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Keywords:

  • diet;
  • health;
  • proteomics;
  • transcriptomics;
  • metabol/nomics;
  • nutrigenomics

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. DIET AND DISEASE
  5. DIET AND GENES
  6. NUTRIGENETICS
  7. BENEFITS AND RISKS
  8. MANY HANDS MAKE LIGHT WORK?
  9. CONCLUSIONS
  10. REFERENCES

The science of nutrigenomics allows us to consider not only the response of our genes, proteins and metabolism to diet but also life-stage and lifestyle. Public health messages are failing to change people's behaviour and to counteract the flashy advertising promoting cheap nutritionally-empty foods. Proponents suggest that using the information supplied by nutrigenomics to develop personalised diet and lifestyle regimens would enable consumers to make healthier choices for themselves. For some this will mean accessing new food products and genetic testing but for others it will mean better dietary advice that can be applied in their situation. Opponents argue that this approach merely panders to the worried-wealthy-well – those least in need of intervention because they are already diet and health conscious – and that nutrigenomics fails to address the real issues associated with diet-related disease. Is nutrigenomics another over-hyped science, which will ultimately disappoint, or is it an ideal tool for nutrition research? Copyright © 2007 Society of Chemical Industry


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. DIET AND DISEASE
  5. DIET AND GENES
  6. NUTRIGENETICS
  7. BENEFITS AND RISKS
  8. MANY HANDS MAKE LIGHT WORK?
  9. CONCLUSIONS
  10. REFERENCES

The European Nutrigenomics Organisation (NuGO) is a network of excellence (CT2004-505 944 www.nuo.org). It is funded by the EU Research Directive General Sixth Framework Programme for Research and Technological Development under Priority Thematic Area 5 Food Quality and Safety. In 2004, the Commission invested 17.3 million Euros (over 6 years) because, although nutrigenomics appeared to have great potential, the technology was not validated and the research effort was fragmented. Whilst this is a substantial amount of money, it is relatively small for one of the biggest revolutions in nutritional science. It is also becoming increasingly controversial; whether the EU or, for that matter, national governments should be investing money in an unproven science as compared with public health initiatives. It might be argued, however, that this investment is not only valid but also essential.

Crick and Watson had their own controversies, but they discovered the structure of DNA at a time when the scientific world was not required to justify its expenditure or explain the science. The world has moved on and, to differing extents, science must justify itself to those who pay for the research done in their name, be it taxpayers or shareholders. In the early 1950s, when Crick and Watson were pursuing their goal, many Europeans were still worried about how to ensure there was enough food, not whether we had too much or what proportion of energy was coming from fat as compared with carbohydrates. Diet dictated by government is not a realistic prospect in the 21st century. Whether personalised nutrition—one possibility to come from nutrigenomics—is any more realistic remains to be seen.

DIET AND DISEASE

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. DIET AND DISEASE
  5. DIET AND GENES
  6. NUTRIGENETICS
  7. BENEFITS AND RISKS
  8. MANY HANDS MAKE LIGHT WORK?
  9. CONCLUSIONS
  10. REFERENCES

There are three factors—all inextricably linked—that affect our risk of developing age-related diseases: our genes, our lifestyle and our life-stage. Our life-stage and our genes are not in our control. Some of us have inherited genetic disease unrelated to diet (e.g. cystic fibrosis) and some carry a high risk of specific disease (e.g. breast cancer), which may or may not have a link with diet.

As we grow older, our bodies are less effective at avoiding disease. Our immune systems are less able to detect and mount a defence; DNA becomes more error prone; and proteins are less efficient. The resulting breakdown in cellular structure and function leads to those diseases we associate with old age: cancer, cardiovascular disease (CVD), type II diabetes, cataract and macula degeneration, arthritis etc. Diet has a role to play both in the maintenance of our bodies and the prevention of these diseases.1

At first glance, lifestyle would appear to be the only factor that we do control. We are, for example, able to control our weight for height, our intake of alcohol, choose whether or not to smoke, eat a diet rich in fruit and vegetables, cereals and plant-derived oils, and take regular exercise. These factors alone will determine whether the majority of the population are at high or low risk of developing age-related disease. However, you can only make these choices if you have the education to access and act upon the information available, and if poverty and related issues do not dictate where you live, what you eat, and what you do for employment and recreation.

Food has always been linked with politics whether it is farming subsidies, the power of the retailer over the supplier, or access to safe, nutritious, and ethical food. In the UK, the latest issues to be brought to the fore are school dinners and hospital meals, and quite rightly so since both represent nutrition for vulnerable populations who should be offered the best choices. Because in the end, food is about choice: what we eat, where we eat it and with whom, and we should be able to make the choice to eat healthy food just as easily. Some 80% of case-control studies support the hypothesis that diet can reduce the risk of chronic age-related illness.1 As European children and young people have exchanged their parents' traditional diets for the fast-food culture of north-western Europe and the United States so incidences of diet- and age-related have increased. In the past, southern Europeans have been much less likely to develop age-related disease, which has meant they experience a much higher quality, disease-free life in later years.1–3

DIET AND GENES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. DIET AND DISEASE
  5. DIET AND GENES
  6. NUTRIGENETICS
  7. BENEFITS AND RISKS
  8. MANY HANDS MAKE LIGHT WORK?
  9. CONCLUSIONS
  10. REFERENCES

We are exposed to a complex mixture of foods throughout life and intricate biochemical processes extract energy and use nutrients and other compounds to enable us to grow and function properly. In the past, many food compounds were dismissed as being unimportant, having no obvious nutritional role. However, dietary intake is not just about avoiding deficiency diseases but also optimal health or the avoidance of age-related disease, and what is obvious is that the benefits of some dietary choices are not the same for everyone. In the past, we have been limited in our scientific exploration to a few dietary compounds, a handful of relevant biochemical pathways and perhaps latterly a small number of genes that might be pertinent to the disease in question. The result has been some specific examples of benefit provided by individual/groups of food compounds.

For example, eating foods that contain plant polyphenols (e.g. apples, onions etc.) reduces an individual's risk of developing gastrointestinal tract cancers.4 Consumption of cooked tomato sauces reduces a man's likelihood of developing prostate cancer, and may also offer protection from some breast cancers where there is a family history of breast or prostate cancers. The benefits have been attributed to lycopene (the carotenoid that makes tomatoes red) but, oddly, eating raw tomatoes does not provide the same defence.5 A high folate intake reduces plasma homocysteine, which is an independent risk factor for CVD. Folate also maintains proper DNA synthesis and repair, and optimises gene regulation protecting against neural tube defects in the fetus, and neurodegeneration in later years.6 Associated with these general benefits are some more specific diet-gene interactions.

NUTRIGENETICS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. DIET AND DISEASE
  5. DIET AND GENES
  6. NUTRIGENETICS
  7. BENEFITS AND RISKS
  8. MANY HANDS MAKE LIGHT WORK?
  9. CONCLUSIONS
  10. REFERENCES

Perhaps more easily understood than nutrigenomics, nutrigenetics is the science behind single-gene/single-food compound relationships. One of the best-described examples is the relationship between folate and the gene for 5,10-methylenetetrahydrofolate reductase (MTHFR).7

MTHFR has a role in supplying 5-methylenetetrahydrofolate, which is necessary for the re-methylation of homocysteine to form methionine. Methionine is essential to many metabolic pathways include production of neurotransmitters and regulation of gene expression. Folates are the essential dietary component for this biochemical pathway. There is a common polymorphism in the gene for MTHFR that leads to two forms of protein: the reference sequence (C), which functions normally, and the thermal-labile variant (T), which has a significantly reduced activity. People with two copies of the reference sequence (CC) or one copy of each (CT) appear to have normal folate metabolism. Those with two copies of the unstable variant (TT) and low folate intake accumulate homocysteine and have less methionine, which increases their risk of vascular disease and premature cognitive decline.

Supplemented with folic acid (or increased intake of folate from food sources), these individuals quickly metabolise the excess homocysteine restoring their methionine levels to normal. Currently, we are aware of about 20 genes that that have polymorphisms that appear to confer a significant disadvantage, which may be overcome with specific dietary modification. Businesses such as Sciona Inc. (www.sciona.com) and Genelex Inc. (www.genelex.com) in the US base their services on this knowledge and the scientific literature that supports it.

There are, however, a number of wider issues to consider. In the first place, genotypes that confer a substantial survival disadvantage are not usually preserved in a population. Those that are, have been shown to offer some other benefit. For example, it was widely assumed that both the genes for sickle cell disease and thalassaemias were for the individuals involved tragic and for the population at large disadvantageous. We now know that individuals with a single copy of these genes have inherent protection from malaria, which is endemic in regions where these variants are most commonly found. The fact that the most common polymorphism for the MTHFR gene is present in 15–20% of European population must at least raise the question why it and the other genes have persisted so successfully. Secondly, these 15–20 genes represent 0.1% of human genes; Ensembl (www.ensembl.org) estimates there are 22 218 protein coding genes in the human genome. Currently, we neither know how or which of these genes interact with one another nor the consequences of modifying the response of a few on the majority and the effects of that on our immediate or long term health. Thus, while increasing your intake of folate may be beneficial in the long term, it may be shown at some point in the future that increased intake has unforeseen risks for some individuals or sub-populations.

BENEFITS AND RISKS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. DIET AND DISEASE
  5. DIET AND GENES
  6. NUTRIGENETICS
  7. BENEFITS AND RISKS
  8. MANY HANDS MAKE LIGHT WORK?
  9. CONCLUSIONS
  10. REFERENCES

Intervention studies from the 1990s demonstrated the risks associated with long-term, high-dose supplementation (e.g. Carotene and Retinol Efficacy Trial—CARET and ATBC Study).1 Smokers and asbestos workers were given β-carotene and either vitamin E or vitamin A at levels far in excess of normal dietary intake with the aim of preventing lung cancer, and reducing incidences of other cancers and CVD in general. The studies were stopped when early data indicated lung cancer rates had increased by up to 8%, entirely contrary to the prediction made from existing epidemiological and data in vitro.

Hindsight has demonstrated that whilst the studies were developed on current information, there were a number of confounding factors some but not all of which could have been predicted. Cell culture model systems are exposed to high concentrations of oxygen making benefits more likely to be detected because the cells are normally under oxidative stress. The cells are transformed, immortalised or otherwise derived from tumour tissue, which means their response to food compounds may be abnormal. Certainly, delivery, absorption, metabolism and excretion of food compounds in culture systems are very different to those in the body. For the majority of food compounds, tissue stores are not known or not accessible in healthy volunteers. Plasma and other surrogate tissues (e.g. peripheral blood lymphocytes) are generally neither the target tissue for disease nor exposed to the same concentrations of bioactive compounds as target tissues. Thus, their response(s) may not be representative. Finally, studies in vivo are, for very practical reasons, unable to examine the whole person, or use whole food, which means researchers are forced to make assumptions about the compound that is responsible and its mechanism of action.

Post-genomic technologies take a more holistic perspective and use the information provided by the sequencing of the human genome, allowing us to measure how what we eat interacts with our bodies, or more specifically our genes, proteins and metabolism. Nutrigenomics is the science that examines the response of individuals to food compounds using post-genomic and related technologies (e.g. genomics, trascriptomics, proteomics, metabol/nomic etc.). The long-term aim of nutrigenomics is to understand how the whole body responds to real foods using an integrated approach termed ‘systems biology’. The huge advantage in this approach is that the studies can examine people (i.e. populations, sub-populations—based on genes or disease—and individuals), food, life-stage and life-style without preconceived ideas.

MANY HANDS MAKE LIGHT WORK?

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. DIET AND DISEASE
  5. DIET AND GENES
  6. NUTRIGENETICS
  7. BENEFITS AND RISKS
  8. MANY HANDS MAKE LIGHT WORK?
  9. CONCLUSIONS
  10. REFERENCES

Three years ago the application of these technologies in nutrition was relatively untried and untested. They were clearly powerful tools with enormous potential, but there was a need for standardised in approach both in terms of the logistics and study design. The European Nutrigenomics Organisation (NuGO) was formed to establish the use of post-genomic and related technologies for the benefit of European nutritional science, facilitate their application, and train a new generation of European scientists. It brought together 22 organisations from across 10 European countries (Eire, France, Germany, Italy, Netherlands, Norway, Poland, Spain, Sweden and UK). Three years in and there are two new partners, one SME (small–medium sized enterprise) and one academic, as well as six collaborating centres.

Returning from NuGO week where 270 representatives from the partner organisations, the food and biotech industries and worldwide nutrigenomics research were present, it was easy to see where progress has been made, not least the interaction between individuals from different organisations but also across specialities; it seems molecular biologists and mathematicians can talk to one another.

The post-genomics technologies are still an enormous challenge in humans. Much of the work already in the literature or being prepared for publication is in animal or cell models, not free-living humans. Consideration of a handful of related genes, biochemical pathways and single food compounds has been replaced by contemplation of complex interacting biochemical pathways in parallel. For example, if you want to consider the role of vitamin E in the prevention of CVD then it is necessary to also include analysis of lipid and lipoprotein genotypes; glucose metabolism (i.e. the insulin–glucagon regulatory mechanism); triglyceride regulation (which retinoids, and therefore some carotenoids, may also act on); and fatty acid metabolism.

Currently, it is metabol/nomics that is making the most rapid inroads into this complex critical thinking. This is partly because nuclear magnetic resonance (NMR) and mass spectroscopy (MS) are established techniques, but also because the application of pattern-recognition statistics, such as principal component analysis, is conventional in this field. Metabol/nomics also has the advantages of offering more immediate information about our metabolism, which is not presented by changes in gene transcription or protein expression since both can occur without apparent metabolic consequences.

Microarrays represent a powerful tool for studies of diet–gene interactions but their use is still associated with a number of technical challenges as well as questions about biological significance.8 There are only three papers published to date that describe the use of microarrays to examine the expression of genes on a day-to-day basis in apparently health humans without any dietary intervention.9–11 In the most recent of these studies, transcript levels for the majority of genes examined were found to be consistent within samples from a single donor. Conversely, marked differences were observed in samples obtained from different donors. Genes that exhibited differential expression dependent on sex, age, body mass index, and the presence of varying proportions of different leucocyte subsets were also identified. These results emphasise the important contributions of genetic and environmental factors as well as varying representation of different cell types in determining the overall gene transcriptional profiles of human tissues. In short, whilst intra-individual gene expression is generally consistent from day-to-day, inter-individual differences are significant and the relationships between long-term health and genes, and gene transcription, protein translation and functionality, and our metabolism are still unknown.

Similarly, although every nutritional process relies on the interaction of cellular proteins, very few reports have used proteomics as a tool for nutrition research.12 This is in part because although there are alternatives, the method most commonly employed relies on old technology, namely two-dimensional gel electrophoresis, which is time-consuming and labour-intensive. Furthermore, intra- and inter-experimental comparisons are complicated by differences in gel size (e.g. 18 cm vs 24 cm) and pH range, choice of dyes, and the natural warping or tearing of the fragile gel. The image analysis software, particularly spot detection, is both technically poor in practice and expensive. Gene expression is a multi-step process involving transcription (production of RNA), translation (production of protein) and post-translational processing of proteins (eliciting effects such as activation and inactivation) and regulatory shifts in these different steps often do not parallel each other. For this reason, analysis of RNA levels, using approaches such as microarrays is not sufficient on its own. Determining the presence or absence of metabolic proteins and their relative abundance is critical in understanding the role and impact of food compounds on our metabolism, and health.

NuGO has considered the practical and theoretical considerations in use of microarrays and proteomics, which represent potential sources of technical variation and error, and wherever possible made recommendations to offer a basic framework of advice for researchers who are new to these technologies. Similar publications describing metabol/nomics, and the storing and sharing of data from nutrigenomics studies will follow. NuGO does not intend that it should dictate progress in any of these fields but rather promote discussion of standardisation and best practice.

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. DIET AND DISEASE
  5. DIET AND GENES
  6. NUTRIGENETICS
  7. BENEFITS AND RISKS
  8. MANY HANDS MAKE LIGHT WORK?
  9. CONCLUSIONS
  10. REFERENCES

Coupled with cost of post-genomics and associated technologies, both financial and in terms of manpower, the complex logistical issues associated with performing nutritional microarray and/or proteomic studies often means compromises have to be made in the number and type of samples analysed as well as the design of the original study. Additionally, technical variations between array platforms and analytical procedures/proteomics approaches lead to differences in the responses observed. Consequently, conflicting data have, and will, continue to be produced; important effects may be missed and/or false leads generated. This is particularly pertinent in the field of nutrition since many dietary bioactive agents at nutritionally relevant concentrations will elicit subtle changes in gene transcription/protein translation—unlike those generally associated with pharmaceutical products—which may be critically important in biological terms but difficult to detect. This is not, however, an excuse for poorly designed studies subjected to inadequate statistics; quite the reverse.

Similarly, the ethical, legal and societal aspects of nutrigenomics are as complex as the technical difficulties but they are infinitely more sensitive. Some of the information emerging from nutrigenomics research is difficult to handle. For example, a variant in the apolipoprotein E protein (e4/e4) is associated with increased risk of early CVD.13 Changes in the intake of dietary fats are successful in reducing this risk but, unlike the examples of single gene disorders given above, the individual may or may not become ill in the future. He or she is only more likely to experience CVD at an earlier age than someone without this mutation; when and in what form remains uncertain. However, this genotype is also linked with a 60% increased risk of developing Alzheimer's disease. Currently, there is no means of preventing or curing Alzheimer's disease, and it is not clear whether reduced risk of CVD, following modification of an individual's dietary lipid intake, is concomitant with reduced risk of Alzheimer's disease. And, here again, it is only a 60% increased chance, not a certainty, of developing Alzheimer's disease at some time in the future. For this reason, it is considered unethical to tell volunteers participating in human nutrition studies that they have this particular apolipoprotein E mutation, despite the potential benefits with respect to CVD risk. Deeper understanding of the effects of differences in genetic code will come in the future but we need to consider what we do with this information now.

Just as with genetic diseases, nutrigenomics must allow choice; the right to opt out of knowing whether you are a carrier of a particular genotype, and the right to full employment and insurance benefits regardless of whether you choose to access that information, and the right to ignore dietary and lifestyle advice. The pharmaceutical industry has much to offer nutritional science in trial design, and understanding of risk–benefit. Sadly, it also has much to teach us about economic access to ‘treatment’ and the right not to be discriminated against. Promotion of healthy patterns of nutrition and lifestyle are paramount and key messages on a healthy diet are well established. We should not risk diluting these messages with premature speculation about what nutrigenomics can achieve or raise unrealistic expectations. It would also be unfortunately to scare people about increased risk of age-related disease unnecessarily. The reality is, however, that poor dietary choice within a sedentary lifestyle is contributing to increased obesity and associated diseases including type II diabetes. The ‘one-size-fits-all’ strategies in public health have not always been delivered consistently, which may be why they do not appear to be working to change people's dietary habits, and personalising nutrition may be more effective in achieving long term change. Nutrigenomics is not an alternative to public health policies but it does have much to contribute.

In the end, humans are complex and so too are their diets; these make nutrition science and the questions it must address fiendishly difficult. Although they still seem impossibly complicated, nutrigenomics and systems biology are the ideal, and perhaps, only tools able to answer the question—what should we be eating?

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. DIET AND DISEASE
  5. DIET AND GENES
  6. NUTRIGENETICS
  7. BENEFITS AND RISKS
  8. MANY HANDS MAKE LIGHT WORK?
  9. CONCLUSIONS
  10. REFERENCES