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    July 2007: 301315 Lead Article

    Personalized Nutrition: Nutritional Genomics as a Potential

    Tool for Targeted Medical Nutrition TherapySina Vakili, BS, and Marie A. Caudill, PhD, RD

    An emerging goal of medical nutrition therapy is to

    tailor dietary advice to an individuals 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. Thegoal 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.301315

    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 13910C3T 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,

    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 SNPsthose 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

    ones 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-

    Please address all correspondence to: Dr. MarieCaudill, 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: [email protected].

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    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

    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 homocysteineconversion 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 atp36.3, 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, 677C3T and 1298A3C. 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 677C3T in exon 4. The 677C3T 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 thepropensity 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 677C3T 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 677C3T variant and CVD risk,

    a meta-analysis of 40 studies concluded that the MTHFR

    677TT genotype was a modest but statistically signifi-

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    cant risk factor for CAD predominately in those with low

    folate levels.17

    A second meta-analysis reported that thisgenotype 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 1298A3C

    polymorphism in exon 7. The 1298A3C 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 1298A3C 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

    677C3T 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

    achieve folate and homocysteine levels comparable to

    individuals with the MTHFR 677CC genotype, higherfolate 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 bymethionine synthase for conversion of homocysteine to

    methionine. The MTHFR 677C3T polymorphism is the

    best-characterized common genetic variant within the

    MTHFR gene and is frequently featured in nutrigenetic

    heart health profiles. The MTHFR 677C3T 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 MTHFRC3T SNP may be

    ameliorated with increased folate intake (i.e., 400 g

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    DFE/d). To date, the interaction between the MTHFR

    677C3T 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. Theoverall 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,

    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 allelefrequencies.

    The most widely studied genetic variant in the CETP

    gene and the one frequently featured by nutrigenetic

    companies is the 279G3A 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

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    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, 629C3A, 8C3T, and 383A3G,

    and together comprise the 5 haplotype.31,34 Alterna-

    tively, strong linkage disequilibrium exists between

    408C3T, 16A3G, 82G3A, 159G3A and 9G3C,

    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 16A3G (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 variantalso 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

    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 increasedHDL-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.,

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    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 LPLs 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, 9D3N, 291N3S,

    447Ser3Ter(X), have been identified.57 Table 3 shows

    the common genetic variants in the LPL gene, their

    locations, alternative names, and approximated allele

    frequencies.

    The 447Ser-Ter(X) SNP is the most well-studied

    functional polymorphism and is featured by most nutri-

    genetic companies assessing an individuals CVD risk.

    The 447S3X 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

    447S3X genetic variant is associated with lower trig-

    lycerides, higher HDL, and greater clearance of lipopro-

    tein remnants, all of which are consistent with enhancedLPL 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 447S3X variant com-

    pared with non-carriers.57,60

    The 291N3S and 9D3N genetic variants of the

    LPL gene also modulate lipid profiles, albeit deleteri-

    ously. The 291N3S 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 291N3S genetic variant have up to 82%

    higher triglycerides57 and up to 16% lower HDL57 com-

    pared with non-carriers. The 9D3N 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 9D3N 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.

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    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 9D3N and/or 291N3S in

    groups of patients with CAD or dyslipidemias compared

    with groups of healthy subjects.55,57,68 The opposite is

    true for 447S3X, where the allelic frequency of

    447S3X is significantly lower in CAD patients than in

    disease-free controls.59,69 In a Japanese study population,

    the OR of 447S3X 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

    9D3N and/or 291N3S, as well as individuals without

    the 447S3X 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

    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 LPLgene include 9D3N, 291N3S, and 447S3X. 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 447S3X polymorphism commonly fea-

    tured by companies offering nutrigenetic services. The

    447S3X 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 447S3X SNP

    and/or having the 9D3N/291N3S 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

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    between the genes for Apo A-I and Apo A-IV), consistsof 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 the3-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-IIIgene.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

    The SstI polymorphism is in strong linkage disequi-librium with other polymorphisms on the Apo C-III

    gene, including 1100C3T, 482C3T, 455T3C, and

    641C3A.78,81 Like SstI, 1100C3T 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 sitesand 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 inlinkage 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-

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    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 ofthe 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.

    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-6are 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 (596G3A,

    572G3C, 373AnTn, and 174G3C) 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 themost 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 174G3C 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 hadincreased 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 174G3C on IL-6

    expression may be dependent upon the degree of inflam-

    matory stress. Examination of haplotype data also yields

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    findings that may contribute to heterogeneous findings.

    Terry et al.103 compared the effects of four IL-6 promoter

    polymorphisms (597G3A, 572G3C, 373AnTn,

    174G3C) 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 174G3C 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 theGG 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 174G3C variant

    on response to dietary intake is limited. Eklund et al.114

    reported an interaction between the 174G3C 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

    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 levelsof both IL-6 and CRP have been associated with in-

    creased risk of CVD, and a functional polymorphism at

    position 174G3C 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 acomprehensive 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 epidemiologicalstudies, 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

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    Research Initiative. The authors thank Grace Jooyoung

    Shin for her assistance in creating the tables and in

    reference verification.

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