CHAPTER 1

INTRODUCTION

HISTORY OF NUTRIGENOMICS AND NUTRIGENETICS

As the years have progressed in scientific research, it has become apparent the role our diet and

nutrition play in terms of contributing or being detrimental to health. This is quite apparent from

our knowledge of nutrient deficiencies; kwashiorkor for example. We also know about vitamins

and the deficiencies that result when they are not provided. However, the aforementioned

knowledge was thought to be due to metabolic reactions in the body alone. In fact, no one

imagined that diet could affect genetic expression or that the presence of gene variants could

radically affect the body's response to nutrients. These phenomena have come to light and are

currently being studied in the fields of nutrigenomics and nutrigenetics.

The term nutrigenetics was introduced by Brennan in 1975 in “Nutrigenetics: New Concepts for

Relieving Hypoglycemia” (Brennan and Mulligan, 1975). Nutrigenetics came about through

methodological advances in the study of molecular biology and genetics thus leading to research

on genetic variations and dietary responses. Thus began the field of Nutrigenetics; the study of

the effects of genetic variations on dietary response.

A closely related but distinctively different field also sprang to life, although not as early. This

related field; Nutrigenomics, involved the study of the role of nutrients in gene expression.

Although it was common knowledge that nutrition and gene expression went hand in hand, it

was thought to be a post translational relation where diet provided the substrates needed for

protein synthesis or cofactors for enzymes. However, revolutions in molecular genetics and the

Human Genome Project of the 1990s that helped sequence the entire human genome enabled a

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deeper dive into the effects of diet on gene expression (Debusk and Ruth, 2005). By the year

2007, numerous interrelationships between nutrition, genes and diseases had been discovered.

Nutrigenetics and nutrigenomics are fields which are both still in their infancy. Engagements

with these fields are however popular in many parts of the world and are providing insight into

various diseases that have long puzzled the medical community.

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 CHAPTER 2

NUTRIGENETICS AND NUTRIGENOMICS; LINKS AND BENEFITS

2.1 NUTRIGENETICS AND NUTRIGENOMICS

If we define nutrigenetics as the study of the effects of genetic variations on dietary responses

and nutrigenomics as the study of the roles and effects of nutrients in gene expression, it is quite

apparent that both fields must be connected and intertwined. The fact that they both involve

studying nutrients and gene expression links both fields to a great extent and in some ways show

that one field requires the other.

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Fig 1.1 The relations of genes and nutrition to nutrigenetics and nutrigenomics

2.2 LINKS BETWEEN NUTRIGENETICS AND NUTRIGENOMICS

The interrelation of nutrigenetics and nutrigenomics is without doubt. We shall however

discuss their links in terms of their subjects of research and the commonalities between them.

(a) GENETICS:

It is immediately obvious from the definitions of nutrigenetics and nutrigenomics that both fields

must study the genes, albeit in different contexts. In the case of nutrigenetics, the study of

genetics would be mainly focused on the effects of different gene variants, the resulting variant

proteins and the subsequent effects of these proteins on the metabolism of nutrients. A example

case study would be lactose intolerance.

Research has shown that most people lose their ability to digest lactose after infancy; however,

some people possess lactase persistence alleles so that they don't lose their ability to digest

lactose. This was discovered to be due to various genetic variants of the LCT gene located on the

long arm of chromosome 2 at position 21. (Matter R. et al., 2012)

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Table 1.1 Frequencies of LCT gene variants (Matter R. et al., 2012)

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In the nutrigenomics, the study of genetics would mainly focus on the effect of nutrition and

nutrition-derived metabolites on gene expression, the studying of various transcription factors,

epigenetics and epigenomics. An example case study of this would be the study of the effects of

lactose on gene expression in bacteria. The Lac operon and the effects of lactose as an inducer in

the absence of glucose (Rodwell et al., 2018)

(b) NUTRITION:

It is imperative in both fields that nutrition be a major concern. Nutrigenetics and nutrigenomics

study nutrition and just ask the case with genetics, they do so in different contexts. In the case of

nutrigenetics, the main focus is on what is done to the ingested nutrients while in the case of

nutrigenomics, the crux of focus is on what the ingested nutrients do. Thus if we refer back to

Table 1.1 and Figure 1.1, nutrigenetics would study what is done on ingested lactose; in the case

of lactose intolerant people, it is undigested and for people with lactose persistence alleles, it is

digested. Nutrigenomics, however, would study what lactose does while in the body and the

variations of its effects in the presence or absence of other nutrients. The change effected by

lactose here is on the synthesis of enzymes needed for lactose catabolism which are synthesized

only in the presence of lactose only.

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Fig 1.2 Lac operon (Rodwell et al., 2018)

(c) DISEASES:

These are usually metabolic disorders or nutrient deficiencies, both of which are studied and

related to nutrigenetics and nutrigenomics. A classic example in Nutrigenetics would be a case of

inherited pyruvate dehydrogenase deficiency. This deficiency would prevent the citric acid cycle

in cells and thus restrict them to anaerobic respiration forming toxic products such as lactic acid

and causing very little ATP to be produced. In this case, nutrigenetics would focus on the various

genetic variants that lead to the synthesis of pyruvate dehydrogenase. Thiamine deficiency which

would produce similar signs as inherited pyruvate dehydrogenase deficiency would however be

the classic example for Nutrigenomics. Here, nutrigenomics would be concerned with the effects

of dietary thiamine or lack thereof on gene expression (Rodwell et al., 2018).

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 CHAPTER 3

TOOLS FOR RESEARCH IN NUTRIGENOMICS AND NUTRIGENETICS

Nutrigenomics and Nutrigenetics both require the study of nutrients and the study of genes and

gene expression and other fields related to the process. We shall thus discuss the tools used for

researching the major components involved in nutrigenomics and nutrigenetics. These

components are:

(a) Genomics

(b) Proteomics

(c) Metabolomics

(d) Bioinformatics

(a) GENOMICS:

Genomics is the study of the structures, functions, evolution, mapping and editing of an

organism's complete set of DNA, including all of its genes as well as its hierarchical, three-

dimensional structural configuration. Since both nutrigenomics and nutrigenetics are in one way

or the other tied to gene expression, it is imperative that we first of all know what genes there

are, which ones are expressed, the mechanisms etc.

DNA sequencing, the mapping of the genes is done using various methods such as:

* Sanger sequencing

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* Pyro sequencing

* Reversible terminator sequencing

* Sequencing by Oligonucleotide Ligation and Detection (SOLID)

* Proton detection and various other novel methods that are constantly being created (Dovichi et

al., 2012)

Gene editing with tools such as:

* Restriction enzymes

* Zinc finger nucleases

* Transcription activator-like effector nucleases

* CRISPR-Cas9 gene editing

* Base editing

* Prime editing etc. (Amanda, 2022)

Other tools include:

* Genome-Wide Association Studies (GWAS) which help scientists to identify genes associated

with particular traits

*Mendelian randomization which helps to observe the functions of genes in various conditions

* RNA sequencing which can be worked backwards to determine gene sequence (Blank, 2022).

(b) PROTEOMICS:

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Proteomics is the large-scale study of the whole set of proteins produced in an organism. Since

genes code for proteins, it is obvious that the study of gene expression cannot exclude the study

of proteins. Proteomics involves the exploration of protein composition, structure and activity.

The various tools used in proteomics include:

* Immunoassays (protein detection with antibodies)

* Electrophoresis

* X-ray crystallography

* Mass spectrometry

* Protein microarrays

* Various types of chromatography (Graves and Timothy, 2002)

Proteomics is also very much related to genomics and so makes use of some of the tools used in

genomics.

(c) METABOLOMICS:

Metabolomics involves the large-scale study of metabolites, small molecules within within cells

which interact in various ways and enable life processes in living organisms. In nutrigenomics,

the nutrients which affect gene expression are metabolites. Similarly, in nutrigenetics, the

various gene variants affect various dietary responses through metabolites. It is therefore clear

that metabolomics is integral to both nutrigenomics and nutrigenetics. The tools used in

metabolomics include:

Methods used for separation of metabolites such as:

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* Nuclear Magnetic Resonance (NMR)

* Gas chromatography

* High Performance Liquid Chromatography (HPLC)

* Capillary electrophoresis

Methods used for detection of metabolites such as:

* Mass spectrometry

* NMR (Nalbantoglu, 2019)

In addition, various statistical methods are also made use of to assess collected data.

(d) BIOINFORMATICS:

Bioinformatics is the application of tools of computation and analysis to capture and interpret

biological data. This involves an interdisciplinary approach where data obtained from genomics,

proteomics, metabolomics and other biology- related fields are fed into computers which with

the use of various complex algorithms, analyse and interpret vast amounts of data. Without

bioinformatics, the processing of these data would be unimaginable slow and difficult especially

in fields such as nutrigenomics and nutrigenetics where multifactorial analyses are a major

feature. With these vast amounts of data, databases exist which cover various information types

such as:

* Used in biological sequence analysis: Genbank, UniProt

* Used in structure analysis: Protein Data Bank (PDB)

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* Used in finding Protein Families and Motif Finding: InterPro, Pfam

* Used for Next Generation Sequencing: Sequence Read Archive

* Used in Network Analysis: Metabolic Pathway Databases (KEGG, BioCyc), Interaction

Analysis Databases, Functional Networks

* Used in design of synthetic genetic circuits: GenoCAD (Bayat, 2002)

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 CHAPTER 4

APPLICATIONS OF NUTRIGENETICS AND NUTRIGENOMICS IN MEDICINE

Nutrigenetics and nutrigenomics have helped provide insight into the effects of diet on the genes

and conversely, the effects of the genes on diet. These various insights have found various

applications in medicine. These applications include:

I. Treatment/management of metabolic genetic disorders:

Nutrigenetics' insights have helped us to understand the etiologies of various

previously not understood metabolic genetic disorders like obesity (Phillips, 2013).

An example of this is Phenylketonuria, a disorder in which a mutation in the gene for

Phenylalanine Hydroxylase causes the enzyme to be nonfunctional. To manage this

condition, patients are advised to avoid foods which may be p otential sources of

Phenylalanine.

II. Treatment/management of nutrient deficiencies or excess:

Deficiencies of nutrients such as vitamins pose less problems now because

nutrigenomics and nutrigenetics have enabled us to easily monitor nutrient

metabolism and their effects on gene expression. Vitamin A for example acts as a

ligand for transcription factors receptors, thus affecting genetic expression (McGrane,

2007). We now know that deficiencies can cause deterioration of sight and at the

same time, excess can also lead to negative consequences. Therefore, prescriptions

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 are carefully managed so that people who are prone to deficiencies are not deficient

and at the same time are not taking it in excess.

III. Personalized medicine:

The study of gene variants and how they effect various dietary responses has helped

in the progression of personalized medicine. Now, a patient's genes can be sequenced

and after diagnosis, tailored prognoses can be made. This use of tailored treatments

produce better outcomes as opposed to the one size fits all approach that is currently

prevalent (Vogenberg et al., 2010). This is the future of medicine and nutrigenetics is

getting us closer to it.

IV. Gene therapy:

By studying the effects of nutrients on genes and genes on nutrients, genetic

therapies for genetic disorders can now be better created. Thus, in a scenario where

there is a gene mutation leading to a nonfunctional enzyme, the substrate of such

enzyme is avoided in as much as can be physiologically possible. However, in a

situation where a gene is over expressing or under expressing, nutrients which

upregulate or downregulate the expression of the said gene are given to patients. In

addition, genetic alterations that could be potentially cancerous can be prevented by

simply making some dietary recommendations and dietary restrictions. (Braicu et al.,

2017)

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V. Production of pharmaceuticals:

Nutrigenetics and nutrigenomics have enabled us to gain insights into the

mechanisms involved in gene expression and nutrient metabolism. Thus,

pharmaceuticals which are synthetic analogs of the particular nutrients can be made

and can thus be prescribed in cases of deficiencies or scarcity. Thus, things like

dietary supplements and fortified foods are made possible and have allowed us to

decrease the incidences of goiter (Leung et al., 2012), neural tube defects (Honein et

al., 2001)etc.

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 CHAPTER 5

CONCLUSION

The medical relevance of nutrigenomics and nutrigenetics cannot be denied. Their applications

in dietary prescriptions, genetic therapies, treatments of disorders etc, are definitely very

significant to the practice of Medicine in the 21st century. These two new fields have shed light

and are still shedding more light on the biochemical and physiological processes that occur in the

human body. It is up to us to make good use of it. We might also want to consider some ethical

considerations that may come up due to this vast and incredibly powerful knowledge.

In conclusion, the era of a one size fits all medical approach is fading away, the new trend now is

personalized medicine. To achieve this will require nutrigenomics and nutrigenetics. Thus, if

personalized medicine is the future, it is without question that nutrigenomics and nutrigenetics

are part of that future.

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