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Disclosures
Applying Functional Nutrition for Chronic
Disease Prevention and Management:
• RUTH DEBUSK, PHD, RD is an
A Foundational Course in Functional Nutrition
Independent Contractor and/or on the
Speakers Bureau for Interleukin Genetics,
Inc. and is a Scientific Advisory Board
Member for Nutrilite/Alticor.
Ruth DeBusk, PhD, RD
Functional Nutrition Course Hollywood, Florida
December 2010
© 2010, The Institute for Functional Medicine
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ADIME
✔ Assess
Diagnose
Intervene
Monitor &
Evaluate
© 2010, The Institute for Functional Medicine
Regrouping…
The ABCDs
Of
Nutritional
Assessment
Where are we?
Anthropometric
Biomarkers & Labs
Clinical Indicators
Diet & Lifestyle Assessment
© 2010, The Institute for Functional Medicine
© 2010, The Institute for Functional Medicine
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Nutritional Genomics
as a Nutrition Assessment Tool
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Objectives
• Distinguish among:
• Nutritional genomics
• Nutrigenomics
• Nutrigenetics
• Nutritional epigenomics
• Discuss the use of diet and lifestyle to
modify genetic outcomes
• Consider genotype when formulating the
nutrition intervention
© 2010, The Institute for Functional Medicine
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Human Genome Project ushered in a new era M
• Identified DNA sequence
sequence, # of genes E
© 2010, The Institute for Functional Medicine
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Cellular ActivityI
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Overview
Genetics/Genomics
Gene Expression
Metabolomics
• Molecular basis for health and disease
• New disciplines, new technologies
• Launched the emphasis on systems
biology and its relevance to function
© 2010, The Institute for Functional Medicine
Proteomics
Environmental
Factors Tissues/Organs
(“Triggers”)
© 2010, The Institute for Functional Medicine
Organisms
Functional Medicine ATMs
Antecedents
• Genes, information, susceptibilities
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Triggers
• What washes over our genes each day?
• Determines “goodness-of-fit” with the
environment
Mediators
• What prompts or perpetuates the action?
• Suggests interventions to alter outcomes
© 2010, The Institute for Functional Medicine
Medical Applications
• Medicine
• Cancer: diagnosis
diagnosis, risk predictions
predictions, distinguish
similar tumors, predict remission
• Pharmacogenomics
• Warfarin, clopidogrel
• Cancer therapeutics
• Nutritional genomics
• Matching diet and lifestyle choices to genotype
• Using food choices to modify gene expression
© 2010, The Institute for Functional Medicine
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Matching food to genetic capabilities to digest, M
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absorb and using that food to support health
absorb,
Nutritional Genomics
•
• Helpful for Nutrition Assessment and Diagnosis:
• Helpful for Nutrition Intervention:
• Matchingg diet and lifestyle
y to g
genetic variations
• Modifying exposures to triggers for these variations
• Using food to modulate gene expression
© 2010, The Institute for Functional Medicine
© 2010, The Institute for Functional Medicine
Chronic Disease
• 23,000 human genes
• Most have variations/mutations/“changes”
variations/mutations/ changes
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Key Point #1
• Impact of variation on function also a spectrum:
• Strong effects: rare genetic changes
• Weak effects: common changes
• Chronic
Ch i disorders
di d
often
ft d
due tto common changes
h
Genes Underlie Function and
Dysfunction: Overview of Key Genetic Principles
in multiple genes; each has a minor effect but
gains strength by interacting w/ environmental
factors
© 2010, The Institute for Functional Medicine
© 2010, The Institute for Functional Medicine
How Genes, Proteins,
and Function are Related
Genes
Proteins
Function
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Fundamental Principles
Universal biological principle:
Genes + Environmental Factors =
Function/Dysfunction
• Allows use of model systems
• Genes aren’t
aren t destiny
• Lifelong diet and lifestyle choices have
strong influences on genetic outcomes
© 2010, The Institute for Functional Medicine
© 2010, The Institute for Functional Medicine
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Some Fundamentals
What is DNA?
Stored information
What is a Gene?
A unit of stored information, typically
encodes a protein–the cellular workhorses
Wh t is
What
i a Genotype?
G
t
? a Phenotype?
Ph
t
?
Genotype is set
Phenotype is open to interpretation
© 2010, The Institute for Functional Medicine
© 2010, The Institute for Functional Medicine
Decoding DNA
Deoxyribonucleic Acid (DNA)
Gene
. . .TACTCCGAATT. . .
Transcription
Messenger RNA
. . .AUGAGGCUUAA. . .
Translation
Protein
© 2010, The Institute for Functional Medicine
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© 2010, The Institute for Functional Medicine
 metargleulys
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Anatomy of a Gene
Regulatory/Control Regulatory/Control
Region
Impact of Changes
in DNA
Coding/Structural Coding/Structural
Region
5'
3'
Transcription
Translation
Response Elements
Promoter Region
“Start Sequence”
PROTEIN
© 2010, The Institute for Functional Medicine
© 2010, The Institute for Functional Medicine
© 2010, The Institute for Functional Medicine
© 2010, The Institute for Functional Medicine
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Mutation vs. Gene Variant
• All changes to the DNA are mutations
• Mutation
M t ti associated
i t d with
ith changes
h
th
thatt severely
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impair function and result in disease
What’s a SNP (“snip”)?
• Single
Si l Nucleotide
N l tid Polymorphism
P l
hi
• A change in one base in the DNA
• Common in a population
• Leads to individual uniqueness
• Genetic Variation/Gene Variant associated
with changes that have a minor impact on
function and typically require environmental
triggers for expression
• ~10%
10% of our DNA differs from
person-to-person
• Each of us has ~300 million SNPs
Yet another example of a spectrum of effects
© 2010, The Institute for Functional Medicine
© 2010, The Institute for Functional Medicine
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SNP Example
DNA Sequence:
Original
G
G
A
G
C
C
G
A
T
T
T
C
Changed
G
G
A
G
T
C
G
A
T
T
T
C
Where do Food and
Environmental Factors Fit?
Genes
Function
Proteins
Food!
Microbial Metabolites
Consequences:
C
T
Ala
Val
© 2010, The Institute for Functional Medicine
Bioactives
(“environment”)
© 2010, The Institute for Functional Medicine
Rx
Toxins
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Nutritional Genomics
The Science
Th P
The Potential
i l
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Nutritional Genomics in Action
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The Applications
NUTRIGENOMICS (gene expression)
NUTRIGENETICS (polymorphisms)
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N
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S
Adapted from Dr. Peter Gillies. JADA 2003;103:S50‐5. © 2010, The Institute for Functional Medicine
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Nutrigenetics
• Folate and impaired folate metabolism (MTHFR)M
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Examples
• Vitamin
Vit i D and
d ffaulty
lt vitamin
it i D receptors
t
(VDR)
• Every protein’s a potential target for DNA change
• Nutrigenomics
© 2010, The Institute for Functional Medicine
Gene x Environment
interactions are the problem…
Food is the solution.
• Cruciferous vegetables and detoxification
• Anti-inflammatory
Anti inflammatory foods and supplements
© 2010, The Institute for Functional Medicine
© 2010, The Institute for Functional Medicine
Nutrigenomics: Food Speaks to Our Genes
The Power of Food
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•
•
•
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Supplies the building blocks
Ci
Circumvents
genetic
i lilimitations
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Influences gene expression
Conveys info about the environment
Contains “bioactive
bioactive dietary components”
components
Nature Rev Genet. 2003;4:315‐322.
© 2010, The Institute for Functional Medicine
© 2010, The Institute for Functional Medicine
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Influence of Gene Variants
on Postprandial TG Response
Schaefer EJ. Am J Clin Nutr. 2002;191‐212. © 2010, The Institute for Functional Medicine
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Variability in LDL
LDL--C ResponseD
to Fish Oil Supplementation I
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Lovegrove, Gitau. Proc Nutr Soc. 2008;67:206‐213.
© 2010, The Institute for Functional Medicine
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Common examples relevant to chronic disease M
• Type of fat and vascular disease
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Gene--Diet Interactions
Gene
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Exercise‐induced GLUT‐4 translocation
• APOA1, APOE, APOA5
• Polyunsaturated fat and inflammation
• IL1, IL6
• Sodium and hypertension
•
•
• AGT, ACE
Glucosinolates and cancer
• GSTs
Exercise and insulin resistance
• GLUT4
References provided in addendum
© 2010, The Institute for Functional Medicine
© 2010, The Institute for Functional Medicine
We Are More than Our Genes…
Transformation of Offspring by Epigenetics
• Epigenetic "marks“ tell
Maternal
supplementation
l
t ti
with:
g
genes
to switch on or off, to
speak loudly or to whisper.
• Environmental factors,
methionine
choline
folate
B12
zinc
(diet, stress, prenatal
nutrition)
t iti ) make
k an imprint
i
i t
on genes that is passed
between generations
Hypomethylated
© 2010, The Institute for Functional Medicine
Hypermethylated
Cooney et al. J Nutr. 2002;132:2393S
http://www.time.com/time/health/article/0,8599,1951968,00.html
© 2010, The Institute for Functional Medicine
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Controlling Gene ExpressionD
Epigenetic modifications (“markings”)
control access to DNA for transcription:
Histone modification:
DNA modification:
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Why Is all This Important?
Suggests:
• Diagnostic approaches
• Therapeutic approaches (new targets):
• Proteins responsible for chromatin remodeling
or DNA methylation
• MicroRNA targeting
• Prevention
P
ti approaches
h
• Highlights importance of nutrition throughout
multiple generations – i.e., prior to conception
© 2010, The Institute for Functional Medicine
© 2010, The Institute for Functional Medicine
Genetic Testing
Key Point #2
• Long-established technology
• Previously used to confirm a diagnosis
• Newer applications for detecting
susceptibilities to intervene early in life
To Apply Genomics Clinically,
Must Identify Patient’s Variants
© 2010, The Institute for Functional Medicine
• Pharmacogenomics and drug choices
• Nutritional genomics and diet choices
• Type of genetic testing is nutrigenetic testing
© 2010, The Institute for Functional Medicine
From Cheek Swab to DNA
Current Test Panels
• Cardiovascular health
Nucleus
Cell
Chromosome
• Lipids
• Hypertension
• Coagulation
• Detoxification
Cell
• Phase I and Phase II
• Inflammation
DNA double helix
• Major inflammation genes
DNA base pairs
© 2010, The Institute for Functional Medicine
Status of Nutrigenetics
Selecting a testing lab:
• Questions to ask about the test
• Questions to ask about the lab
• Privacy and discrimination concerns
© 2010, The Institute for Functional Medicine
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Present strengths/limitations/ELSI concerns
• Established technology
• Gene-diet-lifestyle associations evolving
• Ethical, legal, social implications to consider
© 2010, The Institute for Functional Medicine
• Female hormones
• Weight management
Key Point #3
Patient Outcomes Can Be Modified Using Nutritional Genomics
© 2010, The Institute for Functional Medicine
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Integrating
ti N
Nutritional
t iti
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Genomics into the
Nutrition Assessment
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© 2010, The Institute for Functional Medicine
Joanne
29 y/o WF not yet pregnant Labs: ↑ LDL, ↓ HDL
↑TGs
CC: hyperlipidemia
FBS WNL
HPI:
Psycho-social:
Diet: “SAD”, eats out
Stress (job, finances)
Exercise: limited
Nutrition physical exam:
Wt hx: 125# at age 20
Ht/wt 64
64”/149#
/149#
Family hx:
BMI 25.6, WC 35.6”
early MI,
Pre-hypertensive
HTN, hyperlipidemia,
Dry skin
overweight
© 2010, The Institute for Functional Medicine
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Chronic Inflammation M
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IL1A
+
–
Nutrigenetic Analysis
Atherosclerosis‐related
APOE
3
4
CETP
+
–
IL1B #1
+
–
SELE
+
+
IL1B #2
+
–
Blood Pressure
GNB3
AGT
–
+
Methylation
MTHFR
+
Serum Lipids
Coagulation
+
+
Factor II
+
–
Factor V
–
–
– Usual + Variant +
© 2010, The Institute for Functional Medicine
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© 2010, The Institute for Functional Medicine
APOE
APOE
Apolipoprotein E
Protein
Function
Clears fat remnants from the blood
Dysfunction
↓ fat clearance, ↑ plaque formation
Alleles
(variants)
E2, E3, E4 (E3 is the more common allele)
Effect
Alters LDL, HDL, TG response to nutrients
Gene-dietlifestyle
Interactions
E4 most responsive to LF diet, E2 least
E2 responds well to soluble fiber, E4 least
E4 least responsive to exercise, E2 best
E4 does not increase HDL in response to alcohol, E2
and E3 appear to respond
© 2010, The Institute for Functional Medicine
Conventional Analysis Info:
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•
•
•
•
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Overweight (BMI 25.6) with central fat deposits
Dyslipidemia
Pre-hypertensive
Fasting blood sugar WNL
hsCRP negative for inflammation
Family hx hyperlipidemia, HTN, overweight
Poor diet and exercise choices
Not Measured:
• Homocysteine, HDL fractions, Na+-sensitive BP
© 2010, The Institute for Functional Medicine
APOE
Genotype:
E3,E4
Therapeutic implications:
 IFM Core Food Plan with  soluble fiber
 Abundant fruits and vegetables, particularly those
rich in polyphenols
 Low saturated fat, increased monounsaturated and
polyunsaturated fats
 Fish and/or omega-3 (EPA/DHA) supplementation
 Alcohol may be helpful—balance against need for
low glycemic load diet
 Regular aerobic exercise
© 2010, The Institute for Functional Medicine
Insights from NGx analysis:
Key data not available without NGx:
• APOE 3/4 (impacts diet
diet, lifestyle choices)
• CETP informs diet/exercise re HDL
• SELE suggests  risk for atherosclerosis
• Sodium-sensitive blood pressure
• Significantly impaired methylation ability
•  risk for inflammation
© 2010, The Institute for Functional Medicine
How this insight informs the
intervention:
• APOE 3/4: use soluble fiber to  LDL
LDL-C
C
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rather than fat-restricted diet
Serious exercise in order to  HDL-C
Restrict dietary sodium
Folate/B12 foods + 5MTHF supplementation
Anti-inflammatory foods, lifestyle
© 2010, The Institute for Functional Medicine
What’s Ahead?
Major
M
j research
h foundation
f
d ti to
t be
b built
b ilt
Gene-diet/lifestyle association discoveries
Nutrigenetic testing validity and clinical utility
© 2010, The Institute for Functional Medicine
Access
Genes, Nutrition, Chronic Disease
Testing Availability
Tests with Clinical
Validity and Utility
ROAD
WORK
AHEAD
Diet-Gene-Disease
Associations
Research Foundation
© 2010, The Institute for Functional Medicine
© 2010, The Institute for Functional Medicine
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The Human Genome Project continues to have M
a broad-reaching impact on health care:
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Overview
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• Identified nucleotide sequence of DNA and
the number of genes in human genome
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Key Technologies from the HGPD
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Genomic technologies for detecting changes in:
M
• DNA sequence (mutation/SNP) – DNA sequencing
E
and DNA probes
• Genomic organization – FISH (fluorescence in situ
hybridization)
DNA copy number – comparative genomic hybridization
DNA methylation – chromatin immuno-precipitation
Gene expression – microarray profiling
•
•
•
• Turned the spotlight on the molecular basis
for health and disease
• U
Ushered
h d iin th
the ““-omics”
i ” era
• Spurred the development of new gene-
Other “omics” with clinical applications:
• Proteomics
• Metabolomics
• Pharmacogenomics
• Nutritional genomics (Nutrigenetics, Nutrigenomics, Epigenomics)
related technologies and tools
• Launched the emphasis on systems biology
© 2010, The Institute for Functional Medicine
© 2010, The Institute for Functional Medicine
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Matching food to genetic capabilities to digest, M
absorb, and use that food to support health
E
Nutritional Genomics
•
• Helpful for Nutrition Assessment and Diagnosis:
• Identifying genetic changes that are antecedents to
disease susceptibility
• Helpful for Nutrition Intervention:
• Matching diet and lifestyle to genetic variations
• Modifying exposures to triggers for these variations
• Using food to:
Marsh, McLeod. Hum Molec Genet. 2006;15:R89‐93.
© 2010, The Institute for Functional Medicine
•
•
Accommodate variations on the human gene theme
Change expression of our genes
© 2010, The Institute for Functional Medicine
What is DNA?
• DNA is:
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The genetic material, our operating system
3 billion nucleotides, in a specific order
Nucleotide = phosphorus + ribose + nitrogenous base
4 base options: Adenine, Thymine, Cytosine, Guanine
Must be decoded and translated into proteins
Faithfully transferred from generation to generation
• Each human has:
• The same base set of DNA characteristic of our species
• A slight variation on that common human DNA theme
• A full complement of DNA (genome) in a cell’s nucleus
© 2010, The Institute for Functional Medicine
• Analogous to a sentence – words that
collectively convey something meaningful
• A sequence of nucleotides within the DNA
that can be translated into a protein
• Proteins do the work: structural, enzymes,
receptors transporters
receptors,
transporters, communicators
communicators, hormones
• Humans have ~23,000 genes
• We have two copies of each gene, one copy
inherited from each parent
© 2010, The Institute for Functional Medicine
Genotype vs. Phenotype
• Genotype
– The sum total of our DNA and its information
– Genotype is stable
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Mutation vs. Gene Variant
• All changes to the DNA are mutations
• Semantics:
S
ti
Mutation = severe impact on function
• Phenotype
– The measurable outcomes of our DNA (genotype)
– Phenotype changes as our genes and environment
interact
•
•
What is a gene?
Genotype is like a musical score
Phenotype is like a symphony played from that
musical score and changes with the conductor
Variant = minor impact
needs environmental trigger(s)
Yet another example of a spectrum of effects
(courtesy of Gail Kauwell, PhD, RD)
© 2010, The Institute for Functional Medicine
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© 2010, The Institute for Functional Medicine
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Genetics vs. Genomics
Genetics
• Old thinking:
g
• Genetic disorders are rare, need 2 “bad” genes
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• New thinking:
• It’s all genetic 
• “Gene dosing concept” - carriers with impaired function
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The Science
M
• Studies how the daily interaction between our genes E
Nutritional Genomics
•
and our environment influences our functioning
• The Applications
• How the environment influences gene expression
• How the individual’s genetic makeup influences
goodness-of-fit with the environment
his/her g
Genomics
• Complex: multigene/multifactorial disorders
• Interactions: gene-food, gene-toxin, gene-gene
• The Potential
• Optimal diet and lifestyle choices for our individual
genetic potential and support for our genetic limitations
© 2010, The Institute for Functional Medicine
Terms to be Familiar With…
• Nutritional Genomics
• The field itself
• Nutrigenetics (genes environment)
• The influence of genes on how good a match
there is between our genes and the
environments
e
o e ts we
e occupy du
during
g ou
our life
e
• Nutrigenomics (environment
•
genes)
The influence of environmental factors on
genes, their proteins, and metabolism
© 2010, The Institute for Functional Medicine
© 2010, The Institute for Functional Medicine
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Supplies the raw materials to run the body M
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The Power of Food
•
• Helps us circumvent genetic limitations
• Influences gene expression
• Can turn genes on/off in response to
environmental signals communicated by food
• Conveys information to the organism
about its environment
• Food contains components called:
“bioactive dietary components”
© 2010, The Institute for Functional Medicine
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We know about clogged arteries, chronic HTN I
CVD, why not counsel everyone to quit smoking,M
exercise, and cut out the saturated fat and salt? E
Why do we need NGx?
•
• Why not just use family history?
• Why bother with nutritional genomics?
• Enhanced patient buy-in to making changes
Implications
• In nutrition research:
Failure to account for genetic variability in a study
population can lead to variability in study outcomes
and confusion about therapeutic efficacy
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• In nutrition practice:
Failure to understand the role of genes in the
condition your patient is struggling with can lead to
limitations in assessment and diagnosis and
ineffective interventions and may even lead to harm
Grant RW et al. Diabetologia. 2009;52:2299–2305.
A k di
Arkadianos
I ett al.
l Nutr
N t J.
J 2007;6:e29
2007 6 29
Gordon ES et al. Eur J Hum Genet. 2005;13:1047-1054.
• Less restrictive diet and lifestyle choices
• Universal dietary guidelines can be harmful to
individuals with particular genotypes
© 2010, The Institute for Functional Medicine
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Common examples relevant to chronic disease M
• Type of fat and vascular disease
E
© 2010, The Institute for Functional Medicine
Gene--Diet Interactions
Gene
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•
•
•
•
• APOA1, HDL-C and polyunsaturated fat level
• APOE, LDL-C and lowfat diet, soluble fiber, alcohol, exercise
• APOA5, triglycerides, dietary fat intake
Polyunsaturated fat and inflammation
• IL1B, IL-1 cytokines (also IL6/IL-6) and polyunsaturated fat
Sodium and hypertension
• AGT (also ACE), sodium and elevated blood pressure
Glucosinolates and cancer
• GSTs, cruciferous vegetables and detoxification/cancer risk
Exercise and insulin resistance
• GLUT4, exercise and increased insulin sensitivity
© 2010, The Institute for Functional Medicine
Epigenetics/Epigenomics
• Influences gene expression without changing
•
•
the DNA sequence
Changes if and when genes can be expressed
Inappropriate expression can lead to disease:
• Development: timing/sequence of events is critical
• Cellular differentiation: activation/silencing is critical
• Tumor development: oncogenes/tumor suppressors
• Diet and lifestyle factors are key epigenetic
influencers
© 2010, The Institute for Functional Medicine
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•
A
Nutritional Epigenomics
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Epigenetic changes tend to occur gradually rather
E
than abruptly
• E.g., gradual loss of methylation that ultimately
•
leads to abnormal gene expression as aging
proceeds
Pencil-and-eraser vs. ink
Methylation Panel
MTHFR
COMT
Inflammation
IL1B-focused
Part of other panels:
IL1 + TNF
IL6
• Where do these covalent modifiers come from:
• Acetyl groups (histone modification)
• Methyl groups (DNA modification)
• Epigenetic markings can be inherited across
generations
© 2010, The Institute for Functional Medicine
APOE
O
CETP
SELE
• Hypertension
GNB3
AGT
AGTR1
© 2010, The Institute for Functional Medicine
IL1B
IL1RN
Th-1 Cytokines
TNF
y
Th-2 Cytokines
IL4
IL6
IL10
IL13
© 2010, The Institute for Functional Medicine
Cardiovascular Panels
• Lipids
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Immune Panel
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Chronic Inflammation E
Current Test Panels
• Coagulation
Factor
acto 2
Factor 5
• Methylation
MTHFR
• Redox Balance
CYB*A
CYB
A H72Y
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Detoxification Panels
Phase I
CYP1A1
CYP1B1
CYP2A6
CYP2D6
CYP2E1
C
CYP2C9
CYP1C19
CYP3A4
© 2010, The Institute for Functional Medicine
Phase II
COMT
GSTM1
GSTP1
GSTT1
NAT1
NAT2
SOD1
SOD2
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Osteo
Bone Formation
COL1A1
CALCR
VDR
Bone Resorption
PTHR
Inflammation
IL1RN
TNF
A
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Weight Management I
M
Diet-related
E
ADRB2 #1
Criteria to Consider
Test Parameters
•
•
•
•
•
•
FABP2
PPARG2
Exercise-related
ADRB2 #2
ADRB3
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Which gene variants are tested?
For each variant tested, is there action that can be taken to
reduce
d
risk,
i k iimprove h
health?
lth?
Is there scientific documentation for each test?
Has each test been documented as to clinical validity & utility?
What is included with the test results? A program to follow?
How long before the results are available?
Lab Parameters
•
•
•
Does the testing lab have the appropriate credentials
credentials, licenses?
Is the test accompanied by informed consent?
Is there a credentialed professional available for assistance??
Privacy/Discrimination Parameters
•
•
© 2010, The Institute for Functional Medicine
How will privacy be protected?
What happens to the DNA sample after testing?
© 2010, The Institute for Functional Medicine
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Strengths/Limitations/Controversies D
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• Strengths
• Provides needed, unique information if we’re to focus M
on health promotion/disease prevention
E
• Genetic testing technology is scientifically sound
• Limitations
•
•
•
•
Limited gene-environmental factor associations
Testing labs not always up to clinical lab standards
Costly – typically declines as test volume increases
Time-consuming
Time
consuming to personalize therapy
CETP
Protein
Function
Dysfunction
↓ HDL-chol, ↑ LDL-chol, ↑ plaque
Allele (variant)
TaqIB (B1 = variant, B2 = common)
Effects
Increased CETP, which leads to ↓ HDL-C
Gene-dietlifestyle
Interactions
 The following moderate the negative
effects of the B1 allele:
 intense exercise
 moderate alcohol consumption
• Controversies
• Ethical, Legal, Social Issues (ELSI)
Passage of the Genetic Information Nondiscrimination
Act expected to ease major consumer concerns about
privacy and fair use of genetic information
© 2010, The Institute for Functional Medicine
Cholesteryl Ester Transfer Protein
Transfers cholesteryl esters between lipoproteins
lipoproteins,
keeps serum chol levels ↓
© 2010, The Institute for Functional Medicine
SELE
CETP
CETP
Genotype:
B1 B2
E-selectin
Protein
Therapeutic implications:
 IFM Core Food Plan
 Regular aerobic exercise, which can:
↑ HDL-cholesterol
↓ LDL-cholesterol
↓ triglycerides
 Soy protein/isoflavones to raise HDL
 Alcohol consumption, if in line with client’s
preferences, may be helpful
© 2010, The Institute for Functional Medicine
TT
© 2010, The Institute for Functional Medicine
Dysfunction
Increased cellular adhesion promotes atherosclerosis,
premature coronary artery disease
Alleles
(variants)
98G>T
Effect
↑ expression of E-selectin
Gene-dietlifestyle
Interactions
Strategy is to decrease transcription factor NFkB
promotion of pro-inflammatory cytokine production;
antioxidant foods and supplements can be helpful
© 2010, The Institute for Functional Medicine
SELE
SELE
Genotype:
Function
E-selectin involved with cellular adhesion to the
endothelium in response to inflammatory cytokines
Therapeutic implications:
 IFM Core Food Plan
 Richly colored fruits and vegetables
 Flavonoid-rich foods and beverages
Red, blue, purple, black fruits, veggies
Green tea, black tea
Dark chocolate
Red wine, purple grape juice
 Antioxidant dietary supplements such as
alpha-lipoic acid, N-acetyl L-cysteine,
vitamin C, vitamin E, silymarin
Endothelial Health:
Blood Pressure
Methylation
Chronic Inflammation
© 2010, The Institute for Functional Medicine
A
D
I
M
E
Renin--Angiotensin Pathway
Renin
AGT
Angiotensinogen
Renin
Angiotensin I
ACE
Angiotensin I-converting
enzyme
Angiotensin II
© 2010, The Institute for Functional Medicine
A
D
I
Guanine Nucleotide Binding Protein
M
beta-3
E
G protein
i important
i
iin cell-to-cell
ll
ll signal
i
l transduction
d i
GNB3
Protein
Function
involving angiotensin effects on raising blood pressure
Dysfunction
Impaired function leads to blunted effect on BP;
increased activity leads to enhanced impact on targets
Alleles
(variants)
825C>T
Eff t
Effect
Higher activity G protein, leading to increased risk of
hypertension, depression, and bipolar disorder
Gene-dietlifestyle
Interactions
May respond to dietary sodium restriction
Typically responsive to the natural diuretic in
dandelion leaves (Taraxacum officinale)
© 2010, The Institute for Functional Medicine
AGT
GNB3
GNB3
yp
Genotype:
CT
Angiotensinogen
Protein
Therapeutic implications:
 IFM Core Food Plan for blood
pressure management
 Sodium restriction may be helpful
 A dietary supplement of dandelion leaves
(T
(Taraxacum
officinale)
ffi i l ) may b
be h
helpful
l f l as a
mild diuretic, without depleting potassium
since dandelion leaves are a source of
potassium
Function
Precursor to potent vasoconstrictor angiotensin II
Dysfunction
Elevated blood pressure
Alleles
(variants)
M235T
Effect
Increased production of angiotensin I
Gene-dietlifestyle
Interactions
 “Salt-sensitive” blood pressure
 BP declines in TT w/ ↓ sodium intake
 BP also declines with weight loss
• Regular aerobic exercise is typically helpful
© 2010, The Institute for Functional Medicine
© 2010, The Institute for Functional Medicine
A
D
I
M
E
AGT
AGT
yp
Genotype:
TT
MTHFR
Protein
5,10-methylenetetrahydrofolate reductase
Function
Essential to folate metabolism, methylation
 IFM Core Food Plan modifications for blood
pressure management
Dysfunction
↑ Risk of CVD, neural tube defects, CRC
Allele (variant)
677C>T
• Restrict dietary sodium
Effects
↓ methylation, ↑ homocysteine levels
Gene-diet
(lifestyle) interactions
 Increased folate requirements due to
gene variant
 Potential increased requirement for
riboflavin since MTHFR is an FAD
enzyme
Therapeutic implications:
• May respond to dietary supplements of
lactotripeptides that mimic ACE inhibitors
 Regular aerobic exercise is typically helpful
© 2010, The Institute for Functional Medicine
© 2010, The Institute for Functional Medicine
MTHFR
MTHFR
677C>T
Genotype is:
Therapeutic implications:
TT
 IFM Core Food Plan
 Calls for greater than “normal” folate levels
 Important to achieve folate adequacy,
particularly due to client’s:
 TT genotype
 Family history of cardiovascular disease
Methionine
Enzyme
5,10 Methylene THF
MTHFR
(B2)
Homocysteine
5MTHF
Enzyme
Cysteine
 Daily folate-rich foods
 MVI containing folate and vitamin B12
© 2010, The Institute for Functional Medicine
Nucleotide synthesis
THF
Sauer et al. Curr Opin Clin Nutr Metab Care. 2009;12:0–36.
© 2010, The Institute for Functional Medicine
IL1B
IL1B
Protein
Function
Interleukin--1beta
Interleukin
Dysfunction
Initiates cascade that leads to inflammation; first
responder in acute response system
Chronic inflammation, increased risk of a variety of
chronic disorders
Alleles
(variants)
-511C>T
Effect
Increased production of IL
IL--1beta cytokines
Omega
mega--3 fats can dampen inflammatory response
through synthesis of anti
anti--inflammatory eicosanoids
and through action on gene expression of
proinflammatory cytokines, including IL
IL--1beta
© 2010, The Institute for Functional Medicine
A
D
I
M
E
IL1B
IL1B
yp
Genotype:
Therapeutic implications:
CT
Gene-dietlifestyle
Interactions
© 2010, The Institute for Functional Medicine
• IFM Core Food Plan, anti-inflammation
• Increase omega-3 consumption
fish and fish oils
plant sources: flaxseed/oil, canola oil,
walnuts/oil, pumpkin seeds, soy oil,
perilla oil, purslane
• Decrease omega-6 consumption
• Increase flavonoid-rich foods:
deeply colored fruits and vegetables
cocoa/dark chocolate, green tea
purple grape products, incl. red wine
A
D
I
Coagulation Factor II (Prothrombin)
M
Plays a critical role in blood coagulation, clot formation E
Factor II
Protein
Coagulation
g
© 2010, The Institute for Functional Medicine
Function
Dysfunction
Increased prothrombin levels, increased propensity for
clot formation, vessel occlusion
Alleles
(variants)
20210G>A
Effect
Elevated incidence of clot formation, venous
thrombosis, coronary artery disease
Gene-dietlifestyle
Interactions
Licorice (Glycyrrhiza glabus), which inhibits
prothrombin
conversion to thrombin, and dietary supplements that
contribute to blood thinning (omega-3 fats, red clover
(Trifolium pratense)
© 2010, The Institute for Functional Medicine
Factor II
yp
Genotype:
Protein
Therapeutic implications:
Function
GA
 IFM Core Food Plan
 Dietary sufficiency of omega fatty acids
 Dietary supplements that may be helpful:
• Licorice
• Omega-3 fatty acids
• Red clover
 Regular physical activity advisable
© 2010, The Institute for Functional Medicine
Dysfunction
Decreased lysis of clots that form, leading to
increased risk of blood clots
Alleles
(variants)
R506Q
Effect
Increased venous clot formation, may predispose to
deep vein thrombosis or pulmonary embolism
Gene-dietlifestyle
Interactions
Omega-3 fatty acid sufficiency may be helpful
© 2010, The Institute for Functional Medicine
Factor V
Factor V
yp
Genotype:
A
D
I
Factor V, Leiden
M
Combines with Factor X to form prothrombin activator,
assisting in the conversion of prothrombin to thrombin E
Factor V
Factor II
Therapeutic implications:
RR
 None indicated beyond the balanced Core
Food Plan with adequate omega-3 fatty acids
Conventional Analysis Info:
• Overweight (BMI 25.6) with central fat deposits
• Dyslipidemia:
–  Total cholesterol
cholesterol, LDL and TGs
–  HDL
• Pre-hypertensive
• Fasting blood sugar WNL
• hsCRP negative for inflammation
• Family hx hyperlipidemia,
hyperlipidemia HTN
HTN, overweight
• Poor diet and exercise choices
Not Measured:
• Homocysteine, HDL fractions, Na+-sensitive
blood pressure
© 2010, The Institute for Functional Medicine
© 2010, The Institute for Functional Medicine
Bottom Line for Clinicians
• The prevalence of chronic disease is escalating
• More effective disease management is needed
• Diet-and-lifestyle approaches can be effective,
•
low-cost, and carry minimal risk
Nutritional genomics provides guidance for
individualizing the diet-and-lifestyle prescription
• Preventing chronic disease is equally as important
• Nutritional genomics identifies susceptibility and allows
References
Background
National Human Genome Research Institute:
g
g
www.genome.gov
Department of Energy/Oak Ridge Nat’l Lab:
www.genomics.energy.gov
www.ornl.gov/sci/techresources/Human_Genome/education/education.shtml
Saito YA, Talley NJ. 2009. AJG series: molecular biology for clinicians.
Am J Gastroenterol 104:2583-7.
intervention from an early age
• Nutritional genomics and genomic tools will
become key tools in assessing nutritional status
© 2010, The Institute for Functional Medicine
References (continued)
Nutritional Genomics
Afman L, Müller M. Nutrigenomics: From molecular nutrition to prevention
of disease.
disease J Am Diet Assoc
Assoc. 2006
2006;106:569-576.
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Corella D, Ordovas JM. Nutrigenomics in cardiovascular medicine. Circ
Cardiovasc Genet. 2009;2:637-51.
Costa V, Casamassimi A, Ciccodicola A. Nutritional genomics era:
opportunities toward a genome-tailored nutritional regimen. J Nutr
Biochem. 2010;21:457-67.
Genuis SJ. Our genes are not our destiny: incorporating molecular
medicine into clinical practice. J Eval Clin Pract. 2008;14:94-102.
© 2010, The Institute for Functional Medicine
© 2010, The Institute for Functional Medicine
References (continued)
Kauwell GP. Emerging concepts in nutrigenomics: a preview of what is to
come. Nutr Clin Pract. 2005;20:75-87.
Kussmann M, Affolter M. 2009. Proteomics at the center of
nutrigenomics:
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Kussmann M, Krause L, Siffert W. Nutrigenomics: where are we with
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Nutr Rev. 2010 Nov;68 Suppl
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Lairon D, Defoort C, Martin JC, Amiot-Carlin MJ, Gastaldi M, Planells R.
Nutrigenetics: links between genetic background and response to
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Lampe JW. 2009. Interindividual differences in response to plant-based
diets: implications for cancer risk. Am J Clin Nutr. 89:1553S-7S.
© 2010, The Institute for Functional Medicine
References (continued)
Mariman EC. Future nutrigenetics: in search of the missing genetic
variation. J Nutrigenet Nutrigenomics. 2009;2:257-62.
Marion Letellier R
Marion-Letellier
R, Déchelotte P
P, Iacucci M
M, Ghosh S
S. 2009
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Minihane AM. Nutrient-gene interactions in lipid metabolism. Curr Opin
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Panagiotou G, Nielsen J. Nutritional systems biology: definitions
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39.
Raqib R, Cravioto A. Nutrition, immunology, and genetics: future
perspectives. Nutr Rev. 2009;67 Suppl 2:S227-36.
Reilly PR, DeBusk RM. Ethical and legal issues in nutritional genomics.
J Am Diet Assoc. 2008;108:36-40.
© 2010, The Institute for Functional Medicine
References (continued)
References (continued)
Rivera RM, Bennett LB. Epigenetics in humans: an overview. Curr Opin
Endocrinol Diabetes Obes. 2010;17:493-9.
R
Ross
SA
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Simopoulos AP. Nutrigenetics/Nutrigenomics. Annu Rev Public Health.
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Smith CE, Ordovás JM. Fatty acid interactions with genetic
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Vakili S, Caudill MA. Personalized nutrition: nutritional genomics as a
potential tool for targeted medical nutrition therapy. Nutr Rev.
2007;65:301-15.
© 2010, The Institute for Functional Medicine
References (continued)
Pharmacogenomics
Pharmacogenomics
Camilleri M, Saito YA. 2008. Pharmacogenomics in gastrointestinal
di d
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2009. Gastroesophageal reflux disease is associated with the
C825T polymorphism in the G-protein beta3 subunit gene (GNB3).
Am J Gastroenterol 104:281-5.
Donohue MM, Tirschwell DL. Implications of harmacogenetic testing for
patients taking warfarin or Ccopidogrel
Ccopidogrel. Curr Neurol Neurosci Rep.
Rep
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Dorn GW. Pharmacogenetic profiling in the treatment of heart disease.
Transl Res. 2009;154:295-302.
Limdi NA, Veenstra DL. Expectations, validity, and reality in
pharmacogenetics. J Clin Epidemiol. 2010;63:960-9.
O'Donnell PH, Dolan ME. Cancer pharmacoethnicity: ethnic differences in
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2009;15:4806-14.
© 2010, The Institute for Functional Medicine
Pilgrim JL, Gerostamoulos D, Drummer OH. Review: Pharmacogenetic
aspects of the effect of cytochrome P450 polymorphisms on
serotonergic drug metabolism, response, interactions, and adverse
effects. Forensic Sci Med Pathol. 2010 Nov 4; Epub ahead of print.
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© 2010, The Institute for Functional Medicine
References (continued)
Vitamin K/Warfarin Pharmacogenomics
International Warfarin Pharmacogenetics Consortium, Klein TE, Altman RB,
E ik
Eriksson
N
N, G
Gage BF
BF, Kimmel
Ki
l SE,
SE Lee
L MT,
MT Limdi
Li di NA,
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© 2010, The Institute for Functional Medicine
References (continued)
References (continued)
Vitamin K/Warfarin Pharmacogenomics
Limdi NA,, Wadelius M,, Cavallari L,, Eriksson N,, Crawford DC,, Lee MT,,
Chen CH, Motsinger-Reif A, Sagreiya H, Liu N, Wu AH, Gage BF,
Jorgensen A, Pirmohamed M, Shin JG, Suarez-Kurtz G, Kimmel
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© 2010, The Institute for Functional Medicine
References (continued)
Epigenetics/Epigenomics
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© 2010, The Institute for Functional Medicine
© 2010, The Institute for Functional Medicine
References (continued)
Epigenetics/Epigenomics
Waterland
W
t l d RA
RA, Ji
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tl RL.
RL T
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© 2010, The Institute for Functional Medicine