ARTICLE IN PRESS

Clinical Nutrition (2003) 22(5): 429–435

r 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0261-5614(03)00064-5

REVIEW

Genetics and nutrition

A. PAOLONI-GIACOBINO,n R. GRIMBLE,y C. PICHARD*
n
Division of Clinical Nutrition, Geneva University Hospital, Switzerland, yInstitute of Human Nutrition, School of Medicine, University of
Southampton, UK (Correspondence to: CP, Division of Clinical Nutrition, Geneva University Hospital, 24 Micheli-du-Crest,1211Geneva)

Abstract*The understanding of the role of nutrients on DNA stability, repair and on the di¡erent gene expression pro-
cesses recently became more prominent in nutritional science. Nutrients and the genomics interact at two levels. Nutri-
ents can induce gene expression thereby altering individual phenotype. Conversely single nucleotide polymorphisms, in
a range of genes important in in£ammation and lipid metabolism, alter the bioactivity of important metabolic pathways
and mediators and in£uence the ability of nutrients to interact with them.
The study on single e¡ects of nutrients on the individual’s phenotype as well as the serial analyses of gene expression
patterns in response to speci¢c nutrients will help us to understand how metabolic homeostasis is maintained. Consid-
ering that there is wide variation in the ability of nutritional factors to modulate the expression of detrimental or protective
proteins at an individual level, the concept of diet-medication could be developed in the light of a better understanding of
nutrient^gene interactions. In this way, ‘good responders’and ‘poor responders’ to diet therapy can be identi¢ed. Further-
more, as several vitamins participate in DNA protection and genomic stabilisation, diet-linked therapies could become
part of cancer prevention and other treatments with relevant consequences for human health.
r 2003 Elsevier Ltd. All rights reserved.

Key words: nutrient; genetics; DNA; regulation;
stabilisation
Introduction
The unravelling of the secrets of the human genome
has provided new opportunities for understanding how
mankind responds to the environment in health and
disease.
The functioning of living organisms depends on the
environmental availability of nutrients. One of the
adaptation pathways is the nutrient-dependent regula-
tion of the genome machinery. Although the nutrients
can, in this way, influence the development of a
particular phenotype, the opposite mechanism has also
to be considered, i.e. the response to a specific nutrient
as determined by the individual’s genotype. The
nutrient–gene interaction is therefore complex and
bi-directional.
It is well known that not all individuals respond to
nutrient therapy in the same way and with the same
intensity. For any nutrient used in dietary therapy
individuals, may be ‘good’, ‘poor’ or ‘non-responders’.
In the past, this phenomenon has created problems in
understanding the responses to nutrients and foods used
in population-based intervention studies. The great
variability in the responses of subjects in nutritional
intervention studies has necessitated the recruitment of
large numbers of individuals in order to obtain sufficient
power to understand what effect, if any, a nutrient may
be having. A closer understanding of how genotype
influences the response to nutrients may permit efficacy
of nutrients to be measured with greater precision than
is presently the case.
This review gives an overview of the role of genetics in
nutritional science. The bi-directional interactions be-
tween nutrients and the genome, referred to above, are
discussed.
It also focuses on the nutrient-specific regulation of
gene expression. A few representative examples of
effects or regulations have been selected rather than an
exhaustive list. The nutrient–gene interactions, the
nutrient-specific regulation of gene expression and the
related technological approaches are overviewed
(Fig. 1).
Gene–nutrients interactions
The human genome contains approximately 2.9 billions
of nucleotides or 30,000 genes (1), part of which
involved in metabolic regulations. The link between
environment and genes has to be considered as bi-
directional, with the pressure of the environment, e.g.
food availability, on gene expression, as well as the
response to those nutrients depending on the genetic
background of the organism.

429
 ARTICLE IN PRESS
430 GENETICS AND NUTRITION

Genotype

SNP - association studies

DNA
Gene isolation - targeted disruption

+/-
transcription

mRNA cDNA - microarrays

+/-

Nutrients translation
+/-

Protein

Phenotype

Fig. 1

The advantage of this plasticity is mainly the
adaptation of the organism to extreme conditions, such
as starvation. The consecutive disadvantage is that
an extreme condition, as nutrient abundance, can
induce a pathology for particular genotypes. An
example of a gene regulated by the nutritional status
of the cell is asparagine synthetase (AS), which encodes
the enzyme catalysing the glutamine- and ATP-depen-
dent conversion of aspartic acid to asparagine. AS gene
expression is triggered by amino acids depletion in the
extracellular environment and there is a consecutive
increase in mRNA levels resulting both from an
elevation in the rate of transcription and in mRNA
stability (2). Similarly, but through a different mechan-
ism, the transcription of the human amino acid
transporter gene 2 (ATA2) is induced by amino acid
deprivation (3). In case of specific nutrient excessive
intake, the organism has also to adapt its metabolic
machinery. It is now well known that lipid- and
carbohydrate-rich diets are linked to obesity, non-
insulin-dependent diabetes mellitus and hyperlipidemia.
In this situation, the organism try to keep cholesterol
levels within a narrow concentration range by
transcription control mechanisms. Thus, excess
cholesterol can be converted into oxysterols, which
modulate the activity of a number of transcription
factors, in order to limit accumulation of excess of
cholesterol (4).
Therefore, if nutrients modulate the gene-expression
profile, the interdependence between genes and diet has
to be considered.
Vitamins, DNA stability and gene expression
A number of vitamins participate in DNA protection
and genomic stabilisation. Therefore, it can be imagined
that dietary deficiencies might lead to an increase in
DNA damages and subsequent cellular dysfunction, as
in ageing and cancer (5).
Carotenoids, the vitamin A precursors, have anti-
oxidant properties through quenching free-radical or O2
and therefore lower DNA damage. The antioxidant
potential of carotenoids has been demonstrated in vitro
by different approaches (6). In human, the protective
effect of carotenoids at the cellular level on DNA
oxidative damage is now clearly established and plasma
carotenoid concentration were shown to correlate
negatively with oxidative damage to lymphocytes
(7–9). Epidemiological studies however yielded contra-
dictory results on the potentially protective effect of
carotenoids on carcinogenic processes. Some showed a
protective effect of consumption of carotenoids against
cancer (10, 11) and others reported no effect (12) or even
a consecutive increased incidence of respiratory cancers
(13, 14). Although the protective effect of carotenoids
on DNA seems now established, the eventual benefit of
carotenoid supplementation is still controversial.
A direct effect of carotenoids on gene expression has
been well studied for few genes, as the one coding for a
gap junction protein connexin 43, whose expression was
reported to be increased by carotenoids, in human
fibroblasts (15). An induction of expression of haem
oxygenase-1 gene, coding for a microsomal enzyme
 ARTICLE IN PRESS
involved in haem catabolism, by b-carotene in UV-
irradiated fibroblasts was also described (16). The
biological roles of the active form of vitamin A, retinoic
acid, are better characterised. Concerning the effect of
retinoic acid on gene expression, the list of known
regulated genes is fastly growing. Among the regulated
genes are those directly involved in retinoic acid
catabolism, as cellular retinol-binding protein (CRBP)
types I and II, proto-oncogenes, as c-fos and c-myc, and
growth factors, as tumor growth factor-b1 (TGF-b1)
and interleukin 6 (IL-6) (17).
Vitamin B12 and folate are essential for DNA
metabolism (18). Folic acid is necessary for the
conversion of deoxyuridine monophosphate (dUMP)
to deoxythymidine monophosphate (dTMP). In case of
folic acid deficiency, dUMP accumulates and uracil is
incorporated into DNA instead of thymine. There is
now evidence that an excessive incorporation of uracil
into DNA may result in DNA and chromosomal breaks.
Vitamin B12 and folic acid are also necessary for the
synthesis of methionine and S-adénosyl-methionine,
required for the maintenance of the DNA conformation
and methylation patterns (19). Although the blood
levels of folate and vitamin B12 preventing anaemia are
defined, the efficiency of those concentrations for
minimising chromosome damage is unknown. There is
also increasing evidence that single nucleotide poly-
morphisms (SNP) might affect the activity of the
proteins required for the absorption, transport and
metabolism of theses vitamin (20). Therefore the
necessary intakes of vitamin B12 and folate for a
genome protective effect could be different for different
genotypes.
Very few studies have explored the role of vitamin
B12 on gene expression. In mammalian cell cultures, an
inductive effect of vitamin B12 on methionine synthase
enzyme was demonstrated, with a proposed post-
transcriptional regulation of expression (21). An inter-
esting study, using a cDNA microarray approach
explored the effects of variations in extracellular folates
on the gene expression pattern, in human carcinoma
cells (22). The authors reported that the expression of 8
genes responded to folate levels variations, 3 of them
being up-regulated (Brain expressed HHCPA78 homolg,
Calmegin, insulin-induced protein 1) and 5 down-
regulated (H-cadherin, keratin type 1 cytoskeleton 14,
cyclin D3, gravin, interferon inducible protein 1-8U).
In vitro, vitamin C has been demonstrated to have
strong antioxidant properties and decrease the level of
DNA oxidative damage (23). In vivo, the intra- and
extracellular levels of ascorbate correspond to those
showing an antioxidant effect in vitro (24). However, it
has not been assessed in human if the consumption of
ascorbate supplements could be beneficial in terms of
genomic stabilisation. Therefore consumption of ascor-
bate supplements seems not justified (24, 25). Never-
theless, there is no evidence that vitamin C
supplementation can be harmful.
CLINICAL NUTRITION 431
Vitamin C has also been shown to modulate the
expression of several genes. It was recently reported, by
a cDNA microarray approach, that ascorbate supple-
mentation can differentially modulate the expression of
genes as fra-1, glutathione S-tranferase Pi, Mut L
homologue-1 (MLH1) and p73 (26). As MLH1 is
involved in DNA-repair processes, and is up-regulation
by vitamin C, it could perhaps explain the anti-
carcinogenic role of vitamin C.
Vitamin D, (1,25(OH)2D3), exerts in vitro an anti-
oxidant activity, and stabilises the chromosomal struc-
ture. A few studies have documented vitamin D as an
antioxidant in vivo (27). Therefore in human, the
question of vitamin D supplementation for adults is
still debated. As vitamin D is potentially toxic, possible
adverse effects have to be taken into account when
thinking on dietary supplementation. It seems however
that in adult, the actual recommended daily allowance
(RDAs) of vitamin D should be increased to have an
effective role on osteoporosis, multiple sclerosis, hyper-
tension and possibly cancer (28, 29). There is an
extensive and still rapidly growing list of genes whose
expression is up- or down-regulated by 1,25(OH)2D3.
The effect of 1,25(OH)2D3 in regard to tumour growth
inhibition has also been proposed to be mediated by an
effect on the expression of genes involved in tumorigen-
esis, as bcl-2 (30) and proto-oncogenes c-fos and c-myc
(31, 32). Using targeted gene inactivation in mice, a
study reported that vitamin D was also a regulator of
renin gene expression (33). Through cDNA microarray
analysis, changes in expression levels of numerous gene
were observed in osteoblastic cells treated with
1,25(OH)2D3 (34). The authors explored the changes
associated to Ca2+ influx mediated by 1,25(OH)2D3 at
different time after treatment and their analysis revealed
variations in gene expression, as protein kinases,
phosphatases, cell adhesion molecules and genes in
Ca2+ signalling pathways.
Vitamin E is a lipid peroxyl radical scavenger
reducing chromosomal damage. It was also suggested
to increase the removal rate of damaged DNA (35).
There is controversy concerning the possibly beneficial
effects of nutritional complements of vitamin E for
cancer, cardiovascular and inflammatory diseases, Alz-
heimer and Parkinson diseases (36, 37). It is therefore
unclear if dietary supplements of vitamin E are
beneficial.
The vitamin E family components, as a and b-
tocopherol, regulate cellular functions by mechanisms
unrelated with the antioxidant function. In some studies,
differential effects of a- and b-tocopherol were observed
(38). Modulatory effects on proto-oncogene c-jun
expression have been described in human breast cancer
cells (39). Vitamin E was also shown to play a role in the
regulation of heat shock protein synthesis in human
fibroblasts (40). Vitamin E down-regulates interleukin 4
(IL-4) expression at the mRNA and protein levels in
human peripheral blood T cells, in a dose-dependent
 ARTICLE IN PRESS
432 GENETICS AND NUTRITION
manner (41). The transcriptional regulation by vitamin
E family members of genes as collagenase (42) and
a-tropomyosin (38) has also been demonstrated.
In conclusion, the definition of the role of vitamins in
maintenance of genomic integrity is essential as well as
the establishment of RDAs in regard to this function (18).
Nutrient-specific regulation of gene expression
Amino acids, fatty acids and carbohydrates can exert a
variety of actions by controlling the expression of genes
involved in different biological systems.
Amino acid regulation of gene expression
Amino acids can play the role of nutritional signals in
the modulation of expression of particular genes. In
fact, recent studies have shown that cells can detect
variations in amino acid levels and respond by mechan-
isms as control of transcription, mRNA stabilisation as
well as by up- or down regulation of translation
initiation (43).
The regulation of the expression of C/EBP homo-
logous protein (CHOP) by amino acids has been
explored. CHOP is a ubiquitously expressed gene
encoding a small nuclear protein related to the
CCAAT/enhancer-binding protein (C/EBP) family of
transcription factors. The induction of CHOP was
demonstrated to be activated by agents that adversely
affected the function of the endoplasmic reticulum (44).
In human cell lines, leucine restriction was shown to lead
to enhancement of CHOP mRNA and protein in a dose-
dependant manner (45).
Varga et al. (46) have also demonstrated in human
cells that amino acid l-tryptophan in supraphysiologic
concentrations was a powerful inducer of collagenase
gene expression at a transcriptional level. The increase in
collagenase mRNA levels was reversible, time- and
l-tryptophan dose-dependent.
However, the molecular mechanisms and mediators
involved in the gene-expression control by amino acid
are not yet fully understood.
Fatty acid regulation of gene expression
Fatty acids (FA) are involved in the regulation of
biological processes through modulation of gene
expression. In response to variations in FA concentra-
tion, the expression of target genes can be turned on or
off. In particular, peroxisome proliferator-activated
receptors (PPAR) have been shown to be involved in
the FA control of gene expression by (47). The PPARs
are ligand-dependent transcription factors acting by
binding to specific peroxisome proliferator response
elements (PPREs) in enhancer sites of regulated genes.
When binding of an agonist, the PPAR conformation is
modified so that a binding cleft is created and the
recruitment of transcriptional coactivators occurs. This
results in an increase in gene transcription (48).
Three PPAR isoforms encoded by different genes are
characterised, namely PPAR type a, d and g.
PPARa is an important lipid sensor and regulator of
cellular energy metabolism. It was shown to be a critical
player in the regulation of cellular uptake and
b-oxidation of FA. PPARa triggers the expression of
two proteins that transport fatty acids across the cell
membrane: the fatty acid transport protein (FATP)
and fatty acid translocase (FAT) (49), suggesting a role
in cellular uptake and lipid homeostasis. Activation of
PPARa also directly up regulates transcription of long
chain fatty acid acyl-CoA synthase (50) and of various
enzymes of the peroxysomal b-oxidation pathways, as
acyl-CoA-oxidase (51), acyl-CoA hydratase and dehy-
drogenase (52), and keto-acyl-CoA thiolase (53).
PPARg plays a unique role among PPAR family
members as a regulator of adipocyte differentiation.
PPARg controls the expression of numerous genes
involved in lipid metabolism, as fatty acid-binding
protein and phosphoenolpyruvate carboxykinase (54,
55), as well as acyl-CoA synthase and lipoprotein lipase
(50, 56). PPARg also regulates genes that control
cellular energy homeostasis. It has been shown to
increase the expression of the mitochondrial uncoupling
proteins (UCP), UCP-1, UCP-2, and UCP-3 in brown
adipose tissue, in vitro and in vivo (57). PPARg has also
been associated with genes affecting insulin action, as
TNFa (58), and leptin (59). To date, no PPARd-specific
gene targets have been identified.
Carbohydrate regulation of gene expression
The question of the carbohydrates regulation of gene
expression has only recently been addressed and the
most studied pathway is the one involving glucose.
It is now well documented that a high glucose
concentration induces the transcription of several genes
of the glycolytic and lipogenic pathways. In yeast,
glucose has been shown to turn on processes involved in
its own utilisation, and off those involving other carbon
sources (60). In mammals, the effect of dietary glucose
on gene expression are tricky to study because they
involve hormones like insulin or glucagon, whose
secretion varies with a high glucose intake.
Studies on glucose regulation have been performed
in vitro in different types of cultured cells, for various
potential target enzymes: l-pyruvate kinase in hepato-
cytes and pancreatic b-cells (61, 62), lipogenic
enzymes like acetyl-CoA carboxylase in pancreatic b-
cells, adipocytes (63, 64), fatty acid synthase in
hepatocytes and adipocytes (64, 65). In all these
studies, a high glucose concentration was shown to
increase the transcription of the target enzymes. How-
ever, in hepa-tocytes and adipocytes, the stimulation of
gene expression was at least partially dependent on
insulin (66).
 ARTICLE IN PRESS
In conclusion, although numerous studies have now
demonstrated the role of nutrients in the regulation of
some of the processes of gene expression, our under-
standing remains scarce.
Technological approaches
One way of exploring the nutrient–gene interaction is to
determine how a specific nutrient modulates the expres-
sion of target genes, without considering a particular
genetic background. The opposite approach is to
analyse the inter-individual variability to nutrient
response, by the study of gene polymorphisms. An
animal-based complementary strategy is to modify the
expression of a single gene involved in a particular
metabolic pathway, and look at the consequences in
terms of nutrient-response.
DNA microarrays
Through DNA microarrays strategy, a global approach
and the comprehension of the effect of a specific
stimulus on a gene or on gene families are possible.
Using microarrays, it will hopefully be possible to
understand what are the targets of specific nutrients and
which of them are regulated in extreme conditions. The
arrays of nucleotide sequences can be constituted of
genes of the entire human genome or of a family of
genes of interest. The first step is the deposition of spots
of purified nucleotide sequences generally on a glass
surface but sometimes on nylon substrates. Then, the
slide is hybridised with fluorescent-labelled RNA or
cDNA. If the RNA or cDNA molecule has a sequence
complementary to a given spot it will hybridise to that
spot on the array and be detectable by its fluorescence,
and the emitted light captured by a detector. The
differential gene expression pattern is interpreted as the
different signal ratios from the fluorescent dyes. Once
the results are obtained, they can be compared with
other microarray data in a cluster analysis. This builds a
study of comparative gene expression patterns (67, 68).
To our knowledge, this type of large-scale nutritional
study has not yet been performed in human. In
mammalian, a recent report tested the modulation of
intestinal gene expression by dietary zinc status (69).
The authors succeeded in demonstrating changes in
mRNA abundance of genes as zinc transporter-2 or
metallothionein 1, produced by a zinc deficency.
The main difficulty related to this approach, excluding
the price is that the number of modulated candidate
genes can be impressively high making the biological
interpretation tricky.
Association studies
The individual genetic background is an essential
determinant of nutrient requirements. The most com-
mon type of genetic variability is the single nucleotide
CLINICAL NUTRITION 433
polymorphism (SNP), which is a base change in the
DNA sequence, occurring approximately once every
1.9 kb in human genome (70). Genetic SNP databases
are now in development, making possible the screening
for individuals variations.
Association studies represent one way of investigating
nutrient–gene interactions. A candidate-gene approach
has to be chosen for such exploration, meaning that
polymorphisms within a gene of interest are tested for
family or population-based associations in response to
different dietary intakes.
Frequent polymorphisms in folate metabolism genes
have been linked to pathologies as neural tube defect and
homocystinemia (71, 72). Genes of the lipid metabolism
pathways, as the Apolipoprotein AI, AIV, B, C-III, E,
lipoprotein lipase, cholesterol-ester transferin protein,
lecithin-cholesterol acyltranserase and LDL receptor gene
clusters have been studied for an association to dietary
intakes response. However, discrepancies were observed
among the different studies (73). The main difficulty in
association studies is to have large and homogenous
sample groups. Association studies, as opposed to
microarray approach, first require a hypothesis concern-
ing the putative role of a gene possibly involved in
metabolic pathways, then looking for sequence variants
and finally testing their possible association.
Targeted gene inactivation, from mouse to human
Targeted gene inactivation, or gene knockout, is another
approach to explore the biological role of a candidate
gene in vivo and study the consequences of a gene
disruption on metabolic processes or diet response. The
most common technique for knocking out a gene is
homologous recombination in embryonic stem cells,
which are then micro-injected into embryos and reim-
planted into a foster mother, and production of animals
with defects in expression of the specific gene (74).
For example, dietary cholesterol absorption efficiency
has been shown to be regulated by multiple genetic
factors (75). A gene knockout approach has been used
to explore the role of some genes involved in cholesterol
metabolism. Knockout of the pancreatic cholesterol
esterase showed that this enzyme mediates intestinal
absorption of cholesteryl esters and is not determinant
for the absorption of unesterified cholesterol (76).
Knockouts for the acylCoA cholesterol acyltransferase
(77) have also been generated and helped for the
understanding of the cholesterol absorption pathways.
Although the generation of knockout animals is an
extremely important tool, the main problem is that not
all the phenotypes will be comparable to those of human
subjects.
Conclusion
The 21st century has started with the completion of the
human genome sequencing and we are now entering the
 ARTICLE IN PRESS
434 GENETICS AND NUTRITION
-omics area, with genomics, proteomics, metabolomics
and perhaps dietomics. However, we will not get from
this knowledge immediate benefits to human health,
longevity and quality of life without further insights into
nutrient gene interactions. In order to develop nutri-
tional science, we will now have to integrate the studies
on single effects of nutrients on phenotype and the serial
analyses of gene expression patterns in response to
specific nutrients. The concept of diet medication, or
diet therapy, with nutritional factors modulating the
expression of detrimental or protective proteins should
then become one of the goals of nutritional research.
Acknowledgements
We acknowledge the Fondation Nutrition 2000 Plus for financial
support.
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