Implementing food-based dietary guidelines for - United Nations ...

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maximal rate of catalysis and usually represents the
rate of breakdown of the ES complex to product (P) at
infinite substrate concentration (all enzyme is present
as an ES complex). Genetic variation that alters amino
acid coding sequence can influence k cat and thereby
influence rates of nutrient uptake or clearance of
metabolic intermediates and overall net flux through a
metabolic pathway in a substrate-independent manner.
Severe alterations in k cat can indicate food or nutrient
intolerances. Therefore, a detailed understanding of
the functional consequences of allelic variants can be
used to predict nutrient intolerance and may indicate
genotype-specific variation in nutritional requirements,
and can lead to the development of tailored nutritional
interventions and therapies for populations and individuals.
Specific examples are discussed below.
One-carbon metabolism
Folate-mediated one-carbon metabolism is required for
purine, thymidylate, and methionine biosynthesis and
affects genome synthesis, genome stability, and gene
expression [77]. Several polymorphic alleles have been
identified to be associated with metabolic perturbations
that can confer both protection and risk for specific
pathologies and developmental anomalies [78]. SNPs in
MTHFR (A222V) and MTHFD1 (R653Q) [79], which
encode folate-dependent enzymes, are associated with
increased risk of neural tube defects; MTHFR (A222V)
is protective against colon cancer in folate-replete
subjects [80]. The MTHFR A222V variant protein has
reduced affinity for riboflavin cofactors and is thermolabile,
resulting in reduced cellular MTHFR activity;
its stability is increased when folate is bound [81].
Although the biochemical role of these polymorphisms
in the etiology of neural tube defects and cancer is
unknown, it has been demonstrated that some carriers
of MTHFR variants require higher folate intakes than
others in order to stabilize the MTHFR protein, lower
the concentration of the metabolic intermediate homocysteine,
and decrease women’s risk of bearing children
with developmental anomalies [1]. The MTHFR variant
is prevalent in Caucasian and Asian populations but
is nearly absent in African populations [1]. Fortification
of the food supply with folic acid, as practiced in
many countries, targets women of childbearing age for
prevention of birth defects, with genetically identifiable
subgroups receiving the most benefit.
Fructose metabolism
Hereditary fructose intolerance (HFI) is an autosomal
recessive disorder of fructose metabolism caused by
low fructose-1,6-aldolase activity, which results in
an accumulation of the toxic metabolic intermediate
fructose-1-phosphate. Twenty-five allelic variants of
the human liver isozyme aldolase B have been identi-
fied that impair enzyme activity by altering K m , k cat ,
and/or protein stability [82]. The prevalence of these
variants differs throughout Europe; the L288 delta C
frameshift mutation is restricted to Sicilian subjects.
The accumulation of fructose-1-phosphate inhibits
glycogen breakdown and glucose synthesis, resulting
in severe hypoglycemia following ingestion of fructose.
Prolonged fructose ingestion in infants leads ultimately
to hepatic and/or renal failure and death. Affected individuals
are asymptomatic in the absence of fructose or
sucrose consumption and can avoid the recurrence of
symptoms by remaining on a fructose- and sucrose-free
diet. The incidence of HFI intolerance has increased
since the widespread use of sucrose and fructose
as nutrients and sweeteners, providing an excellent
example whereby an environmental shift resulted in the
apparent conversion of normally nonpenetrant “silent”
aldolase B alleles into HFI disease alleles.
Lipid metabolism
Apolipoprotein E (apoE) is a polymorphic protein that
functions in lipid metabolism and cholesterol transport
[83]. The three common allelic variants, ε2, ε3, and ε4,
encode proteins that differ in their affinity both for
lipoprotein particles and for low-density lipoprotein
receptors. All human populations display apoE polymorphism,
but the relative distribution varies among
populations; the frequency of the ε4 allele declines
from northern to southern Europe. The ε4 allele
increases the risk of late-onset Alzheimer’s disease and
arteriosclerosis with low penetrance. Carriers of the ε2
allele tend to display lower levels of plasma total cholesterol,
whereas carriers of the ε4 allele, which may be
ancestral, display higher cholesterol levels. Therefore,
serum cholesterol levels are likely to be more responsive
to low-fat and low-cholesterol diets in carriers of
the ε4 allele [84, 85].
Genetic variation and human nutrition
P. J. Stover
Nutrients and the genome interact reciprocally;
genomes confer differences in food tolerances and
nutrient requirements, and nutrients can influence
genome expression, stability, and viability [77]. Characterization
of gene variants that modify optimal
nutrient requirements has diagnostic value; it enables
the classification of genetic subgroups for which
generalized nutritional requirements may not apply.
Parallel advancements in understanding the interactions
among human genes, including all genetic variants
thereof, and environmental exposures is enabling
the development of genotype-specific nutritional
regimens that prevent disease and promote wellness for
individuals and populations throughout the life cycle.
Current challenges associated with the incorporation