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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? and (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
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
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 upstreammarkers, 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.
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 affected, and an understanding of nutrigenomics is the key to developing effective and meaningful dietary and lifestyle interventions. This three-pillar approach demands that practitioners undertake 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.
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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).
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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.
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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."
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