Nutrition Medicine: Genes, Nutrition

www.nutritionmedicine.org

Nutrition Medicine:Genes, Nutrition & Health

Dr Melvyn A Sydney-Smith. KGSJ.MBBS. PhD. Dip Clin Nutrit. FACNEM.

Australian College of Holistic MedicineDoolandella. Qld.


Gene~Environment InteractionThe interplay between genetic inheritance and

the environment is a major factor that determines propensity towards disease or health.


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.

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 healthand resistance to disease

Poor nutrition leads to ill-healthand susceptibility to many diseases.

Oxford Textbook of Medicine, Third Edition. 1999.


Gene~Environment InteractionNutrigenomics 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



The basic tenets of nutrigenomic are:1) Dietary chemicals affect the genome,

altering gene expression or structure2) Diet can be a serious risk factor for a variety

of diseases3) 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


The human genome: is comprised of 46 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.


Gene Polymorphism

Each gene is composed of 2 alleles which may be: the same ~ homozygous ~ AA or

aaor

different ~ heterozygous ~ AaHowever, there may be more than 2

allele variants {polymorphisms} ~

e.g: APO E2, APO E3, APO E4Thus a person’s APO E genotype may be:

E2/E2, E2/E3, E2/E4E3/E3, E3/E4, E4/E4

NB: 6 different genotypes


Gene Polymorphism

Polymorphism vs MutationVariant alleles occurring in over 1% of population are called

polymorphismsVariant alleles in less than 1% of population are mutationsAllele frequency varies between populations & families ~

Thus, nutritional requirements & disease susceptibility vary between populations

Allelic variation fostered by population isolation and cultural, preferential mating behaviour


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


Gene Polymorphism and Disease

Fragile X syndrome

Maple syrup urine disease

Cystic fibrosis

Phenylketonuria

Tay Sachs disease

Homocystinuria

Methylmalonyl CoA deficiency

Sideroblastic anaemia

Carboxylase

deficiency

MTHFR deficiency

G-6-PD deficiency

Thalassemia

Monogenic DiseaseMonogenic Disease



Multigenic disease: e.g. arteriosclerosisPolymorphisms 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 & pharmacologicalConfound epidemiological & interventional

research

Knoblauch H, Bauerfeind A et al. Hum Molec Genet, 2002; 11(12):1477–85.



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


Gene PolymorphismPopulations ApoE2 ApoE3 ApoE4

Caucasians (Tyroleans) Hallman et al., 1991 9.0% 78.9% 11.7%

Blacks (Khoi San) Sandholzer et al., 1995 7.7% 55.3% 37.0%

Asians (Chinese) Kao et al., 1995 7.6% 87.5% 4.9%

Alaskans (Inuit) Scheer et al., 1995 2.0% 78.7% 19.3%

Amazonian (Amerindians) Marin et al., 1997 0.0% 83.1% 16.9%

GB Marin et al. 1997. Braz. J. Genet. 20(4)

Tribes Yanomami Wayana Wayampi Arara Kayapo

ApoE3 95.6 82.0 57.7 92.8 90.4

ApoE4 4.3 18.0 42.3 7.2 9.6


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 677CT variant increases folate

requirementsContributes to a wide range of 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 phenotypeHypertension, coronary heart disease, Type 2 diabetes


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



Carbohydrate Response-element Binding Protein (ChREBP) ~ major gene-metabolic molecule

Transcription factor coded for by a polymorphic geneUpregulates genes that code for lipogenesisDownregulates genes that code for glucose and lipid oxidationActivated by dietary carbohydrate (glucose & sucrose) and insulinChREBP activity inhibited/normalised by omega-3-EFA

Uyeda et al, 2002


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

Nutritional & lifestyle modification can counter a disease promoting genome

Kaput & Rodriguez, 2004


Gene-nutritionMany 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 : BiotinVitamin E : Vitamin K : Vitamin DLipoic acid, Carnitine, SAMe, TetrahydrobiopterinAmino acids: alanine, serine, glycine, isoleucine, inosineMinerals: zinc, copper, potassiumAscorbic acid – species genetic deficiency

Ames et al, 2002.


Nutrient insufficiencyNutrient 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

NeurodegenerationAmes, 2005 and Ho, 2002


However, The major influence on genomic disease is probably

the gross discrepancy between our human ancestral genome

and the modern consumer-age diet


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


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


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


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



Before European contact, hunter-gatherer population diets approximated the Paleolithic Diet~ Australian Aborigines ~ migrated 50,000 yrs ago and

isolated until 1778Diet 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 ADDiet was based on seafood, poultry, pig + taro, cassava, various greens, tropical fruits, nuts, seeds and coconut


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.

PopulationAnimal food

(%)Plant food

(%)

Ache (Paraguay) 25S 78 22

!Kung (Africa) 20S 68 32

Aborigines (Arnhem Land) 12S 77 23

Anbarra (Australia) 12S 75 25

Hiwi (Venezuela) 6N 75 25

Onge (Andaman Is) 12N 79 21


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.


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 affecta) disease development and b) response to nutritional and pharmacological therapy


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.


Thank youfor your care and attention

andmay your genes always

work with you

Technology

Nutrition Medicine: Genes, Nutrition