Nutrition Medicine: Genes, Nutrition & Health

1. Nutrition Medicine:Genes, Nutrition & Health Dr Melvyn A Sydney-Smith. KGSJ. MBBS. PhD. Dip Clin Nutrit. FACNEM. Australian College of Holistic Medicine Doolandella. Qld. www.nutritionmedicine.org

2. Genotype PHENOTYPE Lifestyle Factors Nutrient Status Gene~Environment Interaction The interplay between genetic inheritance and the environment is a major factor that determines propensity towards disease or health. www.nutritionmedicine.org

3. Gene~Environment Interaction This has long been known to physicians: “Positive health requires a knowledge of man’s primary constitution and the powers of various foods, both those natural to them and those resulting from human skills … If there is any deficiency in food or exercise, the body will fall sick.” Hippocrates ~ circa 5th Century BC. www.nutritionmedicine.org

4. Gene~Environment Interaction Compare Hippocrates’ statement with OTM: Nutritional state with genetic endowment, interacts with aetiological agents in a way which causes, or fails to cause, disease Good nutrition leads to health and resistance to disease Poor nutrition leads to ill-health and susceptibility to many diseases. Oxford Textbook of Medicine, Third Edition. 1999. www.nutritionmedicine.org

5. Gene~Environment Interaction Nutrigenomicsfocuses on how: • genetic inheritance affects metabolic nutrient requirements ~AND~ • diet and nutrient intake affects gene expression and tissue metabolism; ~AND~ • common dietary chemicals affect the propensity towards health or disease. Nutrigenomic studies will hopefully identify individual genotypic diet and nutrient requisites to enable: • early prevention of disease ~and~ • specific nutritional interventions to remediate disease-related metabolic dysfunction Kaput J & Rodriguez. 2004. Physiol Genomics. 16:166-77 www.nutritionmedicine.org

6. Gene~Environment Interaction The basic tenets of nutrigenomic are: 1) Dietary chemicals affect the genome, altering gene expression or structure 2) Diet can be a serious risk factor for a variety of diseases 3) Diet-regulated genes affect onset, incidence, progression and severity of chronic diseases 4) The degree of dietary influence on the health~disease balance depends on individual genotype 5) Medical intervention based on knowledge of genotype, nutrient requirement and current nutritional status can be used to prevent, mitigate or remediate chronic disease Kaput J & Rodriguez. 2004. Physiol Genomics. 16:166-77 www.nutritionmedicine.org

7. The human genome: is comprised of46 chromosomes • 22 autosomal pairs plus 2 sex chromosomes • The 3 billion base pairs of DNA contain about 30,000 - 40,000 protein-coding genes. • a much smaller number than predicted – • only twice as many as in the worm or fly • The coding regions are less than 5% of the genome • function of the remaining DNA is not clear • some chromosomes have a higher gene density than others. • Understanding Genetics: available from: http://www.geneticalliance.org/ksc_assets/pdfs/manual • Accessed 12th July 2006. www.nutritionmedicine.org

8. Gene Polymorphism Each gene is composed of 2 alleles which may be: • the same ~ homozygous ~ AA or aa or • different ~ heterozygous ~ Aa However, there may be more than 2 allele variants {polymorphisms} ~ e.g: APO E2, APO E3, APO E4 Thus a person’s APO E genotype may be: E2/E2, E2/E3, E2/E4 E3/E3, E3/E4, E4/E4 NB: 6 different genotypes www.nutritionmedicine.org

9. Gene Polymorphism Polymorphism vs Mutation Variant alleles occurring in over 1% of population are called polymorphisms Variant alleles in less than 1% of population are mutations Allele frequency varies between populations & families ~Thus, nutritional requirements & disease susceptibility vary between populations Allelic variation fostered by population isolation and cultural, preferential mating behaviour www.nutritionmedicine.org

10. Gene Polymorphism Single nucleotide polymorphisms ~ • Single base-pair DNA differences observed between people • simplest and most common form of DNA polymorphism ~ • frequency about of 1/1,000 base pairs • In any individual, gene polymorphism is estimated to affect about 10% of the genome • SNPs may cause disease if they affect expression of an enzyme-coding gene • About 1000 monogenic diseases due to SNPs have been identified Jimenez-Sanchez G et al. 2001. Nature. 409:853-55 www.nutritionmedicine.org

11. Maple syrup urine disease Thalassemia MTHFR deficiency Fragile X syndrome Cystic fibrosis Homocystinuria Monogenic Disease G-6-PD deficiency Phenylketonuria Carboxylase deficiency Sideroblastic anaemia Methylmalonyl CoA deficiency Tay Sachs disease Gene Polymorphism and Disease www.nutritionmedicine.org

12. Gene Polymorphism and Disease Multigenic disease: e.g. arteriosclerosis Polymorphisms that regulate expression and activity of genes involved in blood lipid control are common: • Occur in 7 – 16% of population • Apolipoproteins: Apo A-IV, Apo A, Apo B, Apo E • Lipoprotein lipase • Cholesterol ester transfer protein • Affect cholesterol binding and clearance • Promote hyperlipidaemia, arteriosclerotic disease and dementia • Alter responses to cholesterol reducing interventions • Both dietary & pharmacological • Confound epidemiological & interventional research Knoblauch H, Bauerfeind A et al. Hum Molec Genet, 2002; 11(12):1477–85. www.nutritionmedicine.org

13. Gene Polymorphism and Disease Incidence of specific allele variants between populations often varies: Example: APO E4 ~ • Caucasian population • mean frequency15% ~ • North-South variance ~ 23% in Finland and 20% in Sweden down to 8% in Italy • Non-Caucasian populations • About 30% in Africans (Nigeria) • 35% in Papua New Guinea • 5% in China www.nutritionmedicine.org

14. Gene Polymorphism www.nutritionmedicine.org

15. Multi-Genetic Disease In multigenic disease, single polymorphisms may exert a pronounced influence: • Hypertension ~ Glycine 460 Trp gene variant that codes for Adducin • Alters renal salt excretion  hypertension in presence of high-salt diet • These patients respond well to low salt diet and diuretic therapy • Osteoporosis ~ influenced by VDR gene variants • BB + tt genotypes have increased osteoporosis risk • Homocystinaemia ~ polymorphism of the gene coding for MTHFR • 677CT variant increases folate requirements • Contributes to a wide range of disease www.nutritionmedicine.org

16. Multi-Genetic Disease More usually, multiple polymorphisms interact to: • modify nutrient demand and metabolism • affect enzyme production and efficiency • alter epigenetic regulatory mechanisms • cytokines, hormones, sensor molecules and transcription factors • Ppars, MAP kinases, NF-Kappa-B • modulate expression of other genes • further alters metabolism and regulatory elements • change responses to environmental factors • nutrition, exercise, xenobiotics • Leads to development of disease phenotype • Hypertension, coronary heart disease, Type 2 diabetes www.nutritionmedicine.org

17. Genomic and metabolic complexity currently obscures clear definition ~ several promising links have been identified ~ for example: • Peroxisome proliferator activated receptor • Regulates genes coding for inflammatory mediators, lipogenesis and glucose metabolism • Gene variants contribute to cholesterol metabolism, insulin resistance & obesity • Sterol regulatory element-binding protein 1c (SREBP-1c) • activates insulin-dependent increase in lipogenic gene expression • Carbohydrate Response element Binding Protein (ChREBP) • Glucose sensor that regulates glyco-lipid metabolism www.nutritionmedicine.org

18. Multi-Genetic Disease • Carbohydrate Response-element Binding Protein (ChREBP) ~ major gene-metabolic molecule • Transcription factor coded for by a polymorphic gene • Upregulates genes that code for lipogenesis • Downregulates genes that code for glucose and lipid oxidation • Activated by dietary carbohydrate (glucose & sucrose) and insulin • ChREBP activity inhibited/normalised by omega-3-EFA Uyeda et al, 2002 www.nutritionmedicine.org

19. Gene-Nutrients-Lifestyle Genotype is NOT an immutable prescriptionfor disease Multiple external and internal factors, (dietary, nutritional & lifestyle) strongly influence: • Nuclear & mitochondrial gene expression • Promoter & suppressor codon activity • Transcription factor production & activity • Modulatory epigenetic molecules Nutritional & lifestyle modification can counter a disease promoting genome Kaput & Rodriguez, 2004 www.nutritionmedicine.org

20. Gene-nutrition Many polymorphic gene-regulated enzymes exhibit an altered Michaelis constant (Km) with reduced cofactor or coenzyme binding • About 30% of the 1000 disease phenotypes related to SNP polymorphisms reportedly exhibit reduced specific enzyme binding • At least 50 diseases have been shown to respond to high-dose nutrient supplements • Vitamin B1, Vitamin B2, Vitamin B3, Vitamin B5, Vitamin B6 • Vitamin B12, Folic acid : Biotin • Vitamin E : Vitamin K : Vitamin D • Lipoic acid, Carnitine, SAMe, Tetrahydrobiopterin • Amino acids: alanine, serine, glycine, isoleucine, inosine • Minerals: zinc, copper, potassium • Ascorbic acid – species genetic deficiency Ames et al, 2002. www.nutritionmedicine.org

21. Nutrient insufficiency Nutrient deficiency/insufficiency in 10% population increases nuclear & mitochondrial DNA damage from: Progressive oxidative damage ~AND~ Molecular glycation (AGEs) • Increased DNA mutation and cancer risk • Decreased metabolism, loss of functional reserve and tissue pathology Folate, B6 & B12 deficiency may cause chromosomal breakage Zinc & iron deficiency increase DNA damage and impair DNA repair • Mitochondrial decay and Neurodegeneration Ames, 2005 and Ho, 2002 www.nutritionmedicine.org

22. However, The major influence on genomic disease is probably the gross discrepancy between our human ancestral genome and the modern consumer-age diet www.nutritionmedicine.org

23. The human genome evolved under harsh selection conditions over a period of 3.5 million years ~ The spontaneous mutation rate for nuclear DNA is estimated at about 0.5% per million years Over the past 10,000 years, the human genome is calculated to have changed only 0.05% from our paleolithic ancestors ~ The human genome is now struggling to cope with the vastly different diet and lifestyle of the modern era Eaton SB. 2006. Proc Nutrit Soc. 65(1):1-6 www.nutritionmedicine.org

24. The modern Homo sapiens genome evolved in northeast Africa about 200,000 years ago ~ then migrated throughout the rest of the world The first migration occurred following hominid decimation about 70,000 years ago and gave rise to the hunter-gatherer societies of the Middle East, Asia and Australia www.nutritionmedicine.org

25. Following the last Ice-Age 12,000 years ago, the birth of agriculture 10,000 years ago  Settled lifestyle and increased population density ~ increased demand for intensive farming & animal husbandry – which occurred about 8,000 years ago ~ greater starch-yielding grain crops ~ increased gluten content in grains ~ altered fat content in animals from supplemental feeding ~ Industrial revolution altered food supply even further ~ farming monoculture developed ~ increased dependence on grains ~ refined sugars became more accessible ~ increased fat and trans-fat intake ~ increased omega-6/omega-3 EFA ratio Bradshaw Foundation. www.bradshawfoundation.com/stephenoppenheimer www.nutritionmedicine.org

26. Paleolithic diet: Modern Diet Protein ~ 30-40% 10-20% Carbohydrates ~ 35% 60-70% sugars ~ 2-3% 15% Fats ~ 30-35% 30-35% Saturated fats ~ 7.5% 15-30% Trans-fat < 1% 5-10% of fats Omega-6/omega-3 ~ 2:1 10-20:1 www.nutritionmedicine.org

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28. Before European contact, hunter-gatherer population diets approximated the Paleolithic Diet ~ Australian Aborigines ~ migrated 50,000 yrs ago and isolated until 1778 Diet based on wild game, seafood, nuts, seeds, yams & greens ~ Pacific Islands ~ Fiji 1500 BC, Samoa & Cook Islands 200 BC, Hawaii 600 AD, ~ New Zealand about 1250 AD Diet was based on seafood, poultry, pig + taro, cassava, various greens, tropical fruits, nuts, seeds and coconut www.nutritionmedicine.org

29. Plant and animal intake in hunter-gatherer diets. Analysis of dietary intake of 229 Hunter-Gatherer populations around the world showed median animal food intakes of 66 – 75% of total energy and plant food intakes 26 – 35% of total energy.Cordain L, Eaton SB et al. 2002. EJCN.56,Suppl 1:S42–S52. www.nutritionmedicine.org

30. Traditional diet improves chronic disease: In full-blood Aborigines with diabetes, hypertension and CHD, reversion for 7 weeks to a “traditional” diet resulted in: ~ mean wt loss of 8kg over 7 weeks ~ reduced blood pressure ~ reduced fasting insulin & glucose ~ improved glucose and insulin responses on GTT ~ reduced triglyceride and VLDL levels ~ reduction or cessation of medication The traditional diet consisted of: ~ 64% protein, ~ 13% fat and ~ 23% low-GI/GL CHOs~ 1200 Cal/person/day K O'Dea. 1984. Diabetes, 33(6): 596-603. www.nutritionmedicine.org

31. Summary: The broad perspective of human metabolic and archeological data suggests that human genes are adapted to a nutrient intake which approximates that of the Paleolithic Diet Genomic research has identified several gene-regulated transcription binding proteins that are:a) responsive to dietary lipid and CHO intake and b) propel metabolism towards common disease phenotypes CHD, Hypertension, Insulin Resistance, Diabetes etc. Individual gene variants have also been identified that affect • disease development and • response to nutritional and pharmacological therapy www.nutritionmedicine.org

32. In the short-term, the assessment and management of genotypic disease will remain limited, and clinicians must perforce remain dependent on: • Thorough family history • Knowledge of ethnic disease links • Careful patient nutritional assessment and • Restricted range of validated genetic tests whilst we await the clinical access to genomic analysis However, the years ahead are exciting, as the genetic influences on disease ~AND~ the effect of dietary-nutrient modulation on gene expression & activity are clarified. www.nutritionmedicine.org

33. Thank you for your care and attentionandmay your genes alwayswork with you www.nutritionmedicine.org