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beause it is a mixim, " you are what you eat "

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  1. 1. Nutrigenomics – An emerging field of science and technology unrevealing interrelationships between nutrients and human genome using modern tools such as Transcriptomics, Metabolomics, Epigenomics and Proteomics By Raffia Siddique, Hafsa Iftikhar, Rabia Ejaz, Tahira Karim Interaction of food with human genome- Nutrigenomics
  2. 2. NUTRIGENOMICS-AN EMERGING FIELD 2013 List of contents                 Introduction to Nutrigenomics Emerging faces of nutrition, nutrigenomics and nutrigenetics Experimental Approaches and Technologies used in Nutrigenomics Metabolomics-newest tool for Nutrigenomics Epigenomics has relation in Nutrigenomics The importance of single nucleotide polymorphisms Transcriptomics - Nutrigenomics interrelationship Transcriptomics and micro-array technology Proteomics Proteomic technologies Biomarkers Effects of different nutrients on human genome Elements present in food cause potential damage to human genome Coffee and cigarettes combat rare liver diseases Nutrigenomics and Ethical control Looking forward to things which can resolve the ethical , social, legal issues  Conclusion and future perspective 2 Siddique.R, Ejaz.R, Iftikhar.H and A.Karim.T NUST-ASAB
  3. 3. NUTRIGENOMICS-AN EMERGING FIELD 2013 Nutrigenomics – An emerging field of science and technology unrevealing inter-relationships between nutrients and human genome using modern tools such as Transcriptomics, Metabolomics, Epigenomics and Proteomic Hafsa Iftikhar, Raffia Siddique, Rabia Ejaz, Tahira Karim and Dr.Alvina-The supervisor National University of Sciences and Technology,,, Abstract Nutrigenomics is emerging field in 20th century, as the old maxim ―we are what we eat‖. Nutrition and genetics both are play significant role in the maintenance of human health as well as the development of lethal diseases. Genetic variations toward dietary response and the nutrients response in gene expression can also be explored by nutrigenetics and nutrigenomics According to different research studies nutrients is also having the abilities of altering the genetic expression at gene regulation level, signal transduction or by altering chromatin structure or changing protein function. The emerging fields of sciences and technology such as Transcriptomics, metabolomics, Epigenomics, which are very advanced studies, are being used to go through the nutrigenomics. Metabolomics applications in crop or food analysis are continually growing and the use of mass spectrometry (MS) and liquid chromatography (LC), GC-MS and NMR are being used. Epigenetics also known by the soft inheritance is the ability to change gene activity without changing gene sequence. Diet can alter the epigenetic state of the genome leading to dramatic deprogramming or reprogramming of large numbers of genes in metabolic pathways and physiological systems. Transcriptomics extensively report all data that happens in RNA pool within a system. Genome-wide monitoring of gene expression allows us assessment of transcription of thousands of genes along with their expression in normal and diseased cells before and after their exposure to different bioactive components. 3 Siddique.R, Ejaz.R, Iftikhar.H and A.Karim.T NUST-ASAB
  4. 4. NUTRIGENOMICS-AN EMERGING FIELD 2013 Key words Nutrigenomics, SNPs, Transcriptomics, Epigenomics, Metabolomics, nutrigenetics, NMR, mass spectrometry. Introduction As the scientific knowledge of nutrigenomics is increasing day by day, the old maxim ―we are what we eat‖ has been proved a true statement. Nutrigenomics mainly involves the relationship between diet and genetics, it also discover the beneficial and the inimical effects of different components. Nutrigenomics deals with the study of effects of diet on activity of individual‘s gene and health. Dietary components can affect gene expression and genome structure which means that effect is directly made on Transcription and DNA structure. So, we should completely know that how diet can interact with human genome and how it affects phenotype. Up till now the researchers have concluded that dietary health has more importance for optimal health and disease anticipation than proteins, fats and carbohydrates which can only meet the minimum daily requirements for the minerals and vitamins. The crux of nutrigenomics is that variations in genetic make-up and gene expression define our individual specific nutritional requirements, including how well we absorb and utilize nutrients, and even the amount of food that we need to consume for optimal health. The genes that an individual inherits are merely one factor in the exhibition of health or disease. Also, nutrition and genetics both are equally important in the maintenance of human health an important part in human health as well as the development of lethal diseases like cancer, osteoporosis, diabetes and cardiovascular disease. So, nutrigenomics is actually the mixture of nutritional sciences which also include the other highthroughput ‗OMICS‖ technologies like transcriptomics, proteomics and metabolomics. By this collective knowledge the effects of nutrition on health can be investigated. Variable behavior has been observed between individuals in response to dietary intervention which is the main topic under research and practice (Trichopoulou et al., 2008). There are many factors that can influence the response to diet such as age, sex, physical activity, smoking and genetics(Ordovas, 2007). Many other factors, particularly diet, play a significant role in gene health. There is no question that we affect the expression of our genes through our dietary choices. Therefore, the logical conclusion is that our diets can be personalized to influence our genes. Personalized nutrition could be proving as a dietary advice to individual‘s genetic outline so can be used in both prevention and curing of chronic disease. Many whole foods and herbs contain a wide variety of active phyto-nutrients including carotenoids, coumarins, flavonoids, lignans, plant sterols, polyphenols, phthalides, sulfides, saponins, and terpenoids all of which have been recently researched and found to retain important actions in health promotion and disease prevention. The recent spreading out of interest in this area of research indicates that many diseases can be lessened by 50% or more—or better yet, prevented—through simple dietary modifications and appropriate supplementation. (Bouchard and Ordovas, 2012). 4 Siddique.R, Ejaz.R, Iftikhar.H and A.Karim.T NUST-ASAB
  5. 5. NUTRIGENOMICS-AN EMERGING FIELD 2013 Genotype Diet Health and disease Phenotype Figure 1 – Diet‘s relation with health and disease Emerging faces of nutrition, nutrigenomics and nutrigenetics. Due to transition in a population shift our health care systems are doing reflecting changes due to transition in a population shift we need to reduce the costs and chronic diseases by concentrating on prevention. For this reason, new scientific studies in these specific areas that generate keenness which seems to be solution of constantly growing issues in our society. Genetic variations toward dietary response and the nutrients response in gene expression can also be explored by nutrigenetics and nutrigenomics. In the prevention, management of chronic diseases, in addition to obesity, diabetes and cardio-vascular another factor has been introduced as new community-based model of care where affected individuals and his care givers play an effective role. (Carmen et al., 2012). 5 Siddique.R, Ejaz.R, Iftikhar.H and A.Karim.T NUST-ASAB
  6. 6. NUTRIGENOMICS-AN EMERGING FIELD 2013 Molecular Nutrition Proteins Fats Carbohydrates Figure 2 – showing the molecular mechanism of effect on human genome Nutrigenetics and nutrigenomics have different impacts on health outcomes by two ways either by affecting genes expression in different metabolic pathways or distressing the frequency genetic mutation in the bases of DNA or in the chromosomes which result in the alteration of gene expression. Inherited genetic variations also specifies the health effects of nutriomes (nutrients or combination of nutrients) as inherited genetic variation can modify the uptake and metabolism of nutrients and hence can also involve in the activity of biochemical reactions by the interaction of nutrient co factor with molecular enzymes. If the nutritional requirements are customized according to the genetic characteristics of each individual better health outcomes can be achieved. In addition the acquired genetic individuality also depends on age, diet and health status (Frazer et al., 2009). Both the nutrigenomics and nutrigenetics are having common goal of improving health by the interaction of diet and genes. The optimization of diet provides us a powerful to unstitch the compound relationship between nutritional molecules, genetic polymorphisms, and the biological system as a whole. Nutrigenomics explains how food chemicals affecting gene expression, while nutrigenetics discusses SNPs-single nucleotide polymorphisms which define an individual‘s response to food according his/her own specific states of health and disease. In the near future people will prefer to a DNA analysis to have a guideline for avoiding disease and optimizing health issues. How an individual reacts to a specific ingredient and how it can effects the genes variations can be explained well by nutrigenetics. It recognizes an individual‘s hereditary predisposition to disease based on his or her genetic makeup. (Sanchez et al., 2008) Nutrigenomics and nutrigenetics are two different but closely related terms but not compatible. Nutrigenetics also involves how the effects of acquired mutations such as cancer can be 6 Siddique.R, Ejaz.R, Iftikhar.H and A.Karim.T NUST-ASAB
  7. 7. NUTRIGENOMICS-AN EMERGING FIELD 2013 modified in genes related to nutrition specially in uptake of micro nutrients as well as in metabolism.(Corbin and Zeisel, 2012) Experimental Approaches and Technologies Used in Nutrigenomics Genetic information differs at multiple sites of regulation which may be affected by diet. New developments in genomics, transcriptomics, metabolomics and proteomics have given a more completed thoughtful that how the effect is being produced by the bioactive compounds over human health. Healthy bioactive substances can be used for the promotion of health and is being tested in laboratory by using altered knowhow like cell culture and also research on animal or human studies regarding bioactive compounds. Each experimental technique gives different result with unique strength and also having some exact limitations. In these untried studies the specific role of nutrients and bioactive compounds role should be cleared as it is in vitro, animal, clinical and epidemiologic studies. In human research studies a variety of ‗OMIC‘ technologies should be measured as the nutritional lifestyle, clinical physiological, environmental and demographic factors are involved. How micro flora interacts with host genome, is the topic under research these days(Ordovas and Corella, 2004a) 7 Siddique.R, Ejaz.R, Iftikhar.H and A.Karim.T NUST-ASAB
  8. 8. NUTRIGENOMICS-AN EMERGING FIELD 2013 Large complex data sets can be generated and managed by using bioinformatics. High throughput datasets can be managed stored and analyzed by using bioinformatics knowledge (de Graaf et al., 2009). Physiological processes can also affect the biological effects of nutrients and food bioactive. The physiological processes include ―absorption, transportation, biotransformation, up taking mechanism, storing mechanism and excretion, and cellular mechanisms of action‖. For example transcription factors regulations. These processes involve different genes which can change their functional and physiological response to different nutritional compounds. Diet and gene interactions explains genes affecting different homeostatic pathways Figure 3- Using the “omics” of nutrition to identify the dietary factor contribute to form a phenotype (Garcia-Bailo et al., 2009) Novel food products has been produced on the genetic basis considering food been liked or disliked which escort to the development of new food products according to the ethical rules of society, which may reduce the risk of chronic diseases(Corbin and Zeisel, 2012) According to different research studies nutrients is also having the abilities of altering the genetic expression at gene regulation level, signal transduction or by altering chromatin structure or changing protein function. Diet can cause epigenetic changes for example methylation of DNA or it may affect the genes expression at genes level. Molecular signatures also express the genes profile considering specific nutrients. (van Ommen et al., 2010). For biomarkers identification and the measure of response of individuals to different dietary products can be measured by using knowledge of proteomics and metabolomics, which could be used to 8 Siddique.R, Ejaz.R, Iftikhar.H and A.Karim.T NUST-ASAB
  9. 9. NUTRIGENOMICS-AN EMERGING FIELD 2013 block the exposure of diseases and can be incorporated into existing bio banks for nutritional exposures. But this is not as simple, a number of challenges need to be resolved relating to handling and processing After experimentation data should be analyzed by epidemiologically which can examine the dietary effects and its exposure considering genetic variations in humans. But it is Also having some limitations like inaccuracies related with estimate nutrient uptake (Scalbert et al., 2009). However the biological dose will be different in different individuals because of genetic variability but in case if precise intake levels are known. Its dose is different because the genetic variability may affect different mechanism differently like metabolism distribution or elimination of nutrient.(Scalbert et al., 2009). The epidemiological studies also identify some limitation and flaws regarding genetic polymorphism incorporation into nutrition. For examples recall bias among case-control studies. One more example is the study on coffee and heart diseases which clarifies the concept of nutrigenomics and some special dietary factors (Cornelis et al., 2006). Several studies had examined this connotation and decided that coffee whichever increases risk, has no effect or decreases danger (Ordovas and Corella, 2004b). As coffee is complex beverage composed of bioactive compounds. It also contains caffeine which may be harmful to cardiovascular system. Caffeinated coffee also increases the risk of heart attack among those individuals who are slow caffeine metabolizers but have no risk of harm in those who are fast caffeine metabolizers (Cornelis et al., 2006) Coffee and cigarettes, combat some of the liver diseases (rare liver disease) Norwegian researchers have conducted out the research which showed that coffee drinkers and cigarette smokers either male or female have a less chance of getting some of the liver diseases such as primary sclerosing cholangitis (PSC). PSC is a rare liver condition and it affects the 30 – 40 years aged persons and it is related to cancer of bile ducts. The researchers from the Norwegian PSC research Center at the Oslo university hospital and the University of Oslo observed 20% of the daily drinkers and smokers and compared it with 43% healthy controls. It was concluded that the PSC patients drank less coffee in the present as well as past than those of healthy controls. So it was shown that coffee drinking helps protect against liver cirrhosis and liver cancer. The science behind it is that cigarette and coffee drinking produces components such as nicotine and caffeine, both of which are sympathomimetic and may increase levels of intracellular cyclic adeno-monophosphate. This adeno-monophosphate is key component which then prevents from liver cancer or liver cirrhosis(Andersen et al., 2013) Metabolomics-newest tool for Nutrigenomics Metabolomics represents the newest ‗omics‘ technology being applied within nutrigenomics. It exploits several technologies like analytical chemistry such as mass spectroscopy (MS) and nuclear magnetic resonance (NMR) to capture complete data on the low molecular weight metabolites, nutrients and other compounds in various human bio fluids, referred to as the metabolome. Metabolomics applications in crop or food analysis are continually growing and the use of mass spectrometry (MS) and liquid chromatography (LC), GC-MS and NMR are being used to acquire more comprehensive view into variation in composition of food in both nutritional contexts and quality of food. Nutritional quality of crop plant is a direct function of metabolite content (Memelink, 2004). Metabolomics technology is used to understand well what 9 Siddique.R, Ejaz.R, Iftikhar.H and A.Karim.T NUST-ASAB
  10. 10. NUTRIGENOMICS-AN EMERGING FIELD 2013 especially happens during crop domestication in order to plan new ideas for more targeted crop improvements, conduct more adaptations to current requirements. Now we have to identify molecular markers that can be used to conduct future development of food products (Abulencia et al., 2006).(Lenhard et al., 2005) used GC-MS based profiling of wild, and a number of cultivated, tomato species to gain a better insight into what has happened and what has been lost during domestication. The major analytical methodologies of metabolomics are nuclear magnetic resonance (NMR) gas chromatography along with the liquid chromatography-mass spectrometry (LC-MS), and desorption ionization-electrospray ionization-mass spectrometry. Bioinformatics is applied for the examination and analysis of the data that is derived by the comparison of different cell conditions. However, metabolomics is not a standardized procedure. It is not yet possible to compute the whole metabolome or proteome, it is not identified that exogenous food derived metabolites or how many endogenous metabolites can be quantify in samples of human or to which amount changes in diet draw changes in metabolic profiles. Quantitative lipid metabolome data revealed differential effects of dietary fats on cardiac and liver phospholipid metabolism (Watkins et al., 2001a) and (Watkins et al., 2001b) . This approach mapped changes in the concentration of lipid metabolites to their biochemical pathways (Watkins et al., 2001b). This approach was also employed to evaluate the effects of the insulin-sensitizing drug rosiglitazone on liver, plasma, heart and adipose lipid metabolism in mice and is currently being used to build a large database of lipid metabolite concentrations in humans. Because many of the effects of dietary macromolecules on tissue metabolism are reflected in the plasma lipid metabolomics, metabolome has excellent potential for estimate restrained differences in the metabolic response to diet among individuals. Using a metabolomics approach to identify key loci will play a significant role in helping to deconstruct complex metabolic interactions and provide the knowledge ‗to design better crops to feed the world‘ (Baxter et al., 2006). For example, knowing the genetic basis of the accumulation of important nutritional vitamins will enable genetic markers to be identified, which can be incorporated into a standard marker-assisted breeding programme to enable targeted breeding for the desired level of these highly important micronutrients in our food alongside existing marker-assisted approaches for more traditional traits such as yield and disease resistance. Rice is one of the most important food crops in the world; it is the staple of almost half of the world‘s population and it provides around three-quarters of the calorific intake of people in Asia To date, few applications for metabolomics on rice have been reported (Tarpley and Vietor, 2007) most of which are not actually directed to grain issues. Metabolomics has, however, great potential to help advance our knowledge of some of the key nutrition-related targets and processes currently driving rice breeding and rice research in genera. Rice is a model crop for genetic analyses because it has the smallest genome of the grasses and synteny provides a common denominator for using rice to analyses other cereal crops (Balkau et al., 2002). The rice genome has been sequenced and is being mapped and annotated. The allelic variability is being catalogued using a diverse set of rice varieties, enabling whole-genome variability to be associated with different phenotypes (McNally, 2006). Of all the food crop genomes, that of rice is the most decoded. This will strongly facilitate a synergistic linkage between genetics and metabolomics for specific improvement of the quality and nutritional value of rice, in highyielding backgrounds, for different environments. Rice breeders strive to develop varieties for every environment with high yield potential, stress tolerance and excellent grain quality. However, it is very rare to capture both superior grain quality and superior agronomic 10 Siddique.R, Ejaz.R, Iftikhar.H and A.Karim.T NUST-ASAB
  11. 11. NUTRIGENOMICS-AN EMERGING FIELD 2013 characteristics in one variety, especially for those bred for unfavorable environments. The financial benefits of agronomic improvement are lost without high quality. From this short overview it is apparent that metabolomics has quickly gained its place in modern plant science in both a fundamental and applied context; nowhere more so than in the field of nutrition and food quality. Metabolomics is already being applied in fundamental approaches aimed at gaining a better understanding of the interactive nature and control of important biochemical pathways in plants. On the more applied side, metabolomics is providing novel information regarding the composition and potential nutritional imbalance of plant-based foodstuffs and is helping indicate how more tailor-made strategies could be designed to tackle key issues of global food quality in the highly contrasting situations typifying developing and developed countries. Epigenomics has relation in Nutrigenomics Our diet interacts with our genes. Nutrigenomics is diet-induced changes in gene expression that can influence network interactions and cellular information flow and nutritional epigenomics is Diet-informed epigenetic modifications of chromatin (DNA methylation and histone acetylation) that can alter gene function and long term health outcomes(National WIC Conference September 23, 2010) Epigenetics also known by the soft inheritance is the ability to change gene activity without changing gene sequence , it means that there are no mutations involved. Typical epigenetic affects include DNA methylation which means gene silencing and Histone acetylation describing gene activation. Diet can alter the epigenetic state of the genome leading to dramatic deprogramming or reprogramming of large numbers of genes in metabolic pathways and physiological systems. Foods contain many inhibitors and stimulators of chromatin remodeling enzymes (DNA methylases and histone acetylates and deacetylases), making nutritional intervention a possible way to ―reprogram‖ the epigenome to promote health and prevent disease. Nutritional genomics represents a new approach for translating the exciting discoveries of genomic research into appropriate actions for using nutrition to prevent disease and promote health for individuals, families, and communities. Observational studies have generated the hypothesis that during critical periods of growth, the fetus and the newborn may be programmed (fetal and postnatal programming) in a permanent manner by conditions such as nutritional insults, and environmental effects in utero and during early life. New knowledge now shows that epigenetic modifications may account for the increasingly predictable links between the prenatal and early postnatal nutritional environment and adult health and disease. Limited nutrient availability in early and later life appears to precipitate the appearance of adult-onset diseases (and also childhood) obesity, cardiovascular disease, type 2 diabetes, and cancer. 11 Siddique.R, Ejaz.R, Iftikhar.H and A.Karim.T NUST-ASAB
  12. 12. NUTRIGENOMICS-AN EMERGING FIELD 2013 . Figure-4 Dietary signals /profiles These are patters of gene expression, protein expression and metabolite production in response to particular nutrient or nutritional regimes can be viewed as dietary signature. Use of Dietry signals in Nutrigenomics research Nutrigenomics seeks to examine these dietry signatures in specific cells, tissues and organisms and to understand how nutrition influences homeostasis. Dietry signatures can be used to identify (early ) molecular biomarkers. The importance of single nucleotide polymorphisms In simple classification of nutritionally modifiable genes as constitutive or inducible, it is the second order classification of these genes as being polymorphic or wild type that motivates highly variable response of humans to a given diet. Most commonly used form of polymorphism is single nucleotide polymorphism (SNP).In consideration of facts that approximately one SNP per 1.08 kilo base of gene sequence or 1 SNP per 1.91 kilo bases of DNA sequence(Chakravarti, 2001). Herein some criteria may offer some regulation. As SNP is of practical importance in nutrigenetic standards, the SNP is probably be present with several numbers of properties such as reveal high frequency in general population of interest, regulating proteins at rate limiting steps or at biological cascades in intermediary metabolism, and having helping biomarkers that offer substitute measures of clinical effect. Now days, only few SNPs can fulfill our criteria, but we can learn a great contract from those that follow the whole criteria. The biology of interleukin 1 (IL-1) and methylene tetra hydro folate reductase (MTHFR) are instructive examples of the significance of coding and non-coding SNPs respectively, as genetic levers for organization health. (Chakravarti, 2001). 12 Siddique.R, Ejaz.R, Iftikhar.H and A.Karim.T NUST-ASAB
  13. 13. NUTRIGENOMICS-AN EMERGING FIELD 2013 Transcriptomics - Nutrigenomics interrelationship Transcriptomics is defined as the main sub leading of molecular biology that deals with the study of messenger RNA molecules being produced in discrete individual or population of a particular cell type, which means that the study of transcriptosome, where transcriptosome is reffered as complex of all RNA molecules in residents of cells (Chakravarti, 2001). This field can be applied to all sets of records in known organisms. The transcriptosome reproduce those types of genes that are being dynamically articulated at any time. The study of transcriptosomics also reffered to as expression profiling, often using productive techniques based on DNA micro-array technology and RNA sequencing. Transcriptomics extensively report all data that happens in RNA pool (that is transcriptome or all expressed genes) within a system (for example body fluid, a cell or tissue).Cellular functions are arbitrate by gene expression relating messenger RNA (mRNA) (Cordero et al., 2008b). Transcriptomics does not provide direct summary of information from the genome, nor is it produced only during DNA-dependent RNA synthesis (Jones and Ashrafi, 2009) . We can modify the sequence of RNA molecule by using different processes such as RNA editing and differential splicing method. Many vital nutrients and bioactive food components can provide as important regulators of gene-expression patterns by modifying gene translation and transcription, thereby changing biological responses such as cell growth, differentiation and metabolism. These all methods play important role in disease process (Jones and Ashrafi, 2009). DNA microarray techniques allow immediate estimation of thousands of genes of transcription and theirFigure-5 Nutrigenomics and comparative expression between diseased cells and normal cells both before and after contact to different dietary components nutrigenetics inter-relationships (Jones and Ashrafi, 2009). Transcriptomics and Microarray Technologoies ―The impact of a number of dietary factors on human phenotype is not completely figured out by DNA modification. The phenotype of a person can be regulated by the regulation of the pace of transcription of genes which is by food components and this aspect is really intriguing aspect of Transcriptomics. The regulation of gene expression pattern is controlled by not only bioactive food components but host of some essential nutrient elements as well. The processes which mediate important role in disease onset in human body such as metabolism, cell growth and differentiation are all modified by the process of transcription and translation which in turn are modified by vitamins, minerals, various phytochemicals, and macronutrients. The interaction of bioactive food components with various cellular processes and their action is widely studied by the development of latest microarray technologies and these technologies are being used by nutritional scientists. Genome-wide monitoring of gene expression allows us assessment of 13 Siddique.R, Ejaz.R, Iftikhar.H and A.Karim.T NUST-ASAB
  14. 14. NUTRIGENOMICS-AN EMERGING FIELD 2013 transcription of thousands of genes along with their expression in normal and diseased cells before and after their exposure to different bioactive components. Changes which occur in diseased cells compared with normal cells are provided by latest microarray technology tools. This statistics should assist in the detection of promising biomarkers for diagnosis of disease, prognosis prediction and in the discovery of new therapeutic tools. The discovery of appropriate clinical strategies and introduction of modified medicine, including nutritional preemption related strategies had been made possible by the use of molecular approach in health and disease. The expression of a particular gene can be stopped by the use of a phenomenon called RNA interference. The action of bioactive food and disease condition and characteristics are demonstrated by the use of RNA interference technology (Cordero et al., 2008a) . An experiment has been performed by investigators on worm model by using the phenomenon of RNA interference Caenorhabditis elegans was used as model and its gene expression was disrupted by the use of this technology to determine the genes which control its fat storage and which is responsible for increased fat in body. This is tolerable for the identification of fat regulatory genes core set and specific fat regulators specific pathway (Cordero et al., 2008a). the site of action of isothiocyanate compounds such as sulforaphane, that arise from broccoli and other food components was determined by using this technology (Jones and Ashrafi, 2009). As transcriptomics information becomes available, the targets for treating obesity and other unhealthful conditions with foods or their bioactive components were also determined. Proteomics Proteomics is a central platform in nutrigenomics that describes how our genome expresses itself as a response to diet (Enzinger et al., 2005). Nutrigenetics deals with our genetic predisposition and susceptibility toward diet and helps stratify subject cohorts and discern responders from nonresponders Epigenetics represent DNA sequence-unrelated biochemical modifications of DNA itself and DNA-binding proteins and appears to provide a format for life-long or even trans generation imprinting of metabolism (Hine et al., 2003). Proteomics in nutrition can identify and quantify bioactive proteins and peptides and addresses questions of nutritional bio efficacy (Hine et al., 2003)The interplay between nutrition and health has been known for centuries: the Greek doctor Hippocrates (fourth century B.C.) can be seen as the father of ‗‗functional food,‘‘ because he recommended using food as medicine and vice versa. Another example of such long-term experience is the record of traditional Chinese medicine: Sun Si- Miao, a famous doctor of the Tang dynasty (seventh century A.D.), stated that, the doctor should first regulate the patient‘s diet and lifestyle, when the person is sick. The new era of nutritive exploration translates this rather experimental knowledge to molecular science which is evidence based, because diet constituents interact with human body at micro and macro level as well. Latest dietary and fitness study emphases on health promotion, the onset of disease prevention or delay, and performance optimization. Dietary components are in the form of complex mixtures, which not only involve the presence and concentrations of a single compound but also relations of numerous compounds influence food compound bio availability and bio efficacy. Hence, the necessity of developing and applying comprehensive analytical methods to reveal bioactive ingredients and their action becomes evident (Kussmann and Affolter, 2009).Proteomics is a central platform in elucidating these molecular events in nutrition: it can identify and quantify 14 Siddique.R, Ejaz.R, Iftikhar.H and A.Karim.T NUST-ASAB
  15. 15. NUTRIGENOMICS-AN EMERGING FIELD 2013 bioactive proteins and peptides and addresses questions of nutritional bio efficacy. In this article, we focus on these latter aspects, update the reader on technologic developments, and review major applications: we summarize mass spectrometry (MS)-rooted proteomic techniques for protein identification and quantification and go through a selection of nutritional intervention and bio efficacy studies assessed by proteomic means. Many nutrients can modify RNA translation to proteins and the events which are posttranslation, protein activity is also affected by these events. Proteomics is very challenging process technically; metabolic changes do not necessarily affected by the presence or absence of proteins. All the nutritional study comprising profile and features of body and dietary proteins, assimilation, captivation and uptake of nutrients, their function and their role in progression, duplicate , and fitness, biomarkers of disease and diet status ,individual requirement of nutrition elements these all have been discovered by using proteomics latest technologies. The proteome exploration is found to play a role in solving all the major nutrition-associated problems in living beings for example fatness, diabetes, heart disease, melanoma, aging process, and intra uterine fetal obstruction are solved by using proteome analysis(Kussmann and Affolter, 2009). Proteomic technologies There are number of technologies used for separation of proteins such as two-dimensional polyacrylamide gel electrophoresis and number of chromatography methods have been applied as efficient tools for long times(Knowles and Milner, 2003). The analysis of protein has become possible using MS technologies which include electrospray ionization (ESI), soft ionization technique and matrix-associated laser desorption ionization (MALDI). These technologies were invented in late 1980‘s and these techniques are used to vaporize proteins and peptides (Knowles and Milner, 2003). ). These techniques make use of charge to mass ratio; flight time and electron trap as chief discriminating parameters for analysis of ionized and vaporized proteins and peptides in high vacuum of the MS and other latest technologies such as MALDI and ESI respectively. MS is being used for more than 20 years in proteomics only because of its very high speed, sensitivity, specificity, resolution of mass ability and mass precision during protein documentation processes When MS is merged with LC-GC or with MS, and then its efficiency can further be enhanced in proteomics. Techniques which involve specific protein consumption 2D-PAGE MS and multi-dimensional protein separation and their analysis after protein separation are mainly four as they are being used frequently in proteomics. These techniques also involve their analysis after their chromatographic separation. The type of technology being used depends on the purpose of study and availability of facility in laboratory. Although all of these methods involve preparation of sample, separation of protein, analysis of MS, and identification of protein. Several dietary components are recognized that post-transnationally modify proteins and thus influence their activity. For example, shifts in phosphorylation occur after exposure to diallyl disulfide (DADS), a compound found in processed garlic. Western blot analysis revealed that DADS exposure did not affect ERK protein content per se but increased its phosphorylation resulting in cell-cycle arrest. Using MALDI-TOF MS, major differences in the metabolic pathway in mitochondria of young and aging monkeys and between males and females monkeys were reported by a group of scientists, which helps explain risk of cardiovascular diseases with an aging-associated gender difference. Proteomics also identified up and down regulated proteins such as vitamin and glucose controlled protein in adipocytes which are treated by insulin and mammalian cells transcription factors. There are processes such as glycolysis, gluconeogenesis, oxidation of fatty acid and metabolism of amino acid involve the enzymes whose level differ 15 Siddique.R, Ejaz.R, Iftikhar.H and A.Karim.T NUST-ASAB
  16. 16. NUTRIGENOMICS-AN EMERGING FIELD 2013 significantly between obese and lean diabetic mice, however their level can be regulated with peroxisome proliferator triggered receptor activators in these processes (Bluher et al., 2004) . Future perspective of proteomics Proteomics is a powerful tool in the transformation of the field of nutritional research. The comprehensive information about the identification and characterization of dynamic ranges of protein, diverse physical and chemical properties, and intricate relations is provided by amalgamation of various proteomics techniques. Chief nutrition related problems in human and animals are solved by the use of proteome analysis (Davis and Milner, 2004). The vital proteins that function to control the metabolic pathway and whose degradation ,production and alteration also affect certain nutrients or other dietary factors are discovered by the use of advance proteomic technologies ( e.g. genomics, metabolomics, bioinformatics and Transcriptomics (Wu et al., 2004a, Rhind, 2004) . The complex interactions responsible for nutrient utilization are aided by these technologies, it also help in identification of promising biomarkers for nutritious status and advancement of disease, scheming a modern model for food prevention and mediation of disease (Wu et al., 2004b, Wu and Meininger, 2002). Biomarkers New biomarkers are needed for the relationship between health and nutrition to reflect the efforts of the body to maintain this homeostasis and changes in homeostasis (van Ommen and Stierum, 2002). Biomarkers linking health with diet will be different than those linking disease with nutrition. Ideally, the biomarkers should permit simultaneous monitoring of both the efficacy and safety aspects of the dietary constituents. Classical biomarkers, e.g., single gene or protein or metabolite, do not allow assessment of physiological actions of a single nutrient and number of known and unknown biochemical targets. The scenario becomes more complicated when assessing the efficacy of a nutritional component, because single dietary components are not spent as separate objects but as component of a dietary mixture. Thus, for prevention of disease in the development of functional foods is important to get a holistic impression of early phases of the disease procedure. (van Ommen and Stierum, 2002) 16 Siddique.R, Ejaz.R, Iftikhar.H and A.Karim.T NUST-ASAB
  17. 17. NUTRIGENOMICS-AN EMERGING FIELD 2013 Effect of different nutrients on human genome Nutrigenomics is the study of interactions of nutrients present in the food with the human genome. The variations which do occur in the human genome, it is because of the complexity of nature of foods prepared as desired by them. There are many examples which illustrate and explain the existence of different elements present in the foods interacting with the human genome and leading to the different variations occurring in the human genome such as CoQ10 which is present in human muscle cells has shown effects on 12,000 genes(Rosenfeldt et al., 2002). Also the most important vitamin which is vitamin D is responsible for the absorption of intestinal calcium and phosphate. Research has shown that vitamin D3 affect 20,000 genes in human prostate cancer cells(Rengaraj et al., 2003) While Nutrigenomics is dealing with the effect of diet on genome mean while new research at University of Florida was made which studied the effect of specific diet on human genome and chronic diseases caused by it. According to the research the effect of zinc was studied on human genome. They found that zinc has equal ability to turn off and turn on genes in human. some of the genes were tuned off by less zinc in diet but after experimentation it was found that they resulted in activation of the variety of white blood cells which protect the body against infections , but when zinc level increases in body those genes were turned on. In this way scientists treated various immune related disorders such as diarrhea and malaria by setting value of zinc(Woods, 2003) ―A study conducted in Europe Japan and USA, in which they for the first time showed the comparison of domestic and wild tomato genes and DNA sequence which were active in them. This leads to enable breeders to breed new traits into tomato or other crops along with genetic changes involved in. For example, propagation of new traits into tomatoes often involves crossing with their wild relatives. The recent study provides with the evidence that there is a large block of genes from a species of wild tomato is present in domestic tomato, and has prevalent, unforeseen effects across the whole genome. Maloof and his colleagues studied the domestic tomato(Solanum lycopersicum) and wild relatives (S. pennellii, S. habrochaites and S. pimpinellifolium).Comparison of the plant‘s genomes shows the effects of evolutionary traffic jam, Maloof noted — for example at the original taming in South America, and later when tomatoes were brought to Europe for agronomy. Among other outcomes, genes associated with fruit color showed rapid evolution among domesticated, red-fruited tomatoes and green-fruited wild relatives. In the desert habitats S. pennellii, had quicker development in genes related to drought tolerance, heat and salinity‖ New technology is giving biologists the extraordinary aptitude to look at all the genes in an organism, not just a select handful. The researchers studied not just the plants' DNA but also the messenger RNA being transcribed from different genes. RNA transcription is the process that transforms information in genes into action. If the DNA sequence is the list of parts for making a tomato plant, the messenger RNA transcripts are the step-by-step instructions.(Koenig et al., 2013) 17 Siddique.R, Ejaz.R, Iftikhar.H and A.Karim.T NUST-ASAB
  18. 18. NUTRIGENOMICS-AN EMERGING FIELD 2013 Elements present in food cause potential damage to human genome Elements present in Potential damage caused by over dose of these food elements Kidney damage and osteoporosis. Skin burns caused by white Phosphorous Zinc Copper Aluminum Nickel Sodium Iodine Potassium Iron Lead phosphorous. Stomach cramps, nausea and vomiting. anemia, metal fume fever, skin-irritation Breathing Cu can cause nose and throat irritation and assimilation of it can lead to vomiting and diarrhea. Dementia, memory loss, listlessness, and severe damage to central nervous system Lung and nose cancer, larynx cancer along with prostate cancer Perspiration of sodium hydro-oxide fumes causes irritation to skin, eyes, nose and throat. Breathing sodium causes coughing and sneezing. Elemental iodine I2 is toxic and its vapours irritates eyes and lungs Irritates eyes and nose, throat along with lungs causing sneezing, coughing and sore throat. Conjunctivitis and retinitis, inhalation of result in development of a benign pneumoconiosis, called siderosis. anemia, hypertension, Kidney damage, Miscarriages and subtle abortions Table 2- Elements present in food cause potential damage to human genome Nutrigenomics and Ethical control Human beings are so complex and more complex their habits and desires are. Nutrigenomics is the science of interaction of gene and nutrients, when this knowledge to human interest they start to develop the products of their interest or might be they are in need to get that product so they artificially make the foods having particular nutrient having such modifications which does act on human genome but everything achieved so quickly and artificially have some drawbacks, along with the benefits which are got, to be more simple, these are the ethical issues which affect the lives of the people and the society. Although it is not a bad thing to search but to take 18 Siddique.R, Ejaz.R, Iftikhar.H and A.Karim.T NUST-ASAB
  19. 19. NUTRIGENOMICS-AN EMERGING FIELD 2013 care of people rights, more importantly their lives, and to keep them happy is the awesome thing to be achieved. Customized diets have now been formed such as genetically modified foods (GMO) which serve to get achieve the purpose but there are some ethical and legal issues related with it. It is who which decide that whether the GMOs are being liked or disliked, it is the people, some population of whom loves GMOs and other half of them call it is as Franken foods. Joint center of bio-ethics (JCB) in university of Toronto in collaboration with the university of Guelph philosophy, have set to sort out the ethical questions about the Nutrigenomics and all fields of Nutrigenomics in their joint project of a paper nutrient and genes; science, society and the supermarket in which they sorted out that if Nutrigenomics is the study of interaction of nutrients with the food then how the variations in the human genome is brought about the foods, lead to produces the ethical concerns, so in order to sort out and resolve them. Research had been started since 2oth century, which is still in the beginning stage, but it had made scientists to at least propose their actions which they need to perform in order to help improve the ethical concerns related to customized diets being produced as a result of advancement in Nutrigenomics. Scientists are interested in the radical changes which are they going to bring about how food is grown, processed, consumed and hence the formation of customized diets which alter their genetic makeup. The thing which is the most considerable is the fact that although Nutrigenomics is beneficial but there is very less Nutrigenomics experts which do serve the purpose. Primary care physicians are there but they have minimal training so they are not expert in this field and hence they need improvement. There is shortage of geneticists and molecular nutritionists. It is required that Nutrigenomics should be brought in to practice and more work is required in this field (Castle and Ries, 2007) The major parts of Nutrigenomics services are classified in to three; one is the utilization of nutrigenomic knowledge and on the basis of which formulation of genetic test and its understanding, secondly the calculation of disease vulnerability based on the test results, thirdly using the nutrigenomic knowledge formulate the dietary commendations. These things are worth to mention priorly because, these are the components which arise issues ethically, legally and socially. DTC which means direct to consumer is the most encountering potential ethical issue faced nowadays because of this emerging knowledge of nutrigenomics which the people don‘t bother to wait for the results of taking dietary supplements and directly take those supplements which can prove to very harmful for their health(Holyday et al., 2012) The current controversy creating ethical social and legal issues arise from the delivery if nutrigenomic services focusing on the instruction of DTC genetic testing which the nonpracticed people is carrying out. The only solutions to this problem is direct access to testing services and goes for results first and then go for applying to one own self. So personalization of diets, followed by the genetic tests can lead to better health of individuals and help reduce the issues regarding social, legal and ethics. 19 Siddique.R, Ejaz.R, Iftikhar.H and A.Karim.T NUST-ASAB
  20. 20. NUTRIGENOMICS-AN EMERGING FIELD 2013 Looking forward to things which can resolve the issues The steps which can be taken to make the future secured and take the possible benefits out of nutrigenomics and free of the ethical, social and legal issues are genetic tests and more importantly the assessment of dietary intake with the proper genetic and nutritional counseling to inform behavioral effects and hence better and healthy outcomes will be produced. If the genetic tests are considered then, highest standard of laboratory are required. For-example in United States, the laboratories whether in-house or out sourced, meet the CLIA certification standards, also other tests might need FDA approvals, especially in those tests where the health outcomes are involved. Dietary practitioners have competency in nutritional genomics, have professional skills in doing to the counseling the patients related to their diet and health. Also it is now evident that the deficiencies in physicians genetic and nutritional knowledge is very much alarming. It is because of the financial and other barriers which limit their genetic training in dietetic education so dietetic professionals face the pressure in this way. Perspective for future/ Conclusion Nutrigenomics can benefit from a systems biology approach that use a number of the highthroughput ‗omics‘ technology platforms to identify the nutrient-sensitive gatekeepers of these disease processes. Each analytic platform (genomics, proteomics, Transcriptomics or metabolomics) provides essential complimentary information implicit in the unraveling of mechanisms underlying diet and health. In order to progress the field, a number of simple, yet fundamental experiments will be required. For example, within the context of insulin resistance, the metabolic syndrome and T2DM, there are several organs involved in adipose tissues, skeletal muscle, liver and pancreatic β-cells How do the gene and protein expression change within and between organs relate to each other. Which tissue(s) is most affected by nutritional interventions? What are the nutrient sensitive targets for intervention? How do tissue specific alterations in gene/protein expression relate to the traditional metabolic markers of insulin, glucose and lipid metabolism? How does metabolomics profiling reflect differences in metabolism? Is the metabolomics approach sensitive enough to detect nutrient sensitive aspects of insulin resistance? Can these technologies provide nutrient sensitive fingerprint that reflects metabolic health? It is probable that a lot of this fundamental work will not be possible in man. Some initial studies investigating the effects of nutrients on gene or protein expression and the metabolome will be reliant on cell models and animal studies. Nevertheless we have to determine whether more accessible tissues (e.g. mononuclear cells in peripheral blood) can be used as a surrogate marker for the more inaccessible tissues, such as the liver, pancreas, etc. The biggest challenge for nutrigenomics will be to bring all of this technological expertise to the level of human nutrition. Within the context of nutrigenetics, it is clear that good advice for one individual may not be beneficial for another. Therefore the era of ‗personalized nutrition‘ is predicted; wherein genetic variation and an individual's different responses to food and nutrient interventions present an opportunity for diet-related disease prevention. To date the nutrigenetics approach has been over simplistic, focusing on one SNP, a single dietary component and single disease risk factor. The challenge will be to identify the functional polymorphisms, define interplay between several 20 Siddique.R, Ejaz.R, Iftikhar.H and A.Karim.T NUST-ASAB
  21. 21. NUTRIGENOMICS-AN EMERGING FIELD 2013 genes, identify the nutrient-sensitive genes, account for gene–nutrient–environment interactions and understand how dietary interventions can be tailored to be most effective. Human health and agriculture make use of application of nutrigenomics. This help in production of enhanced animal and food sources. The application to individual differences in metabolism is used to focus how the field could proceed to address this challenge and this is just for the purpose of discussion. The variation in metabolism in response to nutrition is caused by a mechanism which is not fully known yet. So the main focus of study involves genetic variation and epigenetic mechanisms. A complete data set which describes the interaction of nutrition and gene with each other is needed to be studied in order to move forward and develop an overarching theory for predicting effects of genes on different metabolic variations and requirement of nutrition. Any practical application to human without the use of these mechanisms will be defective. There are number of genes whose function is still not known. There is possibility that these genes might have role in regulation of metabolism in human. The impact of gene deletion is being studied on mice phenotype by researchers across Europe and United States. For this purpose more than 9000 genes are being analyzed by using mice as model animal. A systematic approach is needed to discover the function of these genes. The latest techniques of genetics and epigenetics are being evolved rapidly (Wu and Meininger, 2002). . The cost efficient and capacity bearing ,new generation of techniques are being introduced for high throughput gene sequencing. These make possible the practical use of these genetic and epigenetic techniques in large population marks. The cost for gene sequencing can be lowered by using these practical approaches of gene sequencing in single batch. When identifying sequence is attached to each individual‘s DNA then it mix together with many subject‘s DNA sequenced ,after that it is sorted using barcode so that gene sequence of the person can be assembled, this technique is known as Barcoding technique. Barcoding technique offers the promise for cost-efficient use of sequencing in nutrigenomic studies. This technique also make possible methylated gene sequencing(van Ommen and Stierum, 2002). Acknowledgements First of all, thanks to Almighty Allah, who had made us such able to think and work as such a team and then we are very thankful to Dr.Alvina Gull, because of her patient and very sweet nature, her support and guide was the major reason we are over this article. We as a team are very happy with this teacher and always be obliged to her. 21 Siddique.R, Ejaz.R, Iftikhar.H and A.Karim.T NUST-ASAB
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