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Nutrition Medicine: Genes, Nutrition & Health: DR Melvyn A Sydney-Smith. KGSJ
Nutrition Medicine: Genes, Nutrition & Health: DR Melvyn A Sydney-Smith. KGSJ
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Gene~Environment Interaction
The interplay between genetic inheritance and the environment is a major factor that determines propensity towards disease or health.
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Gene~Environment Interaction
This has long been known to physicians: Positive health requires a knowledge of mans 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.
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Gene~Environment Interaction
Oxford Textbook of Medicine, Third Edition. 1999.
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.
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Gene~Environment Interaction
Nutrigenomics focuses 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
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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
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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 persons APO E genotype may be:
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
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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
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Thalassemi a
Cystic fibrosis
Monogenic Disease
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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
Gene Polymorphism
Populations Caucasians (Tyroleans) Hallman et al., 1991 Blacks (Khoi San) Sandholzer et al., 1995 Asians (Chinese) Kao et al., 1995 ApoE2 9.0% 7.7% 7.6% 2.0% 0.0% Wayana 82.0 18.0 Wayampi 57.7 42.3 ApoE3 78.9% 55.3% 87.5% 78.7% 83.1% Arara 92.8 7.2 ApoE4 11.7% 37.0% 4.9% 19.3% 16.9% Kayapo 90.4 9.6
Alaskans (Inuit) Scheer et al., 1995 Amazonian (Amerindians) Marin et al., 1997
Tribes ApoE3 ApoE4 Yanomami 95.6 4.3
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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
Homocystinaemia ~ polymorphism of the gene coding for MTHFR 677CT variant increases folate
requirements Contributes to a wide range of disease
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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
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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
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Multi-Genetic Disease
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Gene-Nutrients-Lifestyle
Genotype is NOT an immutable prescription for 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
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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.
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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
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However, The major influence on genomic disease is probably the gross discrepancy between our human ancestral genome and the modern consumer-age diet
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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
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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
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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
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Carbohydrates ~
sugars ~ Fats ~ Saturated fats ~ Trans-fat Omega-6/omega-3 ~
35%
2-3% 30-35% 7.5% < 1% 2:1
60-70%
15% 30-35% 15-30% 5-10% of fats 10-20:1
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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
Population Ache (Paraguay) 25S !Kung (Africa) 20S Aborigines (Arnhem Land) 12S Anbarra (Australia) 12S
Hiwi (Venezuela) 6N
Onge (Andaman Is) 12N www.nutritionmedicine.org
75
79
25
21
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.
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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 a) disease development and b) response to nutritional and pharmacological therapy
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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 dietarynutrient modulation on gene expression & activity are clarified.
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Thank you for your care and attention and may your genes always work with you
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