July 2007: 301–315
Lead Article
Personalized Nutrition: Nutritional Genomics as a Potential
Tool for Targeted Medical Nutrition Therapy
Sina Vakili, BS, and Marie A. Caudill, PhD, RD
An emerging goal of medical nutrition therapy is to
tailor dietary advice to an individual’s genetic profile.
In the United States and elsewhere, “nutrigenetic”
services are available over the Internet without the
direct involvement of a health care professional.
Among the genetic variants most commonly assessed
by these companies are those found in genes that
influence cardiovascular disease risk. However, the
interpretation of DNA-based data is complex. The
goal of this paper is to carefully examine nutritional
genomics as a potential tool for targeted medical
nutrition therapy. The approach is to use heart health
susceptibility genes and their common genetic vari-
ants as the model.
Key words: heart health susceptiblity genes, medical
nutrition therapy, nutritional genomics
© 2007 International Life Sciences Institute
doi: 10.1301/nr.2007.jul.301–315
INTRODUCTION
Nutritional genomics is comprised of nutrigenetics
and nutrigenomics, terms that are loosely defined and
often used interchangeably. In this paper, “nutrigenetics”
refers to genetically determined differences in how indi-
viduals react to specific foods, while “nutrigenomics”
refers to the functional interactions of food with the
genome. An explicit example of nutrigenetics is the
influence of the –13910C3 T genetic variant, located
approximately 14 kilobases upstream of the LCT (lac-
tase) gene, on lactose tolerance. Ennatah et al.1 reported
that adult lactase persistence (i.e., lactose tolerance) was
completely associated with the variant T allele (one or
two copies), whereas adult lactase non-persistence (i.e.,
lactose intolerance) was completely associated with car-
rying two copies of the more common C allele. Thus,
Please address all correspondence to: Dr. Marie
Caudill, Human Nutrition and Food Science Depart-
ment, Cal Poly Pomona, 3801 W. Temple Ave.,
Pomona, CA 91768; Phone: 909-869-2168; Fax: 909-
869-5078; E-mail: macaudill@csupomona.edu.
Nutrition Reviews姞, Vol. 65, No. 7
regarding lactose tolerance, possession of the less com-
mon T allele is beneficial, not detrimental. An excellent
example of nutrigenomics is the influence of omega-3
fatty acids (i.e., eicosapentaenoic acid [EPA] and doco-
sahexaenoic acid [DHA]) on gene expression.2 EPA and
DHA, found primarily in marine sources, are generally
associated with decreased expression of inflammatory
genes and increased expression of genes involved in
energy and fat metabolism.2
The human genome project has demonstrated that
any two individuals share 99.9% of their DNA se-
quence.3,4 The 0.1% difference between any two indi-
viduals may explain why some individuals are more
susceptible to common diseases than others. The most
prevalent form of genetic variability in the human ge-
nome is single nucleotide polymorphisms (SNPs), which
are changes in a single base pair that exist in more than
1% of the population. SNPs occur at about every 1000
base pairs, yielding approximately 3,000,000 in the hu-
man genome. Of interest to research scientists and health
professionals are the functional SNPs—those that alter
gene expression, mRNA processing, and protein activi-
ties/function.
The completion of the human genome project and
subsequent efforts such as the HapMap consortium5 have
catapulted efforts aimed at investigation of the influence
of SNPs on common diseases and nutrient tolerances/
requirements. Encouragingly, many of the deleterious
SNPs are diet responsive and can be rendered harmless
with the “right” diet. In addition, the identification of
protective SNPs, along with knowledge of their influence
on the protein product, may provide genetic targets for
genes that respond to dietary signals. This paradigm is
analogous with the overall goal of nutritional genomics,
which is to provide information on gene-nutrient inter-
actions (and vice versa) that may allow for individual-
ization of dietary advice for the purposes of reducing
one’s risk of chronic disease.
“Nutrigenetic” services are currently available over
the Internet without the direct involvement of a health
care professional. The client/customer submits a self-
administered buccal swab along with dietary informa-
301
tion. The company analyzes the DNA for a specific set of
SNPs, which are generally limited to those believed to
influence disease risk and to be diet responsive. The
company then provides the consumer with specific di-
etary recommendations based on his or her genetic pro-
file. However, interpretation of the data is complex. Most
consumers and health care professionals may not know
the function of the gene and/or how the SNP under
investigation influences the function of the gene product
(i.e., protein). SNPs may be identified in variety of ways,
including restriction fragment length polymorphism
(RFLP) analysis, nucleotide change, amino acid change,
or location in an intron/exon. These variations in SNP
identification, and ultimately nomenclature, complicate
making comparisons across studies. Many SNPs com-
monly included in genetic profiles are non-functional
SNPs and do not influence gene expression or protein
function. The influence of the SNP in one gene may be
influenced by allelic variation in another gene (i.e.,
gene-gene interactions). SNPs located on the same gene
and/or chromosome are often co-inherited in blocks or
groups (i.e., haplotype). This non-random inheritance of
SNPs is referred to as linkage disequilibrium. Data re-
garding the influence of a genetic variant on disease risk
is often conflicting and frequently lacks information on
how specific dietary components may interact with the
SNP to influence phenotype.
The goal of this paper is to carefully examine nutri-
tional genomics as a potential tool for targeted medical
nutrition therapy. The approach is to use heart health
susceptibility genes and their common genetic variants
as the model. Our analysis includes the function of the
gene, the influence of the SNP on the protein product and
cardiovascular disease (CVD) risk, and the role, if any,
of using these variants as genetic cues for making spe-
cific dietary recommendations.
HEART HEALTH SUSCEPTIBILITY GENES
The term “CVD” refers to the class of diseases that
involve the heart and/or blood vessels (arteries and
veins), and is used in this paper to refer to diseases
related to atherosclerosis (i.e., coronary artery disease or
CAD). In the United States, the most common forms of
CVD are heart disease and stroke, which together ac-
count for nearly 40% of all annual deaths.6 CVD is a
multifactorial, polygenic disorder that is associated with
inflammation,7,8 dyslipidemia,9 and/or hyperhomocys-
teinemia.10 Thus, genes that have the potential to mod-
ulate homocysteine, lipids, and/or inflammation repre-
sent viable choices for heart health susceptibility genes.
The genes included in this review are methylenetetrahy-
drofolate reductase (MTHFR), a gene critical to the
metabolism of homocysteine; cholesteryl ester transfer
302
protein (CETP), lipoprotein lipase (LPL), and apoli-
poprotein C-III (Apo C-III), genes involved in lipid
metabolism; and interleukin 6 (IL-6), a gene linked to
inflammation.
Methylenetetrahydrofolate Reductase
Function
MTHFR is a flavoprotein that is ubiquitously ex-
pressed and catalyzes the reduction of 5,10-methyl-
enetetrahydrofolate to 5-methyltetrahydrofolate. Flavin
adenine dinucleotide (FAD) serves as the cofactor in this
reaction and accepts reducing equivalents from
NAD(P)H. The binding sites for FAD, NAD, and 5,10-
methylenetetrahydrofolate are housed in the N-terminal
domain of the protein, while the C-terminal domain
regulates enzyme activity in response to S-adenosylme-
thionine (SAM). Formation of 5-methyltetrahydrofolate
by MTHFR provides one-carbon units for homocysteine
conversion to methionine in a reaction catalyzed by
methionine synthase. Severe MTHFR deficiency as a
result of rare genetic mutations is characterized by hy-
perhomocysteinemia, neurological abnormalities, vascu-
lar thrombosis, and changes similar to atherosclerosis.11
Case-control and prospective studies suggest that mildly
elevated plasma total homocysteine is an independent
risk factor for CVD.10
Genetic Variants
The MTHFR gene, located on chromosome 1 at
p36.3, consists of 11 exons and spans a region of about
20 kilobases.12 Several rare genetic mutations have been
identified within the MTHFR gene, along with two
common SNPs, 677C3 T and 1298A3 C. Table 1
shows the common genetic variants in the MTHFR gene,
their locations, alternative names, and approximated al-
lele frequencies. The most broadly studied MTHFR SNP
and the one frequently featured by nutrigenetic compa-
nies is the 677C3 T in exon 4. The 677C3 T base
change encodes for a valine instead of an alanine at
position 222 in the protein.13 Studies performed in Esch-
erichia coli show that the genetic variant increases the
propensity for bacterial MTHFR to lose its essential
flavin cofactor.14 Heterozygosity and homozygosity for
the genetic variant are associated with about a 35% and
70% reduction in enzyme activity, respectively.13 Ho-
mozygosity for the 677C3 T variant is the most com-
mon genetic cause of mildly elevated plasma homocys-
teine15 and is often associated with lower folate status.16
Regarding the MTHFR 677C3 T variant and CVD risk,
a meta-analysis of 40 studies concluded that the MTHFR
677TT genotype was a modest but statistically signifi-
Nutrition Reviews姞, Vol. 65, No. 7
cant risk factor for CAD predominately in those with low
folate levels.17 A second meta-analysis reported that this
genotype was a modest risk factor for CAD, deep vein
thrombosis, and stroke; folate status was not measured.18
The second common polymorphism in the MTHFR
gene that modifies enzyme function is the 1298A3 C
polymorphism in exon 7. The 1298A3 C variant results
in alanine rather than glutamate in the protein product
and modifies enzyme activity but not plasma homocys-
teine or folate.19,20 However, individuals who are het-
erozygous for both the 677T and 1298C polymorphisms,
the 677CT and 1298AC genotype, may be at risk of
mildly elevated homocysteine concentrations.19,21 The
MTHFR 677C3 T and 1298A3 C variants are in com-
plete negative linkage disequilibrium22,23 in that the two
genetic variants never occur on the same gene. Thus,
people with the MTHFR 677TT genotype always pos-
sess the 1298AA genotype and vice versa. Studies ex-
amining the influence of the MTHFR 1298A3 C variant
on CVD are rare. One study reported that the 1298C
allele of the MTHFR gene was associated with early
onset of CAD independently of homocysteine.24 Other
polymorphisms in the MTHFR gene have been identi-
fied, but most of them are either silent (i.e., do not change
the codon) or intronic.25
Dietary Interactions
Numerous investigations have unequivocally shown
that enzymatic impairments associated with the MTHFR
677C3 T genetic variant can be overcome with in-
creased folate consumption.16,26 In women with the
MTHFR 677TT genotype, folate and homocysteine con-
centrations within the normal range can be achieved with
consumption of the US folate RDA, 400 ␮g/d as dietary
folate equivalents (DFE).16,27 However, in order to
Nutrition Reviews姞, Vol. 65, No. 7
achieve folate and homocysteine levels comparable to
individuals with the MTHFR 677CC genotype, higher
folate intakes are needed. In a controlled feeding study,
consumption of 800 ␮g DFE/d was sufficient to over-
come differences in folate status between MTHFR
677CC and TT genotypes in young Mexican-American
women.16 In the United States, Canada, and a few other
countries, folic acid has been added to enriched cereal
grain products and delivers approximately 340 to 400 ␮g
DFE/d (or 240 ␮g folic acid/d).28 Combined with the
approximately 200 ␮g DFE/d that is consumed from
non-fortified foods, the average person in the United
States is consuming about 600 ␮g DFE/d. The general
lack of difference in homocysteine concentration be-
tween women with the MTHFR 677CC and TT geno-
types in studies conducted in the era of folic acid forti-
fication suggest that about 600 ␮g DFE/d may be enough
to achieve comparable folate and homocysteine levels.23
Studies conducted in E. coli suggest that folate may
ameliorate enzyme function by increasing the propensity
for MTHFR to retain its essential flavin cofactor.14
Conclusions
Homocysteine is an independent risk factor for
CVD. MTHFR provides the folate derivative utilized by
methionine synthase for conversion of homocysteine to
methionine. The MTHFR 677C3 T polymorphism is the
best-characterized common genetic variant within the
MTHFR gene and is frequently featured in nutrigenetic
heart health profiles. The MTHFR 677C3 T polymor-
phism is associated with reduced enzyme activity, mild
homocysteinemia, and a modestly higher risk of cardio-
vascular disease. The biochemical disruptions associated
with homozygosity for the MTHFRC3 T SNP may be
ameliorated with increased folate intake (i.e., ⱖ 400 ␮g
303
DFE/d). To date, the interaction between the MTHFR
677C3 T genetic variant and folate may be the best
example of the potential benefits of genetically driven
medical nutrition therapy.
Cholesterol Ester Transfer Protein
Function
Cholesterol ester transfer protein (CETP) is a hydro-
phobic glycoprotein that is secreted mainly from the liver
and circulates in plasma. The majority of CETP in
human plasma is found in loose association with HDL.
CETP facilitates the transfer of cholesterol esters from
Apo-A containing HDLs to Apo-B containing VLDLs
and LDLs with a hetero-exchange of triglycerides. The
overall effect of CETP is a decrease of the cardioprotec-
tive HDL fraction and an increase of the pro-atherogenic
VLDL and LDL fractions in plasma. However, CETP
may have some beneficial effects because of its key role
in reverse cholesterol transport. By exchange of choles-
terol esters for triglycerides in HDL, the resulting trig-
lyceride-enriched HDL particles are more susceptible to
hydrolysis by hepatic lipases, which generates smaller
HDL particles.29 Smaller HDL particles are more effi-
cient at promoting cholesterol efflux from macrophages,
304
the initial step in the reverse cholesterol transport pro-
cess.29 Even so, most experimental evidence derived
from animal and human studies favor a pro-atherogenic
role for CETP and support the viewpoint that inhibition
of CETP is anti-atherogenic.30-34
Genetic Variants
The CETP gene, located on chromosome 16 at q21,
consists of 16 exons and spans a region of about 25
kilobases.35,36 All of its exons and extensive regions
upstream and downstream of the expressed gene have
been sequenced, and most of the common SNPs (there
are about eight) have been identified.31 Table 2 shows
the common genetic variants in the CETP gene, their
locations, alternative names, and approximated allele
frequencies.
The most widely studied genetic variant in the CETP
gene and the one frequently featured by nutrigenetic
companies is the 279G3 A genetic variant, or TaqIB (B2
with TaqIB cutting site, B1 without TaqI cutting site).
The 279A allele (or B2 allele) is associated with lower
CETP levels and modestly higher HDL-C,30-32,34,37,38
although ethnic and gender differences have been de-
scribed.32 The TaqIB SNP is characterized by a silent
base substitution affecting the 277th nucleotide in intron
Nutrition Reviews姞, Vol. 65, No. 7
1, and has no obvious functional connection with the
regulation of CETP levels. However, linkage disequilib-
rium studies have shown that TaqIB is inherited along
with VNTR-1946, – 629C3 A, 8C3 T, and 383A3 G,
and together comprise the 5⬘ haplotype.31,34 Alterna-
tively, strong linkage disequilibrium exists between
408C3 T, 16A3 G, 82G3 A, 159G3 A and 9G3 C,
which comprise the 3⬘ haplotype.31,34
The majority of studies have reported that the 5⬘-
haplotype is associated with lowered CETP mass and
modestly higher levels of HDL-C.30,31,33,34 Thus, having
a lower CETP mass and/or activity appears to be protec-
tive by increasing HDL-C. Interestingly, all of the SNPs
in the 5⬘-haplotype are located in either the promoter
region or intron, and thus none of them causes an amino
acid change in the protein. Therefore, it is likely that one
or more of the promoter region SNPs influence CETP
mass and HDL levels by diminishing the expression of
the CETP gene.
The phenotype associated with the TaqIB polymor-
phism appears to be cardioprotective, but is it actually
associated with lower risk of CVD? Boekholdt et al.32
conducted a meta-analysis including data from 10 rela-
tively large studies. The results suggested that people
who carried two copies of the variant allele (i.e., B2B2)
had a 23% lower risk of CVD (odds ratio [OR] ⫽ 0.77;
P ⫽ 0.001) compared with those who carried two copies
of the normal allele (B1B1).32 The OR for people who
possessed one copy of the variant allele (B1B2) was 0.93
and did not reach statistical significance. Similarly, Free-
man et al.39 reported that compared with B1B1 homozy-
gotes, people with the B2B2 genotype had a 30% re-
duced risk of a cardiovascular event, whereas no
reduction was observed for the B1B2 genotype. The
protective effect of the TaqIB genetic variant is consis-
tent with recent reports of decreased carotid intimal
medial thickness, a surrogate measure of global athero-
sclerosis burden, in men possessing the TaqIB2 allele.40
The influence of the 3⬘-haplotype on CETP and
HDL-C is less conclusive. The main 3⬘-SNP associated
with HDL-C is the 16A3 G (I405V) genetic vari-
ant.30,31,34 This SNP causes a functional change in the
protein by replacing an isoleucine with a valine and is
associated with decreased CETP activity and higher
HDL-C.38 Paradoxically, however, this genetic variant
also appears to be associated with increased risk for heart
disease.41,42
Dietary Interactions
Only a few studies have investigated possible inter-
actions between genetic variants in the CETP gene and
diet. Clifton et al.43 reported that the TaqI polymorphism
does not significantly influence changes in HDL-C in
Nutrition Reviews姞, Vol. 65, No. 7
response to dietary fat and cholesterol. However, Wal-
lace et al.44 reported that changes in plasma cholesterol
and LDL-C in response to a high-fat diet were signifi-
cantly greater in subjects with the CETPB1B1 genotype
compared with those with one or more B2 alleles. The
effect appeared to be independent of the type of dietary
fat (i.e., saturated vs. polyunsaturated).
Given the apparent protective effect of CETP SNPs
in the 5⬘-haplotype, persons without such SNPs are more
likely to benefit from specific dietary advice aimed at
countering the disadvantages of having a more abundant
or active CETP. Based on a limited number of studies, it
appears that cholesterol45,46 and saturated fat47 up-regu-
late the expression of the CETP gene, an effect that may
be inhibited by monounsaturated fats,46,48 garlic,49 and
red pepper.50 Jansen et al.51 conducted a study involving
41 healthy, young, normolipidemic men who consumed
three consecutive 4-week dietary periods of a high satu-
rated fat diet (38% fat, 20% saturated fat), a National
Cholesterol Education Program Step I diet (28% fat, 10%
saturated fat), and a Mediterranean type diet high in
monounsaturated fats (38% fat, 22% monounsaturated
fat). Compared with the saturated fat diet, plasma CETP
concentrations were lower in response to the low-fat diet
and the diet high in monounsaturated fats.
Conclusions
There is a general consensus that functional CETP
polymorphisms causing a reduction in CETP mass
and/or activity are cardioprotective. CETP inhibition is
associated with increased HDL-C and the anti-athero-
genic properties that accompany it, including reduced
risk of CVD. The TaqIB variant is one of the most
studied CETP polymorphisms and is commonly featured
in nutrigenetic heart health profiles. However, it is likely
that TaqIB is a non-functional genetic variant and thus a
marker of one (or more) functional SNPs in the 5⬘-
haplotype. It appears that persons without such SNPs are
more likely to benefit from targeted nutritional advice
aimed at countering the disadvantages of having a more
active CETP. However, more data are needed to identify
the type of diet people without the Taq1B variant (or
those in the 5⬘-haploblock) would need to achieve the
desired effect (i.e., reduced CETP activity and increased
HDL-C).
Lipoprotein Lipase
Function
Lipoprotein lipase (LPL) is a glycoprotein involved
in the hydrolysis of the triglyceride core of circulating
chylomicrons and VLDL. The hydrolytic products (i.e.,
305
free fatty acids and glycerol) may then be used by
peripheral tissues for energy or storage. LPL is predom-
inantly found in capillaries, muscle, and adipose tissue,
where it is bound at the luminal surface of the vascular
endothelium, and also on macrophages. By acting as a
ligand in lipoprotein-cell surface interactions, LPL also
mediates the cellular uptake of lipoproteins. In addition,
LPL modulates plasma HDL cholesterol by contributing
surface components to HDL during hydrolysis of trig-
lyceride-rich lipoproteins. Thus, a more active LPL is
related positively to serum levels of HDL-C and nega-
tively to triglycerides, making it a potentially atheropro-
tective enzyme.52 Due to this pivotal role in lipid metab-
olism, LPL is a strong candidate gene for atherogenic
lipid profiles and CVD.
Genetic Variants
The human LPL gene is located on chromosome 8 at
p22, consists of 10 exons, and encodes a 448-amino acid
mature protein after cleavage of a 27-amino acid signal
peptide.53,54 Full expression of enzyme activity requires
the formation of a homodimeric complex.55 LPL is
believed to be organized in an N-domain (residues 1 to
312), which is important for the catalytic function of the
enzyme, and a C-domain (residues 313 to 448), which is
important for LPL’s role in the uptake of lipoproteins by
receptors on the cell surface.56 The LPL gene has been
sequenced and functional SNPs that influence triglycer-
ide and lipoprotein variability, 9D3 N, 291N3 S,
447Ser3 Ter(X), have been identified.57 Table 3 shows
the common genetic variants in the LPL gene, their
locations, alternative names, and approximated allele
frequencies.
306
The 447Ser-Ter(X) SNP is the most well-studied
functional polymorphism and is featured by most nutri-
genetic companies assessing an individual’s CVD risk.
The 447S3 X creates a premature stop codon and trun-
cates the protein by 2 amino acids (serine and glycine)
from the carboxy end of the protein.55 This substitution
has been shown to increase the activity of LPL, possibly
by enhancing the binding affinity of the shortened LPL to
receptors or facilitating the formation of dimers.58 The
447S3 X genetic variant is associated with lower trig-
lycerides, higher HDL, and greater clearance of lipopro-
tein remnants, all of which are consistent with enhanced
LPL activity and the potential cardioprotective effects of
this enzyme.57,59-62 Generally, plasma triglycerides are
approximately 8% to 19% lower and HDL-C up to 0.04
mmol/L higher in carriers of the 447S3 X variant com-
pared with non-carriers.57,60
The 291N3 S and 9D3 N genetic variants of the
LPL gene also modulate lipid profiles, albeit deleteri-
ously. The 291N3 S SNP induces an asparagine-to-
serine change and is associated with an LPL protein with
decreased dimer stability and reduced LPL activity.63
Carriers of the 291N3 S genetic variant have up to 82%
higher triglycerides57 and up to 16% lower HDL57 com-
pared with non-carriers. The 9D3 N genetic variant
changes an aspartate residue to asparagine, and results in
enzyme secretion deficiency57 as well as reduced LPL
expression by approximately 25% to 30%.64 Carriers of
the 9D3 N genetic polymorphism have approximately
20% higher triglycerides57,60 and a 4% reduction of
HDL.57 Overall, these two N-domain functional poly-
morphisms support the theory that any mutation that
results in a partial deficiency of LPL would result in a
modest increase in plasma triglyceride levels.
Nutrition Reviews姞, Vol. 65, No. 7
 While the modulatory role of genetic variants in the
LPL gene on plasma lipids are generally well docu-
mented, the literature is less consistent with respect to
associations between LPL polymorphisms and CVD end
points, possibly due to potential confounders including
age,58,65 ethnicity,58,64 smoking,66 gender,58,59,67 and/or
lack of statistical power to detect effects. A meta-analy-
sis published by Wittrup et al.60 reported that risk of
ischemic heart disease in heterozygous carriers was mod-
estly increased for Asp9Asn (OR ⫽ 1.4) and Asn291Ser
(OR ⫽ 1.2) and decreased for 447X carriers (OR ⫽ 0.8).
In a subsequent meta-analysis by gender, the 447X
variant was associated with a significant 17% reduction
in ischemic heart disease risk in men, whereas risk was
unaffected in women.67 Case-control studies have re-
ported higher frequencies of 9D3 N and/or 291N3 S in
groups of patients with CAD or dyslipidemias compared
with groups of healthy subjects.55,57,68 The opposite is
true for 447S3 X, where the allelic frequency of
447S3 X is significantly lower in CAD patients than in
disease-free controls.59,69 In a Japanese study population,
the OR of 447S3 X for CAD was found to be 0.38 for
the carriers relative to non-carriers.69
Dietary Interactions
Data providing information on potential interactions
between LPL polymorphisms and diet are generally
lacking. In a study conducted in 12 pairs of male
monozygotic twins, carriers of the 447X allele (n ⫽ 4)
had significantly higher HDL-C levels after overfeeding
than non-carriers (n ⫽ 20).70 Lopez-Miranda et al.65 re-
ported that 447X carriers had a lower postprandial lipi-
demia response assessed by measuring triglyceride-rich
lipoproteins after a vitamin A-fat load test. However,
Clifton et al.43 reported no influence of the 447X variant on
LDL-C and HDL-C after a high-fat/high-cholesterol diet.
It would seem that the people who would benefit
most from dietary intervention would be individuals with
decreased LPL activity due to their being carriers of
9D3 N and/or 291N3 S, as well as individuals without
the 447S3 X SNP and the cardioprotective properties
that accompany it. In this regard, there are dietary com-
ponents that may increase LPL expression and/or activ-
ity. In a randomized, double-blind, placebo-controlled,
crossover study, 51 male subjects expressing an athero-
genic lipoprotein phenotype had their diets supplemented
with fish oil for 6 weeks.71 Supplementation produced a
decrease in fasting plasma triglycerides, attenuation of
the postprandial triglyceride response, and a decrease in
small dense LDL. These changes were accompanied by
an increase in the expression of LPL mRNA in adipose
tissue and post-heparin LPL activity, suggesting that the
favorable effects of consuming n-3 PUFAs may be due
Nutrition Reviews姞, Vol. 65, No. 7
in part to increased LPL gene expression.71 Herb ex-
tracts, including mulberry and banaba, along with pow-
dered Korean ginseng, have also been shown to increase
LPL expression.72
Conclusion
Common influential polymorphisms of the LPL
gene include 9D3 N, 291N3 S, and 447S3 X. The first
two tend to promote more atherogenic lipid profiles and
have been seen to occur more frequently in people with
CVD than in healthy individuals. The opposite trend is
seen with the 447S3 X polymorphism commonly fea-
tured by companies offering nutrigenetic services. The
447S3 X polymorphism causes a premature stop codon
and truncates the protein by 2 amino acids, which in turn
are associated with enhanced LPL activity and reduced
CVD risk. At present, there is a lack of data upon which
to base specific dietary recommendations. However, it
appears that individuals without the 447S3 X SNP
and/or having the 9D3 N/291N3 S SNPs may benefit
from specific dietary interventions aimed at increasing
the expression and/or activity of LPL.
Apolipoprotein C-III
Function
Apo C-III is a glycoprotein that is mainly synthe-
sized in the liver and to a smaller extent in the intestine.
It is a component of chylomicrons, VLDL, and HDL, and
is believed to regulate triglyceride metabolism by mod-
ulating both lipolysis and receptor-mediated uptake of
triglyceride-rich lipoproteins. Specifically, Apo C-III is a
known inhibitor of LPL activation, which delays lipoly-
sis and clearance of triglyceride-rich lipoproteins.73 It
also has a functional relationship with Apo E, which is
needed for efficient removal of triglyceride-rich lipopro-
teins. Elevated Apo C-III causes displacement of Apo E
on the triglyceride-rich lipoprotein, causing further re-
duction in the removal of triglyceride-rich lipoproteins
from the blood.74 Thus, an increase in Apo C-III con-
centrations could potentially create unfavorable lipid
profiles, making it a candidate gene for CVD.
Genetic Variants
A region on the long arm of chromosome 11q23-q24
codes for three apolipoprotein genes: Apo A-I, Apo
C-III, and Apo A-IV.75 These genes are similar in struc-
ture and are in close physical linkage.75 Thus, it is not
surprising that several polymorphisms for the three genes
are in linkage disequilibrium.76,77 The gene for Apo C-III
has been mapped to chromosome region 11q23.3 (in
307
between the genes for Apo A-I and Apo A-IV), consists
of four exons, and encodes for a 79-amino acid glyco-
protein.78 On either side of the Apo C-III gene, there is
an “intergenetic” region between the Apo C-III gene and
its neighbors, Apo A-I and Apo A-IV.79 These “interge-
netic” regions, which may influence the transcription of
the Apo AI-CIII-AIV genes, also have variations that
could affect the regulation of these genes.80 Table 4
shows the common genetic variants in the Apo C-III
gene, their locations, alternative names, and approxi-
mated allele frequencies.
The polymorphism that nutrigenetic companies have
targeted is the cytosine to guanine substitution in the
3⬘-untranslated region. This genetic variant is commonly
referred to as SstI (S1/S2 site), since the variant form (S2
allele) causes a loss of the recognition sequence for the
restriction enzyme SstI.80 The literature describes two
nucleotide positions for this genetic variant, position
317564,81 and position 3238.77-79 In this paper, the vari-
ant will be referred to as SstI. Since the SstI site is in the
3⬘-untranslated region, it does not change the amino acid
sequence of the protein. This suggests that SstI alone
may not be responsible for observed changes in blood
lipids, but that it may be in linkage disequilibrium with
other functional SNPs on or near the Apo C-III
gene.78,79,81,82
The SstI variant is associated with increased triglyc-
erides of up to about 38%,78,79,83,84 as well as increased
Apo C-III expression64 and increased LDL.85 In an early
meta-analysis, Ordovas et al.83 concluded that compared
with non-carriers, the risk of CVD was significantly
higher in carriers of the SstI variant in a Caucasian
population (relative risk: 1.96). However, more recent
studies have reported no associations between the SstI
variant and CVD risk.77,81,86
308
The SstI polymorphism is in strong linkage disequi-
librium with other polymorphisms on the Apo C-III
gene, including 1100C3 T, – 482C3 T, – 455T3 C, and
– 641C3 A.78,81 Like SstI, 1100C3 T does not code for
an amino acid change but is associated with modestly
increased triglycerides (about 10%),78 and is thus a
possible marker for another SNP. In a haplotype study
including the SstI, – 482, and – 455 variants (both of
which are located in the insulin response element), hy-
pertrigylceridemia was observed in patients with hyper-
insulinemia, suggesting that insulin influences the ex-
pression of Apo C-III with this haplotype.82 This finding
is consistent with the location of the polymorphic sites
and suggests these polymorphic variants prevent the
down-regulation of Apo C-III normally produced by
insulin. This causes an increase in the plasma levels of
Apo C-III and leads to higher levels of triglycerides.82
Tobin et al.81 conducted a haplotype analysis for the
polymorphisms at positions – 641, – 482, – 455, 1100,
SstI, and 3206 on the Apo C-III gene. It was found that
a haplotype with polymorphic sites at the 1100 and 3206
had a 41% increase of CVD risk, and another haplotype
having all polymorphic sites except those at 1100 and
SstI raised risk of CVD by 71%.
Polymorphic sites within Apo C-III are also in
linkage disequilibrium with polymorphisms on the Apo
A-I and Apo A-IV genes and their respective intergenetic
areas.77,83,86,87 The SstI allelic associations with neigh-
boring genes include the MspI83,86 and XmnI77 sites of
the Apo A-I gene, and the XabI site of the Apo A-IV
gene.83 In a study by Liu et al.,77 a haplotype consisting
of the Apo A1-XmnI (X1/X2) and the Apo C-III SstI
variations was found to have a significant effect on
triglycerides but not on myocardial infarction risk. Poly-
morphic sites within Apo C-III are also in linkage dis-
Nutrition Reviews姞, Vol. 65, No. 7
equilibrium with intergenic SNPs. In this regard, Groe-
nendijk et al.79 described two high-risk haplotypes for
familial combined hyperlipidemia: one containing and
one lacking the SstI variant.
Overall, data on the relationships between Apo C-III
polymorphisms and CVD risk are heterogeneous even
when co-inheritance of other polymorphic sites is con-
sidered. Ethnic differences,64,86,87 gene-gender interac-
tions,85,88,89 gene-environment interactions (i.e., smok-
ing),78 and gene-gene interactions (i.e., genes involved in
the regulation of blood pressure)40 are all possible con-
founders.
Dietary Interactions
The research on dietary interventions and the SstI
variant is not extensive. Salas et al.90 reported that
carriers of the S2 allele had elevated insulin concentra-
tions in response to an oral glucose tolerance test. The
elevated insulin concentrations could lead to an increase
in insulin resistance and subsequently increase the risk of
CVD. Lopez-Miranda et al.91 reported that LDL-C de-
creased in young men carrying the S2 allele in response
to a diet high in monounsaturated fat (22%), whereas an
increase was observed in those with the S1S1 genotype.
These results suggest that a diet high in monounsaturated
fats may be a viable choice of intervention to reduce
plasma LDL-C in S2 carriers. An additional dietary
approach to help counter the Apo C-III-raising effects of
the SstI variant is the use of n-3 PUFAS contained in fish
oil.92 These have been shown to have an Apo C-III-
lowering effect in vitro, although the mechanisms are not
clear and it is unknown if this effect can be achieved
through diet alone or if supplementation is needed.92
Conclusions
The effect of the SstI variant allele (S2) on blood lipids
has been studied widely and is generally associated with
increased Apo C-III and triglycerides. However, the rela-
tionship between the SstI S2 allele and CVD risk is unclear.
The SstI site occurs in the 3⬘-untranslated region of the Apo
C-III gene, and does not change the amino acid sequence of
the protein. Thus, the SstI variant is likely a marker of other
functional SNPs residing on or near the Apo C-III gene with
which it is in strong linkage disequilibrium. Because of the
strong linkage disequilibrium that exists between the SstI
variant and other SNPs, haplotype data are more informa-
tive than analysis of SstI alone. A diet high in monounsat-
urated fats and possibly omega-3 fatty acids (i.e., EPA and
DHA) may be beneficial in improving lipid profiles of
persons carrying the S2 allele.
Nutrition Reviews姞, Vol. 65, No. 7
Interleukin-6
Function
IL-6 is a pleiotropic cytokine that plays a central role
in immune and inflammatory responses and up-regulates
the synthesis of acute-phase reactants such as C-reactive
protein (CRP) in the liver.93 Two major sources of IL-6
are macrophages activated by infection or inflammation
and adipose tissue.94,95 Inflammation is strongly impli-
cated in the process of atherosclerosis,7,8 and elevated
levels of IL-6 are common in patients with CVD96,97 and
unstable angina.98 IL-6 mRNA is present in atheroscle-
rotic arteries at 10- to 40-fold higher levels than in
non-atherosclerotic arteries99 and has the ability to stim-
ulate differentiation of monocytes to macrophages,100 a
process that is relevant in the formation of atheroscle-
rotic plaque. Because of the dynamic relationships be-
tween IL-6, inflammation, and CVD, IL-6 represents a
heart health susceptibility gene. Thus, genetic polymor-
phisms that affect the production of IL-6 represent strong
candidates as CVD susceptibility alleles.
Genetic Variants
The IL-6 gene is located on chromosome 7 at p21
and spans about 5 kb.101 Four SNPs have been found in
the promoter region of this gene (–596G3 A,
–572G3 C, –373AnTn, and –174G3 C) and individually
and/or collectively affect gene transcription.102,103 Ac-
cession numbers (i.e., dbSNP) are not available for IL6
SNPs. The G3 C substitution at position –174102 is the
most widely studied IL-6 polymorphism and is the SNP
featured by nutrigenetic companies. The prevalence of
the –174C variant allele in European populations is
approximately 36%.104 A few studies have reported that
the IL-6 –174G3 C genetic variant is associated with
lower IL-6 levels102,105 and thus decreased expression of
the IL-6 gene. Fishman et al.102 reported that IL-6 levels
were about twice as high in GG homozygotes relative to
homozygotes for the C allele in healthy young men.
However, in a study conducted in patients with abdom-
inal aortic aneurysm, a disease known to be associated
with inflammatory response, carriers of the C allele had
increased expression of the IL-6 gene relative to GG
homozygotes.106 Further, Brull et al.107 reported that
IL-6 levels were 26% higher in those homozygous for
the –174C allele than among G allele carriers 6 hours
after coronary artery bypass surgery, an inflammatory
stimulus. No differences in IL-6 expression were de-
tected among the genotypes at baseline. These data
suggest that the influence of the –174G3 C on IL-6
expression may be dependent upon the degree of inflam-
matory stress. Examination of haplotype data also yields
309
findings that may contribute to heterogeneous findings.
Terry et al.103 compared the effects of four IL-6 promoter
polymorphisms (–597G3 A, –572G3 C, –373AnTn,
–174G3 C) and their naturally occurring haplotypes on
IL-6 gene expression. Functional differences of the hap-
lotypes were found in the ECV304 cell line, with the
[G-G-A9T11-G] haplotype showing increased expression
and the [A-G-A8T12-G] haplotype showing lower ex-
pression. Thus, both haplotypes, with opposite effects on
IL-6 gene expression, contained the –174G allele. Their
results also indicated different transcriptional regulation
in different cell lines, suggesting cell type-specific reg-
ulation of IL-6 expression.
Not surprisingly, the influence of the –174G3 C vari-
ant on CVD risk is also inconsistent. Humphries et al.94
reported that men carrying the –174C allele had a relative
risk of CVD of 1.54 compared with those with the GG
genotype. Similarly, Georges et al.108 reported that the
carriers of the C allele were approximately 34% more likely
to have myocardial infarction compared with those with the
GG genotype. However, Rauramaa et al.109 reported that
intima-media thickness, a surrogate marker of heart disease,
was 11% greater in men with the GG genotype compared
with men with the CC genotype. Further, a recent meta-
analysis involving 6434 study participants 55 years of age
or older reported no associations between the genotype,
IL-6 levels, and/or risk of CVD.104 However the presence
of the –174C allele was associated with higher C-reactive
protein levels,104 which is consistent with some,94,110 but
not all,111,112,113 previous work.
Dietary Interactions
Information on the influence of the –174G3 C variant
on response to dietary intake is limited. Eklund et al.114
reported an interaction between the –174G3 C variant and
calorie restriction (2 months) on CRP levels in obese men.
No differences (P ⬎ 0.05) in plasma CRP levels were
detected between the genotypes at baseline. However,
following caloric restriction that led to weight reduc-
tion, CRP levels declined in men carrying the G allele,
but not in men with the CC genotype. Decreases in
CRP after weight reduction have been reported previ-
ously.115 Data from the study of Eklund et al.114
suggest that, for the purposes of reducing CRP, dietary
approaches that extend beyond caloric restriction/weight
loss are warranted in obese men with the IL6 –174CC
genotype. In this regard, EPA, DHA, alpha-linolenic acid
(ALA), and vitamin E are dietary factors that may reduce
markers of inflammation.2,115,116 Rallidis et al.117 reported
significant declines in CRP (38%) and IL-6 (10%) in 50
hyperlipidemic patients supplemented with 15 mL/d of
linseed oil, rich in ALA, for 3 months. Saturated and trans
310
fatty acids, in contrast, are generally associated with in-
creased CRP levels.115,118,119
Conclusions
IL-6 plays a central role in immune and inflamma-
tory responses as well as in up-regulating the synthesis of
acute-phase reactants, in particular CRP. Increased levels
of both IL-6 and CRP have been associated with in-
creased risk of CVD, and a functional polymorphism at
position –174G3 C is associated with altered expression
of the IL-6 gene. To date, the majority of studies have
reported that the –174CC genotype is associated with
increased levels of CVD and/or CRP levels. Moreover,
data from one nutrition study suggest that dietary ap-
proaches that go beyond caloric restriction are warranted
in obese men with the IL-6 –174CC genotype for the
purposes of CRP reduction. Although it is clear that
additional work is needed to fully assess the use of this
promoter SNP as a genetic cue for dietary recommenda-
tions, the totality of evidence thus far suggests that
individuals with the –174CC genotype may benefit from
increased consumption of foods with anti-inflammatory
properties.
CONCLUSIONS
Common genetic variants in heart health suscepti-
bility genes modestly influence classical risk factors for
CVD that may be responsive to dietary change. Further,
many common genetic variants interact with diet to
influence plasma risk-trait levels. At present, however,
there is insufficient data to formulate and/or prescribe a
comprehensive dietary intervention based on these ge-
netic cues. It is also becoming increasingly apparent that
the inclusion of many functional common variants (i.e.,
haplotype data) is needed to more fully elucidate the
relationships among genes, health, and diet. At the same
time, it is certain that the demand for nutrigenetic ser-
vices will increase and that most consumers and health
care professionals will be unequipped with the knowl-
edge and training required for the meaningful interpre-
tation of these data. To realize the usefulness of nutri-
tional genomics as a tool for targeted medical nutrition
therapy, further basic research, extensive epidemiological
studies, and controlled intervention trials are needed. Prep-
aration of health care professionals (i.e., registered dieti-
tians) through education and training is also warranted for
the appropriate usage of genetically based information as
genetic cues for targeted medical nutrition therapy.
ACKNOWLEDGEMENTS
This paper was supported by NIH grant no.
S06GM53933 and funds from the California Agricultural
Nutrition Reviews姞, Vol. 65, No. 7
Research Initiative. The authors thank Grace Jooyoung
Shin for her assistance in creating the tables and in
reference verification.
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