**4.1 Nutrigenetics**

Nutrigenetics term was used first time by Dr R. O Brennan in 1975 (Farhud et al., 2010). Nutrigenetics is concerned with the effect of gene variations or gene variant or individual's genetic make-up on the organism's functional ability, specifically its ability to digest, absorb, and use food (DeBusk., 2009; Ordovas & Corella., 2004; Lovegrove & Gitau., 2008). Nutrigenetics embodies the science of identifying and characterizing gene

The recognition that nutrients have the ability to interact and modulate molecular mechanisms underlying an organism's physiological functions has prompted a revolution in

For the field of nutrition, this would encompass the ongoing efforts to understand the relationships between the genome and diet, currently termed nutrigenomics and

Nutrigenetics and nutrigenomics are promising multidisciplinary fields that focus on studying the interactions between nutritional factors, genetic factors and health outcomes. Their goal is to achieve more efficient individual dietary intervention strategies aimed at preventing disease, improving quality of life and achieving healthy aging (Ordovas., 2004). In contrast to most single gene disorders, chronic disorders (e. g., cardiovascular disease, cancer, diabetes) are far more complex. First, they involve multiple genes, each of which comes in more than one variation, that likely contribute in small ways to the overall condition rather than have the dramatic impact that is more typical with single gene disorders. Second, the genes are more likely to be influenced by environmental factors, which make the resulting phenotype murkier than with single-gene disorders. An individual might have gene variants that predispose to a particular chronic disorder but, depending on that individual's nutritional and other lifestyle choices, the disorder may or

Nutritional genomics or nutrigenomics is the newly developing field of science that focuses on the complex interaction among genes and environmental factors, specifically bioactive components in food and how a person's diet interacts with his or her genotype to influence the balance between health and disease (DeBusk., 2009; Much et al., 2005; Fisler &

Nutritional genomics is the umbrella term (Ryan-Harshman., 2008). There are two major subcategories of nutritional genomics: nutrigenetics and nutrigenomics (Much et al., 2005). The creation of nutrigenomics and nutrigenetics, two fields with distinct approaches to elucidate the interaction between diet and genes but with a common ultimate goal to optimize health through the personalization of diet, provide powerful approaches to unravel the complex relationship between nutritional molecules, genetic polymorphisms,

Thus, nutrition in the 21st century is poised to be an exciting and highly relevant field of research, as each new day is accompanied by advances in our understanding of how the interactions between lifestyle and genotype contribute to health and disease, taking us one step closer to achieving the highly desirable goal of personalized nutrition (Much et

Nutrigenetics term was used first time by Dr R. O Brennan in 1975 (Farhud et al., 2010). Nutrigenetics is concerned with the effect of gene variations or gene variant or individual's genetic make-up on the organism's functional ability, specifically its ability to digest, absorb, and use food (DeBusk., 2009; Ordovas & Corella., 2004; Lovegrove & Gitau., 2008). Nutrigenetics embodies the science of identifying and characterizing gene

the field of nutrition (Much et al., 2005).

**4. Nutritional genomics** 

may not develop (DeBusk., 2008).

and the biological system as a whole (Much et al., 2005).

Warden., 2005).

al., 2005)**.** 

**4.1 Nutrigenetics** 

nutrigenetics (Much et al., 2005; Ommen., 2004)

variants associated with differential responses to nutrients or dietary pattern, functional food or supplement on a specific health outcome, and relating this variation to disease states (Much et al., 2005; Michael., 2008). The particular gene variants a person has to determine the nutritional requirements for that person and the gene-based differences in response to dietary components and developing nutraceuticals that are most compatible with health based on individual genetic makeup (DeBusk., 2009; Subbiah., 2007). Nutrigenetics will assist clinicians in identifying the optimal diet for a given individual, i. e., personalized nutrition (Much et al., 2005; Svacina., 2007; Zak & Slaby., 2007; Gillies., 2003).

Furthermore, the concept is that if an individual is genotyped at various genes for diseaseassociated risk alleles, a genotype-based diet or nutritional supplement regimen may be useful to overcome the genetic variation and reduce risk or prevent the disease altogether (Wood., 2008; Xacur-GarcAa et al., 2008; Kussmann & Fay., 2008).

#### **4.2 Nutrigenomics**

Nutrigenomics, is concerned with how bioactive components within food affect genes. The field of nutritional genomics is still evolving, and it is common to see "nutrigenomics" used as a shorthand version of "nutritional genomics ". However, keeping the concepts separate can be helpful when sorting out the underlying mechanisms involved (DeBusk., 2009). Nutrigenomics will unravel the optimal diet from within a series of nutritional alternatives, whereas nutrigenetics will help clinicians in identifying the optimal diet for a given individual, i. e., personalized nutrition (Much et al., 2005)**.** 

Although these two concepts are intimately associated, they take a fundamentally different approach to understanding the relationship between genes and diet. Despite the immediate goals differing, the long-term goal of improving health and preventing disease with nutrition requires the amalgamation of both disciplines (Much et al., 2005)

Nutrigenetics is the more familiar of the two subtypes of nutritional genomics (DeBusk., 2009) At one end of the spectrum of nutritional genomics are the highly penetrant monogenic disorders that give rise to inborn errors of metabolism such as phenylketonuria (DeBusk., 2009). More recently less penetrant, more subtle variations have been identified that also affect the gene-encoded protein's function. However, such variations do not in themselves cause disease. Instead, they alter a person's susceptibility for developing a disease. Depending on the specific gene variant, the person's likelihood of developing a disorder may be increased or reduced. These genes are the primary focus of nutritional genomics, because they are common within the global population, they affect dietary recommendations about the types and amounts of food that best fit a person, and practical interventions are possible. These interventions can potentially improve the health potential of individual people and, by extrapolation, the populations in which they live (DeBusk., 2009).

Current nutrition recommendations, directed towards populations, are based on estimated average nutrient requirements for a target population and intend to meet the needs of most individuals within that population. They also aim at preventing common diseases such as obesity, diabetes and cardiovascular disease. So diet has been reported as a major contributor to alarming prevalence of obesity (Shalileh et al, 2010). For infants with specific genetic polymorphisms, e. g. some inborn errors of metabolism such as phenylketonuria, adherence to current recommendations will cause disease symptoms and they need personalized nutrition recommendations (Hernell & West., 2008; Farhud & Shalileh., 2008).

Nutrigenetics and Dyslipidemia 47

A really personalized diet will be a diet considering the nutritional status, the nutritional needs based on age, body composition, work and physical activities, but also considering the genotype. That is, define the "nutritional phenotype (Perez-Martinez et al., 2011; Miggiano & De Sanctis., 2006). It is clear that integrating knowledge of gene variants into dietary recommendations for populations and individuals will increasingly play a role in

Nutrigenetics will provide the basis for personalized dietary recommendations based on the individual's genetic makeup. This approach has been used for decades for certain single gene diseases; such as phenylketonuria, however, the challenge is to implement a similar concept for common multi factorial disorders and to develop tools to detect genetic predisposition and to prevent common disorders decades before their manifestation. The preliminary results involving gene-diet interactions for cardiovascular diseases and cancer are promising, but mostly inconclusive. Success in this area will require the integration of different disciplines and investigators working on large population studies designed to adequately investigate gene-environment interactions (Ordovas & Corella., 2004; Ordovas &

From a health perspective, the major concerns regarding genes and lipid metabolism center on susceptibility to vascular disease. Genes involved with cholesterol homeostasis offer examples of how genetic variations affect lipid metabolism and, thereby, disease risk

The blood lipid response to diet is influenced by polymorphisms within genes for the apolipoproteins as well as within those for enzymes, such as hepatic lipase, that are

The major focus of nutritional genomics research is on identifying (1) gene-disease associations, (2) the dietary components that influence these associations, (3) the mechanisms by which dietary components exert their effects, and (4) the genotypes that

The following section takes a brief look at some of the key diet-related genes and their known variants and how these variants affect the person's response to diet. Keep in mind that chronic diseases involve complex interactions among genes and bioactive food components, and unraveling the details will require population and intervention studies large enough to have the statistical power needed to draw meaningful conclusions. Although what is known today is but the tip of the iceberg compared to what will come in

Over the last two decades there has been an explosion of research in this area, with often

The candidate gene approach involves the selection and study of biologically relevant genes. Genetic polymorphisms in these genes, known as Single-Nucleotide Polymorphism (SNPs), can alter susceptibility to a disease. Candidate or "susceptibility" genes should meet one or more of the following conditions: genes that are chronically activated during a disease state and have been previously demonstrated to be sensitive to dietary intervention; genes with

conflicting findings reported in the literature (Rimbach & Minihan., 2009).

nutrition counseling and policy making (DeBusk., 2008).

**4.3 Nutritional genomics and lipid metabolism** 

involved in lipid metabolism (fisler & Warden., 2005)**.** 

benefit most from particular dietary choices (DeBusk., 2008).

Mooser., 2004).

(DeBusk., 2009).

the years ahead (DeBusk., 2008).

**5. Candidate gene approach**

Some other monogenic polymorphisms, e. g. adult hypolactasia, are common but with varying prevalence between ethnic groups and within populations. Ages at onset as well as the degree of the resulting lactose intolerance also vary, making population-based as well as personalized recommendations difficult. The tolerable intake is best set by each individual based on symptoms. For polygenetic diseases such as celiac disease, and allergic disease, current knowledge is insufficient to suggest personalized recommendations aiming at primary prevention for all high-risk infants, although it may be justified to provide such recommendations on an individual level should the parents ask for them.

New technologies such as nutrigenetics and nutrigenomics are promising tools with which current nutrition recommendations can possibly be refined and the potential of individualized nutrition be explored. It seems likely that in the future it will be possible to offer more subgroups within a population personalized recommendations (hernell & West., 2008).

The possibility of offering personalized nutritional advice to the individual is an attractive option for dietitians and nutrition scientists and is becoming practicable with the emergence of nutritional genomics. This developing field promises to revolutionize dietetic practice, with dietary advice prescribed according to an individual's genetic makeup to prevent, mitigate or cure chronic disease (Lovegrove & Gitau., 2008). It has been also termed "personalized nutrition" or "individualized nutrition" (Ordovas & Corella., 2004; Perez-Martinez et al., 2011). The practical applications of this research include a new set of tools that nutrition professionals can use to identify disease susceptibilities and a growing body of knowledge that will form the basis for developing strategies for disease prevention and intervention that are specifically targeted to the underlying genetic mechanisms (DeBusk., 2008).

Nutrigenetics and personalized nutrition are components of the concept that in the future genotyping will be used as a means of defining dietary recommendations to suit the individual. Over the last two decades there has been an explosion of research in this area, with often conflicting findings reported in the literature (Rimbach & Minihane., 2009).

According to WHO reports, diet factors influence occurrence of more than 2/3 of diseases. Most of these factors belong to the categories of nutrigenetics and nutrigenomics. In the future both, nutrigenetics and nutrigenomics, will induce many changes in preventive medicine and also in clinical medicine (Svacina., 2007).

Nutrients interact with the human genome to modulate molecular pathways that may become disrupted, resulting in an increased risk of developing various chronic diseases. Understanding how genetic variations influence nutrient digestion, absorption, transport, biotransformation, uptake and elimination will provide a more accurate measure of exposure to the bioactive food ingredients ingested. Furthermore, genetic polymorphisms in the targets of nutrient action such as receptors, enzymes or transporters could alter molecular pathways that influence the physiological response to dietary interventions. Knowledge of the genetic basis for the variability in response to these dietary factors should result in a more accurate measure of exposure of target tissues of interest to these compounds and their metabolites. Examples of how 'slow' and 'fast' metabolizers respond differently to the same dietary exposures will be discussed. Identifying relevant diet-gene interactions will benefit individuals seeking personalized dietary advice as well as improve public health recommendations by providing sound scientific evidence linking diet and health (EL-Sohemy, 2007; Amouyel., 2000).

Some other monogenic polymorphisms, e. g. adult hypolactasia, are common but with varying prevalence between ethnic groups and within populations. Ages at onset as well as the degree of the resulting lactose intolerance also vary, making population-based as well as personalized recommendations difficult. The tolerable intake is best set by each individual based on symptoms. For polygenetic diseases such as celiac disease, and allergic disease, current knowledge is insufficient to suggest personalized recommendations aiming at primary prevention for all high-risk infants, although it may be justified to provide such

New technologies such as nutrigenetics and nutrigenomics are promising tools with which current nutrition recommendations can possibly be refined and the potential of individualized nutrition be explored. It seems likely that in the future it will be possible to offer more subgroups within a population personalized recommendations (hernell &

The possibility of offering personalized nutritional advice to the individual is an attractive option for dietitians and nutrition scientists and is becoming practicable with the emergence of nutritional genomics. This developing field promises to revolutionize dietetic practice, with dietary advice prescribed according to an individual's genetic makeup to prevent, mitigate or cure chronic disease (Lovegrove & Gitau., 2008). It has been also termed "personalized nutrition" or "individualized nutrition" (Ordovas & Corella., 2004; Perez-Martinez et al., 2011). The practical applications of this research include a new set of tools that nutrition professionals can use to identify disease susceptibilities and a growing body of knowledge that will form the basis for developing strategies for disease prevention and intervention that are specifically targeted to the underlying genetic mechanisms (DeBusk.,

Nutrigenetics and personalized nutrition are components of the concept that in the future genotyping will be used as a means of defining dietary recommendations to suit the individual. Over the last two decades there has been an explosion of research in this area, with often conflicting findings reported in the literature (Rimbach & Minihane., 2009). According to WHO reports, diet factors influence occurrence of more than 2/3 of diseases. Most of these factors belong to the categories of nutrigenetics and nutrigenomics. In the future both, nutrigenetics and nutrigenomics, will induce many changes in preventive

Nutrients interact with the human genome to modulate molecular pathways that may become disrupted, resulting in an increased risk of developing various chronic diseases. Understanding how genetic variations influence nutrient digestion, absorption, transport, biotransformation, uptake and elimination will provide a more accurate measure of exposure to the bioactive food ingredients ingested. Furthermore, genetic polymorphisms in the targets of nutrient action such as receptors, enzymes or transporters could alter molecular pathways that influence the physiological response to dietary interventions. Knowledge of the genetic basis for the variability in response to these dietary factors should result in a more accurate measure of exposure of target tissues of interest to these compounds and their metabolites. Examples of how 'slow' and 'fast' metabolizers respond differently to the same dietary exposures will be discussed. Identifying relevant diet-gene interactions will benefit individuals seeking personalized dietary advice as well as improve public health recommendations by providing sound scientific evidence linking diet and

medicine and also in clinical medicine (Svacina., 2007).

health (EL-Sohemy, 2007; Amouyel., 2000).

recommendations on an individual level should the parents ask for them.

West., 2008).

2008).

A really personalized diet will be a diet considering the nutritional status, the nutritional needs based on age, body composition, work and physical activities, but also considering the genotype. That is, define the "nutritional phenotype (Perez-Martinez et al., 2011; Miggiano & De Sanctis., 2006). It is clear that integrating knowledge of gene variants into dietary recommendations for populations and individuals will increasingly play a role in nutrition counseling and policy making (DeBusk., 2008).

Nutrigenetics will provide the basis for personalized dietary recommendations based on the individual's genetic makeup. This approach has been used for decades for certain single gene diseases; such as phenylketonuria, however, the challenge is to implement a similar concept for common multi factorial disorders and to develop tools to detect genetic predisposition and to prevent common disorders decades before their manifestation. The preliminary results involving gene-diet interactions for cardiovascular diseases and cancer are promising, but mostly inconclusive. Success in this area will require the integration of different disciplines and investigators working on large population studies designed to adequately investigate gene-environment interactions (Ordovas & Corella., 2004; Ordovas & Mooser., 2004).

#### **4.3 Nutritional genomics and lipid metabolism**

From a health perspective, the major concerns regarding genes and lipid metabolism center on susceptibility to vascular disease. Genes involved with cholesterol homeostasis offer examples of how genetic variations affect lipid metabolism and, thereby, disease risk (DeBusk., 2009).

The blood lipid response to diet is influenced by polymorphisms within genes for the apolipoproteins as well as within those for enzymes, such as hepatic lipase, that are involved in lipid metabolism (fisler & Warden., 2005)**.** 

The major focus of nutritional genomics research is on identifying (1) gene-disease associations, (2) the dietary components that influence these associations, (3) the mechanisms by which dietary components exert their effects, and (4) the genotypes that benefit most from particular dietary choices (DeBusk., 2008).

The following section takes a brief look at some of the key diet-related genes and their known variants and how these variants affect the person's response to diet. Keep in mind that chronic diseases involve complex interactions among genes and bioactive food components, and unraveling the details will require population and intervention studies large enough to have the statistical power needed to draw meaningful conclusions. Although what is known today is but the tip of the iceberg compared to what will come in the years ahead (DeBusk., 2008).

Over the last two decades there has been an explosion of research in this area, with often conflicting findings reported in the literature (Rimbach & Minihan., 2009).

### **5. Candidate gene approach**

The candidate gene approach involves the selection and study of biologically relevant genes. Genetic polymorphisms in these genes, known as Single-Nucleotide Polymorphism (SNPs), can alter susceptibility to a disease. Candidate or "susceptibility" genes should meet one or more of the following conditions: genes that are chronically activated during a disease state and have been previously demonstrated to be sensitive to dietary intervention; genes with

Nutrigenetics and Dyslipidemia 49

increasing dietary Polyunsaturated Fat (PUFA) levels from less than 4% of total energy to 4% to 8% to greater than 8% resulted in a corresponding decline in HDL levels as PUFA levels increase. However, in women with the A allele, increasing PUFA concentrations (>8% of energy derived from PUFA) increased HDL levels and the increase is more dramatic in the presence of two copies of the A alleles than it is with just one. For these women, a diet low in saturated fat, moderate in polyunsaturated fat (8% or greater of total calories), and supplying the rest in monounsaturated fat has the greatest benefit in raising HDL levels. Clearly, whether a person has the -75G>A *A*po *AI* variant, and how many copies are present, will affect any therapeutic intervention developed to correct dyslipidemia (DeBusk.,

Juo et al (Hank Juo., 1999) used a meta analysis approach to show the lack of consistency between the less common A-allele and higher HDL-cholesterol concentrations. In view of the significant gene-diet interaction observed for those intervention studies, they examined whether these results could be extrapolated to a free living population, consisting of about 1600 Framingham Offspring Study participants (Ordovas et al., 2002). The results from the straightforward association between genotype and phenotype were disappointing and suggested that the G/A polymorphism was not associated with HDLcholesterol, Apo A-I concentrations, nor with any other anthropometrical or plasma lipid variable examined. To examine the potential modifying effect of dietary fat on these associations, they fitted multivariate linear regression models, including interaction terms for fat intake [total, Saturated Fatty Acid (SFA), Monounsaturated Fat (MUFA), and PUFA fat]. No significant interactions were observed between the G/A polymorphism, total, SFA, and MUFA fat intakes. However, in women, HDL-cholesterol concentrations were associated with a significant interaction between PUFA intake and Apo A1 genotype (p = 0. 005). Using PUFA as a dichotomous variable, their data show that G/G women consuming *<*6% PUFA/day had higher HDL-cholesterol (1. 48 ± 0. 40 m mol/L) than Acarriers (1. 43 ± 0. 40 m mol/L). Conversely, when consuming ≥6% PUFA/day, G/G had lower HDL-cholesterol concentrations (1. 44 ± 0. 39 m mol/L) than A-carriers (1. 49 ± 0. 39 m mol/L). In men, the situation was more complex because the effects were observed using three-way interactions, including smoking and alcohol consumption, in the

The most evident application of these results may be to help us make more efficacious dietary recommendations based on genetic profile. It is clear that subjects with the A-allele at this Apo A1–75 (G/A) polymorphism will benefit from diets containing a high percentage (it is important to underscore that we are talking about percent in the diet and not about total amounts) of PUFA (i. e., vegetable oils, fish, nuts, and so on). According to their data, this should result in higher HDL-cholesterol concentrations, which in turn should lower CVD risk. These findings suggest that the expression of the Apo A1 gene may be regulated

On the other hand**,** of 13 reports, 5 found that the presence of the Apo A-I–75 (*G/A*) A allele instead of the common *G* allele resulted in greater LDL-cholesterol responses to changes in dietary. In addition, significant interactions between the *G/A* genotype and diet were found for changes in total and LDL cholesterol when subjects changed from a low-fat diet to a diet high in MUFAs. No significant interactions between diet and other polymorphisms in the

2009; Much et al., 2005; Debra., 2008).

analyzes (Ordovas & Corella., 2004).

by PUFA (Ordovas & Corella., 2004).

Apo A-I gene were shown (Ordovas & Corella., 2004).

functionally important variations; genes that have an important hierarchical role in biological cascades; polymorphisms that are highly prevalent in the population (usually >10% for public health relevance); and/or genes with associated biomarkers, rendering clinical trials useful (Lovegrove & Gitau., 2008).

Many studies have investigated this possibility and have largely focused on genes whose products affect lipoprotein metabolism, eg, apolipoproteins, enzymes, and receptors. Although there have been several reviews of such studies, many of them may have led to articles being omitted and introduced bias toward positive findings (Ordovas., 2006).
