Does Genetic Makeup Affect Calorie Needs
ABSTRACT
Genetic variation is known to affect food tolerances among human being subpopulations and may also influence dietary requirements, giving ascension to the new field of nutritional genomics and raising the possibility of individualizing nutritional intake for optimal wellness and disease prevention on the ground of an private's genome. Withal, considering factor-diet interactions are complex and poorly understood, the use of genomic noesis to suit population-based dietary recommendations is not without risk. Whereas electric current recommendations target most of the population to prevent nutritional deficiencies, inclusion of genomic criteria may signal subpopulations that may incur differential benefit or risk from generalized recommendations and fortification policies. Electric current efforts to identify factor alleles that impact food utilization take been enhanced by the identification of genetic variations that accept expanded equally a upshot of pick under extreme weather. Identification of genetic variation that arose as a outcome of diet as a selective pressure helps to place cistron alleles that affect nutrient utilization. Understanding the molecular mechanisms underlying gene-nutrient interactions and their modification by genetic variation is expected to result in dietary recommendations and nutritional interventions that optimize private health.
INTRODUCTION
Nutritional requirements are non usually generalized to a population as a whole; rather, they are tailored to population subgroups, for example, the elderly or women who are pregnant or breastfeeding. To appointment, noesis of human genetic variation has not contributed significantly to the identification of subpopulations that would benefit from individualized nutritional requirements, although in that location are examples of genetic variation influencing food intolerances (i, 2). The recent availability of genomic information and our increased agreement of the relations among genetic variations and nutrition permits a quantitative examination of the contribution of genetic variation to nutritional requirements.
The Human Genome Project is ane of the key factors that enables the study of gene-environment interactions. Information technology provides the list of the 25 000 to thirty 000 genes in human being DNA (3), in essence, a "parts list" for the proteins and molecules that institute the processes and pathways that perform all cellular functions, whether they be conversion of food into energy or the generation of thoughts. Having this parts list, nosotros tin can assemble these networks and sympathize how they part, how they interact, and, most importantly, how they are regulated. With this information in hand, molecular pathways tin exist manipulated for benefit by exposure to exogenous agents, among the about strong being dietary components and pharmaceutical agents.
The next phase of the Human Genome Project is focused on cataloguing and classifying all the variation that exists within the homo genome. Each human is unique and phenotypically distinct, not only in physical advent but also in physiology and response to environmental stimuli. Single-nucleotide polymorphisms (SNPs) are a primary component of human genetic variation and found a molecular basis for phenotypic variation. SNPs are differences in the Dna blueprint and can exist single-nucleotide base pair insertions, deletions, or substitutions of one base pair for another. At that place are an estimated 7 million SNPs in the human genome (4), only simply a small percentage of these have a functional consequence. The goal is to identify which SNPs influence cellular networks and thereby create a variation in phenotype. SNPs contribute to complex traits, including susceptibility to chronic diseases and drug efficacy, and this has resulted in the evolution of the field of pharmacogenomics, which is a simpler model for the field of nutrigenomics.
PHARMACOGENOMICS
Pharmaceutical products can arm-twist a broad range of furnishings. For some patients, these agents are constructive and beneficial and accept the desired event, whereas in others they take no effect at all. In some instances, pharmaceuticals can crusade unintended and even unanticipated damage. The field of pharmacogenomics aims to understand the relation between the genetic makeup and responses to a specific pharmaceutical product, with the goal of better matching the drug to the individual to achieve the intended outcome without incurring the run a risk of an agin upshot or side effect.
The importance of pharmacogenomics is well illustrated past the link between genetic polymorphism of the enzyme thiopurine Southward-methyltransferase (TPMT) and toxicity associated with the drug half dozen-thiopurine (five, 6). 6-Thiopurine is an immunosuppressant that is also used in the treatment of childhood acute lymphoblastic leukemia. On entering a cell, 6-thiopurine is converted into a nucleoside and interferes with nucleic acrid synthesis. In virtually patients, TPMT, which is found in the liver and in blood-red blood cells, inactivates 6-thiopurine, and the standard dose is set high enough to business relationship for this effect (7). Withal, TPMT activity exhibits genetic polymorphism, and near 1 in 300 people inherit TPMT deficiency as an autosomal recessive trait (5). If treated with a standard dose of 6-thiopurine, TPMT-deficient patients develop severe, and in some cases, lethal myelosuppression; in these patients, a 10- to 15-fold lower dose is needed for successful treatment (5, 6). Assays are now bachelor for the 3 polymorphisms that account for most mutant alleles, and this is one example where genetic testing has a real role to play in determining the appropriate employ of a drug (seven).
NUTRITIONAL GENOMICS
The field of nutritional genomics aims to identify the genetic variations that account for why some individuals react differently to dietary components, in much the same style the pharmacogeneticist aims to place the polymorphisms that affect drug efficacy and rubber. The impact of genetic variation on nutritional requirements is inevitably more than subtle than that of pharmaceutical agents for ii reasons. First, for each nutrient, there is a window of intake between the Recommended Dietary Allowance (RDA), which is defined as the dietary intake that is sufficient to meet the requirement of 97% of healthy individuals in a particular life stage and sexual practice group, and the tolerable upper limit (UL), which is the highest food intake that can exist accomplished without incurring risk of agin health furnishings for most individuals in the general population (Effigy 1; 8). If the data used to set the RDA and the UL are established with the use of a diverse population, these benchmarks should accommodate most of the genetic variation in existence. If a genetic variation were identified that required a different RDA or UL, these parameters could exist adjusted to adapt the requirements of these individuals. The concept of the generalized nutritional requirement becomes compromised only when the RDA of a nutrient for one individual encroaches on the UL of another.
Effigy i.
The Dietary Reference Intake model encompasses 4 nutrient-based values: the estimated average requirement (EAR), the recommended daily assart (RDA), the acceptable intake (AI), and the upper level (UL). Increased risks are associated with both inadequate intake and excessive intake.
Effigy 1.
The Dietary Reference Intake model encompasses four nutrient-based values: the estimated average requirement (EAR), the recommended daily allowance (RDA), the adequate intake (AI), and the upper level (UL). Increased risks are associated with both inadequate intake and excessive intake.
Second, the impact of nutrition takes identify over a lifetime, whereas that of pharmaceutical agents occurs over a short menstruation of time. Therefore, any genetic variation that confers an atypical nutritional requirement will near certainly exist incompatible with life and early development and therefore not viable. For case, unmarried-nucleotide polymorphisms that bear on folate utilization are risk factors for miscarriage and are non in Hardy-Weinberg equilibrium in populations that otherwise are in equilibrium (9–xiii). In other words, a woman whose fetus carries 2 alleles that prevent sufficient utilization of a given nutrient is more probable to expel than a adult female whose fetus carries the more common functional variants.
Nonetheless, several genes and alleles accept been constitute to affect nutrient utilization. A well-studied polymorphism (Ala222Val) in the methylene tetrahydrofolate reductase (MTHFR) gene has been shown to alter folate metabolism quite severely (14, 15), then that risk is increased for neural tube defects (NTDs) and cardiovascular disease (CVD) only decreased for colon cancer (16–xx). The biochemical disruptions and disease risk can exist ameliorated with increased folate intake (21). To date, this may be the best example of a genetic variation that can influence an RDA and supports the concept that genetic variation modifies nutrient utilization and potentially dietary requirements. Other polymorphisms accept also been found to alter homocysteine metabolism as well as folate uptake and transport (9, 22–24).
Polymorphisms for enzymes that utilize and metabolize vitamin B-12 have been associated with NTDs and the development of Downwards syndrome and colon cancer, and this suggests a potential to affect nutrient requirements (25–27). Vitamin D receptor polymorphisms have been associated with childhood and developed asthma (28). A mutual polymorphism in the HFE gene (Cys282Tyr) is associated with the fe storage disease hereditary hemochromatosis in Europeans, and this might affect the UL for iron intake (29–32). Polymorphisms in other genes also affect lipid pathways (33–37), booze metabolism (38), and lactose metabolism (2). Interestingly, many of these SNPs are associated with specific ethnic groups or geographic ancestral subpopulations and display genomic signatures for positive selection, indicating that although these SNPs nowadays risk of adverse outcomes today, they were likely benign in the ancestral environment where they first arose (39–41).
Interestingly, polymorphisms for the aldolase B enzyme, which metabolizes fructose, have been discovered (1). The gene for this enzyme is highly polymorphic, but until recently, many of these polymorphisms were considered silent. But when fructose was added in high quantities to the food supply as a sweetener did these polymorphisms present as disease alleles (42). This is an example where a change in surround has challenged a unremarkably silent allele to the caste that information technology begins to present as a affliction allele.
IDENTIFICATION OF GENETIC POLYMORPHISMS AFFECTING DIETARY REQUIREMENTS
Genetic variations that touch dietary requirements may exist identified by using 2 approaches: the candidate gene approach and evolutionary genomics. The candidate gene approach looks for associations between a particular pathologic condition and genetic polymorphisms that affect the metabolic pathways known to be associated with that condition. This approach has been successful in many cases, merely it is problematic in nutrition for iii reasons:
Most nutrition-related diseases are complex diseases; that is, they are both multigenic and modifiable by multiple ecology factors. The penetrance and prevalence of a polymorphism touch on the sample size needed to identify associations betwixt the allele of interest and the pathologic condition.
Many functional SNPs are not coding SNPs simply instead fall in the promoter regions of genes. In fact, it has been estimated that most of the genetic variation that influences physiology one fashion or another is really in the promoter regions of genes (43, 44). Two-thirds of polymorphisms identified in human being promoter regions bear upon transcription rates by 2-fold or greater (43). Promoter regions tin can span many thousands of base pairs and tend to be more heterogeneous than the coding regions of genes (43).
The candidate cistron approach is limited by cognition of the pathways and networks contributing to a particular pathologic status: if all the players in the pathway or a network are non known, it will not be possible to identify all the genes that affect it.
Evolutionary genomics is based on the contempo availability of genomic sequences from humans and nonhuman primates that enables the identification of sequence "signatures" for positive option (39, 41, 44–46). The molecular footing for this arroyo is change in the Deoxyribonucleic acid sequence, which in the absenteeism of selection pressure takes place at a background charge per unit of about 2.5 × 10−8 mutations per nucleotide site (47, 48). However, regions of the sequence that are under option pressure level evolve more quickly, and the rate can be as much as 400 times as fast (49). A rapidly evolving cistron is an adaptive sequence that enables an organism to match its environmental challenges, and these challenges can occur in distinct geographic regions. In the case of nutritional genomics, nutrients and dietary components act every bit ecology pressures, shaping today's homo genome though millennia of selection pressure. This highly selected genome in turn may affect nutrient requirements. When a genome that has adapted to a certain environment is put in a unlike context, adaptive genes may become disease alleles, which must and so be managed or modified through nutritional intervention (50–52).
The aim of evolutionary genomics is to place the genes that evolve chop-chop, within and among species. Once these high-variable genes are identified, nosotros tin infer selective pressures on the basis of their cellular function. In fact, genes that rapidly evolve tend to cluster as amnesty genes, metabolism genes, or genes involved in reproduction (41, 46).
What would be the signs that genes are subjected to positive selection? Variants would be expected to concentrate in specific geographic regions or ethnic groups where a common selective pressure level exists and to exist absent in other places or in other indigenous groups. We would see an excess of rare variants, large allele frequency differences among the population, and a mutual haplotype that remains intact over many generations (41, 45).
Many genes identified through the utilise of evolutional genomics were previously identified by employ of the candidate gene approach, for example, the lactase gene polymorphism (53). This variant arose in northern Europeans and in people inhabiting the barren regions of northern Africa, areas where in that location might have been a selective benefit in being able to drink milk and consume dairy products every bit a source of diet. The HFE Cys282Tyr polymorphism shows evidence of positive selection (54), every bit does the alcohol metabolism cistron, alcohol dehydrogenase (55), and the HbS allele in the β-globin gene (56). The A− and MED alleles of glucose-6-phosphate dehydrogenase showroom positive pick as well considering of their conferred protection against malaria (three, 46, 53, 57).
MTHFR POLYMORPHISM AND NUTRITIONAL REQUIREMENTS FOR FOLATE
1 case suggesting that genetic variation can bear on nutritional requirements is the MTHFR Ala222Val polymorphism that affects folate metabolism. Folate is a B vitamin whose part is to carry and activate one-carbon units (58). The one-carbon units are carried on the N-5 or N-x of tetrahydrofolate. One-carbon metabolism is required for the de novo synthesis of purine nucleotides and thymidylate and for the remethylation of homocysteine to methionine (Figure 2). Methionine can be adenylated to course S-adenosylmethionine, a cofactor for numerous methylation reactions including those that affect cistron regulation (58).
FIGURE 2.
Folate-dependent one-carbon metabolism. MS, methionine synthase; MTHFR, methylene tetrahydrofolate reductase; MTHFS, 5,10-methenyltetrahydrofolate synthetase; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine (a feedback inhibitor of MTHFR); cSHMT, cytoplasmic serine hydroxymethyltransferase; THF, tetrahydrofolate; TS, thymidylate synthase.
FIGURE 2.
Folate-dependent one-carbon metabolism. MS, methionine synthase; MTHFR, methylene tetrahydrofolate reductase; MTHFS, 5,10-methenyltetrahydrofolate synthetase; SAH, S-adenosylhomocysteine; SAM, Southward-adenosylmethionine (a feedback inhibitor of MTHFR); cSHMT, cytoplasmic serine hydroxymethyltransferase; THF, tetrahydrofolate; TS, thymidylate synthase.
The MTHFR Ala222Val polymorphism is a C-to-T transition in the coding region, resulting in the conversion of an alanine to a valine in the protein (14). This has ii effects on 1-carbon metabolism: Commencement, it impairs remethylation of homocysteine to methionine, which thus alters DNA methylation and gene expression (59, lx). Second, because the two pathways compete, it also increases the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP), which leads to more folate-dependent thymidine biosynthesis (61).
Folate deficiency increases the take a chance of several diseases and anomalies, including NTDs and CVD, and folate supplementation can ameliorate or completely negate the effects of this polymorphism. Therefore, the risk of NTDs is about credible in individuals who are folate scarce (16–19).
The same polymorphism is actually protective against several cancers, most notably colon cancer (20). The Doctor's Health Study examined the associations of MTHFR mutation, plasma folate concentrations, and their interaction with chance of colon cancer in 202 colorectal cancer cases and 326 cancer-free controls matched by age and smoking status (20). The study showed that in men with normal folate concentrations (serum folate > 3 ng/mL) who were homozygous for the mutant allele, the risk of colon cancer was ane-third that in carriers of the wild-type allele (odds ratio: 0.32; 95% CI: 0.xv, 0.68). In men who were folate-deficient, even so, this protection was absent. The same polymorphism and downstream consequence on metabolism presents a adventure of NTD but is simultaneously highly protective in colon cancer (62).
EFFECT OF GENOMICS ON DEFINING DIETARY REQUIREMENTS
Can nosotros use genomics approaches to determine dietary requirements? Persons who are homozygous for the rarer MTHFR T allele (T/T) demand a college folate intake than exercise carriers of the C allele to lower their risk of folate-related pathologies. Although at that place is no written report indicating that this polymorphism has been subject field to positive selection, at that place is wide geographic variation in terms of the prevalence of the T/T genotype (Table 1; 63–68). This has the potential to influence public wellness policy in that fortification with folate may not be required in populations where the T/T genotype is rare. However, the current RDA really may cover both MTHFR genotypes, and there is no definitive testify to date that the current RDA for folate should be modified for persons who are homozygous for the MTHFR 677T allele (69).
Tabular array ane
The prevalence of the MTHFR 667T/T genotype in various ethnic groups 1
| Population | Prevalence |
|---|---|
| % | |
| Mexicans (64, 68) | 27–35 |
| Brazilians (68) | 7 |
| Sub-Saharan Africans (63, 68) | 0–1.5 |
| African Americans (66) | 2 |
| Yemenite Jews (65) | ii |
| Muslim Arab Israelis (65) | 16 |
| Toscanians (Italy) (67) | 30 |
| Irish (64) | 6 |
| Dutch (64) | v |
| Europeans (68) | 17 |
| Japanese (64) | 19 |
| Pakistanis (68) | four |
| Chinese (68) | 16 |
| Population | Prevalence |
|---|---|
| % | |
| Mexicans (64, 68) | 27–35 |
| Brazilians (68) | 7 |
| Sub-Saharan Africans (63, 68) | 0–1.five |
| African Americans (66) | 2 |
| Yemenite Jews (65) | two |
| Muslim Arab Israelis (65) | 16 |
| Toscanians (Italy) (67) | thirty |
| Irish (64) | 6 |
| Dutch (64) | v |
| Europeans (68) | 17 |
| Japanese (64) | 19 |
| Pakistanis (68) | 4 |
| Chinese (68) | 16 |
1 MTHFR, methylenetetrahydrofolate reductase.
TABLE i
The prevalence of the MTHFR 667T/T genotype in various ethnic groups 1
| Population | Prevalence |
|---|---|
| % | |
| Mexicans (64, 68) | 27–35 |
| Brazilians (68) | vii |
| Sub-Saharan Africans (63, 68) | 0–ane.5 |
| African Americans (66) | 2 |
| Yemenite Jews (65) | 2 |
| Muslim Arab Israelis (65) | sixteen |
| Toscanians (Italy) (67) | 30 |
| Irish (64) | half dozen |
| Dutch (64) | five |
| Europeans (68) | 17 |
| Japanese (64) | nineteen |
| Pakistanis (68) | iv |
| Chinese (68) | 16 |
| Population | Prevalence |
|---|---|
| % | |
| Mexicans (64, 68) | 27–35 |
| Brazilians (68) | 7 |
| Sub-Saharan Africans (63, 68) | 0–one.5 |
| African Americans (66) | 2 |
| Yemenite Jews (65) | 2 |
| Muslim Arab Israelis (65) | sixteen |
| Toscanians (Italy) (67) | 30 |
| Irish (64) | 6 |
| Dutch (64) | v |
| Europeans (68) | 17 |
| Japanese (64) | 19 |
| Pakistanis (68) | four |
| Chinese (68) | xvi |
1 MTHFR, methylenetetrahydrofolate reductase.
On the other hand, the HFE gene Cys282Tyr polymorphism has already affected government policy, with 2 countries in northern Europe halting their iron fortification policies, in function because of a potential hazard to persons at risk of hereditary hemochromatosis (seventy, 71). Notwithstanding, no definitive show exists suggesting that the UL for persons at risk of hereditary hemochromatosis encroaches on the RDA. For the fourth dimension being, it appears there is no need to individualize iron intake recommendations according to genotype (72).
Genetics is likewise driving a reevaluation of how nosotros define nutritional inadequacy. Currently, the RDA for a particular nutrient is defined by the evolution of deficiency diseases, but with advances in the field of genomics, in that location is a view that nosotros should exist more sophisticated and use biomarkers to ascertain inadequacy and safe upper limits of intake. An case of this would exist the epigenetic furnishings of nutrients. Epigenetics refers to the inheritance of traits that are not linked to DNA sequence, only rather to modifications of DNA, and amongst these modifications is DNA methylation, which affects gene expression.
In 2002 Cooney et al (73) illustrated how nutritional intake can touch epigenetics very dramatically. Those authors showed that in inbred mice, the folate intake of the mother during pregnancy affects the coat color of the offspring through an epigenetic issue on expression of the agouti gene. Expression of the agouti poly peptide produces yellowish-furred mice. However, methylation of the agouti gene promoter region during gestation blocks agouti expression and the offspring have darker fur (73). The more methylation of the promoter region that takes place, the less yellow fur there is on the mouse. Methylation patterns established during gestation remain metastable throughout the lifetime of the animal; thus, by affecting methylation levels during gestation, it is possible to manipulate permanently the coat color of the offspring.
Folate metabolism is critical for DNA methylation, and in the pups of mothers whose diet while pregnant included a high intake of folate, the promoter region was methylated and the agouti gene was not well expressed. However, less Deoxyribonucleic acid methylation took identify during gestation in pups whose mothers were more folate deficient during pregnancy, which allowed the agouti to be expressed and the appearance of the characteristic xanthous coat color (73, 74). This example illustrates how maternal nutrition can permanently touch on how genes are expressed in the fetus and ultimately the offspring, with potentially lifelong consequences that may alter various health outcomes.
Another such biomarker is genomic stability. Studies on twins betoken that ≈25% of the variation in life span tin be attributed to genetic differences (75). Therefore, ecology factors play a key role in determining longevity (73, 76, 77). As we historic period, mutations accumulate in our genomes (78) and epigenetics seems to become dysregulated (79). Several B vitamins, as well equally some antioxidants, are known to affect the mutation rate for both chromosomal and mitochondrial DNA. When determining the RDA, maybe we should consider what concentration of individual vitamins volition lower the mutation rate sufficiently to foreclose disease (77).
RATIONAL Design OF NUTRITIONAL REGIMENS TO PREVENT Affliction
Many SNPs confer both reward and risk, depending on the health outcome of interest, as illustrated by the MTHFR allelic variants. Understanding the physiologic and biochemical consequences of specific gene variants and the mechanisms that confer disease protection or risk enables the rational design of nutritional approaches that can give maximal benefit to all individuals by precise manipulation of metabolic networks. Our laboratory seeks to understand the mechanism whereby impairments in homocysteine remethylation, as occurs in individuals who are homozygous for the MTHFR 677T allele, lowers take a chance of cancer, as described previously (20). The changes in metabolism conferred by this polymorphism confer protection against colon cancer while increasing the run a risk of NTDs. Folate supplementation tin lower the risk of NTDs associated with the T allele, but how can we provide the benefit of the T allele to carriers of the common C allele in terms of colon cancer risk?
Colon cancer is an epithelial cancer, the risk of which increases with age (80). Folate deficiency is a risk factor for colon cancer (81), and patients with cancer exhibit folate deficiency due to increased folate turnover (82). Deoxyribonucleic acid hypomethylation induced past folate deficiency affects the mammalian genome, both in terms of gene expression and mutation rate (lxxx). One of the first biomarkers for the transformation of normal epithelium into a metastatic tumor in colon cancer is a methylation defect (83). The MTHFR 677T/T polymorphism may office to lower Dna mutation rates by increasing the efficiency of dTMP synthesis or may somehow lessen the penetrance of the methylation defect that is characteristic of cellular transformation.
Metabolic alterations resulting from MTHFR genotypes tin can be recapitulated by altering the expression of other genes in the folate metabolic network, namely, cytoplasmic serine hydroxymethyltransferase (cSHMT). This enzyme is expressed in a tissue-specific manner and increases the flux of one-carbon units through the thymidylate pathway, thereby suppressing the homocysteine methylation pathway by sequestering 5-methyltetrahydrofolate (Figure 2; 84). This is similar to the consequence of the mutant MTHFR allele on the homocysteine-methionine wheel.
As mentioned earlier, the gene for cSHMT is not expressed in all tissues. In the mouse embryo, information technology is expressed in the neural tube, hind brain, midbrain, craniofacial structures, and crypt cells of the colon, all of which are areas associated with folate-related pathologies. This pattern of expression is consequent with a signaling or patterning factor rather than a metabolic gene.
The expression and activity of the cSHMT cistron is regulated robustly by several nutrients, including folate, zinc (51), and ferritin (85). Within the prison cell, ferritin sequesters atomic number 26 and chelates it. It also degrades folate; cancer cells have lower concentrations of folate because they increment expression of ferritin (58). Ferritin also upward-regulates cSHMT expression at the level of translation (85), which has the same metabolic outcome every bit the MTHFR mutant allele. Ferritin expression is also increased during inflammation and it is nuclear cistron-κB sensitive.
Therefore, the cSHMT factor is affected robustly by several environmental stimuli, and alterations in cSHMT expression can mimic the metabolic states that event from all MTHFR allelic variants. Currently, we are using mice that lack or overexpress the cSHMT gene to investigate its effects on Deoxyribonucleic acid stability and gene transcription and to determine the effects of contradistinct cSHMT expression on susceptibility to NTDs and colon cancer. Thus far, we accept established that cSHMT robustly regulates the expression of ≈100 genes that cluster in pathways that are known to be associated with cancer (PJ Stover, unpublished observations, 2004). This information will be used to improve empathize how the MTHFR mutant allele reduces the risk of colon cancer and to develop rational strategies to reproduce this issue by manipulating the folate metabolic network through nutrition.
Outcome OF NUTRITIONAL INTAKE ON GENOMICS
1 cautionary note must be raised. Elevating dietary requirements may hibernate the phenotypic effects of a mutation—the concept of genetic rescue—thereby allowing information technology to be inherited and become established in a population. In transgenic mice bred with a dysfunctional HOX gene, for example, the effect of the genetic mutation on bone development—these mice are ordinarily born with bones so fragile the ribcage cannot withstand the pressures of animate—tin be masked past high concentrations of folate in their mother's diet (86).
A study in humans suggests that the frequency of a polymorphism can be affected by dietary intake: ≈25 y ago, the Castilian government started recommending that women of changeable years take folate. In 2002 Reyes-Engle et al (10) tracked the frequency of the MTHFR 677C→T polymorphism in Spanish men and women of differing ages and plant that the allelic frequency was stable in those born >24 y agone. In those aged ≤24 y, yet, the prevalence of the mutant T/T allele, which is a gamble factor for miscarriage and spontaneous abortion as well as nascence defects (87–89), was higher than in the older populations.
This report suggests that folate non only prevents birth defects but may also rescue embryos that usually would not be viable. Although this study has not been replicated in other populations and has been criticized for errors such as population bias (ninety), the concept is yet valid: we may be able to override certain genetic lesions by changing nutrient intake and thereby increase the frequency of the disease alleles within the population.
CONCLUSION
Genetic variation certainly has an important influence on human nutritional requirements, and the introduction of genomics has both highlighted the complexity of the interaction between genes and diet and offered opportunities to reevaluate the criteria used to determine RDAs and the contribution of genetic variation to optimal nutrition for individuals. As the interactions betwixt genetic variation and nutritional requirements become more than fully understood, information technology will allow dietary recommendations to exist individualized according to genotype to ultimately reduce our adventure of degenerative diseases and increase health and well-existence in former age.
The author had no conflicts of interest to report.
FOOTNOTES
2 Presented at the conference "Living Well to 100: Diet, Genetics, Inflammation," held in Boston, MA, November 15–xvi, 2004.
three Supported by the Partition of Nutritional Sciences, Cornell Academy.
REFERENCES
i.
Esposito
G
, Vitagliano L Santamaria R Viola A Zagari A Salvatore F
Structural and functional analysis of aldolase B mutants related to hereditary fructose intolerance
.
FEBS Lett
2002
;
531
:
152
–
6
.
2.
Swallow
DM
.
Genetics of lactase persistence and lactose intolerance
.
Annu Rev Genet
2003
;
37
:
197
–
219
.
3.
Venter
JC
, Adams MD Myers EW
The sequence of the human genome
.
Scientific discipline
2001
;
291
:
1304
–
51
.
4.
Hinds
DA
, Stuve LL Nilsen GB
Whole-genome patterns of common Dna variation in 3 human populations
.
Scientific discipline
2005
;
307
:
1072
–
ix
.
5.
McLeod
HL
, Krynetski EY Relling MV Evans WE
Genetic polymorphism of thiopurine methyltransferase and its clinical relevance for childhood acute lymphoblastic leukemia
.
Leukemia
2000
;
fourteen
:
567
–
72
.
half dozen.
Scheuermann
TH
, Keeler C Hodsdon ME
Consequences of bounden an S-adenosylmethionine counterpart on the structure and dynamics of the thiopurine methyltransferase protein backbone
.
Biochemistry
2004
;
43
:
12198
–
209
.
seven.
Corominas
H
, Baiget M
Clinical utility of thiopurine S-methyltransferase genotyping
.
Am J Pharmacogenomics
2004
;
iv
:
1
–
eight
.
8.
Plant of Medicine
.
Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin and choline.
Washington, DC
:
National Academy Press
,
1998
.
ix.
Brody
LC
, Conley M Cox C
A polymorphism, R653Q, in the trifunctional enzyme methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase is a maternal genetic risk cistron for neural tube defects: study of the Birth Defects Research Group
.
Am J Hum Genet
2002
;
71
:
1207
–
15
.
10.
Reyes-Engel
A
, Munoz E Gaitan MJ
Implications on human being fertility of the 677C→T and 1298A→C polymorphisms of the MTHFR gene: consequences of a possible genetic selection
.
Mol Hum Reprod
2002
;
8
:
952
–
7
.
eleven.
Munoz-Moran
East
, Dieguez-Lucena JL Fernandez-Arcas North Peran-Mesa S Reyes-Engel A
Genetic selection and folate intake during pregnancy
.
Lancet
1998
;
352
:
1120
–
1
.
12.
Nelen
WL
, Steegers EA Eskes TK Blom HJ
Genetic run a risk factor for unexplained recurrent early pregnancy loss
.
Lancet
1997
;
350
:
861
(letter).
xiii.
Nelen
WL
, Blom HJ Thomas CM Steegers EA Boers GH Eskes TK
Methylenetetrahydrofolate reductase polymorphism affects the modify in homocysteine and folate concentrations resulting from depression dose folic acid supplementation in women with unexplained recurrent miscarriages
.
J Nutr
1998
;
128
:
1336
–
41
.
fourteen.
Goyette
P
, Sumner JS Milos R
Human methylenetetrahydrofolate reductase: isolation of cDNA mapping and mutation identification
.
Nat Genet
1994
;
seven
:
551
(erratum).
fifteen.
Guenther
BD
, Sheppard CA Tran P Rozen R Matthews RG Ludwig ML
The construction and properties of methylenetetrahydrofolate reductase from Escherichia coli suggest how folate ameliorates human hyperhomocysteinemia
.
Nat Struct Biol
1999
;
half-dozen
:
359
–
65
.
16.
Smithells
RW
, Nevin NC Seller MJ
Further feel of vitamin supplementation for prevention of neural tube defect recurrences
.
Lancet
1983
;
1
:
1027
–
31
.
17.
Czeizel
AE
, Dudas I
Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation
.
N Engl J Med
1992
;
327
:
1832
–
5
.
18.
Prevention of neural tube defects: results of the Medical Research Quango Vitamin Study. MRC Vitamin Report Research Grouping
.
Lancet
1991
;
338
:
131
–
vii
.
nineteen.
Voutilainen
South
, Rissanen TH Virtanen J Lakka TA Salonen JT
Depression dietary folate intake is associated with an excess incidence of acute coronary events: The Kuopio Ischemic Heart Disease Adventure Factor Written report
.
Circulation
2001
;
103
:
2674
–
80
.
20.
Ma
J
, Stampfer MJ Giovannucci E
Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer
.
Cancer Res
1997
;
57
:
1098
–
102
.
21.
Molloy
AM
, Scott JM
Folates and prevention of disease
.
Public Health Nutr
2001
;
four
:
601
–
nine
.
22.
Leclerc
D
, Campeau E Goyette P
Homo methionine synthase: cDNA cloning and identification of mutations in patients of the cblG complementation grouping of folate/cobalamin disorders
.
Hum Mol Genet
1996
;
5
:
1867
–
74
.
23.
Chango
A
, Emery-Fillon N de Courcy GP
A polymorphism (80G->A) in the reduced folate carrier gene and its associations with folate status and homocysteinemia
.
Mol Genet Metab
2000
;
70
:
310
–
5
.
24.
Afman
LA
, Trijbels FJM Blom HJ
The H475Y polymorphism in the glutamate carboxypeptidase Ii cistron increases plasma folate without affecting the gamble for neural tube defects in humans
.
J Nutr
2003
;
133
:
75
–
vii
.
25.
Wilson
A
, Platt R Wu Q
A common variant in methionine synthase reductase combined with low cobalamin (vitamin B12) increases run a risk for spina bifida
.
Mol Genet Metab
1999
;
67
:
317
–
23
.
26.
Gueant
JL
, Gueant-Rodriguez RM Anello G
Genetic determinants of folate and vitamin B12 metabolism: a common pathway in neural tube defect and Down syndrome?
Clin Chem Lab Med
2003
;
41
:
1473
–
7
.
27.
Ma
J
, Stampfer MJ Christensen B
A polymorphism of the methionine synthase gene: association with plasma folate, vitamin B12, homocyst(e)ine, and colorectal cancer chance
.
Cancer Epidemiol Biomarkers Prev
1999
;
8
:
825
–
ix
.
28.
Raby
BA
, Lazarus R Silverman EK
Association of vitamin D receptor gene polymorphisms with babyhood and adult asthma
.
Am J Respir Crit Intendance Med
2004
;
170
:
1057
–
65
.
29.
Feder
JN
, Gnirke A Thomas West
A novel MHC grade I-like gene is mutated in patients with hereditary haemochromatosis
.
Nat Genet
1996
;
13
:
399
–
408
.
30.
Beutler
E
, Gelbart T West C
Mutation assay in hereditary hemochromatosis
.
Blood Cells Mol Dis
1996
;
22
:
187
–
94
; give-and-take 194a–b.
31.
Jazwinska
EC
, Cullen LM Busfield F
Haemochromatosis and HLA-H
.
Nat Genet
1996
;
fourteen
:
249
–
51
.
32.
A simple genetic test identifies 90% of United kingdom patients with haemochromatosis. The UK Haemochromatosis Consortium
.
Gut
1997
;
41
:
841
–
4
.
33.
Endo
K
, Yanagi H Araki J Hirano C Yamakawa-Kobayashi K Tomura S
Association found between the promoter region polymorphism in the apolipoprotein A-Five factor and the serum triglyceride level in Japanese schoolchildren
.
Hum Genet
2002
;
111
:
570
–
2
.
34.
Jang
Y
, Kim JY Kim OY
The -1131T→C polymorphism in the apolipoprotein A5 factor is associated with postprandial hypertriacylglycerolemia; elevated pocket-sized, dense LDL concentrations; and oxidative stress in nonobese Korean men
.
Am J Clin Nutr
2004
;
lxxx
:
832
–
xl
.
35.
Juo
SH
, Wyszynski DF Beaty TH Huang HY Bailey-Wilson JE
Balmy clan between the A/G polymorphism in the promoter of the apolipoprotein A-I gene and apolipoprotein A-I levels: a meta-analysis
.
Am J Med Genet
1999
;
82
:
235
–
41
.
36.
Kao
JT
, Wen HC Chien KL Hsu HC Lin SW
A novel genetic variant in the apolipoprotein A5 gene is associated with hypertriglyceridemia
.
Hum Mol Genet
2003
;
12
:
2533
–
9
.
37.
Matsunaga
A
, Sasaki J Han H
Compound heterozygosity for an apolipoprotein A1 gene promoter mutation and a structural nonsense mutation with apolipoprotein A1 deficiency
.
Arterioscler Thromb Vasc Biol
1999
;
xix
:
348
–
355
.
38.
Bosron
WF
, Li TK
Genetic polymorphism of human being liver alcohol and aldehyde dehydrogenases, and their relationship to alcohol metabolism and alcoholism
.
Hepatology
1986
;
vi
:
502
–
10
.
39.
Wooding
S
.
Natural option: sign, sign, everywhere a sign
.
Curr Biol
2004
;
14
:
R700
–
i
.
40.
Wooding
South
.
PopHist: inferring population history from the spectrum of allele frequencies
.
Bioinformatics
2003
;
19
:
539
–
40
.
42.
Cox
TM
.
The genetic consequences of our sweetness tooth
.
Nat Rev Genet
2002
;
3
:
481
–
7
.
43.
Rockman
MV
, Wray GA
Abundant raw textile for cis-regulatory evolution in humans
.
Mol Biol Evol
2002
;
19
:
1991
–
2004
.
44.
Wray
GA
, Hahn MW Abouheif E
The evolution of transcriptional regulation in eukaryotes
.
Mol Biol Evol
2003
;
20
:
1377
–
419
.
45.
Bamshad
Thousand
, Wooding SP
Signatures of natural selection in the human being genome
.
Nat Rev Genet
2003
;
4
:
99
–
111
.
46.
Clark
AG
, Glanowski S Nielsen R
Inferring nonneutral development from human-chimp-mouse orthologous gene trios
.
Science
2003
;
302
:
1960
–
3
.
47.
Nachman
MW
, Crowell SL
Estimate of the mutation rate per nucleotide in humans
.
Genetics
2000
;
156
:
297
–
304
.
48.
Tishkoff
SA
, Verrelli BC
Patterns of man genetic diversity: implications for man evolutionary history and illness
.
Annu Rev Genomics Hum Genet
2003
;
iv
:
293
–
340
.
49.
Diamond
J
.
The double puzzle of diabetes
.
Nature
2003
;
423
:
599
–
602
.
50.
Schork
N
, Fallin D Lanchbury JS
Unmarried nucleotide polymorphisms and the future of genetic epidemiology
.
Clin Genet
2000
;
58
:
250
–
64
.
51.
Perry
C
, Sastry R Nasrallah IM Stover PJ
Mimosine attenuates serine hydroxymethyltransferase transcription by chelating zinc: implications for inhibition of DNA replication
.
J Biol Chem
2004
;
280
:
396
–
400
.
52.
Schork
N
, Cardon LR Xu X
The future of genetic epidemiology
.
Trends Genet
1998
;
14
:
266
–
72
.
53.
Bersaglieri
T
, Sabeti PC Patterson Due north
Genetic signatures of potent recent positive selection at the lactase gene
.
Am J Hum Genet
2004
;
74
:
1111
–
twenty
.
54.
Toomajian
C
, Ajioka RS Jorde LB Kushner JP Kreitman Yard
A method for detecting contempo selection in the human genome from allele age estimates
.
Genetics
2003
;
165
:
287
–
97
.
55.
Osier
MV
, Pakstis AJ Soodyall H
A global perspective on genetic variation at the ADH genes reveals unusual patterns of linkage disequilibrium and diversity
.
Am J Hum Genet
2002
;
71
:
84
–
99
.
56.
Pagnier
J
, Mears JG Dunda-Belkhodja O
Evidence for the multicentric origin of the sickle cell hemoglobin gene in Africa
.
Proc Natl Acad Sci U Due south A
1984
;
81
:
1771
–
iii
.
57.
Tishkoff
SA
, Varkonyi R Cahinhinan N
Haplotype variety and linkage disequilibrium at human G6PD: recent origin of alleles that confer malarial resistance
.
Science
2001
;
293
:
455
–
62
.
58.
Suh
JR
, Herbig AK Stover PJ
New perspectives on folate catabolism
.
Annu Rev Nutr
2001
;
21
:
255
–
82
.
59.
Oyama
K
, Kawakami Chiliad Maeda K Ishiguro K Watanabe Thou
The association between methylenetetrahydrofolate reductase polymorphism and promoter methylation in proximal colon cancer
.
Anticancer Res
2004
;
24
:
649
–
54
.
60.
Shelnutt
KP
, Kauwell GP Gregory JF
Methylenetetrahydrofolate reductase 677C→T polymorphism affects DNA methylation in response to controlled folate intake in young women
.
J Nutr Biochem
2004
;
15
:
554
–
sixty
.
61.
Quinlivan
EP
, Davis SR Shelnutt KP
Methylenetetrahydrofolate reductase 677C->T polymorphism and folate status impact 1-carbon incorporation into human Deoxyribonucleic acid deoxynucleosides
.
J Nutr
2005
;
135
:
389
–
96
.
62.
Ma
J
, Stampfer MJ Giovannucci E
Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and hazard of colorectal cancer
.
Cancer Res
1997
;
57
:
1098
–
102
.
63.
Schneider
JA
, Rees DC Liu YT Clegg JB
Worldwide distribution of a mutual methylenetetrahydrofolate reductase mutation
.
Am J Hum Genet
1998
;
62
:
1258
–
sixty
.
64.
Mutchinick
OM
, Lopez MA Luna L Waxman J Babinsky VE
Loftier prevalence of the thermolabile methylenetetrahydrofolate reductase variant in United mexican states: a land with a very loftier prevalence of neural tube defects
.
Mol Genet Metab
1999
;
68
:
461
–
7
.
65.
Almawi
WY
, Finan RR Tamim H Daccache JL Irani-Hakime Northward
Differences in the frequency of the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene among the Lebanese population
.
Am J Hematol
2004
;
76
:
85
–
7
.
66.
McAndrew
PE
, Brandt JT Pearl DK Prior TW
The incidence of the factor for thermolabile methylene tetrahydrofolate reductase in African Americans
.
Thromb Res
1996
;
83
:
195
–
8
.
67.
Abbate
R
, Sardi I Pepe G
The high prevalence of thermolabile 5–ten methylenetetrahydrofolate reductase (MTHFR) in Italians is not associated to an increased risk for coronary avenue illness (CAD)
.
Thromb Haemost
1998
;
79
:
727
–
30
.
68.
Fukui
K
, Onodera K Shinkai T Suzuki Due south Urano Southward
Impairment of learning and memory in rats acquired by oxidative stress and aging, and changes in antioxidative defense systems
.
Ann N Y Acad Sci
2001
;
928
:
168
–
75
.
69.
Bailey
LB
, Gregory JF
Polymorphisms of methylenetetrahydrofolate reductase and other enzymes: metabolic significance, risks and affect on folate requirement
.
J Nutr
1999
;
129
:
919
–
22
.
70.
Milman
North
, Byg KE Ovesen L Kirchhoff One thousand Jurgensen KS
Fe condition in Danish women, 1984–1994: a cohort comparing of changes in atomic number 26 stores and the prevalence of fe deficiency and iron overload
.
Eur J Haematol
2003
;
71
:
51
–
61
.
71.
Olsson
KS
, Vaisanen M Konar J Bruce A
The effect of withdrawal of nutrient iron fortification in Sweden as studied with phlebotomy in subjects with genetic hemochromatosis
.
Eur J Clin Nutr
1997
;
51
:
782
–
half dozen
.
72.
Moirand
R
, Guyader D Mendler MH
HFE based re-evaluation of heterozygous hemochromatosis
.
Am J Med Genet
2002
;
111
:
356
–
61
.
73.
Cooney
CA
, Dave AA Wolff GL
Maternal methyl supplements in mice bear upon epigenetic variation and DNA methylation of offspring
.
J Nutr
2002
;
132
:
2393S
–
400S
.
74.
Waterland
R
, Jirtle RL
Transposable elements: targets for early nutritional effects on epigenetic factor regulation
.
Mol Cell Biol
2003
;
23
:
5293
–
300
.
75.
Skytthe
A
, Pedersen NL Kaprio J
Longevity studies in GenomEUtwin
.
Twin Res
2003
;
6
:
448
–
54
.
76.
Abbott
A
.
Ageing: growing old gracefully
.
Nature
2004
;
428
:
116
–
eight
.
77.
Fenech
G
.
Micronutrients and genomic stability: a new prototype for recommended dietary allowances (RDAs)
.
Food Chem Toxicol
2002
;
40
:
1113
–
7
.
78.
Ames
BN
.
DNA damage from micronutrient deficiencies is likely to be a major cause of cancer
.
Mutat Res
2001
;
475
:
7
–
20
.
79.
Huang
C
, Sloan EA Boerkoel CF
Chromatin remodeling and human being affliction
.
Curr Opin Genet Dev
2003
;
13
:
246
–
52
.
80.
Jubb
AM
, Bell SM Quirke P
Methylation and colorectal cancer
.
J Pathol
2001
;
195
:
111
–
34
.
81.
Giovannucci
E
, Stampfer MJ Colditz GA
Folate, methionine, and alcohol intake and risk of colorectal adenoma
.
J Natl Cancer Inst
1993
;
85
:
875
–
84
.
82.
Kim
YI
.
Folate and cancer prevention: a new medical application of folate beyond hyperhomocysteinemia and neural tube defects
.
Nutr Rev
1999
;
57
:
314
–
21
.
83.
Goelz
SE
, Vogelstein B Hamilton SR Feinberg AP
Hypomethylation of Deoxyribonucleic acid from benign and cancerous man colon neoplasms
.
Science
1985
;
228
:
187
–
ninety
.
84.
Herbig
K
, Chiang EP Lee LR Hills J Shane B Stover PJ
Cytoplasmic serine hydroxymethyltransferase mediates competition between folate-dependent deoxyribonucleotide and South-adenosylmethionine biosyntheses
.
J Biol Chem
2002
;
277
:
38381
–
9
.
85.
Oppenheim
EW
, Adelman C Liu Ten Stover PJ
Heavy chain ferritin enhances serine hydroxymethyltransferase expression and de novo thymidine biosynthesis
.
J Biol Chem
2001
;
276
:
19855
–
61
.
86.
Kappen
C
, Mello MA Finnell RH Salbaum JM
Folate modulates Hox gene-controlled skeletal phenotypes
.
Genesis
2004
;
39
:
155
–
66
.
87.
Zetterberg
H
, Regland B Palmer M
Increased frequency of combined methylenetetrahydrofolate reductase C677T and A1298C mutated alleles in spontaneously aborted embryos
.
Eur J Hum Genet
2002
;
x
:
113
–
eight
.
88.
Unfried
G
, Griesmacher A Weismuller W Nagele F Huber JC Tempfer CB
The C677T polymorphism of the methylenetetrahydrofolate reductase gene and idiopathic recurrent miscarriage
.
Obstet Gynecol
2002
;
99
:
614
–
ix
.
89.
Botto
LD
, Yang Q
five,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review
.
Am J Epidemiol
2000
;
151
:
862
–
77
.
90.
Whitehead
A
.
Changes in MTHFR genotype frequencies over time
.
Lancet
1998
;
352
:
1784
–
5
.
© 2006 American Society for Clinical Nutrition
© 2006 American Order for Clinical Nutrition
Source: https://academic.oup.com/ajcn/article/83/2/436S/4650208
Posted by: fishersaity1935.blogspot.com
0 Response to "Does Genetic Makeup Affect Calorie Needs"
Post a Comment