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© 2007 The American Society for Nutrition J. Nutr. 137:270S-274S, January 2007

Supplement: International Research Conference on Food, Nutrition, and Cancer

Using Genetic Variation to Optimize Nutritional Preemption1,2

Peter J. Gillies3,* and Elaine S. Krul4

3 Central Research and Development, E.I. duPont de Nemours and Company, Wilmington, DE 19880 and 4 Global and Regulatory Science, The Solae Company, St. Louis, MO 63188

* To whom correspondence should be addressed. E-mail: peter.j.gillies{at}usa.dupont.com.


   ABSTRACT
TOP
 ABSTRACT
LITERATURE CITED
 
One of the promises of nutritional genomics is a set of dietary recommendations that leverage our understanding of nutrient-gene interaction in the preemptive dietary management of complex chronic diseases. Whether nutritional genomics can deliver on this promise is a matter of debate and controversy. Although nutritional genomics is often viewed as an extension of pharmacogenomics, the pharmacogenomics paradigm is a disease-centric reductionistic model that overshadows both the complexities and opportunities to be leveraged in preemptive nutritional pharmacology. Moreover, the pharmacogenomics model tends to set clinical expectations that nutritional genomics may not be able to achieve. The biological boundaries of nutritional pharmacology are being tested in many areas of preventive medicine such as cardiovascular disease and cancer. In this regard, the lessons learned in one disease may be germane to the other. Recent results from the Vitamin Intervention for Stroke Prevention (VISP), the Norwegian Vitamin (NORVIT), and the Heart Outcomes Prevention Evaluation (HOPE) 2 trials underscore the incertitude of translating epidemiologic data into preemptive nutritional guidance. Moving ahead, the genetic determinism of the nutrigenomic model needs to take on a more holistic and phenotypic focus. To the extent this can be done, preemptive nutrition may one day become a safe and practical reality.

With the advent of molecular nutrition, nutrition scientists have a special opportunity to become major players in the health sciences and in the development of public health policy. The human genome project, coupled with the recent completion of the HapMap [a catalogue of single-nucleotide polymorphisms (SNPs)5 within the genome], provides modern-day nutritionists with a knowledge base and a set of tools to explore nutrient-gene interaction to an unprecedented level of inquiry. This new and molecular endeavor has been called nutritional genomics. Initially the term nutritional genomics referred to the analysis of the effects of nutrients on gene expression; more recently the term has been expanded to include effects on proteins, metabolites, and pathways in a globally integrated model (1,2). As a subset of nutritional genomics, nutrigenetics focuses on the effect of structural variations in genes, most commonly SNPs, in an effort to understand the highly variable response of humans to diet. In an ideal scenario, it may be possible to leverage our understanding of nutritional genomics to tailor diets to the genetic background of an individual to optimize health and offset disease (3). To the extent we are successful in reaching this goal, we can maximize the application and impact of nutrition science in terms of dietary recommendations and guidelines. Along the way we will face both the opportunity and the challenge of molecular nutrition in terms of balancing the specific needs of the individual with the general needs of the population. However, before this Gordian knot is unraveled, the solution to which lies as much in ethics as it does in science, some technical challenges have to be addressed.

Pharmacogenomics to nutrigenomics

To a certain extent the principles of nutrigenomics can be modeled after the principles of pharmacogenomics, as illustrated in Figure 1 (4). However, in moving from patients with diagnosed disease to healthy consumers, there is a significant shift from disease management to disease prevention or optimization of physiological function. In moving from consumers to patients, nutrigenetics offers a preemptive nutritional strategy for delaying the onset of disease and its clinical manifestations and may even offer adjunctive approaches to pharmacotherapy.


Figure 1
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  		Figure 1  Migrating principles of pharmacogenomics (PGx) to nutrigenomics (NGx) to enable the practice of preemptive nutrition. Adapted from Gillies (4).

 
In keeping with the pharmacogenomics {leftrightarrow} nutrigenomics analogy, the progress and pitfalls encountered in putting pharmacogenomics into practice are germane to nutrigenomics. Despite its remarkable potential to provide clinical benefit, pharmacogenomics has been slow to evolve, and its successes have been modest (5). The formation and funding of the Pharmacogenetics Research Network via NIH; the efficacy of drugs such as Herceptin, Erbitux, and Gleevec; and the utility of molecular diagnostics for managing absorption, distribution, metabolism, and excretion and adverse reactions are obvious successes of the pharmacogenomic model. However, issues of patient privacy and consent, social and ethical considerations, lack of professional education, and an unclear regulatory landscape limit the integration of pharmacogenomics into widespread medical practice. Nutrigenomics will certainly encounter similar challenges to its adoption (6), a process that is likely to be even slower, given that it operates in the realm of a self-empowered consumer rather than a medically supervised patient.

Nutrigenomics to nutritional pharmacology

In the context of nutrigenomics, preemptive nutrition strives to optimize health or offset the risk and/or progression of disease through an integrated understanding of genetic predisposition, nutrient-gene or -SNP interaction, and appropriately timed nutritional pharmacology. Preemptive nutrition faces some special challenges in terms of nutritional pharmacology that need to be borne in mind to manage our clinical expectations. Although there may be a continuum of effector activity for a given biological target with nutrients at one end and drugs at the other, bioactivity is but 1 variable in the efficacy equation. There are many notable differences between drugs and nutrients in terms of how they elicit biological change (Fig. 2).


Figure 2
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  		Figure 2  Comparison of medical vs. nutritional pharmacology.

 
Differences between drugs and nutrients aside, nutritional pharmacology can be quite successful. For example, nutritional pharmacology is a strategic component of the disease management protocols for cardiometabolic disease and cancer (7,8). The nutritional management of hyperlipidemia and metabolic syndrome provides good examples of how nutritional epidemiology and medical pharmacology provide a mechanistic foundation for nutritional pharmacology. Because the number of sites of biological intervention capable of bringing about clinically meaningful changes in lipid and lipoprotein metabolism is limited, it is perhaps not surprising that drugs and nutrients tend to overlap in their sites and mechanisms of action (Fig. 3 A) (9). SNPs that are important to the response of patients to drugs may also be factors in their response to various nutrients (Fig. 3 B); this has been well documented with respect to lipid and lipoprotein metabolism (10). A similar trend was observed with respect to the prevention and treatment of breast cancer (11,12).


Figure 3
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  		Figure 3  Drugs (Rx) and nutrients (Nx) have (A) common sites of intervention and (B) can share common response modifying SNPs in their regulation of lipid and lipoprotein metabolism. Modified from Katcher et al. (9); A is reprinted with permission from ILSI Press (9).

 
Although the pharmacological activity of a given nutrient may be of limited potency and efficacy, the integrated actions of a specific suite of routinely ingested nutrients can elicit clinically meaningful change. This principle was recently put into practice in the "cholesterol-lowering portfolio diet" (13). Although the extent of cholesterol lowering elicited by this diet was greater in a carefully controlled metabolic study (14) than in an open-label real-world study (15), clinically significant LDL-cholesterol lowering was achieved in both cases. Of note, however, long-term compliance with the diet and individual variability in response to the diet were significant response variables. The efficacy of the cholesterol-lowering diet is affected not only by what is included in the dietary portfolio but also by what is excluded (e.g., foods high in cholesterol, saturated fatty acids, and trans fatty acids).

The nutrigenomic model of preemptive nutrition

The integration of nutrigenetic information in the practice of nutritional pharmacology ultimately leads to preemptive nutrition. The complexity of the nutrigenomic overlay is illustrated in Figure 4 A. Conceptually, there are multiple dimensions or axes inherent in the model, including a basic science axis linking the disease state with a set of genes and a nutritional solution; a clinical axis linking the key genes, tests for functionally important SNPs in these genes, and attendant biomarkers for both the SNP and the nutritional solution; and a health service axis involving nutrigenomic counseling and an empowered consumer.


Figure 4
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  		Figure 4  The nutrigenetic model of preemptive nutrition (A) is highly interdependent on its component parts. (B) The model in practice: folate x MTHFR (C677T) x homocysteine interaction.

 
As complicated as the nutrigenetic model may be, there are cases where it all appears to come together, a notable example being the biology of 1-carbon methyl metabolism of sulfur-containing amino acids (16,17), the gene for methylenetetrahydrofolate reductase (MTHFR), and its common population polymorphism C677T (Fig. 4 B). The importance of this particular gene-SNP combination is underscored by its many effects on pregnancy complications and birth defects, cardiovascular disease, cognitive impairment, some types of cancer, and possibly osteoporosis.

The cardiovascular-homocysteine hypothesis and recent clinical tests thereof are worthy of discussion as a heuristic example of preemptive nutrition. The C677T mutation in MTHFR substitutes a valine for alanine at position 222 of the primary protein, resulting in an increase in Km for its cofactor, FAD; this in turn results in a decrease in enzyme activity (18). Pursuant to the Michaelis-Menten equation, the aberration in reaction kinetics is obviated in the presence of high levels of folate (19). Left unmanaged, decreased MTHFR activity subsequently leads to high levels of homocysteine that are associated with a higher risk of coronary heart disease. Based on a meta-analysis of observational studies, it was predicted that a 25% decrease in serum homocysteine levels would be associated with 11% and 19% lower risk of ischemic heart disease and stroke, respectively (20). Unexpectedly, 3 recent intervention trials that were specifically designed to test the clinical hypothesis (VISP, HOPE-2, and NORVIT) all demonstrated that there was no cardiovascular benefit and possibly some harm associated with the use of folic acid and B vitamin supplements to correct hyperhomocysteinemia (21–23).

The homocysteine interventional trials offer a number of lessons and caveats central to the nutrigenomic model of preemptive nutrition. First, discordant outcomes between epidemiologic and clinical trials are not unusual. Notable examples of this lesson include the use of various antioxidant vitamins for heart disease (24), calcium for hip fractures (25), (n-3) fatty acids for cancer (26), and folate for cognition (27). Were all of these nutritional hypotheses wrong? We hope not, or at the very least categorical conclusions may be premature for the data in hand. It is more likely that the underlying biology of some very complex metabolic pathways has been simplified beyond the point of value in the tenets of the clinical hypothesis. Biological reductionism is a major caveat when targeting pathways that impinge on multiple biological systems wherein metabolic flux through 1 arm provides clinical benefit but can adversely affect another arm. Thus, although supplemental folic acid can effectively lower homocysteine levels, it may also trigger cell proliferation, change methylation potential, and modify gene expression (28). In this regard, the complexity of genetic variations within the folate-mediated 1-carbon transfer pathways (29) and the biological significance of epigenetic regulation of gene expression are just beginning to be elucidated (30,31).

Second, pharmacology is inevitably juxtaposed with toxicology, and even nutritional interventions, particularly those using dietary supplements to provide high levels of bioactive substances, may have unexpected risks. Notable examples of this untoward scenario include the higher postinfarction mortality associated with the use of arginine to reduce vascular stiffness and improve ejection fraction (32), the progression of coronary disease associated with the use of antioxidants in combination with simvastatin plus niacin (33), and the adverse shifts in LDL phenotype observed in a subset of the general population following a low-fat high-carbohydrate diet (34). At the genetic level, there is also the question of whether or not the substrate rescue of a given SNP could have unfavorable evolutionary consequences. As a case in point, folate supplementation selects for an increased frequency of C677T alleles with potential adverse effects on fertility (35). In this regard, the nutrigenomic model has some complicated timing considerations in terms of when to initiate the preemptive nutrition strategy.

Third and finally, nutritional interventions in established progressive diseases, such as atherosclerosis and cancer, may not represent the best-test scenarios for a preemptive nutritional hypothesis. In these diseases it may be critical to carefully position preemptive nutritional strategies in the context of pathobiological processes that are relevant to the initiation and progression of the disease and monitored by appropriate surrogate markers that may or may not be the same as the usual clinical outcome variables.

Nutrigenomics to nutritional phenotype

The major challenge of preemptive nutrition is to determine when we know enough to act in a preemptive manner and to have a path to reach this state of knowledge. The nutrigenomic model, although grounded in genetics, needs to develop a more holistic phenotypic focus (Fig. 5). To this end, the concept of nutritional phenotype has been put forth by the long-range planning committee of the American Society for Nutrition (36). The underlying premise of the nutritional phenotype is that there is "a defined and integrated set of genetic, proteomic, metabolomic, functional, and behavioral factors that, when measured, form the basis for assessment of human nutritional status." The assessment of this nutritional phenotype for the disease states of interest provides us the guide to what we really need to know to reduce preemptive nutrition to practice.


Figure 5
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  		Figure 5  The ultimate goal of preemptive nutrition is to manage a given nutritional phenotype to optimize health and offset disease.

 

   FOOTNOTES
 
1 Published in a supplement to The Journal of Nutrition. Presented as part of the International Research Conference on Food, Nutrition, and Cancer held in Washington, DC, July 13–14, 2006. This conference was organized by the American Institute for Cancer Research and the World Cancer Research Fund International and sponsored by (in alphabetical order) the California Walnut Commission; Campbell Soup Company; Cranberry Institute; Hormel Institute; IP-6 International, Inc.; Kyushu University, Japan Graduate School of Agriculture; National Fisheries Institute; and United Soybean Board. Guest editors for this symposium were Vay Liang W. Go, Susan Higginbotham, and Ivana Vucenik. Guest Editor Disclosure: V.L.W. Go, no relationships to disclose; S. Higginbotham and I. Vucenik are employed by the conference sponsor, the American Institute for Cancer Research. Back

2 Author Disclosure: No relationships to disclose. Back

5 Abbreviations used: HOPE, Heart Outcomes Prevention Evaluation; MTHFR, methylenetetrahydrofolate reductase; NORVIT, Norwegian Vitamin; SNP, single-nucleotide polymorphism, VISP, Vitamin Intervention for Stroke Prevention. Back


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