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Genome health nutrigenomics and nutrigenetics – diagnosis and nutritional treatment of genome damage on an individual basis

Genome health nutrigenomics and nutrigenetics – diagnosis and nutritional treatment of genome damage on an individual basis

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Published by Disiciencia
The term nutrigenomics refers to the effect of diet on gene expression. The term nutrigenetics refers to the impact of inherited traits on
the response to a specific dietary pattern, functional food or supplement on a specific health outcome. The specific fields of genome health
nutrigenomics and genome health nutrigenetics are emerging as important new research areas because it is becoming increasingly evident
that (a) risk for developmental and degenerative disease increases with DNA damage which in turn is dependent on nutritional status and
(b) optimal concentration of micronutrients for prevention of genome damage is also dependent on genetic polymorphisms that alter
function of genes involved directly or indirectly in uptake and metabolism of micronutrients required for DNA repair and DNA replication.
Development of dietary patterns, functional foods and supplements that are designed to improve genome health maintenance in
humans with specific genetic backgrounds may provide an important contribution to a new optimum health strategy based on the diagnosis
and individualised nutritional treatment of genome instability i.e. Genome Health Clinics.
The term nutrigenomics refers to the effect of diet on gene expression. The term nutrigenetics refers to the impact of inherited traits on
the response to a specific dietary pattern, functional food or supplement on a specific health outcome. The specific fields of genome health
nutrigenomics and genome health nutrigenetics are emerging as important new research areas because it is becoming increasingly evident
that (a) risk for developmental and degenerative disease increases with DNA damage which in turn is dependent on nutritional status and
(b) optimal concentration of micronutrients for prevention of genome damage is also dependent on genetic polymorphisms that alter
function of genes involved directly or indirectly in uptake and metabolism of micronutrients required for DNA repair and DNA replication.
Development of dietary patterns, functional foods and supplements that are designed to improve genome health maintenance in
humans with specific genetic backgrounds may provide an important contribution to a new optimum health strategy based on the diagnosis
and individualised nutritional treatment of genome instability i.e. Genome Health Clinics.

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Genome health nutrigenomics and nutrigenetics – diagnosisand nutritional treatment of genome damageon an individual basis
Michael Fenech
*
CSIRO, Human Nutrition, P.O. Box 10041, Adelaide BC, SA 5000, Australia
Abstract
The term nutrigenomics refers to the effect of diet on gene expression. The term nutrigenetics refers to the impact of inherited traits onthe response to a specific dietary pattern, functional food or supplement on a specific health outcome. The specific fields of genome healthnutrigenomics and genome health nutrigenetics are emerging as important new research areas because it is becoming increasingly evidentthat (a) risk for developmental and degenerative disease increases with DNA damage which in turn is dependent on nutritional status and(b) optimal concentration of micronutrients for prevention of genome damage is also dependent on genetic polymorphisms that alterfunction of genes involved directly or indirectly in uptake and metabolism of micronutrients required for DNA repair and DNA repli-cation. Development of dietary patterns, functional foods and supplements that are designed to improve genome health maintenance inhumans with specific genetic backgrounds may provide an important contribution to a new optimum health strategy based on the diag-nosis and individualised nutritional treatment of genome instability i.e. Genome Health Clinics.
Crown Copyright
Keywords:
Genome health; Nutrigenomics; Nutrigenetics; DNA damage; Micronutrients; Vitamins; Minerals; Polymorphisms
1. Introduction
The central role of the genetic code in determining gen-ome stability and related health outcomes such as develop-mental defects and degenerative diseases such as cancer iswell established (Ames, 2006; Ames and Wakimoto, 2002;Ames, 2003; Fenech and Ferguson, 2001; Fenech, 2005;Egger et al., 2004; Fenech, 2002; Rajagopalan and Leng-auer, 2004; Nathanson et al., 2001; Thompson and Schild,2002). In addition it is evident that DNA metabolism andrepair is dependent on a wide variety of dietary factors thatact as co-factors or substrates in these fundamental meta-bolic pathways (Ames, 2006; Ames and Wakimoto, 2002;Ames, 2003; Fenech and Ferguson, 2001; Fenech, 2005).DNA is continuously under threat of major mutationsfrom conception onwards by a variety of mechanismswhich include point mutation, base modification due toreactive molecules such as the hydroxyl radical, chromo-some breakage and rearrangement, chromosome loss orgain, gene silencing due to inappropriate methylation of CpG at promoter sequences, activation of parasitic DNAexpression due to reduced methylation of CpG as well asaccelerated telomere shortening (Egger et al., 2004; Fenech,2002; Rajagopalan and Lengauer, 2004). The main chal-lenge to a healthy and long life is the ability to continueto replace senescent cells in the body with fresh new cellswith normal genotypes and gene expression patterns thatare tissue-appropriate. Understanding the nutritionalrequirements for genome health maintenance of stem cellsis essential in this regard but has so far not been adequatelyexplored.While much has been learnt of the genes involved inDNA metabolism and repair and their role in a varietyof pathologies, such as defects in BRCA1 and BRCA2
*
Tel.: +61 8 8303 8880; fax: +61 8 8303 8899.
E-mail address:
 
genes that cause increased risk for breast cancer (Nathan-son et al., 2001; Thompson and Schild, 2002), much lessis known of the impact of cofactor and/or micronutrientdeficiency on DNA repair. Put simply, a deficiency in amicronutrient required as a co-factor or as an integral partof the structure of a DNA repair gene (e.g. Zn as a compo-nent of the DNA repair glycosylase OGG1 involved inremoval of oxidised guanine or Mg as a co-factor forseveral DNA polymerases) could mimic the effectofa geneticpolymorphism that reduces the activity of that enzyme(Ames, 2006; Ames and Wakimoto, 2002; Ames, 2003).Therefore nutrition has a critical role in DNA metabolismand repair and this awareness is leading to the developmentof the new fields of genome health nutrigenomics and gen-ome health nutrigenetics (Fenech, 2005). The critical aim of these fields is to define optimal dietary intakes for preven-tion of DNA damage and aberrant gene expression forgenetic sub-groups and ultimately for each individual.
2. Evidence linking genome damage with adverse healthoutcomes
Genome damage impacts on all stages of life. There isgood evidence to show that infertile couples exhibit ahigher rate of genome damage than fertile couples (Trkovaet al., 2000) when their chromosomal stability is measuredin lymphocytes using the cytokinesis-block micronucleus(CBMN) assay (Fenech, 2000, 2007)(Fig. 1). Infertility may be due to a reduced production of germ cells becausegenome damage effectively causes programmed cell deathor apoptosis which is one of the mechanisms by whichgrossly mutated cells are normally eliminated (Narulaet al., 2002; Ng et al., 2002; Hsia et al., 2003). When the lat-ter mechanism fails reproductive cells with genomic abnor-malities may survive leading to serious developmentaldefects (Liu et al., 2002; Vinson and Hales, 2002). Thatan elevated rate of chromosomal damage is a cause of can-cer has been demonstrated by ongoing prospective cohortstudies in Italy and the Scandinavian countries whichshowed a 2 to 3-fold increased risk of cancer in those whosechromosomal damage rate in lymphocytes was in thehighest tertile when measured 10–20 years before cancerincidence was measured (Bonassi et al., 2000). It has alsobeen shown that an elevated micronucleus frequency inlymphocytes predicts cancer risk in humans (Bonassiet al., 2007). Chromosomal damage is also associatedwith accelerated ageing and neurodegenerative diseases(Thompson and Schild, 2002; Fenech, 1998; Bonassiet al., 2001; Joenje and Patel, 2001; Shen and Loeb, 2001;Lansdorp, 2000; Migliore et al., 1999, 2001). Those individ-uals with accelerated ageing syndromes (e.g. Downsyndrome) and sub-optimal DNA repair (e.g. carriers of deleterious mutations in the ATM or BRCA1 genes) maybe particularly susceptible to the genome damaging effectsof sub-optimal micronutrient intake.
3. The concept of genome damage as a marker of nutritional deficiency
There is overwhelming evidence that several micronutri-ents (vitamins and minerals) are required as cofactors forenzymes or as part of the structure of proteins (metalloen-zymes) involved in DNA synthesis and repair, preventionof oxidative damage to DNA as well as maintenance meth-ylation of DNA. The role of micronutrients in maintenanceof genome stability has recently been extensively reviewed(Ames, 2006; Ames and Wakimoto, 2002; Fenech and Fer-guson, 2001; Fenech, 2003). The main point is that genomedamage caused by moderate micronutrient deficiency is of the same order of magnitude as the genome damage levelscaused by exposure to significant doses of environmentalgenotoxins such as chemical carcinogens, ultra-violet radi-ation and ionising radiation. An example from our labora-tory is the observation that chromosomal damage incultured human lymphocytes caused by reducing folateconcentration (within the normal physiological range) from120 nmol/L to 12 nmol/L is equivalent to that induced byan acute exposure to 0.2 Gy of low linear energy transfer(LET) ionising radiation (e.g. X-rays), a dose of radiationwhich is approximately ten times greater than the annualallowed safety limit of exposure for radiation workers
Micronucleus formation - Chromosome breakage or lossNucleoplasmic bridge -Chromosome translocation
 C  O C H S I  N- O C  C  OI  N S I   S - O C 
Fig. 1. Expression of micronuclei (MNi) and nucleoplasmic bridges(NPBs) during nuclear division. MNi originate from either (a) laggingwhole chromosomes (top panel) that are unable to engage with the mitoticspindle due to a defect in the spindle, or a defect in the centromere/kinetochore complex required to engage with the spindle or (b) an acentricchromosome fragment originating from a chromosome break (top andbottom panel) which lags behind at anaphase because it lacks acentromere/kinetochore complex. Mis-repair of two chromosome breaksmay lead to an asymmetrical chromosome rearrangement producing adicentric (i.e. two centromeres) chromosome and an acentric fragment(bottom panel) – frequently the centromeres of the dicentric chromosomeare pulled to opposite poles of the cell at anaphase resulting in theformation of a nucleoplasmic bridge (NPB) between the daughter nuclei.NPBs are frequently accompanied by a micronucleus originating from theassociated acentric chromosome fragment. Because MNi and NPBs areonly expressed in cells that have completed nuclear division it is necessaryto score these genome instability biomarkers specifically in once-dividedcells. This is readily accomplished by blocking cytokinesis using cytocha-lasin-B (for more detailed explanation refer toFenech (2002, 2000, 2007)).
 
(IAEA, 1986) (Fenech, 2005). If moderate deficiency in justone micronutrient can cause significant DNA damage it isreasonable to be concerned about the possibility of additiveor synergistic effects of multiple moderate deficiencies ongenome stability. Clearly there is a need to start exploringthe genotoxic effects of multiple micronutrient deficiencies,as well as excesses, which are prevalent in human popula-tions. This aspect is analogous to genetic studies thatexplore, for example, the combined effects of polymor-phisms in DNA repair genes on DNA damage.
4. Results from a recent epidemiological study suggest thatat least nine micronutrients affect genome stability inhumans in vivo
We recently reported the results of an epidemiologicalstudy on 190 healthy individuals (mean age 47.8 years,46% males) designed to determine the association betweendietary intake, measured using a food frequency question-naire and genome damage in lymphocytes (Fenech et al.,2005a) measured using the CBMN assay (Fig. 1). Multivar- iate analysis of base-line data showed that (a) highest tertileof intake of vitamin E, retinol, folic acid, nicotinic acid(preformed) and calcium is associated with significantreductions in MN frequency, i.e.
À
28%,
À
31%,
À
33%,
À
46%, and
À
49%, respectively, (all
< 0.005) relative tolowest tertile of intake and (b) highest tertile of intake of riboflavin, pantothenic acid and biotin was associatedwith significant increases in MN frequency, i.e. +36%(
= 0.054), +51% (
= 0.021), and +65% (
= 0.001),respectively, relative to lowest tertile of intake (Fig. 2).Mid-tertile
b
-carotene intake was associated with an 18%reduction in MN frequency (
= 0.038), however, the high-est tertile of intake (>6400
l
g/d) resulted in an 18% incre-ment in MN frequency. We were interested in investigatingthe combined effects of calcium or riboflavin with folateconsumption because epidemiological evidence suggeststhat these dietary factors tend to interact in modifyingthe risk of cancer (Lamprecht and Lipkin, 2003; Willett,2001; Xu et al., 2003) and they are also associated withreduced risk of osteoporosis and hip fracture (Cagnacciet al., 2003; Sato et al., 2005; Macdonald et al., 2004).Interactive additive effects were observed such as the pro-tective effect of increased calcium intake (
À
46%) and theexacerbating effect of riboflavin (+42%) on increased gen-ome damage caused by low folate intake. The results fromthis study illustrate the strong impact of a wide variety of micronutrients and their interactions on genome healthdepending on level of intake.As shown inFig. 3, the amount of micronutrients thatappear to be protective against genome damage varygreatly between foods and careful choice is needed todesign dietary patterns optimised for genome health main-tenance. Because dietary choices vary between individuals,due to taste preferences which may be genetically deter-mined or cultural or religious constraints, several options
   V   i   t  a  m   i  n   E   C  a   l  c   i  u  m   F  o   l  a   t  e   R  e   t   i  n  o   l   N   i  c  o   t   i  n   i  c  a  c   i   d  -   C  a  r  o   t  e  n  e   R   i   b  o   f   l  a  v   i  n   P  a  n   t  o   t   h  e  n   i  c  a  c   i   d   B   i  o   t   i  n
-50-250255075
mid-tertilehighest tertile
************
P < 0.006
   %   v  a  r   i  a   t   i  o  n   i  n  g  e  n  o  m  e   d  a  m  a  g  e
Fig. 2. Percentage variation in genome damage rate for mid- and highesttertile of intake of vitamin E, calcium, folate, retinol, nicotinic acid, beta-carotene, riboflavin, pantothenic acid and biotin relative to the lowesttertile of intake. Genome damage rate was measured in peripheral bloodlymphocytes using the cytokinesis-block micronucleus assay. For moreinformation refer toFenech et al. (2005a).
  A   L   M  O   N   D  S   W   H   E  A   T   B   R  A   N  C   H   E   D   D  A   R   C   H   E   E  S   E   B   R  O  C  C  O   L   I   (    B  O   I   L   E   D   )   T   U   N  A   (   C  A   N   N   E   D   )   B   E   E   F   (   C  O  O   K   E   D   )   B  A   N  A   N  A
0100200300
CALCIUMFOLATENIACINVITAMIN EBETA-CAROTENERETINOL
 AMOUNTS IN 100g EXPRESSED AS % OF MINIMUMREQUIREMENT FOR OPTIMUM GENOME HEALTH
Fig. 3. Content of micronutrients associated with reduced DNA damagein selected common foods. The height of each bar for each micronutrientwithin the separate foods corresponds to the amount of the micronutrientexpressed as the percentage of the minimum daily intake associated with areduced micronucleus frequency index in lymphocytes as determined inthe study of Fenech et al. (2005a). The relative contribution of each of themicronutrients (if present) is indicated by the height of each specificallycoloured bar. The nutrient content of the foods was determined usingpublished food content tables (Paul and Southgate, 1978).

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