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Genomics in the Science of Nutrition John Milner Nutritional Science Research Group Division Cancer Prevention, National Cancer Institute [email protected] While there are opportunities for expanded use of foods, and their components, to achieve one’s genetic potential, increase productivity and reduce the risk of disease. Hippocrates Proclaimed almost 2500 years ago: Let thy food be thy medicine and thy medicine be thy food Worldwide Leading Causes of Mortality (2002) Aged 60> Aged 15-59 Death Rank Cause 1 HIV/AIDS9 (000) 227 Death Rank Cause 1 Ischemic heart disease (000) 5825 2 Ischemic Heart Disease 1332 2 Cerebrovascular disease 4689 3 Tuberculosis 1036 3 Chron obste pulmon disease 2399 4 Road traffic injuries 814 4 Lower respiratory infections 1396 5 Cerebrovascular disease 783 5 Trachea, bronchus, lung cancer 928 6 Self-inflicted injuries 672 6 Diabetes mellitus 754 7 Violence 473 7 Hypertensive heart disease 735 8 Cirrhosis of the liver 382 8 Stomach cancer 605 9 Lower respiratory infections 352 9 Tuberculosis 495 10 Chron obstr pulmon disease 343 10 Colon and rectum cancers 477 Charts, Maps, Tables, The World Health Report, WHO 2003 5 of the 10 Leading Causes of Death of Americans Relate to Dietary Habits Age-Adjusted Incidence Cancer Rates in Males by Region Australia/New Zealand Northern America Western Europe Eastern Europe Southern Europe Northern Europe Southern Africa Eastern Asia South America Polynesia Caribbean Central America Eastern Africa Micronesia Western Asia Melanesia Middle Africa South-Eastern Asia Northern Africa South Central Asia 358.58 357.43 318.69 290.01 275.39 263.37 217.53 205.33 201.35 200.7 187.91 178.54 177.68 Ferlay et al. (2001) ARC CancerBase No. 5. Lyon, IARCPress 175.45 151.13 149.84 141.82 131.13 124.46 106.61 Rate/100,000 (adjusted to world standard population) WHO South-East Asia Report (Oct 2005) Suggests: At least 80% of premature heart disease, stroke and type 2 diabetes, and 40% of cancer could be prevented through a healthy diet, regular physical exercise and avoiding tobacco products. In the South-East Asia Region, a 2% annual reduction in deaths due to chronic disease could save over 8 million lives in the next 10 years. In India, a similar reduction would also result in an economic gain of USD 15 billion over the next 10 years. Public Health Approach U.S. Nutrition Industry ($billion in consumer sales in 2005 ) Supplements 2004 20.4 2005 % Change 21.18 3.8 Natural/Organic Foods 18.38 20.70 12.7 Functional Foods 24.46 26.66 9.0 5.47 5.94 8.5 68.71 74.48 8.4 N & O Personal Care Total Nutrition Business Journal, interim research based on a variety of sources as of April 28, 2006 Much Confusion Exist It Is Illogical to Assume All Individuals are Equally Responsive to Drugs, Foods or Food Components!! Lots of Variability in Response Across Studies Asian Western Lee ‘92 (total soy protein) p < 0.001 Premenopausal NS Postmenopausal Hirose ‘95 (bean curd, miso) Yuan ‘95 (tofu, soymilk) NS Premenopausal NS Postmenopausal NS p = 0.44–0.79 Shanghai, Tianjin Wu ‘96 (tofu) p < 0.01 Premenopausal p < 0.05 Postmenopausal Key ’99 (soy) Tofu Miso Zheng ’99 (urinary isoflavonoids) Dai ‘01 (soy) NS All Breast Cancer S Just ER+/PR+ Wu ’02 (soy) Yamamoto ’03 (isoflavonoid consumption) Premenopausal Postmenopausal Wu ’04 (soy) Ingram ‘97 (urinary isoflavones) NS Diadzein p = 0.009 Equol Witte ’97 (soy) den Tonkelaar ‘01 (urinary phytoestrogens) NS Postmenopausal Horn-Ross ’01 (phytoestrogen intake) Keinan-Boker ‘02 (food content) NS Isoflavones S Lignans Linseisen ’04 (isoflavone intake) daidzein and genistein .1 .3 .6 .6 1.3 .6 .8 .7 2.6 1.0 1.0 1.3 .61 .6 .78 1.47 .87 .68 1.12 .65 .18 2.37 .46 .25 .44 .66 1.07 .95 .78 .4 .6 1.2 .22 .48 1.1 .25 .47 .90 .36 .53 .78 .17 .47 .1 1.33 .27 .2 .69 .5 1.1 .46 .83 .79 .79 .34 .36 1.0 1.08 .58 .98 .57 1.3 .83 1.3 1.59 The “Omics” of Nutrition Bioactive Food Component N u t r i g e n o m i c s Nutrigenetics DNA Nutritional Epigenetics RNA Nutritional Transcriptomics Phenotype Protein Proteomics Metabolomics Metabolite Nutritional Preemption (A Strategy for Health Promotion) Concept that bioactive food components can be introduced at points of initiation & progression for pathway leading to an unhealthy or lethal phenotype Appeal for Nutrigenomics • Individualized/targeted • • • • approach Recognizes cultural differences Hi-technological Approach New Market Niches Suitable for capital investments from food and pharmaceutical companies Skeptics • • • Diet and public health already too complex Only for rich can afford, create more inequalities Ethical minefield • Essential Nutrients- Ca, Zn, Se, Folate, C, E • Non-Essential PhytochemicalsCarotenoids, Flavonoids, Indoles, Isothiocyanates, Allyl Sulfur Zoochemicals - Conjugated linoleic acid, n-3 fatty acids Fungochemicals - Several compounds in mushrooms Bacteriochemical - Those formed from food fermentations and those resulting from intestinal flora Complexity is Illustrated by the Vast Number of Foods and Components which can modify the cancer process Variation in Glucosinolate Among Cruciferous vegetables (µmol/g DryWeight) 12 progoitrin glucoraphanin glucobrassicin sinigrin 10 8 6 4 2 0 Broccoli Brussels Cabbage Cauliflower Kushad et al, J Agric Food Chem. 47(4):1541, 1999 Kale Types of Bioactive Compounds May Vary with New Varieties Tomato Varieties Intake of all Tomatoes and Tomato Products (g/day, log transformed) Individual Consumption of All Tomatoes and Tomato Products and Serum Lycopene Levels (EPIC Cross-sectional Study in 3000 subjects) 6.0 Corr = 0.23 5.0 4.0 3.0 2.0 1.0 0.0 0.0 1.0 2.0 3.0 4.0 5.0 Mean Serum Lycopene (microg/dl, log transformed) Jenab et al. J. Nutr. 135:2032, 2005 6.0 Daidzein in Soy Converted to Equol in Some but not All Individuals! 30-50% of Population 80-90% of Population Intestinal Bacteria F Rafii et al, Arch Microbiol 180: 13, 2003 Tissue Polyphenols (ng/g tissue) Plasma and Tissue Concentrations Are Not Always Identical 1000 EGC EC EGCG 800 600 400 200 0 Plasma Colon Kim et al., Nutrition and Cancer 37: 41-48, 2000 Bladder Lung Bronchodilator Response to Albuterol % Responding 60 50 40 30 20 10 0 Gly-Gly Arg-Gly Arg-Arg b-2 andrenergic Receptor Genotype (codon 27) Drazen et al , Int Arch Allergy Immunol 124: 183, 2001 Dietary Calcium, VDR FokI Genotype and Colon Cancer Risk OR for Colon Cancer 3 * 2.5 Dietary Calcium < 388 mg/day * 2 >388 mg/day 1.5 P for trend=0.004 1 0.5 0 FF Ff ff VDR Genotype Wong et al. Carcinogenesis, 24: 1091-1095, 2003 Change in Diastolic Blood Pressure in Response to Fiber Based on AGT Gene Codon 235 2 1 D DBP (mm Hg) 0 -1 -2 Insoluble -3 Soluble -4 -5 -6 T/T T/M Hegele, et al. Nutr. Res. 17: 1229, 1997 M/M Inflammation Often Linked to Several Diseases: (Fish Oil Response Depends on TNF-α Polymorphism) 12 TNF-α Production (µg/l) Control 10 Fish Oil 8 6 ** 4 2 0 G/G G/A TNF-α Polymorphism at -308 Grimble et al. Am J Clin Nutr 76:454-9, 2002. Influence of Caffeine on Bone Mass May Depend on Genes 6 < 300 mg Caffeine > 300 mg 0 -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 Not Knowing Genomics Can Cause Misinterpretations p21+/+ AIN-76A Diet Percent survival 100 90 p21+/- AIN-76A Diet 80 p21+/+ Western Diet 70 p21-/- AIN-76A Diet p21+/- Western Diet 60 50 40 30 p21-/- Western Diet 20 10 0 0 4 8 12 Yang et al, Cancer Res. 61, 565, 2001 16 20 24 Weeks 28 32 36 Nutrigenomic Testing Promises versus Reality! • Commercial Nutrition-Gene Test – Genelex Sciona 19 genes including MTHFR $395 – Gene Care CVD nutritional genetic test (South Africa) MTHFR (Hcyst), apoA1 (HDL) +9 others $400 • Exceeding complex area since about 30, 000 Genes, 5-8 Million SNPs % of Animals with Tumors Transgenic and Knockout Models Key to Identifying Sites of Action of Food Components 100 Prostate Tumors in Lady mice. 80 Antioxidants= vitamin E, selenium and lycopene 60 40 20 * * 0 Control High Fat Control + Anti Venkateswaran et al., Cancer Research 64: 5891-5896, 2004 High Fat + Anti Diet May Influence Genetic and Epigenetics! Epigenetics: The study of heritable changes in gene expression that occur without a change in DNA sequence. – DNA methylation- CpG islands – Histone posttranslational modifications: Acetylation of lysines Methylation of lysines and arginines Phosphorylations of serines and threonines ADP-ribosylation of glutamic acids Ubiquitination of lysine residues Sumolyation of lysine residues Biotinylation of lysines – Recently, in human cells small-interfering RNAs (siRNAs) have been shown to mediate transcriptional gene silencing (Morris KV, Cell Mol. Life Sci. 62:3057-3066, 2005). LTR Hypomethylated When to Intervene?? LTR Hypermethylated Maternal Supplements with Yellow Mouse High risk cancer, diabetes, obesity & reduced lifespan zinc methionine betaine choline, folate B12 Cooney et al. J Nutr 132:2393S (2002) Agouti Mouse Lower risk of cancer, diabetes, obesity and prolonged life Genistein Can Also Influence Agouti Phenotype Viable yellow Agouti (Avy) Locus 40 Control Diet Control Diet 100 Genistein Diet Genistein Diet p = 0.007 30 Pseudo-agouti 76% Site Specific Methylattion (%) Avy Offspring (% of Total) 75 20 10 Heavily Mottled 57% 50 Mottled 32% 25 Slightly Mottled 15% Yellow 8% 0 0 4 Yellow Slightly Mottled Mottled Heavily Mottled Pseudoagouti 5 6 7 8 9 4 5 6 7 CpG Site Number Dolinoy et al. Envir. Health Perspect. 114: ePublished, 2006 8 9 Histones Can Be Regulated by Isothiocyanates, Allyl Sulfur, Genistein and Butyrate HDAC Co-repressor complex Acetylated histones H3 and H4 associated with P21 and Bax promoters HDAC Inhibition Molecular Target?? Transcription of P21 and Bax mRNA HDAC Co-repressor complex acetyl groups added p21 and Bax protein levels increased Cell cycle arrest Caspase activation APOPTOSIS Transcriptomic Studies Are Providing Clues About Molecular Targets for Specific Food Components Corn Oil Fish Oil Olive Oil Davidson et al., Cancer Res. 64: 6797-6804, 2004 A Molecular Approach to Medicine Recent News Release suggests: Herceptin is a Novel Pioneering Drug for Personalized Medicine Approach Based on Pharmacogenomics to block Her2-neu expression. Evidence Has Existed for Years that: EGCG from Green Tea, Oleic Acid from Olive Oil, and n-3 fatty acids from Fish Oil and Apigenin from parsley, thyme, and peppermint can significantly influence HER2neu expression! So why are we not being more proactive in showcasing dietary effects? Must Focus on Processes Which Are Modified by Single or Multiple Foods/Components Cellular Division Compound Activation DNA Repair Apoptosis Digestion Bioactive Food Components Differentiation “Credentialing” Cellular Energetics Hormonal Homeostasis Inflammation Immunity Pentameric procyanidin (100ug/ml) from Theobroma cacao Can Inhibit Human Breast Cancer Cells Ramljak et al. (2005) Mol. Cancer Ther 4:537-546 Likely Molecular Targets For Isothiocyanates, Allyl Sulfur, Selenium, etc. Bioactive Component GST QR GST QR Proteomics and Metabolomic Technologies and the Response to Bioactive Food Components Mitchell et al. (2005) Proteomics 5: 2238 Identified 2 peaks that reflect with 76% accuracy broccoli intake Wenzel et al. (2004) Proteomics 4:2160 Various proteins modified by quercetin Yang et al (2004) Obesity Res 12:1179 Exercise and quantitative proteomics Mayr et al. (2005) Arterioscler Thromb Vasc Biol. 25:2135. Metabolomics demonstrate gene interactions with inflammation, oxidative stress, and energy metabolism. Metabolomic Analysis of the Biochemical Effects of Dietary Isoflavones Pre-Soy Post-Soy Solanky et al., analytical Biochemistry 323: 197-204, 2003 Another Questions Must Be “What is the Amount Needed to Bring About a Desired Outcome?” Typical Intakes?? Toxicity Response Cell Cycle Inhibition Apoptosis Immune Enhancement Antioxidant Differentiation Carcinogen Metabolism Nutritional Supranutritional Toxic Exposure Modified from Combs and Gray, Parmacol. Ther. 79: 179-192, 1998. Components are “complex mixtures” - act synergistically Combination of Dietary Components Dietary Component % Reduction Wine (150 ml/day) 32% Fish (114 g 4x/week) 14% Dark Chocolate (100 g/day) 21% Fruits and Vegetables 21% (400 g/day) Garlic (2.7 g/day) 25% Almonds (68 g/day) 12% 76% decreased risk of CVD Franco et al. BMJ 329:1447-1450, 2004 Soy Phytochemicals and Green Tea Inhibit Human Mammary Tumors in Mice Zhou et al, Int. J. Cancer 108: 8-14, 2004 Is it ever too later to intervene? When should one stop looking for a preemptive response? Kaplan-Meier Estimates of the Cumulative Hazard for Invasive Breast Cancer Copyright restrictions may apply. Prentice, R. L. et al. JAMA 2006;295:629-642. Women’s Intervention Nutrition Study (WINS) RELAPSE EVENTS (ER NEGATIVE) Diet 28/205 PATIENTS (%) 30 Control 59/273 HR, 95% CI 0.58,0.37-0.91 p-value 0.018 4 6 25 Control Diet 20 15 10 5 0 0 1 2 3 5 Follow-up time (Years) P-value from adjusted Cox proportional hazard model Source: Chlebowski RT et al. Presentation. ASCO 2005. 7 8 Does the Biological Response in Pathologic Conditions Reflect Normal Response ?? Diet Biological Response Physiological Function ??? Pathological Function Functional/Phenotypic Consequences Dual Association of b-carotene with risk of tobacco-related cancers in a cohort of French women. b-carotene intake was inversely associated with risk of tobacco-related cancers among nonsmokers with a statistically significant dosedependent relationship, whereas high betacarotene intake was directly associated with risk among smokers. Touvier et al. J Natl Cancer Inst. 2005;97(18):1338-44. 1a Hydroxylase Activity in Normal (N) Benign Prostatic Hyperplasia (BPH), Prostate Cancer Tissue (PC) and Human Tumor Cells. Schwartz (2005) Seminars in Dialysis 18:276. When I knew all of life’s answers, they changed all the questions! How Will We Optimize Benefits and Minimize Harm? New Research Paradigm-New Hope Discovery Development Delivery Discovery of relevant mechanisms Development of interventions for better detection, diagnosis, treatment, and prevention Delivery to all in need Three Types Biomakers Needed To Identify Responders (Both Positive and Negative) Absorbed Dose Dietary Exposur e Health Effects + and - Inactive Metabolite Biologically Effective Dose Susceptibility Factors Altered Structure/ Structure Function Molecular Target Early Biologic Effect The Future of Nutrigenomics Rest With The: •Identify and validate nutrigenetic, nutritional epigenetic & transcriptomic, proteomic and metabolomic biomarkers of effect and susceptibility •Effective communicate about “omics” information to the health care community and consumers •Ability to work within a responsible bioethical framework Develop Partnerships Which Build on Strengths Occurring In A Borderless Society Foster Triple Helix- Academia, Industry and Government