Mol Diag Ther 2006; 10 (2): 101-108

NUTRITION AND METABOLISM 1177-1062/06/0002-0101/$39.95/0

© 2006 Adis Data Information BV. All rights reserved.

Nutrigenomics
Integrating Genomic Approaches into Nutrition Research
Lynnette R. Ferguson
Discipline of Nutrition/Auckland Cancer Society Research Centre (ACSRC), School of Medical Sciences, Faculty of Medical
and Health Sciences, The University of Auckland, Auckland, New Zealand

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
1. Implications of Human Variation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
1.1 Macronutrient Requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
1.2 Micronutrient Requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
1.3 Effect of Bioactive Components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
2. Implications of Gene-Diet Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
2.1 Food Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
2.2 Lifestyle Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
2.2.1 Anti-Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
2.2.2 Brain Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
2.2.3 Visual Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
2.3 Multifactorial Chronic Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
2.3.1 Energy Homeostasis Regulation and Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
2.3.2 Cardiovascular Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
2.3.3 Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
3. Public Acceptability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106

Abstract It has been suggested that the supermarket of today will be the pharmacy of tomorrow. Such statements have
been derived from recognition of our increasing ability to optimize nutrition, and maintain a state of good health
through longer periods of life. The new field of nutrigenomics, which focuses on the interaction between
bioactive dietary components and the genome, recognizes that current nutritional guidelines may be ideal for
only a relatively small proportion of the population. There is good evidence that nutrition has significant
influences on the expression of genes, and, likewise, genetic variation can have a significant effect on food
intake, metabolic response to food, individual nutrient requirements, food safety, and the efficacy of disease-pro-
tective dietary factors. For example, a significant number of human studies in various areas are increasing the
evidence for interactions between single nucleotide polymorphisms (SNPs) in various genes and the metabolic
response to diet, including the risk of obesity. Many of the same genetic polymorphisms and dietary patterns that
influence obesity or cardiovascular disease also affect cancer, since overweight individuals are at increased risk
of cancer development. The control of food intake is profoundly affected by polymorphisms either in genes
encoding taste receptors or in genes encoding a number of peripheral signaling peptides such as insulin, leptin,
ghrelin, cholecystokinin, and corresponding receptors. Total dietary intake, and the satiety value of various
foods, will profoundly influence the effects of these genes. Identifying key SNPs that are likely to influence the
health of an individual provides an approach to understanding and, ultimately, to optimizing nutrition at the
population or individual level. Traditional methods for identification of SNPs may involve consideration of
individual variants, using methodologies such as restriction fragment length polymorphisms or quantitative
real-time PCR assays. New developments allow identification of up to 500 000 SNPs in an individual, and with
102
increasingly lowered pricings these developments may explode the population-level potential for dietary
optimization based on nutrigenomic approaches.
It is generally believed that to ensure good health an average
adult should eat a balanced diet, comprising approximately
10–15% protein, 55–60% carbohydrate, and 30% or less of fat.
Micronutrients are required at levels dictated by age and sex,
according to the recommended daily intakes (RDIs), and desirable
levels will be affected by other factors such as pregnancy and
lactation. However, the new science of nutritional genomics,
sometimes called ‘nutrigenomics’ and/or ‘nutrigenetics,’ recog-
nizes that what is good advice for one individual may not be
appropriate for another. Although there are several possible defini-
tions of these terms, Debusk and coworkers[1] define them as
follows:
• “Nutrigenetics: The study of the mechanisms by which bioac-
tive dietary components communicate with the genetic material
and how genetic variation affects the interaction between these
bioactive dietary components and the health and disease poten-
tial of a person.”
• “Nutrigenomics: Concerned with the effects of bioactive dieta-
ry components on the genome, proteome (the sum total of all
proteins), and metabolome (the sum of all metabolites) at a
global, population level.”
• “Nutritional genomics: The study of how dietary and other
lifestyle choices influence the function of living beings at the
molecular, cellular, organismal, and population levels; includes
nutrigenetics and nutrigenomics.”
In practice, this article will use the term ‘nutrigenomics’ in the
generic sense.
There are very significant parallels between the fields of
pharmacogenomics, toxicogenomics, and nutrigenomics. Pharma-
ceutical development recognizes that only a proportion of the
population will respond appropriately to a new drug, while a
number of people will be unresponsive, and that there is likely to
be a group in the population that could be adversely affected by
it.[2] This is also true for nutrients and other dietary components.
1. Implications of Human Variation
The publication of the human genome sequence in 2001[3]
provided much important information on the nature of human
DNA. It revealed that we all have around 3.2 billion nucleotide
base pairs, and that the sequence of bases in the human genome is
99.9% identical among individuals. However, 0.1% variation in
3.2 billion nucleotide base pairs still leaves room for considerable
(i.e. millions) of variations. Much of the basis of differences
© 2006 Adis Data Information BV. All rights reserved.
Ferguson
between humans is provided by single nucleotide polymorphisms
(SNPs). These make up about 90% of all human genetic variation,
and are DNA sequence variations that occur when a single nucleo-
tide in the genome sequence is altered. For a variation to be
considered a SNP, it must occur in at least 1% of the population.
These variations occur every 100–300 bases along the 3-billion-
base human genome, and two of every three SNPs involve the
replacement of cytosine (C) with thymine (T). SNPs can occur in
both coding (gene) and non-coding regions of the genome.
It is clearly inappropriate to suggest that individuals could be
studied for dietary optimization by sequencing their entire gen-
ome. Early studies on human variation studied SNPs one at a time,
usually utilizing gel methods such as restriction fragment length
polymorphisms (RFLP),[4] or, more recently, multiplex methods
such as TaqMan®.[5] However, the technical difficulties and cost
of scanning large segments of DNA are being reduced to a point
whereby it is becoming feasible to consider identifying 500 000
SNPs in a single individual.[6] Such methodologies are potentially
extremely powerful, since they make no pre-assumptions as to
which SNPs will be important for a given wellness situation or to
prevent a disease state. For this reason, such methods are being
increasingly applied to human populations. For example, media
releases from the US National Institutes of Health (NIH) reveal
that more than 1200 patient samples will be examined using high-
density SNP arrays, as part of the NIH-funded study of cardiovas-
cular events in 38 000 women.[7]
1.1 Macronutrient Requirements
The structural gene (APOE) is polymorphic, with three com-
mon alleles (ε2, ε3, and ε4) that produce three isoforms of the
protein (E2, E3, and E4). These alleles give rise to six genotypes:
ε2/ε2, ε2/ε3, ε2/ε4, ε3/ε3, ε3/ε4, and ε4/ε4. Comparisons of risk
generally utilize the homozygous ε3/ε3 genotype as the referent
(wild-type), and phenotypically consider ‘APO E2 individuals’ as
those with at least one APOE-ε2 allele, and ‘APO E4 individuals’
as those with at least one APOE-ε4 allele, with the other allele
being ε3 in heterozygotes. ‘APO E3 individuals’ are those homo-
zygous for the wild-type ε3 allele. Each of the three common
phenotypes has a different probability of cardiovascular disease
risk and responds differently to dietary and environmental factors,
including both the level and nature of fats.[8] Most people have the
APO E3 phenotype and respond as expected to reducing fat,
increasing exercise, etc. However, approximately 20% of the
population carry at least one APOE-ε4 variant allele. This in-
Mol Diag Ther 2006; 10 (2)
Genomic Approaches to Nutrition Research
creases total cholesterol, increases the risk of diabetes and
Alzheimer’s disease, and reverses the protective effects seen by
moderate alcohol drinking. It also greatly enhances the cardiovas-
cular risks associated with smoking, leading to a very high
probability of a heart attack in such people. The implication is that
individuals with this genotype should be extremely rigorous about
diet and exercise, and in particular, should give up or avoid
smoking and alcohol, undertake exercise, and eat a diet low in
saturated fat. However, very few of the population are aware of
their APOE genotype at present.
1.2 Micronutrient Requirements
The most obvious variations with relevance to human health are
polymorphisms in genes affecting nutrient requirements. For ex-
ample, folate is necessary for the synthesis of purine and
thymidine deoxyribonucleotides and ademetionine, and is defi-
cient in a significant proportion of many Western populations.
Dietary deficiency in folate and/or vitamin B12 results in a range
of effects including impaired DNA methylation, increased uracil
uptake into DNA, and elevated homocysteine and S-adenosyl-
homocysteine in serum and tissues. Folate and homocysteine
levels have been suggested important in brain function,[9,10] pre-
eclampsia,[11] cancer,[12] renal function and failure,[13] and physical
growth and development.[14] Current RDIs of folate are around 400
g/day, and it is assumed that for most individuals, levels around
this point show a window of benefit. Dietary amounts lower than
this will be too low for efficacy, whereas higher amounts may be
toxic. The position and shape of the curve is affected by exogenous
factors, including interactions with other dietary components, co-
existing exposures (including medication and smoking), behavior,
stage of development, socioeconomic status, and sex.
This complexity is increased by inter-individual differences.
5,10-Methylenetetrahydrofolate reductase (MTHFR) is a key fo-
late-metabolizing enzyme whose substrate functions as the one-
carbon unit donor for thymidine synthesis (and indirectly for
purine synthesis) and whose product contributes to the supply of
methyl groups destined for DNA methylation. A number of com-
mon MTHFR polymorphisms interact significantly with folate
metabolism.[15] For example, the MTHFR 677C>T polymorphism,
a C to T nucleotide transition at position 677 of the gene that
translates to an alanine to valine substitution in the protein, pro-
duces a thermolabile variant of MTHFR. In vitro activity of
MTHFR from MTHFR TT homozygotes is reduced by 70%.
Homozygosity for this polymorphism also results in reduced in
vivo MTHFR enzyme activity and significantly elevated plasma
homocysteine levels. Formylated folates accumulate at the ex-
pense of 5-MTHF in red blood cells. The implications are that
© 2006 Adis Data Information BV. All rights reserved.
103
individuals with MTHFR polymorphisms require higher folate to
maintain the homocysteine levels. Unless we understand the geno-
type, we may be providing the wrong levels of folate, since high
levels can be toxic in some individuals.
Similarly, there are genetic variants affecting both uptake and
activity of selenium, and selenium levels might beneficially be
adjusted upon knowledge of polymorphisms.[16]
1.3 Effect of Bioactive Components
Green tea provides an example that many are aware of. It
contains a number of antioxidant molecules that have been sug-
gested to help protect against chronic diseases, such as cancer and
heart disease. However, a study done by the University of South-
ern California (Los Angeles, CA, USA) showed that not all
women had lowered breast cancer risk after regularly drinking
high levels of green tea.[17] Those women who did respond appear
to have a variant of the COMT gene that produces a less active
form of the catechol-O-methyltransferase enzyme, which is nor-
mally involved in inactivating cancer-suppressing compounds.
2. Implications of Gene-Diet Interactions
Nutrition directly influences hormone synthesis and metabo-
lism, for example through the role of specific nutrients in signal
transduction pathways or by changes in energy status.[18] One of
the best characterized interactions of dietary components and gene
products relates to phytoestrogens, which appear to modulate gene
expression through direct interaction with estrogen receptors
(ERs), thereby mimicking the effects of endogenously produced
estrogens. Although the estrogen receptor binding capacity of
phytoestrogens, such as genistein, daidzein, and equol, is orders of
magnitude lower than that of native estrogens, they have compara-
ble estrogenic effects and their activities are blocked by the
estrogen receptor antagonist 4-hydroxytamoxifen.[19] As another
example, the phytoestrogen resveratrol is a key component of
grapes and has been suggested as likely to contribute to the well
known ‘French paradox,’ whereby people on a Mediterranean diet,
including red wine, appear to have lower levels of cardiovascular
disease than their teetotal counterparts. Resveratrol binds to both
ER subtypes ERα and ERβ and activates gene transcription by
these means.[20] Henry and Witt[20] studied in vivo effects of
resveratrol-supplemented diets on the reproductive physiology
and behavior of adult female rats. Provided the animals had intact
gonads, this dietary regime reduced bodyweight, disrupted the
estrous cycle, and induced ovarian hypertrophy. However, in
ovariectomized females, resveratrol had no such lasting effects.
Mol Diag Ther 2006; 10 (2)
104 Ferguson

2.1 Food Safety using information from genomic or genetic data in order to opti-
mize nutrient intake for optimal health, at the level of an individu-
Polymorphisms in environmental response genes (e.g. encod-
al). However, the available research suggests that the addition of
ing xenobiotic metabolizing enzymes or XMEs) are critical in
new foods into an individual’s diet is less likely to be a successful
determining individual response to foods. Most toxicants produce
approach than the overall reduction of food in general (i.e. calorie
their toxic effects by interference with biochemical and physiolog-
restriction). Animal models suggest that genes, including SIRT2,
ical homeostatic mechanisms. However, most chemicals undergo
which encodes a nicotinamide adenosine dinucleotide (NAD)-
some metabolism in vivo. Xenobiotic metabolism is the sum of the
dependent deacetylase, may mediate the effects of calorie restric-
physical and chemical changes that affect foreign substances in
tion. The activity of SIRT2, one of a class of silent information
living organisms from uptake to excretion.[21] Phase I reactions
regulator (SIR) proteins,[26] leads to physiological changes during
include oxidation, reduction, hydrolysis, hydration, and isomeriza-
calorie restriction in mammals.[27] We propose that these proteins
tion. Phase I metabolites may be substrates for phase II metabo-
regulate calorie restriction by sensing low calorie levels and trig-
lism, which generally involves conjugation of a large polar mole-
gering physiological changes linked to health and longevity.
cule such as a sugar with the substrate to yield a highly water-
The increased lifespan of growth hormone-deficient mouse
soluble product that can be excreted easily. These processes in-
models, although sharing some similarities with caloric reduction,
clude glycosylation (usually glucuronidation), sulphation, acetyla-
was not calorie-reduction mimetic. Instead, Bartke and Brown-
tion, methylation, amino acid conjugation, and/or glutathione con-
Borg[28] related this phenomenon to a range of effects, including
jugation.
reduced hepatic synthesis of insulin-like growth factor 1 (IGF-1),
Mixed function oxidases are quantitatively the most important
reduced secretion of insulin, increased hepatic sensitivity to insu-
group of enzymes involved in phase I xenobiotic metabolism.
lin actions, reduced plasma glucose, reduced generation of reac-
Cytochrome P450 (CYP) enzymes are the terminal oxidases that
tive oxygen species, improved antioxidant defences, increased
bind the substrate in phase I reactions. Glutathione S-transferases
resistance to oxidative stress, and reduced oxidative damage.
(GSTs) perform three main functions in phase II detoxication of
Other genes of interest, in the target of rapamycin (TOR) and the
electrophilic drug metabolites: (i) catalysis of reactions expected
insulin pathways, alter nutrient sensing and appear as major regu-
with glutathione; (ii) storage of protein; and (iii) glutathione
lators of both size and lifespan, at least in Drosophila.[29] Since
peroxidase activity. Their co-factor is the tripeptide glutathione.
many of these genes and their functions appear conserved in
There are multiple enzymes that are distinguished by substrate
different species, this information may be relevant to humans.
specificity, amino acid sequence, and immunoreactivity. Six clas-
ses of GSTs occur in humans. Asian populations have associated green tea consumption with
various effects including cardiovascular protection, anticancer ef-
The activity of the various XMEs will typically determine
fects, and maintenance of cognitive function in aging populations.
whether food components are efficacious and/or toxic at any given
These effects have been commonly attributed to the most abundant
dietary level. If there is a low level of metabolism, this will result
green tea polyphenol, (–)-epigallocatechin-3-gallate. Randomized
in enhanced plasma concentrations and exaggerated pharmacolog-
controlled clinical trails are currently considering whether supple-
ical response or response to food components. For example, there
mentation with green tea polyphenols can act to protect against or
are recognized effects of variation in XMEs in New Zealand that
slow progressive neurodegenerative disorders such as Parkinson’s
may significantly affect the implications of both diet and environ-
and Alzheimer’s diseases.[30] These diseases also have a known
ment. It appears that there are significant differences between the
genetic linkage.[31]
levels and nature of different polymorphisms in the CYP2A6 gene
between Maori and Caucasian populations,[22] and these may
2.2.2 Brain Function
affect the probability that Maori will become addicted to smoking.
These same polymorphisms or differences in levels of other CYP Mood, memory, and cognitive functions are profoundly influ-
enzymes may affect the probability that well cooked red meat is a enced by both genes and diet. The balance of the ratio of two
risk factor for various cancers, including prostate cancer.[23-25] classes of polyunsaturated fatty acids (PUFAs) – omega-3 (such as
α-linolenic acid) and omega-6 (such as linoleic acid) – may be
2.2 Lifestyle Effects critically important in these functions. Both types of PUFAs are
important components of practically all cell membranes, with
2.2.1 Anti-Aging substantial influences on intercellular communication and the
Slowing the aging process is considered desirable by many and expression of various genes. They have opposing physiological
is a potential endpoint of nutrigenomic food (i.e. food developed functions, whose balance is important for homeostasis and normal

© 2006 Adis Data Information BV. All rights reserved. Mol Diag Ther 2006; 10 (2)
Genomic Approaches to Nutrition Research
development. The PUFA composition of cell membranes is, to a
great extent, dependent on dietary intake, and the two classes
cannot be inter-converted in the human body. High intake of
omega-3 relative to omega-6 PUFAs may be especially beneficial
for cognitive function. For example, Kitajka et al.[32] and Barcelo-
Coblijn et al.[33] fed rats on diets that varied in the ratio of these
PUFAs. They described significant changes in the expression of a
number of genes, including those controlling synaptic plasticity,
cytoskeleton and membrane association, signal transduction, ion
channel formation, energy metabolism, and regulatory proteins.
This effect paralleled changes in the molecular composition of
phospholipids in the rat brain. Thus, the authors suggested that the
beneficial impact of omega-3 PUFAs on cognitive functions may
result from the combination of altered membrane architecture and
function, with alterations in gene expression profiles.
Less desirable effects on brain function may be modulated by
diet acting through opioid receptors to regulate (or fail to regulate)
food intake. For example, opioid peptides within the ventral
striatum regulate the response to highly palatable, energy-dense
foods, such as those containing chocolate. Repeated consumption
of such a food (Ensure® nutrition drink; Ross Products Division,
Abbott Laboratories, Columbus, OH, USA) by rats led to adaptive
behavior in a cognitive-motivational circuit, through the induction
of altered striatal enkephalin gene expression.[34]
Other authors have demonstrated the effects of other dietary
chemicals, including micronutrients, on opioid receptors. For ex-
ample, Bi et al.[35] studied the effect of retinoids on the expression
of the kappa opioid receptor gene (KOR, also known as OPRK1) in
normal and transgenic mice. They found that depleting the mouse
diets of vitamin A led to a range of effects, including upregulation
of the three isoforms of the endogenous KOR mRNA species.
Conversely, retinoic acid, the most potent ingredient of vitamin A,
suppressed the expression of all the three KOR isoforms and KOR
protein when added to a mouse embryonal carcinoma P19 culture
system.
2.2.3 Visual Function
Visual acuity is impacted both by genotype and diet. Human
newborns with PUFA deficiencies due to a gene defect are light
sensitive, through a reduction of retinal rod photoreceptors, but
supplementation with docosahexaenoic acid (DHA) can improve
visual acuity.[36] Marine oil or single-cell oil sources of long chain-
PUFA are being developed as human supplements to improve
visual function in both formula-fed and breast-fed human infants.
At least some of these effects occur through regulating the expres-
sion of genes associated with the developing retina and brain, and
may be associated with cognitive function. For example, Tanabe et
al.[37] considered two groups of male Wistar rats, one with and one
© 2006 Adis Data Information BV. All rights reserved.
105
without orally administered DHA over 12 weeks from weaning.
Half-way through the supplementation period, rats were trained to
do a maze, after which the expression of the transcription factor
FOS in the hippocampus was examined immunohistochemically.
The group that were DHA-supplemented showed fewer reference
and working memory errors and an increased number of FOS-
positive neurons in the CA1 hippocampus. Thus, the authors
suggested that increased FOS expression in the CA1 hippocampus
was causally associated with the DHA-induced improvement in
spatial cognition.
2.3 Multifactorial Chronic Diseases
2.3.1 Energy Homeostasis Regulation and Obesity
The control of food intake is profoundly affected by poly-
morphisms in either genes encoding taste receptors or genes
encoding a number of peripheral signaling peptides such as insu-
lin, leptin, ghrelin, cholecystokinin, and corresponding receptors.
Total dietary intake, and the satiety value of various foods, will
profoundly influence the effects of these genes.
A series of studies on the relative roles of diet and genotype in
maintaining energy homeostasis focused on polymorphisms at the
perilipin (PLIN) locus.[38-41] Perilipin is a major lipid droplet
surface protein that is located in adipocytes and steroidogenic
cells. The studies have considered the association with obesity
risk, and resistance to weight reduction, of five common SNPs
(PLIN 6209C/T, 10171A/T, 11482G/A, 13041A/G, and 14995A/
T) in subjects of different ethnic groups. It appears that the
combination of these alleles (the haplotype) is important, and these
haplotyes show different frequencies across ethnic groups. In
addition, carriers of the PLIN 11482A allele appear resistant to
weight loss on low-energy diets.
2.3.2 Cardiovascular Disease
In relation to diet and cardiovascular disease, several gene
polymorphisms for key proteins have been identified. These in-
clude variations in the genes encoding apolipoproteins (APO) E,
B, A-IV, and C-III (gene names APOE, APOB, APOC3, and
APOA4, respectively); the low-density lipoprotein (LDL) receptor
(LDLR); microsomal triglyceride transfer protein (MTTP); intesti-
nal fatty acid-binding protein (FABP2); cholesteryl ester transfer
protein (CETP); lipoprotein lipase (LPL); and hepatic lipase
(LIPC). The various polymorphisms determine variable responses
to diet and age, and lifestyle factors, such as cigarette smoking,
obesity, and alcohol intake, to modulate high-density lipoprotein
cholesterol (HDL-C) levels observed in the general population.[8]
These levels are considered key factors in cardiovascular disease
risk.
Mol Diag Ther 2006; 10 (2)
106
A significant number of human studies in various areas are
increasing the evidence for interactions between SNPs in such
genes and the metabolic response to diets. A study based in
Marseille, France, has enrolled 300 patients randomized into two
groups as part of the RIVAGE (RIsque VAsculaire Groupe d’E-
tude) intervention study.[42] The interactions between diets (Medi-
terranean or low-fat types vs standard Western type), risk factors
for cardiovascular disease, and gene polymorphisms are being
studied. Preliminary data show interactions between SNPs in
APOE (ε2, ε3, ε4), APOB (–516C/T), APOC3 (SstI), APOA4
(Ser347Thr), MTTP (–493G/T), FABP2 (Ala54Thr), CETP
(TaqIB), and LIPC (–480C/T) and diet. For example, APOE
genotype is influential on the levels of LDL-cholesterol and tria-
cylglycerols. LDL-cholesterol is also strongly influenced by
polymorphisms in both APOA4 and MTTP, while FABP2 geno-
type affects the level of triacylglycerols.
2.3.3 Cancer
Many of the same genetic polymorphisms and dietary patterns
that influence obesity or cardiovascular disease also affect cancer,
since overweight individuals are at increased risk of cancer devel-
opment.[43,44] More generally, however, it seems that the overall
probability that an individual will develop cancer results from a
balance of risk and protective factors, both of which appear to
interact with genetic polymorphisms. The way in which genetic
polymorphisms in XMEs are likely to affect the probability of
potentially carcinogenic foods enhancing cancer risk has been
discussed above (section 2.1). Such considerations make it likely
that associations, for example, of heavily cooked meats with
prostate cancer risk,[23,24] would be far more convincing if the
population had been stratified according to metabolic genotype.
Two further examples follow.
Reactive oxygen species are generated endogenously or
through exposure to such external agents as Helicobacter pylori
infection or smoking. Interactions with DNA may lead to the
formation of 8-hydroxydeoxyguanine, a lesion repaired by human
oxoguanine glycosylase 1 (OGG1). The OGG1 gene has a number
of polymorphic variants, among which the Ser→Cys polymor-
phism at position 326 (Ser326Cys) is thought to significantly
modify biological function. Tsukino et al.[45] considered the asso-
ciation between OGG1 Ser326Cys and gastric cancer risk, in
relation to other known risk factors of gastric cancer, using a case-
control study design in Japanese populations. Although the OGG1
326Ser/Ser genotype showed no association with either atrophic
gastritis or with cancer risk, both the Ser/Cys and the Cys/Cys
genotype showed an association with atrophic gastritis. The au-
thors suggested that patients with atrophic gastritis who also have
© 2006 Adis Data Information BV. All rights reserved.
Ferguson
the OGG1 326Cys allele might be more susceptible to induction of
gastric cancer through poor diets.
The efficacy of cancer-protective dietary factors is also modu-
lated by genotype. For example, high intakes of cruciferous vege-
tables, such as broccoli, cabbage or brussels sprouts, have been
associated with a reduced risk of cancer. There is reason to believe
that a major contributor to this chemopreventive effect is a high
content of glucosinolates whose metabolites, including isothiocy-
anates (ITC) and indoles, have the ability to modulate the activity
of XMEs. Although ITC may upregulate detoxification enzymes
such as GST, the efficacy of this process appears to be dependent
upon the isoform (i.e. GSTM1 or GSTT1). There are considerable
geographic differences in glucosinolate content of cruciferous
vegetables, and both levels and distribution of these are affected
by the growth season. Thus, Lampe and Peterson[46] point to the
considerable layers of complexity that affect the study of gene-diet
interactions and the difficulty of predicting the effect of dietary
intake at an individual or even population level, and associating
this with cancer risk in humans.
3. Public Acceptability
While this review points to potentially beneficial effects of
understanding how to relate diet and genotype, it must be ac-
knowledged that there are contrary views. For example, Lucock
and Yates[47] argue that such rationalization of dietary choices will
provide a negative selective pressure that could reduce the viabili-
ty of the human race. The specific example they use is of the B-
group vitamin, folic acid, whereby rational supplementation could
overcome the detrimental affects of polymorphisms in the MHTFR
gene. An undesirable side effect that could result from this would
be a gradual increase in the prevalence of genetic polymorphisms
that were otherwise detrimental to human health. This could also
be true for variants in genes associated with other human life-
threatening diseases. They raise the question “Are we affecting our
genetics – is this a case of human evolution in progress by altering
our diet?”[47]
Heel-prick tests for newborn babies already screen for common
genetic diseases in the population. In 10 years time, such test
procedures may well be expanded to screening the sample for
variations in large numbers of genes. At present we are not in a
position to establish which genes are of key importance, nor are
the genotyping methods able to span the genome. The methods are
already available to look at 500 000 genetic variants, on a screen
as small as two microscope slides.[6] In the meantime, a functional
assay using biomarkers of health may be the most viable approach.
At the moment, such methods are too costly to apply at a popula-
tion level, but as costs go down and understanding of their impor-
Mol Diag Ther 2006; 10 (2)
Genomic Approaches to Nutrition Research
tance goes up we are likely to be soon in a position where we can
apply these outside the limited research base that we are currently
using.
It is important to recognize that the biggest challenges of this
new field may not be scientific. Similar concerns will relate to the
other major -omics technologies. Training and communication
will be critical and may require significant interventions at the
level of both secondary school and university.[48,49] Initiatives such
as the Biotechnology Learning Hub (http://www.biotech
learn.org.nz/) may help to develop understanding at an early age.
The implications of genotyping for all the population are contro-
versial. For example, should insurance companies require this
information and raise the premiums for people with certain varia-
tions in their genes? One of the key challenges will be getting
individual and community acceptance of the need for individual-
ized nutrition. Communicating the importance to consumers will
require community awareness programs, likely to only be effective
after re-education programmes for and with cooperation of health
practitioners, including physicians, pharmacists, nutritionists, and
dietitians. This will all need to be done in the context of a socially
responsible, bioethical framework.
Acknowledgments
Nutrigenomics New Zealand is a research collaboration between the
University of Auckland, AgResearch, HortResearch, and Crop and Food.
However, the views expressed in this article are the author’s own, and not
necessarily that of Nutrigenomics New Zealand. The author thanks the Foun-
dation for Research, Science and Technology (FRST) for their financial
support of this work.
The author has no conflicts of interest that are directly relevant to the
content of this review.
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Correspondence and offprints: Dr Lynnette R. Ferguson, Discipline of Nutri-
tion/ACSRC, School of Medical Sciences, Faculty of Medical and Health
Sciences, The University of Auckland, Private Bag 92019, Auckland, New
Zealand.
E-mail: l.ferguson@auckland.ac.nz
Mol Diag Ther 2006; 10 (2)