Overcoming a Knowledge Gap to Develop Competent Nutrigenomics Practitioners

by Yael T. Joffe, PhD, RD; Christine A. Houghton, BSc (Biochem.), GradDip, R Nutr, PhD Cand

Introduction

The last decade and a half has seen the global proliferation of nutrigenetic testing companies. Overall, the direct-to-consumer (DTC) model has been mostly unsuccessful and the growth has come primarily from companies’ selling tests through practitioners. Many of the more reputable companies insist on their practitioners’ completing an accreditation course before they are “certified” to sell the companies’ tests. Although an admirable insistence, the integrity and depth of these courses vary. In addition, practitioners vary in their qualifications and experience. The result is that most practitioners are inadequately trained to interpret and effectively communicate nutrigenetic results and dietary recommendations.

Parallel to this growth in nutrigenetic tests, there has been a welcome increase in nutritional genomics academic programs, ranging from university short courses and elective modules in masters’ programs, to postgraduate programs, masters’, and doctoral degrees. A number of universities have begun to include a small amount of nutritional genomics teaching in their undergraduate curriculum. Understandably, these programs tend to be research based, and while they potentially offer academic integrity and research skills, they are not helpful in providing practitioners with the skills that they need to work with nutrigenetics in practice.

This article does not address whether or not the field of nutritional genomics is ready for practitioner use. (For this, we recommend “Nutrigenetics and Personalized Nutrition: Are We Ready for DNA-Based Dietary Advice?”)¹ Rather, it addresses the practitioner “knowledge gap,” describing what knowledge practitioners may be missing.

Defining the Knowledge Gap

The Nutrition Knowledge Gap

One of the greatest challenges is in bringing together the fields of nutrition and genetics. For doctors, medical specialists, dentists, homeopaths, and others, there is an acknowledged lack of nutrition education. For those with sufficient training in nutrition such as dietitians and nutritionists, the gap is the understanding of nutrition in a systems biology, functional, and political ecology context.

Nutritionism has become the ruling ideology of our current health care.² There is a great need for a new nutrition ideology, a new way of seeing and knowing about food, nutrition, health, and conditions such as obesity. Food needs to be taught, spoken about and practiced not only in a biomedical model but also with due consideration of the social, environmental, political, and economic relations that govern how food is produced and consumed. This requires an understanding of nutrition that starts with genes and ends with the environment; no easy task.

The Nutritional Genomics Knowledge Gap

Many practitioners, and surprisingly, academics as well, cannot differentiate between nutrigenetics and nutrigenomics (Figure 1). What is often referred to as nutrigenomics is in fact nutrigenetics. In this article we use the term nutritional genomics to mean both nutrigenetics and nutrigenomics. The tests that practitioners work with are more accurately nutrigenetics tests, and the training that they receive usually covers only nutrigenetic interactions (see sidebar: “Defining the Difference Between Nutrigenetics and Nutrigenomics”). This has resulted in an emphasis on SNPs (single nucleotide polymorphisms) and a “superficial” involvement with what the science of nutritional genomics has to offer. It is our contention that practitioners require an understanding of what we call the “three pillars of nutritional genomics” (Figure 2).

These include:

1. nutritional biochemistry

2. nutrigenetics

3. nutrigenomics

• Figure 1: Nutrigenetics and Nutrigenomics: Know the Difference

Figure 2: The Three-Pillar Approach

Biochemical processes are driven and understood through nutritional biochemistry. It is imperative to understand the biochemical pathways and the disruption thereof, which contribute to perturbations in health and potentially the development of disease. Nutrigenetics provides information on genetic sequence variants: SNPs as well as other variation such as copy number variants. These may (but not always) alter gene expression or enzyme function. By understanding nutrigenomics (nutrient impact on gene expression), a practitioner is able to identify and advise on nutrients and lifestyle changes that may alter gene expression. Put together, these three pillars of nutritional genomics will empower the practitioner to construct targeted and clinically useful dietary and lifestyle recommendations.

BOX:

Defining the Difference Between Nutrigenetics and Nutrigenomics

Genetic variability (nucleotide sequence change) influences how we interact with our environment. Nutrigenetics describes the influence of gene variants on our ability to interact with bioactive molecules in the molecular environment surrounding our cells and the consequences of that interaction.

In contrast to nutrigenetic interactions wherein the gene variants acts on the environment, with nutrigenomic interactions, the environment influences gene expression. Nutrigenomics is concerned with the influence of bioactive molecules interacting with a gene, potentially influencing gene expression. Either upregulating or downregulating (turning it up or down) or activating or silencing (on or off). Nutrigenomic interactions may be direct or indirect. In a direct interaction, the molecules are of small molecular weight, carrier mediated, and lipid soluble. In an indirect interaction, the molecules are larger and hydrophilic. These molecules interact at the cell surface.

Employing the Three-Pillar Approach in Practice

The Fundamental Strategy

A key consideration in the three-pillar approach is to focus initially on upstream biochemical events. Each gene codes for an enzyme, and that enzyme is involved in one or more biochemical pathways. If practitioners understand the nature of that pathway when it is functioning normally, they can better predict what may happen when a variant of the gene produces an enzyme operating at lower activity. Understanding the function of the key upstream biochemical pathways is at the core of this approach. Human cells utilize a number of core biochemical processes in maintaining their homeostasis; these include redox regulation, detoxification, inflammation modulation, energetics, and methylation. These five upstream processes form the foundation for the first pillar.

Redox dysregulation and associated inflammation as upstream factors are common elements of numerous chronic diseases.³ Nutrigenetic test profiles typically include SNPs that affect the primary antioxidant enzymes and major inflammatory cytokines, whereas they are unlikely to include many of the disease-specific downstream gene variants.

The following example uses type 2 diabetes to examine the evolving identification of associated genes and their function. Genome-wide association studies (GWAS), linkage, and candidate gene association studies have identified a number of diabetes-related genes; however, these studies are inconsistent in their findings. A 2007 study identified the genes PPARG, KCNJ11 and TCF7L2 as established genes associated with common forms of type 2 diabetes.⁴ Eighteen months later, another study found that the number of gene loci robustly associated with type 2 diabetes had risen from 3 to 18 in the ensuing period.⁵ Their findings included the obesity-related genes FTO and MC4R, and they concluded that 7 of these identified type 2 diabetes gene loci affect beta-cell function, but the function of 9 other genes was unknown. By 2010, largely through GWAS, approximately 20 gene variants associated with type 2 diabetes had been identified, with some overlap of 10 with body mass index (BMI) and obesity, 4 with fasting glucose levels in the normoglycemic population, and over 30 with lipid levels.⁶

Clearly, this field is still evolving, and what is clinically significant is that there are no known interventions to modify the expression of some of these genes. In the three-pillar approach, these downstream genes may be considered only after the core upstream biochemical processes have been addressed.

As with many chronic diseases, redox dysregulation is accepted as a fundamental contributor to both the onset and the progression of type 2 diabetes. Examining the relevant gene variants from a nutrigenetic profile gives the practitioner a guide to the redox regulating potential of that patient. Following such an analysis, the appropriate nutrigenomic interventions can be selected in order to modify the expression of one or more genes.

Case Study

: A 46-year-old female presents with recently diagnosed type 2 diabetes. Her diet is poor and her BMI is 29. Nutrigenetic testing shows the following SNPs in her redox panel (Table 1). Space does not permit a full nutrigenetic analysis.

Pillar

1: The Nutrigenetic Profile

Table 1: Redox Panel

Pillar

2:

The Biochemical Analysis

The superoxide radical is generated continuously by the mitochondria from inhaled oxygen. in certain circumstances such as during exercise, there is an increased flux of oxygen through the mitochondria. This increases the quantity of superoxide radical produced and this acts as the prooxidant signal needed to activate the cells’ endogenous defense mechanisms. As a consequence, the expression of the MnSOD gene is upregulated so that more MnSOD enzyme is produced; the same applies to increased expression of the GPX gene. Just as exercise increases the flux of oxygen, glucose and fatty acids through the mitochondria, so too does overeating. Several pathways in type 2 diabetes contribute further to this increased flux .⁷

These two primary upstream reactions constitute the first line of cellular defense against oxidative stress.⁸ As shown in Figure 3, two superoxide radicals dismute to produce hydrogen peroxide, a nonradical reactive oxygen species (ROS) that can readily react with metal ions to produce highly toxic hydroxyl radicals (OH⁻). If acted upon by GPx in the normal manner, hydrogen peroxide readily converts to unreactive water, thereby removing the oxidative risk.

Figure 3: Superoxide Redox Reaction

Reaction # 1 2O2− + 2h+ SOD H2O2 + O2

Reaction # 2 2 H2O2 GPx 2H2O

In our case study, the patient carries a “normal” MnSOD and so the mitochondria are likely to perform Reaction # 1 adequately, generating hydrogen peroxide. However, she carries a GPx SNP, thereby limiting the activity of the GPx enzyme. As a result, hydrogen peroxide will tend to accumulate at a rate faster than can be handled by the dysfunctional GPx enzyme. Consequently, hydrogen peroxide is more likely to react with available heavy metal ions to produce the hydroxyl radical, which can oxidatively damage a range of proteins, lipids, DNA and RNA, and other biomolecules. What this tells us is that although the patient carries a “normal” MnSOD gene, the potential for oxidative damage is still increased. GPX1 has been implicated in the development and prevention of many common and complex diseases including cancer and cardiovascular disease.⁹

Pillar

3:

Nutrigenomic Interventions

The goal of a nutrigenomic intervention is to provide one or more food-derived compounds known to induce the expression of a specific gene for which increased enzyme activity is desirable. There are two fundamental aspects to consider: (a) Is there an essential cofactor for the enzyme? (b) Are there food-derived bioactive compounds that can induce the expression of the gene itself?

In our case study, the GPX1 variant produces the glutathione peroxidase enzyme that is suboptimal in its activity. The trace element selenium is an essential cofactor in GPx enzyme activity, and so the first approach is to evaluate the nutritional status of this nutrient in the patient and either increase dietary sources of selenium or supplement appropriately if necessary.

The second important strategy is to provide an appropriate bioactive where known; one reported nutrigenomically active food element is a melon/gliadin extract that has been shown to increase activity of GPx, SOD and CAT enzymes.¹⁰ It is important to note that direct-acting antioxidant vitamins (A, C, E, beta-carotene) have no place as nutrigenomic interventions unless there is demonstrable deficiency; altering the cellular redox milieu in this way is likely to mask the subtle signals that cells rely on to activate endogenous defenses.¹¹

Further Implications

The role of redox regulation cannot be underestimated as a primary upstream event in disease etiology. Redox imbalance and inflammation function in a self-perpetuating loop, so that to satisfactorily address inflammation, redox balance must also be considered.¹² Similarly, elevated superoxide levels can inhibit the enzyme aconitase, the rate-limiting step in generation of ATP via the Krebs cycle. In detoxification reactions, phase I generates superoxide, and if phase II is not sufficiently active to prevent accumulation of toxic intermediates, key biomolecules, and delicate organelles can be severely compromised. Similar arguments can be mounted to show how methylation and redox imbalance are closely interrelated.¹³

Case Summary

The approach described very briefly here addresses just a few of the upstream factors contributing to type 2 diabetes and its progression in this patient. In the clinical environment, the nutrigenetic report would identify SNPs from other genes associated with upstream factors such as those coding for inflammatory cytokines, other key protective enzymes such as antioxidant and detoxification enzymes and the nonenzyme antioxidant glutathione.

In the three-pillar approach, the practitioner would consider the possible effects of these SNPs in the relevant biochemical pathways, ordering pathology (functional) tests where indicated. Appropriate pathology tests are useful in assessing whether the particular SNP is compromising biochemical function. These tests can be useful because not all SNPs result in compromised biochemical function for two reasons: (a) there may be other genes which effectively “substitute” for the defective gene – for example, quinone reductase (NQO1), a phase II detoxification enzyme, can quench superoxide radicals if SOD function is less than optimal; and (b) the patient’s diet and/or lifestyle may be such that the expression of that gene has been modified nutrigenomically. Where a patient carries a SNP, and pathology testing confirms compromised function, the practitioner may then provide dietary and supplement recommendations known to modify the expression of the aberrant gene(s).

A recent study highlighted the Mediterranean diet as an effective intervention. in a randomized controlled trial, the researchers examined the effects of the Mediterranean diet in type 2 diabetics, investigating the upstream markers, plasma antioxidant capacity, endothelial function, nitrotyrosine, 8-iso-PGF2a, IL-6, and ICAM-1 levels.¹⁴ They found that this intervention prevented the effect of acute hyperglycemia on endothelial function, inflammation, and oxidative stress.

As in the type 2 diabetes example we described earlier, addressing the upstream factors as shown in the Ceriello study is a strategy that may deliver significant benefit to the patient with or without considering the downstream gene variants for which nutrigenomic interventions are not well understood.

Conclusion

What we have endeavored to identify is the knowledge gap experienced by most practitioners who wish to include the field of nutritional genomics in their practices. We have described why the current educational offerings are inadequate, but we have also shared what we believe to be the knowledge required to integrate nutritional genomics into clinical practice.

It is not enough to be told or even to know what impact a SNP may or may not have on enzyme function and what disease associations have been reported in the scientific literature. Nutrigenetics must exist in the context of nutritional biochemistry to provide a deeper understanding of the biochemical pathways that have been impacted, and an understanding of nutrigenomics is the key to developing effective and meaningful dietary and lifestyle interventions. This three-pillar approach demands that practitioners will require more in-depth, expansive training, but it will also ensure that they will then be in a position to understand the biochemical environment of gene variants and have the skills and knowledge to independently construct dietary recommendations that surpass the recommendations offered by commercial nutrigenetic tests.

Notes

1. Grimaldi KA. Nutrigenetics and personalized nutrition: are we ready for DNA-based dietary advice? Pers Med. 2014/05/01 2014;11(3):297–307.

2. Scrinis G. On the ideology of nutritionism. Gastronomica. 2008;8(1):39–48.

3. Sanghera DK, Blackett PR. Type 2 diabetes genetics: beyond GWAS. J Diabetes Metab. Jun 23 2012;3(198).

4. Zeggini E. A new era for Type 2 diabetes genetics. Diabet Med. Nov 2007;24(11):1181–1186.

5. Perry JR, Frayling TM. New gene variants alter type 2 diabetes risk predominantly through reduced beta-cell function. Curr Opin Clin Nutr Metab Care. Jul 2008;11(4):371–377.

6. De Silva NM, Frayling TM. Novel biological insights emerging from genetic studies of type 2 diabetes and related metabolic traits. Curr Opin Lipidol. Feb 2010;21(1):44–50.

7. Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res. Oct 29 2010;107(9):1058–1070.

8. Bag A, Bag N. Human manganese superoxide dismutase target sequence polymorphism and ovarian cancer. Ann Med Health Sci Res. Mar 2014;4(Suppl 1):S69–70.

9. Lubos E, Loscalzo J, Handy DE. Glutathione peroxidase-1 in health and disease: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal. Oct 1 2011;15(7):1957–1997.

10. Cloarec M, Caillard P, Provost JC, Dever JM, Elbeze Y, Zamaria N. GliSODin, a vegetal sod with gliadin, as preventative agent vs. atherosclerosis, as confirmed with carotid ultrasound-B imaging. Eur Ann Allergy Clin Immunol. Feb 2007;39(2):45–50.

11. Hart C, Cohen R, Norwood M, Stebbing J. the emerging harm of antioxidants in carcinogenesis. Future Oncol. May 2012;8(5):535–548.

12. Sena CM, Pereira AM, Seica R. Endothelial dysfunction – a major mediator of diabetic vascular disease. Biochim Biophys Acta. Dec 2013;1832(12):2216–2231.

13. Lupoli R, Di Minno A, Spadarella G, et al. Methylation reactions, the redox balance and atherothrombosis: the search for a link with hydrogen sulfide. Semin Thromb Hemost. Jun 2015;41(4):423–432.

14. Ceriello A, Esposito K, La Sala L, et al. the protective effect of the Mediterranean diet on endothelial resistance to GLP-1 in type 2 diabetes: a preliminary report. Cardiovasc Diabetol. 2014;13:140.

Yael T. Joffe, PhD, RD

Manuka Science, South Africa

In the rapidly-evolving disciplines of nutrigenomics and nutrigenetics, Dr. Yael Joffe is acknowledged globally as an expert in the field. From her background as a dietician, she obtained her PhD from the University of Cape Town, exploring the genetics and nutrition of obesity in South African women. She is a regular speaker at conferences and workshops, tailoring her presentations to the needs of clinicians. She has coauthored It’s Not Just Your Genes, has published on nutrigenomics in peer-reviewed journals, and has been involved in the development and supervision of nutrigenomics courses around the world. Dr Joffe is currently an adjunct professor, teaching nutrigenomics at Rutgers University, and has developed and teaches the Manuka Translational Nutrigenomics online course.

Christine A. Houghton BSc (Biochem), GradDip Hum Nutr, R Nutr, PhD Cand

School of Human Movement Studies, University of Queensland, Brisbane,

Queensland, Australia

Following 30 years in private practice as a nutritional biochemist, Christine is currently engaged in doctoral research at the University of Queensland, investigating bioactive nutrigenomic phytochemicals with significant clinical potential. Christine’s forte lies in taking complex biochemical concepts and translating their essence into concepts relevant to the needs of practicing clinicians. She is a regular presenter at medical and nutrition conferences, where her knowledge of and enthusiasm for the roles of nutritional medicine and nutrigenomics in human health are very evident. She is the author of Switched On – Harnessing the Power of Nutrigenomics to Optimise Health. Her peer-reviewed publications include the Special Article published in 2013 in Nutrition Reviews: “Sulforaphane: Translational Medicine from Lab Bench to Clinic.”