generate a database that is readily
available to researchers and clinicians alike. Thus,
nutrition in the 21st century is poised to be an exciting
and highly relevant field of research, as each new day is
accompanied by advances in our understanding of how
the interactions between lifestyle and genotype contribute to health and disease, taking us one step closer to
achieving the highly desirable goal of personalized
nutrition.

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