Nutrigenetics and nutraceuticals: the next wave riding on personalized medicine

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    The Human Genome Project and subsequent identification of single nucleotide poly-morphisms (SNPs) within populations has played a major role in predicting individualresponse to drugs (pharmacogenetics) leading to the concept of personalized med-

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    Sub30,icine. Nutritional genomics is a recent off-shoot of this genetic revolution that includes(1) nutrigenomics: the study of interaction of dietary components with the genome andthe resulting proteonomic and metabolomic changes; and (2) nutrigenetics: under-standing the gene-based differences in response to dietary components and devel-oping nutraceuticals that aremost compatible with health based on individual geneticmakeup. Despite the extensive data on genetic polymorphisms in humans, its transla-tion into medical practice has been slow because of the time required to accumulatepopulation data on SNP incidence, understand the significance of a given SNP indisease, and develop suitable diagnostic tests. Nutrigenomics revitalized the field byshowing that nutrients and botanicals can interact with the genome and modify sub-sequent gene expression, which has provided a great impetus for nutrigenetic re-search and nutraceutical development based on nutrigenetics. Polymorphisms inmethlyene tetrahydrofolate reductase (MTHFR) (involved in folate metabolism), apoli-poprotein E (Apo E) and ApoA1 (in cardiovascular disease), and leptin/leptin receptor(obesity) genes are some good examples for understanding basic nutrigenetics. De-veloping nutraceuticals to prevent and manage thrombosis risk in women with throm-bophilic gene mutations are discussed in the context of the opportunities that exist atthe nutrigenetic/pharmacogenetic interphase leading to personalized nutrition. Fur-ther research on individual differences in genetic profiles and nutrient requirements willhelp establish nutrigenetics as an essential discipline for nutrition and dietetics practice.(Translational Research 2007;149:5561)

    Abbreviations: Apo E apolipoprotein E; CAM complimentary and alternative medicine;CHD coronary heart disease; HDL high-density lipoprotein; HRT horomone replacementtherapy; LDL low-density lipoprotein; MTHFR methlyene tetrahydrofolate reductase; PAI-1 plasminogen activator inhibitor; SNP single nucleotide polymorphism; WHI WomensHealth Initiative

    he completion of the Human Genome Project1 hassparked a great deal of research on individual vari-ation in gene sequences, particularly in single nu-

    otide polymorphisms (SNPs), their role in chronic dis-es, and in predicting individual responses to drugs

    (pharmacogenetics). Nutritional genomics is a recent off-shoot of this genetic revolution2,3 that includes (1) nutrig-enomics: The study of interaction of dietary componentswith the genome, the resulting changes in proteins, andother metabolites; and (2) nutrigenetics: Understanding

    m the Department of Internal Medicine, University of Cincinnatidical Center, Cincinnati, Ohio.

    mitted for publication June 15, 2006; revision submitted August2006; accepted for publication September 6, 2006.

    Reprint requests: Dr. Ravi Subbiah, Department of Internal Medicine,University of Cincinnati, College of Medicine M.L. 557, Cincinnati,Ohio 45267. e-mail: Ravi.Subbiah@uc.edu.1931-5244/$ see front matter 2007 Mosby, Inc. All rights reserved.doi:10.1016/j.trsl.2006.09.003EVIEW ARTICLEutrigenetics and nutraceuing on personalized med

    . T. RAVI SUBBIAH

    CINNATI, OHIOals: the next wavee55

  • the gene-based differences in response to dietary compo-nen

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    Translational Research56 Subbiah February 2007ts and developing nutraceuticals that are most compat-e with health for individuals based on their genetickeup. The area of nutrigenomics has been expanding atapid rate in the last decade because of the availability ofhniques that can dissect the interaction of nutrients with

    genome and subsequent modulation of their effectough transcription factors or membrane-related phe-mena. The literature on the ability of dietary fatty ac-,4,5 soy protein,6 and a variety of nutraceutical andbal compounds717 to modulate gene expression ist, and only a few selected references will be mentioned

    this review. Elegant research6,8,10,11,17 on the moleculareraction of botanicals (ie, resveratrol, phytoestrogens,cumin, and others) with the genome and their subse-

    ent metabolic effects has given considerable scientificionale to the areas of herbal medicine and phytotherapy.this review, some examples will be cited of new op-rtunities for the functional food and nutraceutical indus-

    to develop products based on individual genetickeup, which exist not only within the domain of nutri-etics but also at the nutigenetic/pharmacogenetic inter-

    ase.

    TRIGENETICS

    espite the extensive data on genetic polymorphismshumans, its translation into medical practice has beenw in view of the time required to accumulate popu-ion data on SNP incidence, appreciate the signifi-ce of a given SNP in clinical disease, develop suit-

    le diagnostic tests at a reasonable cost, and theysicians ability to offer drug or diet treatment op-ns once the SNP is detected. Therefore, the role oftrigenetics in direct dietary intervention in humans isly beginning. A few examples that have been suc-sful in demonstrating the potential of nutrigeneticshuman health will be cited and opportunities that

    ist in nutrigenetics to develop nutraceuticals leadingpersonalized nutrition will be discussed. In sometances, potential overlap of nutrigenetics with phar-cogenetics will also become evident, as follows:

    One of the best-known examples of applicability ofnutrigenetics are the 2 SNPs (C677T with acytosine-to-thymidine substitution resulting in avaline-to-alanine switch and A1298C with adenine-to-cytosine substitution at position 1298 resulting ina glutamic acid-to-alanine switch) in methylenetetrahydrofolate reductase (MTHFR) gene.18,19MTHFR catalyzes the reaction that produces5-methyl tetrahydrofolate, a cofactor donating amethyl group to a reaction that converts homocys-teine to methionine. The presence of either theC677T mutation or the A1298C mutation in com-associated with reductions in MTHFR enzyme ac-tivity. Reduction in MTHFR activity may causeincreases in plasma concentration of homocysteine,a risk factor for venous thromboembolic disease,ischemic arterial disease, and neural tube de-fects.20,21 Generally, treating with folic acid sup-plementation helps to overcome the negative healtheffect of these SNPs in MTHFR gene.22,23In the cardiovascular disease area, genetic polymor-phisms in several key genes have been reported thathas bearing on blood lipid levels.24 Except for a fewpolymorphisms, many of these genetic polymor-phisms involve complex relationships and are notyet readily interpretable for direct nutritional inter-vention. Apolipoprotein E (Apo E) gene polymor-phisms consist of 3 different alleles (2, 3, and 4),which are a result of 2 SNPs within exon 4 of thegene. Subjects with the 4 variant seem to respondto a high-fat diet negatively with an increased riskfor coronary heart disease (CHD).25,26 In these in-dividuals, a strong dietary recommendation towarda low-fat diet should be useful. In the FraminghamOffspring study, interesting differences were notedon the effect of alcohol on low-density lipoprotein(LDL) cholesterol levels in 2 ApoE gene variants,27with the E2 variant showing lower LDL levels,whereas in E4 subjects, plasma LDL correlatedpositively with alcohol consumption. With regardto the ApoA1 gene, a G-to-A mutation in the pro-moter region alters the response to a polyunsatu-rated diet.28 This difference in the greater amountof a polyunsaturated diet required one to observe anincrease in plasma high-density lipoprotein (HDL)levels with a GA genotype (compared with GGgenotype) that was noted only in women. From adietary recommendation point of view, women withthis mutation should be counseled to consumehigher levels of polyunsaturated fat. The hepaticlipase gene is another promising area that seems todemonstrate differences in terms of plasma HDLlevels and response to drugs.29 A mutation in thepromoter (C514T) is associated with a difference inresponse to the level of dietary fat, especially in TTsubjects whose HDL levels were high only whenconsuming 30% energy from fat. Thus, nutri-tional counseling to reduce the amount of dietaryfat in this genotype would be beneficial.Obesity-related genes. Obesity has become a majorpublic health problem in the United States. Anintense search has occurred for mutations inobesity-related genes, and this area has been sum-marized in an excellent review by Loktionov.24Among potential genes, leptin and leptin receptor

  • gene mutations have emerged as leading candidates3033

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    Translational ResearchVolume 149, Number 2 Subbiah 57toward predicting obesity. Apart from thesegenes, studies reporting mutations in the melano-cortin 4-receptor and melanocortin 5-receptor genesexist.34,35 A study in the Pima, Arizona Indianpopulation36 noted that polymorphisms in noncod-ing regions of the gene for neuropeptide Y(NPYY5R) receptor gene show strong correlationwith the risk of obesity. If these mutations can beidentified in families, dietary restriction/interven-tion based on nutrigenetics starting early in lifemight be an option to combat obesity.

    PORTUNITIES FOR NUTRIGENETICS-BASEDTARY SUPPLEMENTS AND NUTRACEUTICALS INE COMPLIMENTARY AND ALTERNATIVE MEDICINEAM) ARENA

    ietary supplement and herbal use represents alti-billion-dollar industry in the United States. In

    dition, the market for fortified and functional foodsbally is projected to grow by at least 7% each year.37alth food stores and Internet-based retailers offerrbal preparations in capsule, powder, or extract form.e major growth in the dietary supplement industry

    e after the U.S. Congress passed the Dietary Sup-ment Health and Education Act of 1994. This lawowed the sale of herbs to help maintain normalalth and physiology as long as no claims were madetreat a specific disease. A thorough account of theolution of government regulation as it applies to thee of nutritional supplements can be found in a reviewBuchman.38 Herbal therapies come under the broadbrella of CAM, which includes acupuncture, home-

    athy, and spiritual healing. Although one third of theerican population uses some form of CAM, the field

    still trying to find its place among Western health-e practitioners. A detailed discussion of CAM, thesons why it is viewed with skepticism by allopathicysicians, and what it would take to integrate it into

    current health-care system can be found in an ex-lent review by Koretz.39 It seems that 2 seriousalth concerns40,41 exist associated with the use of anyrbal preparation at random: (1) Very few herbalparations have undergone rigorous scientific testinga specific disease risk, and therefore, a possibility

    ists that the public may not receive the benefit theyexpecting after use; and (2) most herbal extracts

    resent hundreds of compounds whose effects areknown and thereby increase the risk of toxicity anderactions with other drugs. A clear example of theficulty in sorting out the benefits and associated risksherbal preparations can be found in a review by

    ojcikowski et al,42 who evaluated potential compli-ntary therapies for chronic kidney disease. It is be-rature on the potential interactions of herbs witheral commonly used drugs. Clearly, the answer tose concerns rests on purifying active ingredients thatbe clinically tested and used as a nutraceutical for

    pecific metabolic problem.

    VELOPMENT OF NUTRACEUTICALS AT THETRIGENETIC/PHARMACOGENETIC INTERPHASE

    n the sections below, opportunities to develop viabletraceuticals derived from herbs and dietaryplements using information at the nutrigenetic/

    armacogenetic interphase are discussed. The Ama-nian herb guarana,43 which is approved as a foodditive in the United States, has been chosen to illus-te this point. Extracts of guarana possess strongtelet aggregation inhibition properties,44,45 and ac-e principles in this extract can be used toward de-loping nutraceuticals capable of decreasing the riskthrombosis, a major risk factor for stroke and CHDwomen with genetic mutations.

    any studies have shown that oral contraceptive usewomen is associated with increased risk of deep veinombosis and stroke.46,47 This risk is even greater forse women with prothrombin and factor V Leidentations.48,49 The response of factor VII to oral con-ceptives was also increased with oral contraceptives.50 Recent studies by Kemmeren et al51 comparedl contraceptives of second (ethinylestradiol/onorgestrel) and third (ethinylestradiol/desogestrel)

    neration in women with factor V Leiden mutationd noted higher thrombotic risk in both regimens, with

    desogestrel group showing a more pronounced risk.European case control study52 noted that, in womeno smoke, oral contraceptives increased the risk ofoke.imilarly, hormone replacement therapy (HRT) in

    stmenopausal women has also indicated the negativeects on the risk of stroke and venous thrombosis.53,54Womens Health Initiative (WHI) trial using estro-n plus progestin combination reported55 a significantrease in the risk of all types of stroke. Cushman et6 reported that estrogen/progestin doubled the risk ofoke and venous thrombosis using the final data from

    WHI study. It is interesting to note that increasedombosis risk was not evident in esterified estrogenopposed to conjugated estrogen) used in the WHI

    dy.57 Similarly, the negative effect of estrogen ther-y on cardiovascular risk was also reported using datarived from the WHI study.5860 The mechanismsolved in the observed increase in thrombosis anddiovascular events after estrogen therapy are notar. A recent cross-sectional study61 of interactionsong the thrombophilic factor V Leiden gene muta-

  • tion, HRT, and CHD in women provides insight intothetriaan

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    Translational Research58 Subbiah February 2007failure of HRT to reduce CHD in the 3 majorls5860 discussed above. The investigators reportedinteraction between HRT-mediated tendency to formod clots and the factor V Leiden mutation (present inof American women). They speculated that when

    T-mediated thrombophilia is...