Introduction
A connection between food and health has been known to exist since the dawn of history. However, the
advent of modern science refined this concept to an understanding that our health depends upon
obtaining certain nutrients in specific quantities. This heralded the concept that improper nutrition may
directly lead to disease states and spawned dozens of professions and fields of research that focus on
the relationship between nutrition and health. This in turn has led to an exponential growth in our
understanding of human nutrition and to the creation of dietary recommendations such as the Institute
of Medicine’s Dietary Reference Intakes (DRI’s). Recently, advances in genetic technologies such as the
sequencing of the human genome have begun to revolutionize the field of nutrition and radically
altering the direction of research. Hundreds of genetic variants that predispose individuals to common
diseases have been identified and as research continues the number of known disease-predisposing
polymorphisms will multiply. However, human health does not solely depend on our genes but also on
our environment. Understanding how these two factors interact is paramount to disease prevention and
our diet has been identified as one of the most important factors to interact with our genes.1 Hence the
creation of a new field within nutrition, nutrigenetics.
Nutrigenetics aims to understand how the genetic makeup of an individual coordinates their response to
diet.2 Therefore, nutrigenetics considers the genetic polymorphisms of an individual and how these
variations interact with disease risk and diet. As research progresses, nutrigenetics will produce
information that will assist clinicians in identifying the optimal diet for a given individual, i.e.,
personalized nutrition. If these goals are to be realized the field of nutrition must move beyond
epidemiological studies using genetically uncharacterized populations and incorporate more complex
models that account for cellular and molecular biology coupled with biochemistry and genetics.3
The burgeoning field of nutrigenetics has already discovered dozens of “candidate gene variants” which
may confer a heightened sensitivity to specific nutritional factors and are known to modulate disease
risk.3-5 Some of these genes have functionally important variations that are highly prevalent in the
population. Genetic variation within these genes may explain discrepancies in previous epidemiologic
studies that sought to find interactions between disease risk and diet. These polymorphisms also have
the potential to alter individual optimal nutrition based upon genotype and in time their
Given the enormous potential of nutrigenetics to redefine optimal nutrition and to create truly
personalized nutrition, the field of dietetics must find a way to incorporate these advances into nutrition
therapy. Commercial nutrigenetic testing is rapidly rising in popularity and decreasing in price.3
However, these tests used by consumers on their own lack the credibility that validated genetic tools in
the hands of licensed nutrition professionals such as registered dietitians (RDs) can provide. RDs may
view commercial nutrigenetic tests as tools or as competitors depending upon point of view. However, if
the use of genetic information is to be of practical value in clinical practice, dietitians must be familiar
with genetic terminology and stay reasonably informed of current nutrigenetic research. Furthermore,
dietitians who seek to utilize genetic testing in clinical practice must have a firm grasp upon the moral,
ethical, and legal implications of inherent to genetic testing.
This paper will examine the current research surrounding five “candidate gene variants” and discuss
how particular polymorphisms in these genes may affect clinical nutrition therapy. To provide a context
for this discussion the following case scenario was constructed:
A woman comes to a private dietetic practice seeking help interpreting the results of a
genetic test she took after seeing an advertisement online. She is particularly concerned
about her risk of breast cancer. Her mother recently died of the disease and the results
mention breast cancer risk. She would also like help losing a “few extra pounds” she has
gained over the past several years. She is a healthy 35 year old female who is 177cm tall,
weighs 82kg (BMI= 26.2), and who exercises moderately. Her genetic test results have
revealed the following genetic polymorphisms: APOA2 -265 CC, DHFR -ND, MGMT -427
AG, CAT -262 CT APOA2 -265 CC, DHFR -ND, MGMT -427 AG, XRCC1 -26304 CT, CAT -262
CT.
Review of genetic polymorphisms
APOA2 -265CC
The APOA2 gene is a member of the apolipoprotein multigene superfamily, which includes genes
encoding soluble apolipoproteins such as APOA1 and APOA4.6 The gene encodes the high density
apolipoprotein A-II (APOA2) which is the second most abundant component of high-density lipoprotein
(HDL) particles. APOA2 has been shown to be a regulator of triglyceride metabolism through its
modulation of lipoprotein lipase activity and the high-density lipoprotein proteome.7,8 It has also been
saturated fat intake.7,8 In animal models overexpression of APOA2 results in hypertriglyceridemia,
obesity, and insulin resistance9,10; however, its exact role in humans remains controversial.11-14
A specific APOA2 promoter variant, a T→C transition at position -265 (rs no. 5082), has been shown by
two independent studies to be associated with a 30% drop in basal transcription activity.11,12 A
relationship between this variant and obesity has been clearly demonstrated. In an initial study, Corella
et al found individuals that were homozygous for the APOA2-265C allele (CC) had statistically higher
body mass index (BMI) than did carriers of the T allele (TC or TT) (OR=1.70, 95% CI: 1.02-2.80, P =
0.039).15 CC individuals were also found to have significantly higher total energy, total fat, and total
protein intake than T allele carriers. This research was then expanded and further confirmed through
replication of the gene–diet interaction in three separate US populations (including Whites and Puerto
Ricans), an elderly Spanish population, and in Asian Indians living in Singapore.16,17 In these studies, the
APOA2 m265 T→C genotype was consistently associated with increased BMI or obesity in the context of
high saturated fat intake. Among the US populations, individuals with the CC genotype and saturated fat
intake >22g/day had a statistically significant increase in BMI ranging from 4.3% to 7.9%. A meta-analysis
pooling data from these populations found the high saturated fat group (>22g/day) showed a
statistically higher OR of obesity for CC homozygotes (OR=1.84, 95% CI: 1.38- 2.47, P=.001). However, in
the low–saturated fat group, no increased OR for obesity was found for CC homozygotes (OR=0.81; 95%
CI: 0.59-1.11; P=.18). This gene-diet interaction was again confirmed in the Mediterranean and Asian
populations. The prevalence of the CC genotype was 15% in the Mediterranean population, ranged from
10.5% to 16.2% in the US populations, and was only 1.6% in the Asian population.17
Much like the overall function of APOA2 the underlying mechanism of the relationship between APOA2
and obesity remains elusive. Smith et al examined this relationship with particular focus on patterns of
eating and ghrelin, a hormonal regulator of food intake, in a Mediterranean population.18 Homozygous
(CC) individuals were found to be more likely to exhibit a behavior identified as an obstacle for weight
loss (‘Do you skip meals’, OR=2.09, P=0.008) and less likely to exhibit the protective behavior of ‘Do you
plan meals in advance’ (OR=0.64, P=0.034). A lower saturated fat diet was associated with lower ghrelin
in CC carriers which could be theorized to be responsible for lower energy intake and BMI; however, the
interaction between saturated fat and APOA2 genotype was only found to be marginally modulated by
plasma ghrelin (P=0.056).
Despite the fact that the mechanism for the association of APOA2 the gene with saturated fat intake and
any other locus. Given the increased risk of obesity associated with a high saturated fat diet among
homozygous CC carriers, dietary recommendations for these individuals should emphasize avoidance of
saturated fats. Homozygous individuals may benefit more from this diet restriction than others and
given the possible connection to hormonal regulators of appetite may find weight loss through a low
saturated fat diet easier to adhere to than other methods. Ultimately, the gene-diet interaction will
need to be further elucidated through intervention studies; however, based on the available evidence
high saturated fat diets are a particular health risk for APOA2 265C carriers.
MGMT 427 A→G
The MGMT gene produces the DNA adduct repair molecule O6-methylguanine DNA-methyltransferase
(MGMT) and is the only known gene to play a critical role in the DNA direct reversal repair (DRR)
pathway, a cellular defense against alkylating agents.19,20 Alkylating agents are ubiquitous and are
produced from both endogenous sources (nitrosation of amines) and exogenously (cigarette smoke, fuel
combustion products).21-23 MGMT repairs DNA adducts caused by alkylating agents via the irreversible
transfer of a methyl adduct to its active site (Cys145 in human MGMT).24 It has the highest affinity for
the potent mutagenic and cytotoxic O6-Methylguanine (O6MeG) which when left unrepaired can lead to
cell cycle arrest, sister chromatid exchanges, chromosomal aberrations and apoptosis.25 MGMT can also
repair a variety of other O6-alkyl lesions including ethyl, chloroethyl, pyridyloxobutyl butyl, benzyl
adducts, and O4-methylthymine.26-32
MGMT is epigenetically silenced in many human cancers and evidence has shown that MGMT plays a
role in decreasing cancer susceptibility in humans.33-35 Several studies have examined the association
between MGMT polymorphisms and risk of lung cancer, melanoma, and glioblastoma36-43 although the
results have been inconsistent and there is little data on how these polymorphisms affect functionality.
These inconsistencies could be explained through a gene-diet interaction present in certain
polymorphisms in the MGMT gene. The single nucleotide polymorphisms (SNP), MGMT-427 A→G, codes
for a non-conservative amino acid substitution (Ile143Val) which is located almost adjacent to the alkyl
acceptor Cys145 in the active site of the MGMT.36 An association between fruit and vegetable
consumption and reduced breast cancer risk has been demonstrated among women with at least one
variant allele for codon 143. Shen et al used biospecimens from the Long Island Breast Cancer Study to
examine how the relationship between several MGMT polymorphisms and breast cancer may interact
with dietary antioxidants and cigarette smoking.44 The AG or GG genotype was found in 22.1% of breast
risk of breast cancer found for any genotype, among women with at least one variant allele for codon
143 (AG or GG genotype) who consumed ≥35 servings of fruits and vegetables per week a significant
reduction in breast cancer risk was found. (OR=0.6, 95% CI=0.5–0.9, compared to <34 servings per week
and AA genotype). The OR for the AG+GG group consuming <34 servings was 1.2 (95% CI: 0.9–1.5),
which represents a 60% reduction in risk. Additionally, similar reductions in risk were observed for high
dietary α-carotene (>267.8µg/day) and supplemental β-carotene (>3817.38µg/day) (OR=0.6, 95% CI:
0.4–0.8 and OR=0.7, 95% CI: 0.5–1.0, respectively, as compared to AA genotype and low intake). The
data also supported an additive interaction between the 143 G-allele combined with high intake of fruits
and vegetables (ICR=-0.5; 95% CI: -0.9,-0.1), and high intake of dietary a-carotene (ICR=-0.6; 95% CI: -0.2,
1.1), however the additive interaction for βcarotene was not statistically significant (ICR= 0.1; 95% CI:
-0.5, 0.2). A significant inverse association between high intake of fruits and vegetables and
postmenopausal breast cancer has been previously demonstrated45; however, this study demonstrates
this protection is partially dependent upon MGMT 143 G-allele status.
The gene-diet interaction between the MGMT-427 A→G polymorphism and breast cancer risk has yet to
be confirmed in among separate populations and the exact mechanism of this interaction remains
unclear. However, based on the evidence from a large population study, women who are MGMT 143
G-allele carriers may significantly reduce their breast cancer risk by consuming ≥35 servings of fruits and
vegetables per week, perhaps by as much as 60%.44 This risk reduction may be partially due to increased
α-carotene, and perhaps increased β-carotene, in the diet. Given this, women with the MGMT 143 G
allele should be encouraged to consume at least 5 servings of fruits and vegetables per day and to
include at least one serving of yellow-orange and dark green vegetables to provide sufficient α-carotene
and β-carotene.
CAT -262 CT
The CAT gene encodes the catalase enzyme (CAT), a primary protector of cells against the damaging
effects of reactive oxygen species (ROS). CAT is located in the peroxisomes of nearly all cells and can
reduce a variety of reactive species, especially the common ROS hydrogen peroxide. A C→T SNP at
position 262 has been shown to reduce enzyme activity46 and has been found to be associated with
increased breast cancer risk.47 Ahn et al studied women in the Long Island Breast Cancer Study Project
and found the high-activity catalase CC genotype was associated with an overall 17% reduction in risk of
breast cancer compared with having at least one variant T allele (OR=0.83, 95% CI: 0.69- 1.00). The CC
interact with vegetable and especially fruit consumption and was greater among women who did not
use vitamin supplements. An increased reduction of 29% (OR=0.71, 95% CI: 0.54, 0.92) was found
among women with the CC genotype and higher consumption of fruits (>10 servings/week), compared
with those with at least one T allele (TC and TT combined) and lower fruit consumption levels. The OR
for CC genotype with ≤10 servings per week was 0.87 (95%CI: 0.68-1.11) representing a 16% reduction in
risk through diet. The effect of dietary vitamin C, vitamin E, and β-carotene was also examined. A 26%
reduction in risk among women with CC genotypes and a higher consumption of dietary vitamin C
(>133.7 mg/day), compared with those with at least one T allele and lower consumption was found
(OR=0.74, 95% CI: 0.57, 0.97), a 17% lower risk than CC carriers with lower vitamin C intake. A similar
reduction in risk of 19% was found for CC genotypes consuming >7.87 α-tocopherol equivalents per day;
however, the association failed to reach significance (OR = 0.81; 95% CI: 0.61-1.08, compared to 1 or
more T allele with lower intake). Surprisingly, when β-carotene was examined reduced risk from high
consumption (>2,673 µg/day) was not only found in CC carriers but also among the combined TC and TT
genotype groups. Furthermore, the reduction in risk was greatest among TC and TT carriers who
consumed >3,152.48 µg of β-carotene per day from both dietary and supplement sources (OR = 0.66,
95% CI: 0.49-0.89). This represents a substantial 34% reduction in risk compared to TC and TT carries
with lower β-carotene intake. No other significant reduction of risk from total antioxidant intake beyond
that conferred by dietary sources alone was found and the lowest risk observed was for women who
were high fruit consumers (>10 servings/week), had CC genotypes, and who did not use supplements
(OR = 0.59, 95% CI: 0.38, 0.89).47
More recently, Li et al conducted a similar nested case–control study of postmenopausal women from
the Cancer Prevention Study-II Nutrition Cohort.48 While similar trends were found, Li et al. did not
observe a statistically significant decreased risk of breast cancer with the CAT CC genotype (OR=0.83,
95% CI: 0.66–1.04). In addition, the interaction between vegetable and fruit intake and genotypes was
only borderline significant, with CAT CC genotype being inversely associated with breast cancer risk only
among women with higher consumption of fruits and vegetables. CC carriers were actually found to be
at increased risk compared to heterozygous carriers when consuming low amounts of fruits and
vegetables (OR=1.33, 95% CI: 0.89, 1.99). The relationships between breast cancer risk and genotypes
was also assessed by low and high intakes of dietary vitamin C, vitamin E, and β-carotene, both from
dietary and supplement sources. In all cases, associations with breast cancer risk were either not found
or attenuated by vegetable and fruit intake. This study had a smaller sample size and included only
The gene-diet interaction between the CAT gene, breast cancer, and fruit and vegetable consumption
remains unclear. As is the case with nearly all gene-diet associations, further research is warranted and
the association must continue to be study in context of multiple populations. Based on the results of the
study by Ahn et al. , the more common CAT 262 CC carriers may have an overall reduced risk of breast
cancer. Both studies discussed indicate a trend toward a reduced risk of breast cancer for all women
when consuming a diet high in fruits and vegetables. This effect may actually be highest among the
lower risk CC carriers or stated simply, a way to make their good genes even better. For the less
common heterozygous genotype women, a diet high in fruit and vegetables may be a way to mitigate a
possible increased risk with the nutrient β-carotene being of particular importance. Based on the results
of the Ahn et al study women with the CT or TT genotype may reduce their risk of breast cancer by 34%
through obtaining >2,673 µg of β-carotene per day from diet and supplemental sources. In all other
cases supplemental antioxidants were not found to confer any protective benefit beyond that of diet.
Consequently, all women should be counseled to consume at least 5 servings of fruits and vegetables
per day in the context of breast cancer risk reduction. Additionally, women with CT or TT genotype for
the CAT gene should be strongly encouraged to eat at least one serving of dark green or yellow-orange
vegetables per day.
XRCC1 26304C→T
The X-ray repair cross complementing group 1 (XRCC1) gene plays an important role in DNA base
excision repair. This process is critical for the molecular repair of DNA damage caused by DNA adducts,
single strand breaks, and replication errors. Without this process, oxidized lesions and non-bulky
adducts may block DNA replication or cause cytotoxic mutations and genetic instability possibly leading
to tumor formation.49 A common variant 26304C→T has been shown to cause a non-conservative amino
acid substitution (Arg194Trp) and may affect protein structure and function.50,51 Although studies on
how the variant may affect DNA repair have had mixed results, some epidemiologic studies have found
the variant it is associated with reduced risk of many types of cancer including: bladder, breast, lung,
and stomach cancer.52-54 Studies examining breast the association between the 26304C→T variant and
cancer risk specifically however have failed to reach a consensus, with some studies showing risk
reduction and some showing no association.55-66
Using the Long Island Breast Cancer Study Project, Shen et al. examined the relationship between the
XRCC1 -26304 C→T polymorphism; breast cancer susceptibility; and intake of fruits, vegetables, and
variant as a whole; however in individuals with at least one copy of the 194Trp allele, there was a
significant reduction in risk associated with high intake of fruits and vegetables (≥35 half-cup servings/
week) (OR=0.58; 95% CI: 0.38-0.89) as compared to individuals with the Arg194Arg genotype and low
intake of these factors. This translates to a considerable 55% reduction in breast cancer risk among
Arg/Trp and Trp/Trp women through dietary factors (OR=1.13, 95%CI: 0.83-1.55 for Arg/Trp and Trp/Trp
with <35 servings/week). A reduction in risk was also found among individuals with at least one 194Trp
allele with high intakes (dietary and supplemental) of Vit C (>131.1 mg/d) (OR= 0.63, 95% CI: 0.43-0.93)
and Vit E (>29.1mg/day) (OR=0.65, 95% CI: 0.44-0.96). Corresponding to a 60% risk reduction for Vit C
and a 57% risk reduction for Vit E (OR=1.23, 95%CI: 0.88-1.73; OR=1.22, 95% CI 0.88-1.70; for at least 1
194Trp allele and lower Vit C and Vit E intake, respectively) After controlling for other sources of
antioxidants (diet and supplemental), these associations remained essentially unchanged. For high
β-carotene (>3817.3µg/d) and α-β-carotene (>267.8µg/d), similar significant reductions were also reported;
however, after adjustment for intake of fruits and vegetables, the ORs were no longer significant. The
incidence of at least one 194Trp allele in the control group was 6.72% which is similar to other reported
incidences (5-7%) from American and European Caucasian women.55,56,58 However, the frequency has
been reported to be much higher (34%) among Asian women. 56,57
A similar study was done by Patel et al. using the American Cancer Society Cancer Prevention Study II
(CPS-II) Nutrition Cohort.68 Unlike the Shen et al. study, a significant reduction in breast cancer risk was
found for Trp194 carriers (Trp/Trp and Trp/Arg) when compared with non-carriers (Arg/Arg) (OR=0.62,
95% CI: 0.40-0.95). In this study, the association between XRCC1 polymorphisms and breast cancer risk
was not found to significantly interact with fruit and vegetable intake. Although this study had a very
large sample size, a significant limitation is that most participants were aged 50 to 74 years at
enrollment. As was the case with evidence surrounding the CAT diet-gene interaction, this may decrease
the ability of the study to detect gene-diet interactions caused earlier in life. The Shen et al. study did
not report data based on menopausal or age status.
Inconsistencies in the research regarding the XRCC1 26304C→T variant and its association with breast
cancer as well as a possible gene-diet interaction continue to exist signaling the need for continued
research and possible additions to the model. The gene-diet interaction found by Shen et al. was not
reproduced in a subsequent study on a separate population; however, significant differences exist
within the study populations. Based on the data from the study by Shen et al., women with at least one
servings of fruits and vegetables per day. Additionally, the vitamins A and E appear to be of particular
importance and 194Trp carriers may also reduce breast cancer risk by consuming >131.1 mg of vitamin C
and >29.1 mg vitamin E per day from diet and supplemental sources combined. This level of vitamin C
may be obtained through diet given at least 5 servings of fruits and vegetables per day, especially if a
variety of colorful fruits and vegetables are eaten. However, obtaining >29.1mg of vitamin E (over twice
the RDA) from dietary sources alone is difficult. As such, women with the 194Trp allele may benefit from
vitamin E and perhaps vitamin C supplementation in the context of breast cancer risk reduction.
DHFR ND
The DHFR gene encodes the enzyme dihydrofolate reductase (DHFR) which plays an essential role in
single-carbon metabolism by converting dihydrofolate (DHF) into the active tetrahydrofolate (THF) form.
The reduction of folate to the THF form is required for DNA synthesis and is essential for cellular
metabolism and growth.69 Dietary folate is absorbed predominantly in the fully reduced 5-methyl-THF
form although other less reduced forms are also found. On the other hand, folate found in supplements
is absorbed in the fully unreduced (e.g., folic acid) form and must be acted upon by DHFR to be
metabolically active.70,71 The Food and Drug Administration began fortifying foods with folic acid in
January of 1998 to prevent neural tube defects; however, folate has also been investigated for its
potential anti-carcinogenic role in breast cancer. Several large epidemiologic studies have found that
adequate folate intake reduces the risk of breast cancer72-74; however, results have been mixed75,76 and a
recent study found folic acid supplementation of >400 µg/day was associated with a 20% increase in
breast cancer risk in postmenopausal women.77 These conflicting results may be due in part to genetic
polymorphisms in the DHFR gene that effect folate utilization from supplement use and in turn also play
a role in breast cancer risk.
A 19 base pair deletion (19-bp) polymorphism in intron 1 of the DHFR gene has been identified78 and
found to be homozygous in about 1 in 5 Americans.79 The 19-bp allele may affect transcription factor
binding and gene regulation thus affecting overall enzyme function.80 Xu et al. utilized the Long Island
Breast Cancer Study Project to investigate the functionality of the polymorphism and its effect on breast
cancer risk.80 The DHFR 19-bp allele was found in 40% and 42% of the cases and controls, respectively.
Overall, the DHFR 19-bp deletion polymorphism was not significantly associated with breast cancer risk.
However, examination of the association between the DHFR polymorphism and breast cancer by
multivitamin (MVI) use revealed the 19-bp -/- genotype and multivitamin use was associated with a 52%
association was dose-dependent and represented a 57% increase in risk associated with multivitamin
use amongst individuals with the 19-bp -/- genotype (OR for non-MVI= 0.95, 95%CI: 0.66-1.36). The -/-
genotype was found in 19.7% and 18.7% of controls, respectively. Approximately half (51.2%) of the
study population used multivitamins on a regular basis (>1 time/wk) over the 10–15 year period before
enrollment, however multivitamin use was not significantly associated with the risk of breast cancer
overall (OR=0.95; 95% CI: 0.83-1.10). In contrast, no significant interaction between the DHFR 19-bp
deletion polymorphism and dietary or total folate intake was found. Using a small sample, Xu et al the
effect of the 19-bp genotype on DHFR functionality and found a significant dose-dependent relation (P
for trend=0.001) between DHFR expression genotype. Compared with the 19-bp +/+ genotype, the +/-
and -/- genotypes had a 2.4-fold and 4.8-fold increase in mRNA levels, respectively. The authors
theorized the 19-bp segment may lie within an inhibitory element of the DHFR gene and on removal
gene expression is up-regulated causing higher DHFR activity. This may lead to depletion of the
5,10-methylene-THF pool and change the balance of single-carbon metabolism in favor of DNA synthesis at
the expense of methyl supply. This could then lead to aberrant DNA methylation, which has been
associated with breast carcinogenesis.81
These findings support more recent data from the Prostate, Lung, Colorectal, and Ovarian Cancer
Screening Trial77 that indicated too much folic acid from supplements may be procarcinogenic and
demonstrate a gene-diet interaction that may be partially responsible. Additional studies will need to be
conducted to confirm the association in separate populations and to establish recommended levels of
folic acid intake based on DHFR 19-bp genotype. However, based on the data from the Xu et al. study,
multivitamins are detrimental to the health of 19-bp -/- women from the standpoint of breast cancer
risk. Given the function of the DHFR gene, this may be due to folic acid content of multivitamins and as
such 19-bp -/- women may decrease their risk of breast cancer from avoiding all supplements containing
high levels of folic acid. The implication of folic acid fortification in food for this subset of women
remains unclear; however, until further research is conducted women with the DHFR 19bp -/- genotype
should avoid exceeding the RDA for folate (320 µg/day for non-pregnant women), especially from
supplemental and fortified sources.
Putting it all together
With the exception of the APOA2 gene, the gene-diet interactions examined above have yet to be
reproduced in multiple populations. As such, the interactions must be viewed as unconfirmed
saturated fat, which has been replicated in three separate populations, needs to be more closely
examined in intervention studies. Given this, the expected benefit of following a low saturated fat diet
or any diet recommendations based upon the gene-diet interactions examined remains unclear.
However, this is not to suggest that the genotypic information obtained by the woman in the sample
case is of no clinical utility. The large size of the risk reductions seen in the studies reviewed indicates an
enormous potential for benefit through optimization of diet. Clinicians must assess the relative strength
of the current evidence verses any potential harm a particular diet intervention may present. In most
cases, the dietary intakes responsible for reduced risk in the gene-diet interactions examined are already
in agreement with current dietary recommendations. For instance, eating at least 5 servings of fruits and
vegetables per day is consistent with the USDA’s 2010 Dietary Guidelines for Americans’ message of
making half your plate fruits and vegetables.82 A diet that limits saturated fat is also certainly congruent
with the DRI of for saturated fat which simply advises individuals to consume an amount as low as
possible while still maintaining a nutritionally adequate diet.83 In such cases where nutrigenetic
optimization is in line with the current standard of care, clinicians may use nutrigenetic information as
further evidence for the benefit of diet modification and as a way to personalize recommendations. In
some cases nutrigenetic information will be able to provide more detailed recommendations on specific
nutrients while still falling with the current standard of care. Whether these personalized and specific
recommendations will translate into improved clinical outcomes is unknown. Clinicians still must find a
way to translate dietary guidance into a form that is understandable and actionable for individuals. The
benefits of nutrigenetic diet optimization are just as dependent on compliance as any other
intervention.
Nutrigenetic studies may also find that certain individuals benefit from dietary intakes that fall outside
of current dietary guidelines. It is probable that these types of gene-diet interactions exist within the
population; however, clinicians must be careful before implementing these recommendations in clinical
practice. Until intervention studies are conducted the true outcome of any such intervention will remain
unknown no matter how compelling the epidemiologic data. Multiple genes interact with any given
nutrient and the human biological system remains too complex to accurately predict outcomes before
clinical trials have been conducted. This represents a significant hurdle for the field of nutrigenetics to
overcome due to the cost and difficulty of conducting long term diet modification intervention studies.
Never the less, clinicians must seek to do no harm first and be wary of making dietary recommendations
Returning to the test case, based upon the research reviewed a number of dietary recommendations
could be made. First, she may reduce her risk of obesity from following a low saturated fat diet
(<22g/day) due to her APOA2 -265CC genotype. Given the possible connection of this gene-diet
interaction to hormonal regulators of appetite, if her diet was previously high in saturated fat this diet
modification may also help her to lose weight. Second, the data indicate she may significantly reduce
her risk of breast cancer by consuming at least 5 servings of fruits and vegetables per day. Due to her
MGMT 143 G allele and CAT -262 CT genotype, she could possibly further reduce her breast cancer risk if
she included at least one serving of yellow-orange or dark green vegetables per day to provide sufficient
α-carotene and β-carotene. The goal for β-carotene would be >2,673 µg/day. The DRIs’ estimated
average requirement (EAR) for vitamin A is 500 µg of retinol activity equivalents (RAEs) per day which
would translate to 6000 µg of β-carotene making this recommendation well within current guidelines.83
Additionally, based upon her XRCC1 26304C→T polymorphism she may also reduce her breast cancer
risk by consuming >131.1 mg of vitamin C and >29.1 mg vitamin E per day. This amount of vitamin C
would be obtainable within the five daily fruits and vegetables, especially if a variety of colors was
included. This level is above the EAR of 60 mg per day but well below the DRIs’ Tolerable Upper Intake
Level (UL) of 2,000 mg. Similarly, 29.1 mg of vitamin E is above the EAR of 12mg per day; however, it is
much lower than the UL of 1000mg.83,84 Unlike the recommended level of vitamin C however, this
amount of vitamin E is not easily obtainable in the diet and may require supplementation. This
represents another layer of complexity for the clinician and issues such as availability and cost verses
benefit and risk must be considered. Finally, avoiding excess folic acid and especially folic acid containing
supplements may decrease her risk of breast cancer based on the evidence surrounding the DFFR 19-bp
-/- genotype. Given that the case is still of reproductive age, one must also consider the risk of neural
tube defects however. A review of the client’s pregnancy risk could be the deciding factor in determining
the most appropriate level of folate to recommend. Regardless, the client could be safely advised not to
exceed the DRI of folic acid equivalents from dietary and supplemental sources combined (320 mg for
non-pregnant women and 520 mg for pregnant women per day).82
The expected benefit from adherence to the recommendations is difficult to predict given the lack of
intervention studies. While high saturated fat diets are associated with obesity risk in APOA2 -265CC
individuals, it remains unknown if low saturated fat diets will be effective at producing weight loss.
Based on the evidence however, one could assume that the case’s risk of gaining weight and becoming
obese would be significantly reduced (OR=1.84 vs OR=0.81) by consuming <22 g of saturated fat per day.
polymorphisms that interact with fruit and vegetable consumption and breast cancer risk. These
polymorphisms may interact with each other to produce even greater reductions in risk than seen in the
research reviewed. Given the significant reductions in the studies reviewed however (60% for MGMT
427 A→G, 16% for CAT -262 CT, and 55% for XRCC1 26304C→T), a large benefit may be expected from
diet modification if the client previously had low fruit and vegetable consumption. Increased fruit and
vegetable consumption is known to have other health benefits as well, although epidemiologic data on
the overall association between fruits and vegetables and breast cancer risk remain unclear.85 Finally,
the research reviewed found a 57% increase in breast cancer risk associated with MVI use among 19-bp
-/- genotype individuals. Given this, if the client regularly took a folic acid containing MVI, a significant
reduction in risk could be expected from discontinuing its use. Again however, this is an assumption as
intervention studies have not been conducted. The chance of a woman having invasive breast cancer
some time during her life is a little less 1 in 8 and the chance of dying from breast cancer is about 1 in
35.86 Although many of these dietary interventions may seem simple, the potential benefit is profound
especially given the clients family history of breast cancer.
Implementation
As seen above, in many cases, nutrigenetic diet optimization will require individual nutrients to be
obtained in specific quantities. This represents a significant challenge for clinicians to translate these
types of recommendations into actionable and consumable advice. Tracking single nutrient intake
requires analyzing all dietary intake through reference food databases. Adjusting intake to meet specific
requirements would then require careful planning of intake each day. This is arduous and unrealistic for
clinicians and incompatible with societal norms for clients so novel tools must be utilized to increase
adherence with these types of nutrient recommendations. Computer programs that track intake could
provide information directly back to the client about the dietary adequacy of any single nutrient and
help to plan meals to better meet recommendations. These programs could be available online or even
through smart phones although they would still require the user to input all dietary intake and to
preplan meals. If clients could be persuaded to track and modify their intake using such programs for
only a few weeks or even days, significant progress toward meeting nutrigenetic goals could be made. If
these dietary changes could then be incorporated into a client’s normal dietary routine improvements in
meeting specific nutrient requirements could be made without permanent tracking of dietary intake. To
realize the full potential benefits of nutrigenetic diet optimization however, individuals would need to
individuals may find this level of attention to diet incompatible with their lifestyle and outside of societal
norms. This represents a significant challenge in implementing nutrigenetic diet optimization and
realizing the goal of personalized nutrition. In this regard however, nutrigenetics is not alone. Creating
meaningful behavior change given societal constraints is a crux for all who seek to prevent disease
through behavior modification. The benefit of nutrigenetics however, is that the underlying guidelines
upon which dietary modification are based would be personalized for each client’s genotype. In other
words, nutrigenetics aims for a more accurate ideal. This may allow for clients to achieve greater benefit
from proportionally equal behavior modification and improve clinical outcomes.
Conclusion
Recent advances in genetic technologies are in the process of reshaping our understanding of nutrition
and have spawned the new field of nutrigenetics. The inclusion of genetic data in nutrition research
enables the complex human biological system, which includes cellular biology and molecular biology as
well as biochemistry and genetics, to be more accurately approximated. Nutrigenetics utilizes data
about the genetic makeup of an individual to better understand their response to diet. As research
advances, nutrigenetics may radically alter our understanding of what constitutes an optimal diet for a
given individual and creates the possibility of personalized nutrition. Dozens of gene-diet interactions
have already been found in large epidemiologic studies that radically alter disease risk based upon
dietary factors. As such, nutrigenetics represents a powerful new tool for clinicians and nutrition
professionals such as registered dietitians.
However, if this tool is to be adeptly utilized, clinicians must expand their scope of knowledge to include
an understanding of basic genetic concepts as well as the practical, ethical, and legal implications of
obtaining and using genetic data for nutrition guidance. They must also stay abreast of current
nutrigenetic research, especially given the rise of direct to consumer nutrigenetic testing that may be
grounded more in sales than in science. This paper has examined the research surrounding five
proposed gene-diet interactions and explored how genotypic data on these genes may affect clinical
practice. While more research is needed to confirm these gene-diet interactions, based upon the
evidence examined certain individuals may significantly reduce their risk of obesity and breast cancer
through nutrigenetic diet optimization.
In the future, nutrigenetic data may become indispensable to the field of clinical nutrition and dietetics;
advice must be developed. The utility of nutrigenetics is in providing the best target to aim for. By
improving the underlying dietary recommendations clinicians may be able to improve outcomes without
requiring increased behavior change. It is also possible that individuals may be more apt to change their
behavior if they receive recommendations that are based upon their unique genetic makeup. However,
the challenge of changing dietary behavior to modulate disease risk will remain.
While nutrigenetics is still in its early stages, significant and clinically relevant findings have already been
made. Future research will undoubtedly increase our understanding of how our genes interact with our
diet and provide a more accurate assessment of optimal diet for any given individual. This will provide
an invaluable tool for nutrition professionals such as registered dietitians and has the potential to
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