“nutrigenomics and bioactive food components”“nutrigenomics and bioactive food components”...
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“Nutrigenomics and BioactiveFood Components”
John Milner, ChiefNutritional Science Research Group
Division Cancer Prevention,National Cancer Institute
[email protected]@mail.nih.gov
Many Important
Unprecedentedopportunities
exist for use toachieve genetic
potential,increase
InterestingMany ImportantConstituents increase
productivity andreduce the risk
of disease,including cancer
InterestingInteractions
1 HIV/AIDS 9227
2 Ischemic Heart Disease 1332
3 Tuberculosis 1036
1 Ischemic heart disease 5825
2 Cerebrovascular disease 4689
3 Chron obste pulmon disease 2399
Worldwide Leading Causes of MortalityMany of Which are Linked with Eating Behaviors
(2002)Aged 15-59 Aged 60>
Death
Rank Cause (000)
Death
Rank Cause (000)
Charts, Maps, Tables, The World Health Report, WHO 2003
3 Tuberculosis 1036
4 Road traffic injuries 814
5 Cerebrovascular disease 783
6 Self-inflicted injuries 672
7 Violence 473
8 Cirrhosis of the liver 382
9 Lower respiratory infections 352
10 Chron obstr pulmon disease 343
3 Chron obste pulmon disease 2399
4 Lower respiratory infections 1396
5 Trachea, bronchus, lung cancer 928
6 Diabetes mellitus 754
7 Hypertensive heart disease 735
8 Stomach cancer 605
9 Tuberculosis 495
10 Colon and rectum cancers 477
Population Growth Will Also Influence Health Issues
Percent Change in Population, Selected Countries: 2008-2050
Haub and Mederios Kent, (2008) World Population Data Sheet.
Worldwide Public Health Approaches Center on Foods
Dr. Lee Jong-wook, Director General WHO
If Prevent Do not needto treat! Diet is clearly
importantin this strategy
OtherOther
Evidence Based Report Showcases Inconsistenciesin the Effect of Diet on Cancer Prevention
TobaccoTobacco30%30%
DietDiet35%35%
OtherOtherFactorsFactors35%35%
The Causes of Cancer– Richard Doll & Richard Peto, 1981
WCRF/AICR Report- Released Nov. 1-2, 2007
• Essential Nutrients- Ca, Zn,
Se, Folate, Vitamin D, C,
• Non-EssentialPhytochemicals Carotenoids,Flavonoids, Indoles,
Isothiocyanates, Allyl Sulfur
Exceedingly Complex Area Since Many Bioactive FoodComponents
Isothiocyanates, Allyl SulfurZoochemicals - Conjugated
linoleic acid, n-3 fatty acidsFungochemicals -- Several
compounds in mushroomsBacteriochemical -- Those
formed from foodfermentations and thoseresulting from intestinalflora
Bacterial Formed Equol MayAccount for Part of the
Anticancer Properties from Soyin Asian-Americans
Human Microbiome: New NIH Roadmap Initiative!
In addition to genistein microorganisms in subpopulations formequol which possesses anticancer properties (J Nutr. 2006Apr;136(4):946-52. Arch Microbiol. 2005;183:45–55). Themechanism by which equol may offer protection remainsunresolved but gene expression differences are evident in equolproducers (Niculescu et al (2006) J Nutr. Biochem)
Fundamental Question Remains About True Site of Actionof Functional Foods and Their Active Constituents
BioactiveFood Component(s)
Lee ‘92 (total soy protein)Lee ‘92 (total soy protein)
p < 0.001 Premenopausalp < 0.001 Premenopausal
NS PostmenopausalNS Postmenopausal
Hirose ‘95 (bean curd, miso)Hirose ‘95 (bean curd, miso)
Yuan ‘95 (tofu, soymilk)Yuan ‘95 (tofu, soymilk)
NS PremenopausalNS Premenopausal
NS PostmenopausalNS Postmenopausal
NS p = 0.44NS p = 0.44––0.79 Shanghai, Tianjin0.79 Shanghai, Tianjin
Wu ‘96 (tofu)Wu ‘96 (tofu)
p < 0.01 Premenopausalp < 0.01 Premenopausal
p < 0.05 Postmenopausalp < 0.05 Postmenopausal
Key ’99 (soy)Key ’99 (soy)
TofuTofu
MisoMiso
Zheng ’99 (urinary isoflavonoids)Zheng ’99 (urinary isoflavonoids)
Dai ‘01 (soy)Dai ‘01 (soy)
NS All Breast CancerNS All Breast Cancer.46 .66 .95
.1 .3 .6
.6 1.3 2.6
.61
.6
.6 .8 1.0
.7 1.0 1.3
AsianAsian
.78 1.07 1.47
.68 .87 1.12
.18 .65 2.37
Literature is Full of InconsistenciesBreast Cancer: Soy Intake
NS All Breast CancerNS All Breast Cancer
S Just ERS Just ER++/PR/PR++
Wu ’02 (soy)Wu ’02 (soy)
Yamamoto ’03 (isoflavonoid consumption)Yamamoto ’03 (isoflavonoid consumption)
PremenopausalPremenopausal
PostmenopausalPostmenopausal
Wu ’04 (soy)Wu ’04 (soy)
Ingram ‘97 (urinary isoflavones)Ingram ‘97 (urinary isoflavones)
NS DiadzeinNS Diadzein
p = 0.009 Equolp = 0.009 Equol
Witte ’97 (soy)Witte ’97 (soy)
den Tonkelaar ‘01 (urinary phytoestrogens)den Tonkelaar ‘01 (urinary phytoestrogens)
NS PostmenopausalNS Postmenopausal
HornHorn--Ross ’01 (phytoestrogen intake)Ross ’01 (phytoestrogen intake)
KeinanKeinan--Boker ‘02 (food content)Boker ‘02 (food content)
NS IsoflavonesNS Isoflavones
S LignansS Lignans
Linseisen ’04 (isoflavone intake)Linseisen ’04 (isoflavone intake)
daidzein and genisteindaidzein and genistein
.25 .44 .78
.17 .47 1.33
.1 .27 .69
.34 .58 .98
.79 1.08 1.59
00 11 22.5.5 1.51.5
.46 .83 1.3
WesternWestern
.2 .5 1.1
.4 .6 1.2
.22 .48 1.1
.25 .47 .90
.36 .53 .78
.79 1.0 1.3
.36 .57 .83
Comparing People Is a Little LikeComparing Apples and Oranges!
What Is Nutrigenomics About? Basically variation in the response
due to the “Omics” coupled with a Molecular Target
DNANutrigenetics
NutritionalEpigenetics
NutritionalTranscriptomics
BioactiveFood
RNA
Phenotype
Nutrigenomic Transcriptomics
Proteomics
Metabolomics
FoodComponent
Protein
Metabolite
Phenotypecs
“Nutritional Preemption”Concept that bioactive food components can be introduced at points of initiation &progression for pathway leading to an unhealthy or lethal phenotype
Future Is To Focus on the Process Needing Modification
Credentialing of nutrients and molecular targets is likely the future?Credentialing is defined as “omic” changes that bring about a phenotypic change
AbsorbedDose Biologically
Effective Dose
Inactive Metabolite
Three Types Biomarkers Needed To IdentifyResponders (Both Positive and Negative)
MolecularTarget
EarlyBiologic
Effect
SusceptibilityFactors
DietaryExposure
AlteredAlteredStructureStructure/FunctionFunction
Health Effects+ and -
• Body weight(p < 0.02):F = 6.8; R = 0.74
• Fat mass(p < 0.01):
Body Weight Change in MZ Twins in Response toNegative Energy Balance
Twin A
Wei
gh
t,k
g-6
-4
-2
Bouchard et al, Obes Res, 1994
(p < 0.01):F = 14.1; R = 0.87
• AVF(p < 0.01):F = 11.7; R = 0.84
Twin B
Wei
gh
t,k
g
-10 -8 -4 -2
-10
-8
-6
-6Weight, kgBouchard et al, New Engl J
Med, 1990 (Positive Wt Gain)
Food preference
Food tolerance
Absorption
Transport
Genomics Can Influence the Responseto Diet at Multiple Points
Transport
Metabolism
Effect in targettissue
Lampe and Potter, in Gene-Envir Interactions (2006)
Modified from Lampe (per communication)
Glucose Transporter Type-2 (GLUT2)
GlucoseGlucoseHomeostasis
110Thr IleGLUT2 Protein
Sugar Intake and GLUT 2 Polymorphism
Visit 1 Visit 2
125
100
125
100
Su
gar
(g/d
)
Su
gar
(g/d
)
**
Eny et al. (2008) Physiol. Genomics, 33:355-60.
Thr/ThrThr/Ille + Ille/Ille
75
50
75
50
Su
gar
(g/d
)
Thr/ThrThr/Ille + Ille/Ille
Su
gar
(g/d
)
Calcium Supplementation & DecreasedColorectal Cancer (7 cohort studies)
Summary Effect Estimate 0.78
Genetic Information May Assist in Identifying
Those Who Must Assure Adequate Intakes
Dietary Calcium
OR
for
Colo
nC
an
cer
*
*
2
2.5
3
< 388 mg/day
>388 mg/day
Wong et al. Carcinogenesis, 24: 1091-1095, 2003
OR
for
Colo
nC
an
cer
P for trend=0.004
0
0.5
1
1.5
FF Ff ff
VDR Genotype
VDR FokI Polymorphism Affects CalciumHomeostasis in Adolescence
Cal
cium
Acc
reti
on
toS
kel
eton
(mg/d
)300
200 * *
Abrams et al. (2005) J. Bone Mineral Res. 20: 945-953.
Cal
cium
Acc
reti
on
toS
kel
eton
(mg/d
)
100
0ff Ff FF ff Ff FFBalance Method Bone Density Method
DNA Strand Breaks and Diet
Pool-Zobel et al. Carcinogenesis1997;18:1847-50
XRCC1 (Arg399Gln) Polymorphisms MayInfluence the Response to Lycopene
n=77 CaP pts; n=174 controls
Lycopene
Intake
(g/day)
Arg/Gln +Gln/Gln
“low-risk”
Arg/Arg
“high-risk”
High 0.82 0.21
Goodman et al., (2006) Nutr. CA, 55(1):13-20.
*P trend < 0.01
(0.33-2.01) (0.06-0.71)
Medium 0.97
(0.39-2.44)
0.59
(0.23-1.50)
Low 1.0 1.0
Genetic Information May Help Identify Those LimitIntakes of Specific Foods
Od
ds
Rat
io:
Co
lon
Can
cer
*
* P = 0.001
Red Meat Intake
France: 1,023 CRC cases and 1,121 controls
** P < 0.001
< 5 Times/Wk5 > Times/Wk
**50
40
Kury et al. (2007) CEBP, 16: 1460-7.
Od
ds
Rat
io:
Co
lon
Can
cer
Diet
Multi-CYP SNPs:†
CYP1A2 -163A>C1548T>C
CYP2E1 -1293G>C-1053C>T
CYP1B1 1294C>GCYP2C9 430C>T
** P < 0.001
SNPInter + Diet
10
30
† Population 4.4%
New Funding Opportunity on theStreet. PA 08-221
Balance of Foods Important High Amylose MaizeStarch and Red Meat Ameliorates DNA Damage
Toden et al. (2007) Carcinogenesis. 28(11):2355-62
< 300 mg Caffeine > 300 mg
6
0
Genetic Information May Help Identify Those At Riskand to Formulate Appropriate Interventions
-12
-6
Vitamin D Receptor GenotypeTT Tt tt TT Tt tt
Rapuri et al. Am J Clin Nutr 2001 Nov;74(5):694-700
*
*
Coffee Intake and Risk of Myocardial Infarction
< 1 cup/d1 cup/d2-3 cups/d4+ cups/d
Od
ds
Ra
tio
2.0
1.5 4X for
* P<0.05
Cornelis et al. (2006) JAMA 295: 1135-41
CYP1A2 Genotype*1A/*1A *1A/*1F + *1F/*1F
Od
ds
Ra
tio
1.5
1.0
0.5 A/A A/C + C/C
4X forUnder50 yr
23 and MeGenotyping
-$999 /salva kit
-Results in 2-4 weeks
-Illumina HumanHap550 + BeadChip readsnearly 600,000 SNP’s
-Uploads information to online databaseSample Kit
-Uploads information to online database
-Has odds calculator to suggest common health concernsfor person with specific genetic composition
Compare your genes with friends, family and theworld!!
Sample Kit
IlluminaHumanHap
550 + BeadChip
Exceeding complex area since about 30, 000Genes, 8-10 Million SNPs
Nutrigenomic TestingPromises vs. Reality!
• Commercial Nutrition-Gene Test
– Sciona 19 genes determines whether your DNAcontains gene variants that have been associated with 5key health areas: bone health, heart health,antioxidant/detoxification, insulin sensitivity, andinflammation.inflammation.
– Cost about $300.
• Genelex The panel examines 19 genes that play majorroles in your body's detoxification capacity, antioxidantcapacity, heart health, bone health, insulin sensitivity, andtissue repair.
– About $500.
The overall contribution of Copy Number Variance(CNV) to complex phenotypes expression levels of
14,925 transcripts with SNPs and CNVs in individualswho are part of the International HapMap project was
evaluated.
SNPs and CNVs captured 83.6% and 17.7% of theSNPs and CNVs captured 83.6% and 17.7% of thetotal detected genetic variation in gene expression,
respectively.
The signals from the two types of variation had littleoverlap
Stranger et al (2007) Science. 315(5813):848-53
Diet and Human Amylase Gene Copy Number
Perry et al. (2007) Nature Genetics 39(10):1256-60.
Foods Can Also Influence Epigenetics
MaternalSupplements
withzinc, methioninebetaine, choline,
folate, B12
LTR Hypomethylated LTR Hypermethylated
Yellow Mouse Agouti Mouse
Cooney et al. J Nutr 132:2393S (2002); Dolinoy et al. Envir. Health Perspect 114: 567 (2006)
folate, B12
OrGenistein
High riskcancer, diabetes, obesity &reduced lifespan
Lower risk of cancer, diabetes,obesity and prolonged life
Bis Phenol A
Maternal Methyl Supplements* Reduce TailKinking Phenotype and Increase Offspring DNA
Methylation at Axin Fused
Waterland RA, et al.Genesis 44:401-6, 2006.
*Folic acid, vitaminB12, betaine, and choline
Oxidation of either a singleguanine to 8-oxoguanine or of asingle 5mC to 5-hydroxymethylcytosine
significantly inhibits binding ofthe methyl-CpG bindingproteins to the oligonucleotideduplex, reducing the bindingaffinity by at least an order of
Valinluck et al. Nucleic Acids Res.(2004) 32:4100.
affinity by at least an order ofmagnitude.
Oxidative damage to DNAcould therefore result inheritable, epigenetic changes inchromatin organization.
Folate Reverses Hyperhomocysteinemia andInfluences Epigenetic Control of Gene Expression
Ingrosso, D., et al. Lancet. 361:1693-9,2003.
SFN-rich Broccoli Sprouts Inhibit HDAC inHuman Volunteers.
Dashwood RH, Ho E. Semin. Cancer Biol. 17:363-9, 2007.
Dietary Intervention Can Cause Shifts inTranscriptomic Expression
Low-Fat Feeding and Gene Expression in Human Prostate Epithelium
Liu et al. Cancer Epidemiol Biomarkers Prev. 2007;16:2150-4
Garlic, fish, broccoli, tomatoes
keap-1 nrf2
HS SH S Skeap-1
Agent
Multiple Food Constituents Can InfluenceOne Nuclear Transition Factor
Active Intermediate (radical??)
Increased GST, QRARE
nrf2smallmaf Nucleus
“antioxidant responsive element”
keap-1 nrf2 keap-1
nrf2
CytoplasmCaloricRestriction
Lack of Protection Against Induced Tumors in40% Caloric Restricted KO mice
Mic
eP
rese
nti
ng
Tum
ors
(%)
100
80
60
40
AL WT
AL KO
Pearson et al. (2008) Proc Natl Acad Sci U S A. 105(7):2325-30.
Mic
eP
rese
nti
ng
Tum
ors
(%)
40
20
0
0 5 10 15 20 25 30 35 40
CR WT
CR KO
EnergyEnergyExpenditureExpenditure
Nutrition, Cell Proliferation, Obesity and CancerPreventionGene-Nutrient
Imbalance
EnergyEnergyIntakeIntake
(Carcinogen)(Carcinogen)
(Phytochemicals)(Phytochemicals)
High Fat/CaloriesHigh Fat/CaloriesHighHigh nn --6 fats6 fats
Growth FactorsGrowth FactorsGeneticGenetic
SusceptibilitySusceptibility(Polymorphisms)(Polymorphisms)
Physical ActivityPhysical ActivityFruitsFruits
VegetablesVegetablesWhole GrainsWhole Grains
Soy ProteinSoy Protein
Additional Strategies: Tea Increases Fat Oxidation
Venables et al. (2008) Am J Clin Nutr 87: 778-84
Recent News Releasesuggests:Herceptin is a Novel Pioneering Drug forPersonalized Medicine Approach Based onPharmacogenomics to block Her2-neuexpression.
A Molecular Approach to Medicine
Evidence Has Existed forYears that:In addition to EGCG from Green Tea, Apigeninfrom parsley, thyme, and peppermint cansignificantly influence HER2neu expression!
Herceptin and Dietary fish oil increased the latencytime to mammary gland tumor development in the
HER-2 transgenic mice
free
Su
rviv
al
0.8
1.0
Herceptin
free
Su
rviv
al
0.8
1.0
Fish Oil
Dis
ease
-fre
eS
urv
ival
4 6 8 10 12 14
Months
0.0
0.2
0.4
0.6
Finkle D et al Clin Cancer Res 10: 2499-511, 2004
Control
Yee LD et al J Nutr 135: 983-8, 2005
Dis
ease
-fre
eS
urv
ival
4 6 8 10 12 14
Months
0.0
0.2
0.4
0.6
Corn Oil
Not All Cells Are Equally Sensitive and Antioxidant Properties May Not beMechanism of Action!
SW620
HCT116
Ban et al. J Pharmacol Sci 104, 374 –383 (2007)
Normal
Herman-Antosiewicz et al (2007)Acta Pharmacol Sin. 28(9):1355-64.
Lycopene Influences Multiple Pathways, which are linked in crosstalk inprostate cancer development, resulting in anti-inflammation, growth reduction
& apoptosis induction
E CdhCell adhesion
gapjunction
neighbouring cellLPSbacterialinfection
IL-6inflammation
TLR4
IL6R/gp 130
Jak Jak
STAT3
IGF-Ior EGF, PDGF..
Wnt
R-PTK Frz
MAPK
PI3K AKT
GSK3
AxinAR
DHT
T
Bad
DSH
Lyc Lyc
Lyc
Lyc
Lyc
Lyc
NFBNFB STAT3
IL-6(and others)
AP1
APC
Axin
TCF -catenin
-catenin
AR
AR ARDHTDHT
STAT3 ARAR -catenin
Badcaspase 9
FHKRFOXO
inhibition of cell growthby G1/S cell cycle delay
Induction ofapoptosis
inhibition ofinflammation
Lyc Lyc
Wentz 2008 Personal Communication
DNANutrigenetics
NutritionalEpigenetics
NutritionalTranscriptomics
BioactiveFood
RNA
Nutrigenom Cellular
Needs&
Insults
Insults Such As Radicals, Bacteria and VirusesMay Modify the Response to Food Components
Transcriptomics
Proteomics
Metabolomics
FoodComponent
Protein
Metabolite
Phenotype
mics
CellularProcess(es)
“Nutritional Preemption”Concept that bioactive food components can be introducedat points of initiation & progression for pathway leading toan unhealthy or lethal phenotype
Could Obesity Be Reflecting Some Other Metabolic Effect??
Snijder, et. al. (2005) J Clin Endo & Metab 90:4119–4123
Total Body Fat (%)
15 25 35 45 55
The Foundation of Nutrition and Cancer Prevention AreControlled Dietary Interventions Studies in Humans
Lappe et al. Am J Clin Nutr 2007;85:1586–91
0 Genistein
10 mM Genistein
100 mM Genistein
Swami et al. ( 2005) Mol Cell Endocrinol. 241(1-2):49-61.
Tota
lCancer
Incid
ence
*30
40
50
60Selenium
Placebo
The Benefits of Selenium Are Likely Dose Dependent
Likely same response in Dogs!Waters et al. Carcinogenesis.2005: 26(7):1256-62
Plasma Selenium (ng/mL)
Tota
lCancer
Incid
ence
0
10
20
<105.2 105.3-
121.6
>121.6
Duffield-Lillico et al., (2002) Cancer, Epidem.Biomarkers & Prev., 11: 630
Dietary Interventions May Not Always beProtective
Today Concern AboutExcess
CalciumIron
Folic AcidSelenium
Albanes et al (1995) AJCN 62:1427S-1430S
SeleniumVitamin AVitamin DOthers???
Why does thisdifferential responseoccur? Normal vsneoplastic cells??
Linxian Nutrition Intervention TrialEsophageal cancer mortality by factor D (N=1515)
Factor D= Selenium, b-carotene, vitamin E
Log-rank P=0.024RR=0.83
<55 years
Placebo
Log-rank P=0.045RR=1.14
55+ years
Factor D
Timing of Use Also Important!!
Esophageal Cancer Death Time (Year) Esophageal Cancer Death Time (Year)Taylor, P. et al., Gastroenterology 2005 (abstract)
Factor D Placebo
Foods AreFUNdamental
For Health
However, all maynot benefit equally
While I have raise lots of Concerns:There Is Light At the End of the Tunnel!
WCRF/AICR Recommendations
1. Be as lean as possible without beingunderweight
2. Be physically active.3. Avoid Sugary drinks.4. Eat more of a variety of
vegetables, fruits, whole grains, and legumes.vegetables, fruits, whole grains, and legumes.5. Limit consumption of red meats6. If consume alcohol do so in moderation7. Limit consumption of salty foods8. Don’t use supplement to protect against cancer
We Must Be Careful About Messages to Public
One Size Does Not Fit All! More is NotAlways Better
SoySoy
TomatoesTomatoes
SpinachSpinach
BroccoliBroccoli
GarlicGarlic
NutsNuts
Suspect Functional Foods With Health Benefits
NutsNuts
SalmonSalmon
OatsOats
BlueberriesBlueberries
CurcuminCurcumin
Green teaGreen tea
Red wineRed wineModified Time Magazine: January 21, 2002Modified Time Magazine: January 21, 2002
The Future
PreemptivePersonalizedPredictive
Participatory