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Sponsored Projects Symposium
February 13, 2008
Nutrigenomics:
Genes in Your Food
and Genes in You
Charles C. Muscoplat, PhD
Vice President for Statewide Strategic
Resource Development
McKnight Presidential Endowed Chair
Professor of Medicine and Food
Science and Nutrition
Goals Today
• Be able to understand how foods and/or nutrients can affect
our health by mechanisms other than as providing simple
nutrients, vitamins or energy
• Illustrate that some foods or food products can treat and/or
prevent major human diseases other than by providing
“adequate” or essential nutrition or energy by altering gene
expression or through existing genetic polymorphisms
• Demonstrate that we can bring together agriculture as a full
partner in human health promotion and disease prevention
by utilizing foods as Medicine “ala Hippocrates”.
• To better establish that we can use foods to alter or
complement gene expression in a dose and time dependent
manner to prevent, ameliorate or cure serious human
diseases.
Diet and Chronic Diseases
• 125 million Americans have 1 or more chronic disease
conditions (e.g., coronary heart disease, diabetes, cancer,
stroke, mental illness) that may be related to diet and/or
lifestyle factors
• Chronic diseases account for 75% of all health care
expenditures
• Costs for chronic diseases is approaching $1 trillion
• Modifiable factors; diet, lifestyle, exercise, alcohol,
tobacco
• Not modifiable factors; age, sex, geneotype, family
history
• Many of these diseases and conditions can be prevented or
treated with modifiable changes in diet and lifestyle:
– GENES IN YOUR FOOD - GENES IN YOU
Today’s Medicine and Nutrition.
One size does not fit all. Not everyone responds
similarly to medications or food:
Patients are “Different” by Polymorphisms
Genetic Variability Exists in our Food: Alleles, Regulation, Epigenetics
If you want health, which varieties do you choose? Why?
Oranges, Grapefruits,
Mandarin Orange, Lemons,
Limes, Citrons, Shaddocks,
Pummelos, Osbecks, Sour
Oranges. Do they share
common genes or are some
genes on or off? Which
alleles are healthful and
which are not?
Soybeans have
several important
nutrients but levels
vary among
varieties. Ancient
varieties have higher
levels of cancer
preventing
compounds than
modern varieties.
Tomatoes, Cherry
tomatoes, yellows,
heirloom, fried
green, Roma, Sun
Gold, Big Boy, Plum,
Purple. Is yellow
lycopene as healthy
as red lycopene?
Broccoli and
Cauliflower share
ancestral genes of
origin, including
nutrient constituent
genes, but are they
equally healthful to
you? Which on is
more healthful?
Choose a Tomato for your own purpose
Carrots?
Are these different?
Do they have different genes?
Are different genes expressed?
Are they equally healthy?
Do they grow the same?
Do rabbits eat them?
To they taste the same?
Monarch caterpillars and butterflies are
genetically identical and have
their genes “On or Off” Depending ?
The concept of genomics is “Gene Expression”
Genetically identical - but differing in gene expression
Genomics and Body Plans:
Which of these plans
is not like the others?
Which of these plans
are kind of the same?
Learning about structural genomics and evolution
Learning about worms and flies can teach us about ourselves and our genes
Embryonic Development Illustrates
Conservation of genes over 600 million years
Flies, worms and People have the same basic body plan origin
– We all have 14 homeotic body plan gene segments:
3 head, 3 chest and 8 abdomen
We all have the same basic body plan…look around you...
Homeotic Hox Genes describe all basic body plans
Fruit Fly Compound Eye
What is so unusual about this fly eye?
It is growing on a fruit fly leg!
Homeotic Genes Work Across Species and Time
Fly eye stimulated
to grow on fly leg
by injecting mouse
Homeotic “eyeless”
genes into fly leg
Nutrigenomics
The science of
nutrigenomics seeks to
provide a molecular
understanding for how
common dietary
chemicals (i.e., nutrients)
affect health by altering
the expression and/or
conformational structures
of an individual’s genetic
makeup.
Example 1: These two genetically identical mice were born of
genetically identical mothers who were fed differently in
pregnancy and they will have very different lives
Their identical mothers were fed different amounts of methylating
nutrients or soy genistein during pregnancy
Palindrome LTR Hypomethylated
Transposon sequence
Yellow Mouse
Epigenetics Occurs
Maternal
Supplements
With
Genistein
zinc
methionine
betaine
choline,
folate
B12
High risk cancer, diabetes,
obesity & reduced lifespan
Cooney J Nutr 2002;132:2393S-2400S.
Palindrome LTR
Hypermethylated
Transposon sequence
Agouti Mouse
Lower risk of cancer,
diabetes, obesity and
prolonged life
Increasing soy supplement genistein alters
gene expression and thus phenotype
Increasing Methylation
Change in coat color
Change to lower lifetime weight
Change to improved lifetime health
PNAS November 14, 2006 Vol. 103 no. 46 17-71-17072
What you eat or what your mothers ate
The role of the environment has been underplayed in developmental
biology – Developmental Plasticity and Epigenetics
Clones of Daphnia
Reared in
absence of
predators
Reared in presence
of predators &
predator kairomones
Daphnia develop
spines, which deter
predation
Developmental biology largely ignores “nongenetic” causes of individual variation. Yet, it is clear
that the environment can exert a strong influence on development; e.g, developmental plasticity.
Although most evolutionary biologists recognize the environment as an important source of
individual variation, many regard environmental responsiveness as developmental “noise” that
has no long-term evolutionary consequences.
Nutrient (Food) Methylation: Modulation of GeneEnvironment and Gene-Diet Interactions may be
through DNA methylation
Nature’s way of allowing environmental factors to tweak
gene expression without making permanent mutations.
Primary DNA does not vary but they can be altered to
read differently
Methylation can alter genes
Methylation can alter genes
Methylation can alter genes
Methylation can alter genes
Methylation can alter genes
Methylation can alter genes
Waterland and Jirtle at Duke University:
What your mother ate can determine your
lifetime outcome through epigenetic mechanisms?
…….. the metastable methylation status of specific transposable element insertion sites
renders them epigenetically labile to early methyl donor nutrition. Our results show that
dietary methyl supplementation of a/a dams with extra folic acid, vitamin B(12), choline, and
betaine alter the phenotype of their A(vy)/a offspring via increased CpG methylation at the
A(vy) locus and that the epigenetic metastability which confers this lability is due to the A(vy)
transposable element. These findings suggest that dietary supplementation, long presumed to
be purely beneficial, may have unintended deleterious influences on the establishment of epigenetic
gene regulation in humans……………….
Dolinoy, Weidman, Waterland and Jirtle at Duke University
………….. Here, we report that maternal dietary genistein supplementation of
mice during gestation, at levels comparable with humans consuming high-soy
diets, shifted the coat color of heterozygous viable yellow agouti (A(vy/a)
offspring toward pseudoagouti. This marked phenotypic change was
significantly associated with increased methylation of six cytosine-guanine sites
in a retrotransposon upstream of the transcription start site of the Agouti
gene. The extent of this DNA methylation was similar in endodermal,
mesodermal, and ectodermal tissues, indicating that genistein acts during early
embryonic development. Moreover, this genistein-induced hypermethylation
persisted into adulthood, decreasing ectopic Agouti expression and protecting
offspring from obesity. Thus, we provide the first evidence that in utero dietary
genistein affects gene expression and alters susceptibility to obesity in
adulthood by permanently altering the epigenome……….
Pseudo-agouti predicts
body weight
throughout adulthood.
Geinstein (soy)
supplementation
increases the incidence
of normal-body-weight
animals as adults.
Very early dietary
events can have
lifelong
consequences!
Timeline of
methylation
consequences.
Failure to
methylate early
results in the obese
and sick mouse
syndrome.
Eating 10 g to 40 g Soy Nuts
What if you need soybeans to treat your disease?
If food can also be a biopharmaceutic, then eating could be viewed as
‘dosing’. e.g, Eat soy genistein to a steady dose of 2,000 nmol/Lh AUC. Eat
to Cmax of 2,000 nmole/L; Eat to Signal Transduction then stop? There is a
goal to eat healthy!
pK data T ½ for genistein ~ 10 hrs and AUC
Soy genistein can markedly augment cytotoxicity
of certain anti-neoplastic agents
Soy genistein plus Cisplatin is profoundly antineoplastic; p< 0.01
25 uM Genistein as a bioharmaceutic agent; was the
dose optimal; was the agent from soy optimal, was
the timing optimal, was the purity high quality?
Soybean genistein
inhibits NF kappa Beta
in a dose dependent
manner promoting
apoptosis:
Cisplatin activates NFkB to prevent
apoptosis.
Thus the two agents
are synergistic as antineoplastic agents
Soy genistein +
Cisplatin caused
tumor reduction and
growth delay
compared to either
cisplatin alone or
genistein alone. The
effects are
biologically
complementary.
Soy isoflavones as cancer therapy
Soy isoflavones as biopharmaceutics. Should all men over age 50
consume soybean extracts of genistein at a dose determined to inhibit
NF-Kappa beta and signal transduction in steady state? How about men
with early lesions in individuals in ‘watchful waiting”. Risk benefit?
Log Level Rise of PSA Levels in Patients Taking Soy Supplements
But? Was the dosing
optimal? This study
used one capsule
daily. The pk data
would support at
least bid dosing? We
do know volume of
distribution and
penetration into
prostate acidic
secretions? There was
no dose titration to
side effects or
optimal efficacy.
Should patients
receiving radiation
be pre-medicated
with soy based
genistein? What is
risk benefit?
Alcohol Dehydrogenase has
3 alleles: only the ADH3
allele is associated with
significantly reduced
myocardial infarction in
relationship to alcohol
consumption. Women
raised HDL to about 72
mg/dl while men raised
HDL to about 51 mg/dl.
HDL was increased in slow
and intermediate alleles but
MI data was not sig in these
2 groups.
Serum Triglycerides are
influenced by both diet and genes
Change in diastolic blood pressure in response to fiber
based diets with alleles of AGT gene codon 235
2
1
D DBP (mm Hg)
0
-1
Insoluble
-2
Soluble
-3
-4
-5
-6
T/T
T/M
Hegele, et al. Nutr. Res. 17: 1229, 1997
M/M
Influence of caffeine on bone mass may depend on VDR allele
6
Caffeine
< 300 mg
0
TT
> 300 mg
Tt
tt
TT
Tt
tt
-6
-12
TT
Tt
tt
TT
Tt
Vitamin D Receptor Genotype
Rapuri et al. Am J Clin Nutr 2001 Nov;74(5):694-700
tt
Control of Homeotic Hox Gene
Expression and Birth Defects: Vitamin A Effect
Malformations caused by high doses of vitamin A, which was
given to mothers on day 8 of pregnancy. Vitamin A has caused
the homeotic HOX genes 1-4 to become expressed in groups of
cells that usually do not express these genes.
Blood Pressure and
Diet
F/V or Dash Diets can
Lower blood pressure
Only in individuals with
AA genotype but not
GG Genotype.
Control of
angiotensinogen
Related SBP and DBP
Via diet is gene-related.
Jose M. Ordovas
HDL Cholesterol
APOA1 G-A Polymorphism and PUFA Intake vs HDL
CONCLUSIONS: We
found a significant genediet interaction associated
with the APOA1 G-A
polymorphism. In
women carriers of the A
allele, higher PUFA
intakes were associated
with higher HDLcholesterol
concentrations, whereas
the opposite effect was
observed in G/G women
= 8% PUFA
= 4-8% PUFA
= <4% PUFA
Pima Indians living on the Gila River Indian Reservation
Pima Indians living on the Gila River Indian Reservation
near Tucson Arizona have the highest rate of diabetes in
the world, while Pimas in Maycoba, in the Mexican state
of Sonora, rarely get the disease. Leslie Schultz has
concluded that the differences in diet and and exercise
may explain the contrast.
Gene specific response to fish oil supplementation
20
% change on fish oil
10
0
TG
LDL-C
HDL-C
-10
-20
-30
-40
ALL
Minihane et al, 2000
apo E2
apoE3
apoE4
The data demonstrate the efficacy of fish oil
fatty acids in counteracting the proatherogenic
lipid profile of the ALP but also that the apoE
genotype influences responsiveness to this
dietary treatment.
CONCLUSION: Intake of coffee was associated with an
increased risk of nonfatal MI only among individuals with
slow caffeine metabolism, suggesting that caffeine plays a
role in this association.
CONTEXT: The association between coffee intake and
risk of myocardial infarction (MI) remains controversial.
Coffee is a major source of caffeine, which is
metabolized by the polymorphic cytochrome P450 1A2
(CYP1A2) enzyme. Individuals who are homozygous for
the CYP1A2*1A allele are "rapid" caffeine metabolizers,
whereas carriers of the variant CYP1A2*1F are "slow"
caffeine metabolizers
Is Coffee associated with CVD?
 Coffee or associated lifestyle?
 Are coffee abstainers at  risk?
 Does risk depend on age?
 Which component of coffee?
Slide permission & courtesy of Ahmed al-Sohemy
CYP1A2
Genotype
rapid
slow
Controls
%
Cases
%
A/A
46
45
A/C
43
44
C/C
10
11
Slide permission & courtesy of Ahmed al-Sohemy
Coffee Intake and Risk of MI
4
Odds Ratio
3
<1 cup/d
1 cup/d
2-3 cups/d
4+ cups/d
2
*
1
0
Total Population
* P<0.05
Slide permission & courtesy of Ahmed al-Sohemy
Coffee Intake and Risk of MI
4
Odds Ratio
3
<1 cup/d
1 cup/d
2-3 cups/d
4+ cups/d
2
*
*
1
0
*1A/*1A
A/A
*1A/*1F
+ *1F/*1F
A/C +
C/C
CYP1A2 Genotype
* P<0.05
Slide permission & courtesy of Ahmed al-Sohemy
Coffee Intake and Risk of MI
Subjects <59 Years of Age
4
Odds Ratio
3
<1 cup/d
1 cup/d
2-3 cups/d
4+ cups/d
*
2
*
1
**
0
*1A/*1A
A/A
*1A/*1F
+ *1F/*1F
A/C +
C/C
CYP1A2 Genotype
* P<0.05
Slide permission & courtesy of Ahmed al-Sohemy
Coffee Intake and Risk of MI
Subjects <50 Years of Age
*
4
Odds Ratio
3
<1 cup/d
1 cup/d
2-3 cups/d
4+ cups/d
*
2
1
**
0
*1A/*1A
A/A
*1A/*1F
A/C ++ *1F/*1F
C/C
CYP1A2 Genotype
* P<0.05 Are
Coffee
Which
coffee
orcomponent
associated
abstainersoflifestyle?
atcoffee?
 risk?
Slide permission & courtesy of Ahmed al-Sohemy
Genistein (soy) & Mammary Cancer:
Timing is Everything
Exposure Period
Tumors/Rat
None
8.9
Prenatal
8.8
Adult
8.2
Prepubertal
4.3
Prepubertal + Adult
2.8
LaMartiniere et al JNutr 132: 552S, 2002
Slide courtesy of Dr. J. Milner, NCI
If you don’t like it,
you won’t eat it
What you like to eat is genetic: are you a
genetic supertaster, genetic non-taster or
moderate taster?
Goals Today
• Be able to understand how foods and/or nutrients can affect
our health by mechanisms other than as providing simple
nutrients or energy
• Illustrate that some foods or food products can treat and/or
prevent major human diseases other than by providing
“adequate” or essential nutrition or energy by altering gene
expression or through existing genetic polymorphisms
• Demonstrate that we can bring together agriculture as a full
partner in human health promotion and disease prevention
by utilizing foods as Medicine “ala Hippocrates”.
• To better establish that we can use foods to alter or
complement gene expressionin a dose and time dependent
manner to prevent, ameliorate or cure serious human
diseases.
The Fog of Nutrition: What can you believe? The public is at a complete loss
to understand what to eat to stay healthy. The minute, hourly, daily, weekly,
monthly contradictions on nutrition recommendations and “diets”
recommendations are nearly irresponsible and misleading. Now is the time
to provide careful, albeit complex recommendations based upon large
prospective controlled clinical trials utilizing well established food
biopharmaceteutics and individualized nutrition guidelines along with
konwledge of genetic polymorphisms of foods and people
OF NUTRITION
Thank you…...