Abstract
The human genome is composed of three billion base pairs that include coding and noncoding sequences. The coding sequences encode for more than 20,000 genes that are responsible for different human phenotypes (Salzberg 2018). While the primary sequence of nucleotide in the human genome dictates the individual’s traits, modification of DNA nucleotide or the histone proteins has profound effects on the gene expression pattern and the resulting phenotypes. Such modifications are known as epigenetic modifications which substantially affects the individual’s phenotypic characteristics without changing the primary structure of the DNA (Yi and Goodisman 2021). A study of identical twins revealed that interaction between the genome and the environment considerably affects the phenotypic outcome irrespective of the similarity of the primary sequence of the DNA (Fraga et al. 2005). While environmental factors can affect the individual’s phenotype through changing the primary sequence of the DNA (induction of mutations), modification of the epigenome has a significant impact as a mediator of environmental effects on the individual’s phenotypic characteristics. Among the environmental factors that modulate the epigenome, nutrition has a great influence (Mullins et al. 2020). A study of the interaction between the nutrition and individual’s genome in order to guide individually tailored nutritional intervention is a promising field not only for diseases prevention and management but also for health improvement (Astley 2007; Peregrin 2001). In the future, personalized nutritional advice will be easily suggested based on the individual genetic variation by the aid of the advanced “omics” approaches.
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3.1 Introduction
The human genome is composed of three billion base pairs that include coding and noncoding sequences. The coding sequences encode for more than 20,000 genes that are responsible for different human phenotypes (Salzberg 2018). While the primary sequence of nucleotide in the human genome dictates the individual’s traits, modification of DNA nucleotide or the histone proteins has profound effects on the gene expression pattern and the resulting phenotypes. Such modifications are known as epigenetic modifications which substantially affects the individual’s phenotypic characteristics without changing the primary structure of the DNA (Yi and Goodisman 2021). A study of identical twins revealed that interaction between the genome and the environment considerably affects the phenotypic outcome irrespective of the similarity of the primary sequence of the DNA (Fraga et al. 2005). While environmental factors can affect the individual’s phenotype through changing the primary sequence of the DNA (induction of mutations), modification of the epigenome has a significant impact as a mediator of environmental effects on the individual’s phenotypic characteristics. Among the environmental factors that modulate the epigenome, nutrition has a great influence (Mullins et al. 2020). A study of the interaction between the nutrition and individual’s genome in order to guide individually tailored nutritional intervention is a promising field not only for diseases prevention and management but also for health improvement (Astley 2007; Peregrin 2001). In the future, personalized nutritional advice will be easily suggested based on the individual genetic variation by the aid of the advanced “omics” approaches.
3.2 Nutrigenomics: How Nutrients Affect Genes
Nutrients can affect the gene expression pattern and consequently the phenotypic characteristics of individuals (Müller and Kersten 2003). Nutrigenomics is the branch of science that deals with the ability of nutrients to modify the gene expression aiming at identifying health-related effects of nutrients (Miggiano and De Sanctis 2006; Remely et al. 2015a). Determining the relation between nutrition patterns and the development of certain diseases, especially the chronic disease, supports the prevention or delay of such diseases (Miggiano and De Sanctis 2006). The ultimate goal of nutrigenomics is, thus, to guide individualized nutritional intervention in order to help treating, modifying, or preventing diseases as well as improving the health of human beings. Epigenetics represent an important link that connects many environmental factors, including nutrition, to the genome. Nutrients can modify the epigenome through different mechanisms. They can supply the required material for DNA methylation or histone modifications. Additionally, they can modulate the enzymatic activity of DNA methyltransferases or one carbon metabolism-related enzymes (Remely et al. 2015a; Zhang 2015). Such modifications modulate the accessibility of gene promoter regions by the transcription factors, affecting the gene expression (Kaput et al. 2007). While the mechanisms mediate the ability of some nutrient to modulate the epigenome have been uncovered, a lot of others still to be addressed.
3.3 Nutrients Modulate DNA Methylation and Histone Acetylation
DNA methylation is the most stable epigenetic modification of the genome (Bordoni and Gabbianelli 2019). Methyl groups are added to the cytosine nucleotide at carbon 5 in the CpG (cytosine-guanine)-rich regions in the DNA. Adding such methyl groups suppresses the gene expression which directly affects several biological outcomes, including cell proliferation and aging (Alam et al. 2019; Jones and Laird 1999). Micronutrients such as vitamin B12, vitamin B6, folate, and methionine which contribute to the one carbon metabolism play critical roles in DNA methylation process (Kaput et al. 2007). They increase the availability of the methyl donor s-adenosyl methionine. Defective methylation of DNA increases susceptibility to cancer and neural tube defects (Stover and Garza 2002). Other nutrients including retinoic acid, resveratrol, and curcumin have been implicated in the modification of DNA methylation (Alam et al. 2019; Shu et al. 2011). In addition to the role of micronutrients, caloric restriction plays important roles in DNA methylation. It has been demonstrated that caloric restriction increases methylation of RAS oncogene (Hass et al. 1993).
Besides DNA methylation, histone acetylation represents an important epigenetic mechanism that controls gene expression through altering the accessibility of the DNA by the transcription factors. Caloric control and NADH/NAD+ ratio play important roles in the histone modifications (Blander and Guarente 2004). Caloric control has been associated with SIRT1 (NAD+-dependent histone deacetylase) and HDAC1 gene expressions which stimulate histone deacetylation and induce expression of a variety of important genes including the tumor suppressor p53 gene (Alam et al. 2019; Blander and Guarente 2004). Permanent epigenetic modifications may be caused by the continuous usage of nutrient that induces such epigenetic modifications (Kaput et al. 2007).
3.4 Genetic Variations Affect the Response to Nutrients
In contrast to the effect of nutrients on the genome, genetic variation between individuals affects their response to the same nutrient. How the genetic makeup of individuals affects their response to the same nutrients is the subject of the nutrigenetics branch of science (German 2005; Hawkinson 2007). Inborn errors of metabolism exemplify how genetic variations affect the individual response to nutrition. Phenylketonuria induces mental retardation due to abnormal metabolic manipulation of the dietary phenylalanine amino acid. Similarly, deficiency in the lactase enzyme causes lactose intolerance (Gaboon 2011). Maple syrup urine disease is another example of the genetic variation that affects the metabolism of the branched-chain amino acids (Bordoni and Gabbianelli 2019; Kohlmeier 2012). Mutation in homogentisate dioxygenase gene results in alkaptonuria (Garrod 1902). While monogenetic variation is responsible for the abovementioned examples, more complex ploygenetic variations that are responsible for diseases such as obesity also exist (Fu et al. 2015; Shungin et al. 2015).
The human genome is almost the same in all individuals. Despite the obvious phenotypic variability between individuals, the genetic makeup of any two individuals differs only in less than 1% (Mullins et al. 2020). Such variations occur mostly in the noncoding regions of the genome which represents about 99% of the entire genome. The most common genetic variation between individual is the single nucleotide polymorphism (SNP) in which individuals differ in only one nucleotide at a certain DNA locus. The human genome contains about 300,000 SNPs that is about 1 SNP for every 1000 base pair (Nelson et al. 2004). The current researches focus on the relation of SNP variability and nutrition although other types of genetic variation such as insertion/deletions/inversion may also have roles (Mullins et al. 2020). Genome-wide genetic association studies are used to associate certain SNPs with certain phenotypic outcomes, but studies that are performed on certain population cannot reliably be applied to other populations (Medina-Gomez et al. 2015). DNA microarray is a widely used technique for these association studies to detect a huge number of SNPs (Hoffmann et al. 2011). While the majority of individual SNPs have no diet-related effects, others have a significant impact on nutrient-gene interaction. Common example of these SNPs include rs762551 in CYP1A2 gene that affects the individual ability to metabolize caffeine, rs1229984 and rs2066702 in ADH1B gene that affect the alcohol metabolism, and rs738409 in PNPLA3 that affects fat accumulation in the liver and the susceptibility to the fatty liver disease (Edenberg 2007; Frary et al. 2005; Mazo et al. 2019; Nehlig 2018; Sachse et al. 2003). Other examples include rs9939609 in FTO gene that affects the susceptibility to obesity and rs7412 and rs429358 in APOE gene that affect susceptibility to cardiovascular diseases and Alzheimer’s disease, respectively (Ağagündüz and Gezmen-Karadağ 2019; Di Renzo et al. 2019; Duicu et al. 2016; Fawcett and Barroso 2010; Hardy et al. 2020; Kühn et al. 2016; Liu et al. 2019; Martins et al. 2006). Additionally, rs1801133 in MTHFR gene affects the folate metabolism, and rs7041 and rs4588 in GC gene affect the transport of vitamin D. While single SNP variability may underline a variety of nutrition-related problems, many nutrition-related problems are multifactorial and involve several genetic variations (Mullins et al. 2020). Identifying such SNPs is currently challenging. Commercially available genetic testing has been recently expanded to test for the common nutrition-related genetic variation in order to guide individually tailored nutritional advice, but its accuracy is still to be improved (Caulfield et al. 2010).
3.5 Nutrigenomics and Control of Chronic Diseases
Chronic diseases represent a leading cause of death in the United States although the majority of them can be prevented (Control, C.F.D. and Prevention 2009). The prevalence of chronic diseases such as cardiometabolic diseases and cancer has been largely attributed to nutrition problems (Afshin et al. 2019; Micha et al. 2017). Diet represents an important modifiable factor that has profound effects on the heath outcome. Consumption of certain types of diet such as fruits, vegetables, nuts, and fiber-rich diets decreases the risk of the cardiometabolic disease and diabetes mellitus (Qian et al. 2019; Satija and Hu 2018). Studies have heighted the role of fruit and vegetable consumption in controlling not only cancer but also the cardiovascular diseases, diabetes, and aging (Atanasov et al. 2015; Braicu et al. 2017). A variety of secondary metabolites in plants (phytochemicals) are responsible for the observed modulatory activity (Milenkovic et al. 2012; Waltenberger et al. 2016). For example, curcumin, a phytochemical, reduces the incidence of type 2 diabetes in the prediabetic subjects (Chuengsamarn et al. 2012). Other phytochemicals including resveratrol and epigallocatechin are implicated in the control of body weight and obesity (Milagro et al. 2013). Biologically active compounds derived from olive oil including oleic acid and biophenols have been shown to play important role in cancer chemoprevention (Braicu et al. 2017; Piroddi et al. 2017). The effect of these compounds is thought to be through the epigenetic modulatory activity (Remely et al. 2015b). Understanding the nutrient-gene-disease interconnection will help in developing strategies for individualized intervention to prevent and control diseases as well as improving health.
3.6 Nutrigenomic in Cardiovascular Diseases
Cardiovascular diseases (CVD) are worldwide prevalent diseases. Despite their complicated multifactorial etiology, CVD are extensively studied for understanding their genetic background (Corella and Ordovas 2009). Nutritional intervention has been explored not only to treat but also to prevent the CVD (Corella and Ordovas 2009; Reen et al. 2015). Olive oil consumption has been associated with improved cardiovascular function, decreased blood pressure, and improved lipid profile (De Santis et al. 2019). The polyphenolic content of olive oil has been implicated in modulation of inflammatory pathways, cellular redox status, and lipid metabolism (De Santis et al. 2019). Oxidative modification of low-density lipoproteins (LDL) has been significantly diminished with administration of olive oil for 3 weeks (Castaner et al. 2012). The underlining molecular mechanism was found to be reduced CD40/CD40-ligand interaction with subsequent reduction in the inflammatory responses and pro-inflammatory cytokine levels (Castaner et al. 2012). Polyphenolic content of the olive oil reduces gene expression of IL8RA that modulates the blood pressure through targeting the renin-angiotensin-aldosterone system (De Santis et al. 2019). Administration of olive oil with high polyphenolic content also suppresses expression of the inflammation-related genes IFN and IL-7R and the oxidative stress-related gene ADRB2 (Konstantinidou et al. 2010). Omega-3 polyunsaturated fatty acids have been shown to reduce the release of leukotriene that is increased at the atherosclerotic sites through modulation of lipoxogenase-5 gene expression (Kaur et al. 2018). Yoo, J. and Park, S. demonstrated that the interaction between low folate levels and the MTHFR gene with C677T SNP determines the risk level of the coronary artery disease (Yoo and Park 2000). Vitamin B interacts with the same SNP to determine the level of homocysteine and subsequently the risk of thromboembolic vulnerability (Yates and Lucock 2003). Yang Y. and colleagues showed that dietary saturated fats interact with E2 and E4 SNP of APOE gene to increase vulnerability to myocardial infarction (Yang et al. 2007). Dietary arachidonic acid interacts with SNPs in 5-lipoxygenase gene and increases the risk of myocardial infarction (Allayee et al. 2008).
3.7 Nutrigenomics in Cancer
Cancer is an uncontrolled cell division with multifactorial etiology. Diet-derived compounds have been demonstrated to modulate different stages of cancer including angiogenesis and metastasis (Braicu et al. 2017). It has been reported that more than a quarter of cancer types can be modulated with diet (Ardekani and Jabbari 2009). Diet rich in fish and green tea has been associated with decreased rate of breast cancer in Asian population (Petric et al. 2015). Phytochemicals are plant-derived secondary metabolites that are produced to defend plants or to provide attractive color or smell (Liu 2004). These phytochemicals can be classified into sulfhydryl compounds, polyphenols, or terpenoids. Among these compounds, quercetin and Kaempferol (flavonols), luteolin and apigenin (flavones), genistein and daidzein (isoflavones), and naringenin and hesperidin (flavanones) have been extensively studied (Braicu et al. 2017; Hardman 2014). Flavones and isolflavones represent plant-derived estrogen-like compounds that interfere with estrogen-related molecular pathways (He and Chen 2013). The isoflavones such as genistein and daidzein have also been demonstrated to control breast cancer and prostate cancer via targeting estrogenic and androgenic receptors, respectively (Adjakly et al. 2013; Choi and Kim 2013; Upadhyay and Dixit 2015). Phytochemicals also have been shown to modulate genomic-related molecular pathways in lung, breast, colon, liver, ovarian, and prostate cancers (Del Follo-Martinez et al. 2013; Du et al. 2013; Hua et al. 2016; Kim et al. 2013; Omene et al. 2013; Ozturk et al. 2012; Singh et al. 2017; Tolba et al. 2013; Weng and Yen 2012; Wubetu et al. 2016). Epigallocatechin-3-gallate, a major polyphenolic compound in green tea, has been implicated in epigenetic regulation of gene expression in cancer cells through histone modification (Meeran et al. 2011; Nandakumar et al. 2011). Apigenin has been shown to downregulate DNMT and HDAC activity in the skin epidermal cells (Paredes-Gonzalez et al. 2014). Genistein plays role in DNA methylation and histone acetylation and activates the tumor suppressor genes (Kikuno et al. 2008; Vardi et al. 2010). These phytochemical compounds have been implicated in modulation of a large variety of cancer-related genes (Braicu et al. 2017).
3.8 Conclusions and Future Directions
Nutrition represents a vital environmental factor that affects our health. Mutual interaction between nutrition and our genes largely determine the individual health outcome. Genes affect the metabolism of nutrition, while nutrients affect gene expression patterns. Switching from the conventional nutrition guideline (i.e., based on factors such as gender or age groups) to the gene-based nutrition is the bright future of nutritional science. Such switch will not only help disease prevention but also will improve the general health. Advancement in the genome-wide studies that associate not only SNPs but also the large genetic variation like insertion-deletion-inversion to the nutrient-related health outcomes are critical for rapid advancement in this field. Improved accuracy in testing approaches such as the DNA base microarray will help in detecting the susceptible individual and will reduced false-positive and false-negative results. Uncovering more underlining mechanisms that clarify how nutrients affect gene expressions will guide the individually tailored nutritional advice.
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Salama, S.A., Dakhlallah, D. (2022). Gene-Gut-Brain Axis: Gene-Based Personalized Medicine. In: Salama, M. (eds) Nutrigenomics and the Brain. Nutritional Neurosciences. Springer, Singapore. https://doi.org/10.1007/978-981-16-9205-5_3
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