Exam Four/Final Exam

Nutrigenetics

mutation causing an inability to metabolize food

gene mutation causes disease

treatment: change diet/food

Nutrigenomics

food changes gene expression

food causes disease through epigenetics

Epigenetics

changes in gene expression from the environment

does not involve mutations

DNA methylation and histone modifications

DNA Methylation

methyl group added to DNA

decreases expression from causing an activator to fall off or a repressor to bind

can be caused by food such as folate and choline

Histone Modifications

changes in affinity for DNA

methylation, acetylation, phosphorylation, ubiquitination

greater affinity means tighter DNA and decreased expression

Acetylation

histone modification

acetyl group added to histone by histone acetyl transferase, neutralizing positive charge

loosens DNA, increasing expression

anti-oxidant foods increase this

Trans Fat Disease Association

heart disease

Sugar Disease Association

metabolic disease

Why Reports Are Inconsistent

different study design (observational vs. interventional)

different populations (social status, age, ethnicity)

FTO Locus

single nucleotide polymorphism with largest genetic effect on obesity

homozygous for the mutation increases obesity risk by 1.7 fold

expression regulated by demethylation of mRNA and it is expressed in the liver

for normal function, FTO should be down regulated in the presence of glucose since its upregulation is involved in gluconeogeneisis and lipogenesis

Major Allele

most common allele

not dominant

Minor Allele

less common allele

not recessive

Vitamin D Receptor

major allele: increased calcium absorption, increased bone density

minor allele: decreased calcium absorption

Monogenic Diseases

one mutated gene causes disease

Phenylketonuria (PKU)

monogenic disease from PAH recessive gene

cannot convert phe to tyr, phe build up causes brain damage

treatment: diet with low proteins

Galactosemia

monogenic disease from GALT recessive gene

cannot convert galactose to glucose, build up of galactose causes brain damage

treatment: diet with low milk

Polygenic Disease

diseases resulting from mutations in more than one gene

each gene has a small contribution leading to a cumulative effect

examples: coronary artery disease (CAD) involved 60 gene, type 2 diabetes (T2D) involves 100 genes

Single Nucleotide Polymorphism in STAT3

causes person to store more saturated fat

treatment: eat less saturated fat

Single Nucleotide Polymorphism in CDKN2A

causes an increase in calcium deposits in arteries

treatment: increase vitamin K₂ which decreases deposits

Clinical Assessments for Singles Nucleotide Polymorphisms

test for levels of organic molecules

One-Carbon (1C) Metabolism

pathway that regulates gene expression

involved in synthesis of DNA and RNA

folate/vitamin B9 is a cofactor for enzymes in this pathway (donor/acceptor of 1C found in beans, peas, and lentils)

decrease in nutrients or mutations disrupts pathway (brain damage in fetus, anemia and cancer in adults)

Methylation Pathway

pathway that regulates gene expression

conversion of two amino acids where a methyl group is added to homocysteine to make methionine

vitamin B12 is the methyl donor and is a cofactor to the MTR enzyme (found in clams and sardines)

decrease in vitamin B12 decreases MTR activity which decreases methionine and protein synthesis

Direct to Consumer Genetic Testing (DTC-GT)

23 and Me and Ancestry

shows risks of monogenic diseases, energy metabolism, obesity, and vitamine requirements

no evidence showing it leads to lifestyle changes even in high risk people

Therapeutic Strategies

tailor diet to ancestors

avoid toxins

diverse foods

control circadian rhythm

control anxiety and mood

PAH Gene

phenylalanine hydroxylase enzyme that adds -OH to go from Phe to Tyr (proteins, enzymes, neurotransmitters)

mutations cause PKU

PKU Symptoms

neurological issues including intellectual disability, developmental delays, hyperactivity, and autistic features

PKU Management and Treatments

avoid foods high in Phe (meat, fish, eggs, cheese, bread, flour, pasta, nuts, seeds, aspartame)

take vitamins and minerals

if poor binding to BH4, increase BH4 intake

inject PAH enzyme

gene therapy

Health Outcomes of PKU

depression

low mood and anxiety

indegestion

Social Outcomes of PKU

social exclusion and bullying

limited menu at restaurants

GALT Gene

codes for enzyme- galactose-1-phosphate uridylyltransferase

mutations cause galactosemia

Diagnosis of Galactosemia

symptoms such as diarrhea and vomiting after milk consumption

poor feeding and no weight gain in infants

newborn screening

blood and urine can be tested for increase in galactose

Symptoms of Galactosemia

vomiting and diarrhea after dairy consumption

neurological defects from altered brain structure affecting coordination, balance, ataxia, memory, speech, and language

ovarian defects in females

avoiding certain foods causes decreased calcium, bone density, nutrients, and height/growth

Treatment for Galactosemia

decrease galactose consumption for life (avoid dairy, cereals, offal meats, fruits, and vegetables)

use soy based infant formula

Lac Operon

lactose turns on three genes to metabolize lactose in bacteria

Carbohydrate-Responsive Element Binding Protein (ChREBP)

transcription factor that turns on genes for carbohydrate metabolism

when glucose is increased, the protein is dephosphorylated, goes into the nucleus, get acetylated, and binds to target genes to increase expression

Genome Wide Association Study (GWAS)

sequence many genomes and look for association/correlation

Type 2 Diabetes (T2D)

has 50% lifestyle/environmental contribution and 50% genetic contribution

increases risk for cardiovascular disease

diet changes to decrease risk and manage

Genes For Monogenic Causes of Type 2 Diabetes

5% of cases

GCK, HNF-1α, HNF-1β, HNF-4α, IPF-1, NEUROD1

Genes For Polygenic Causes of Type 2 Diabetes

95% of cases

CAPN10, KCNJ11, PPARγ, TCF7L2

PPARγ

one of the genes (in combination with others) associated with T2D

polymorphism in Pro12Ala

Ala allele decreases risk for T2D

Pro allele is a risk allele

TCF7L2

one of the genes (in combination with others) associated with T2D

two risk alleles

can decrease risk if fat intake is decreased, fiber intake is increased, and exercise is increased

SLC30A8

transports zinc

if mutated and does not transport zinc as well, increased risk for T2D

for risk alleles, increase zinc intake

Contributing Factors to Cancer

tobacco

diet

deficiency of micronutrients

excess of macronutrients

Phase 1 Genes

metabolize carcinogens

add -OH

from hydrophobic (water insoluble, not excretable, toxic) to hydrophilic (water soluble, excretable, non-toxic)

polymorphisms can affect cancer risk

Phase 2 Genes

metabolize carcinogens

conjugate to other molecules for removal

polymorphisms can affect cancer risk

Histone Deacetylases (HDAC)

remove acetyl group and restore positive charge to histone

decreases transcription

Kinases

involved in phosphorylation

add phosphates (negative charge) and changes binding to DNA, affecting expression

Phosphatases

remove phosphates and affect gene expression

Ubiquitin Ligase

involved in ubiquitination

adds ubiquitin proteins and changes binding to other proteins

Deubiquitinating Enzyme

removes ubiquitin proteins and changes binding to other proteins

ncRNAs

noncoding genes that regulate expression of other genes

changes in expression can lead to cancer

affected by cabbage vegetables

miRNA

complementary to target mRNA and decreases mRNA translation

can decrease the expression of oncogenes

DNA Hypomethylation

caused by decrease in zinc and selenium and increase in retinoic acid

DNA breakage and aberrant repair

Inhibitors of DNMT

increases expression of CDKN2A (tumor supressor)

green tea, soybeans, curcumin, catechin, epicatechin, and lycopene

reduces cancer in animals but unclear in humans

good clinical outcomes but need high doses not dietary amounts

HDAC Inhibitors

increase acetylation and increase gene expression

FDA approved for lymphoma and myeloma

garlic compounds are this and affect the cell cycle and apoptosis

Cardiovascular Disease (CVD)

affects heart and vessels

associated with abdominal obesity and abnormal lipid profiles

prevention: weight loss, normalize lipid profiles, diet, exercise, medication

risk factors: family history, age, gender, genetics, hypertension, obesity, diabetes, smoking

Healthy Diet to Prevent Cardiovascular Disease

4.5 cups fruits/vegetables per day

1.5 g sodium per day

Fiber-rich whole grains 3 servings per day

Oily fish twice per week

36 oz sugar-sweetened drinks per week

7% of total energy intake from saturated fat

Processed meats only twice per week

4 servings nuts, legumes, seeds per week

Simple Cardiovascular Disease

from familial hypercholesterolemia

monogenic cause from mutations in LDLR or PCSK9

Complex Cardiovascular Disease

caused by many genes with a cumulative effect

polymorphisms in eight genes

APOE, PPARs, APOA1, MTHFR, APOA2, APOA5, FADS, 5-LO

Apolipoprotein E (APOE)

gene that can be involved in complex CVD

different alleles, some more common than others

allele determines treatment, only some responsive to diet

PPAR

gene that can be involved in complex CVD

transcription factor in lipid metabolism

polyunsaturated fats bind and change expression of other genes

has different alleles with different associations

APOA1

gene that can be involved in complex CVD

main protein in HDL that transports cholesterol to liver

expression changed by polyunsaturated fat

allele determines diet recommendation

MTHFR

gene that can be involved in complex CVD

needs folate, vitamin B6, and vitamin B12 from diet

T allele increases CVD risk (C to T, homocysteine to methionine)

Fish Oil

omega-3 polyunsaturated fat

affects lipid metabolism, blood pressure, inflammation

in animals, slowed atherosclerosis and decreased CVD

Microbiome/Microbiota/Normal Flora

all microbes in and on our body

mainly found in GI tract

about 1 pound and some consider it an organ

30 trillion microbes (1:1 ration with human cells)

make metabolites that go into blood and affect health

can be affected by diet

Microbial Dysbiosis

loss of equilibrium in microbiome

systemic inflammation and altered gut permeability

Tenericutes

makes TMAO and increases CVD risk in mice

Desulfovibrio

degrades TMAO and decreases CVD risk

diet promotes it and could possibly be used to decrease CVD risk

Sugar Fermentation

byproducts are short-chain fatty acids that regulate gene expression in lipogenesis

E. coli

make LPS and affect inflammation genes

carbohydrate diet- decreases it and LPS and decreases inflammation

saturated fat diet- increases it and LPS and increases inflammation