Nutrigenomics - Lecture 2

Question 1

What is nutrigenomics?

Answer 1

the study of the interaction of nutrition and genes, especially with regard to the prevention or treatment of disease.

Question 2

Give the definition of the following terms:
Gene
Trait
Allele
Phenotype
Genomics
Epigenetic

Answer 2

• Gene ― made up of DNA, our physical unit of heredity. Portion of DNA that codes for a specific function.
• Trait ― an inherited characteristic such as shyness.
• Allele ― a variant form of a gene responsible for the variation in which a trait can be expressed, e.g., eye colour.
• Phenotype ― how genetic and environmental influences come together to create physical appearance and behaviour.
• Genomics ― the study of genes. Determines how they interact and influence biological pathways, networks, and physiology.
• Epigenetics – modulating the gene expression via the environemnet and nutrition

Question 3

How many chromosomes pair is in a celle nucleus?

Answer 3

Every cell nucleus contains 23 pairs of chromosomes, made up of DNA (deoxyribonucleic acid).

23 pairs of chromosomes, 22 pairs and 23rd pair X and Y for gender.

Question 4

What are nucleotides and what are they made of?

Answer 4

DNA contains our genetic information and is made of two paired ‘nucleotide’ chains (the ‘double helix’).

Each nucleotide contains based chemicals a deoxyribose (sugar), a phosphate group, and one of four bases ― A (adenine), C (cytosine), T (thymine) or a G (guanine) => 4 bases each connected to a sugar and a phosphate group to create DNA
* A pair with T
* C pairs with G

Question 5

What is RNA

Answer 5

DNA is ‘transcribed ‘into RNA (ribonucleic acid) which is translated into a protein from amino acids. This process determines property, function and shape of the resulting protein.

Question 6

What are the 4 bases to form amino acids in DNA and in RNA?

Answer 6

A, T, C, G = all amino acids in the DNA

A, U, C, G = all amino acids in the RNA

Question 7

What are codons?

Answer 7

Nucleotides are organised into codons – a sequence of 3 nucleotides that ’code for’ a specific amino acid. Codons make up ’genes’, which relate to specific functions.

Question 8

What happen when the translation of a codon is not correct?

Answer 8

The codon ‘AUG’ codes for the amino acid methionine. However, if translation is not coded correctly (e.g., to ‘AUC’) because of an inherited alteration (next
slide) in the DNA sequence, isoleucine is produced instead.

Question 9

What does the base U stands for in RNA? Which base in DNA does it replace ?

Answer 9

U = ‘uracil’ ― the amino acid found in RNA (replacing thymine)

Question 10

What is a SNPs?

Answer 10

Single nucleotide polymorphisms
Differences in single bases in the sequence of a gene (a genetic variation in humans).

SNPs are a normal occurrence (roughly 4–5 million SNPs in one person’s genome). Many SNPs have very little effect.

Question 11

What happen when a SNP change enzyme or protein function ?

Answer 11

Can lead to differences in phenotype.

Example: A SNP on genes for oestrogen metabolism can result in oestrogen dominance and increase the risk of breast cancer

Question 12

What is a RS number (reference SNP number)? How do you further classify SNPs with base?

Answer 12

Each gene is identified by a RS (‘reference SNP’) number

Each SNP is further classified, by base change and position along from start of the gene e.g., rs1801133 C677T (variant). C represents cytosine, changed to T (thymine)

Question 13

What is a heterozygous variant in a chromosome?
What is a homozygous variant in a chromosome?

Answer 13

heterozygous variant is normal/stable => polymorphism each pair of chromosome, effect is less marked it is more moderate

homozygous indicates some potential change of function => polymorphism is present in both chromosome and is more potent

Question 14

Give an example of SNP for vitamin C - SLC23A1 gene codes for the production of a transporter which supports vitamin C absorption and distribution in the body across cell membrane? And how it can be helpful in clinic? and how you could naturally help that patient?

Answer 14

‘SLC23A1’ (solute carrier family 23 member 1) gene codes for the production of a transporter which supports vitamin C absorption and distribution in the body across cell membrane.

A SNP of this gene is, therefore, associated with a higher demand for vitamin C. Because it reduces the transport of vitamin C across membrane.

• The recommendation would be to optimise dietary intake of vitamin C (e.g., with fresh raw fruit and vegetables, esp. peppers, kiwi fruit, papaya, currants, berries, citrus, tomatoes, crucifers) and consider supplementation.
• We want to optimise our vitamin C intake to make sure any transport function we have even if slow is optimise.

Question 15

How Vit C deficiency may present in clinic?

Answer 15

Dry hair and skin, flu-like symptoms and a tendency to bruise or bleed easily. Tiredness and weakness, Muscle and joint pains, Spots that look like tiny, red-blue bruises on your skin.

Question 16

What areas where genetic information is especially useful for clinic?

Answer 16

Methylation (e.g., production of glutathione and homocysteine regulation)

Detoxification (each phase and the genes involved. e.g., caffeine / alcohol detoxification)

Neurotransmitter / hormone synthesis and metabolism (e.g., in relation to conditions of oestrogen excess) => balance of oestrogen (dominance) + NS health affecting our motivation, mood and memory

Vitamin conversion / receptor function (e.g., vitamin D conversion effect on bone density risk, vitamin A (e.g., reduced conversion of beta-carotene to vitamin A).

Question 17

How should you look at SNP in clinics?

Answer 17

Genetic testing does not replace the case history, considering the whole person, symptoms and concerns, and the way the system functions collectively.

Never treat by SNP or look at SNPs in isolation.

Yet, genetic information used properly can be empowering in terms of understanding potential strengths and weaknesses. The solutions will always be lifestyle or dietary support to enable the person to reach their potential

Look at the whole picture

Question 18

What gene can be affected by a SNP for vitamin A?

What are Vit A deficiency symptoms?

What recommendation if you have that SNP?

Answer 18

Gene: BCO1 gene (beta-carotene oxygenase 1)
― codes for the enzyme that converts beta-carotene to retinol (vitamin A).

Vitamin A deficiency symptoms: Impaired night vision, frequent infections, skin conditions (e.g., acne).

SNP recommendations: Increase preformed vitamin A from food (e.g., liver, fish oils) or supplements as Retinol, especially if plant-based.

Question 19

What gene can be affected by a SNP for vitamin D?

What are Vit D deficiency symptoms?

What recommendation if you have that SNP?

Answer 19

Gene: VDR gene ― codes for the vitamin D receptor

Vitamin D deficiency symptoms: Rickets and osteomalacia, osteoporosis, immune dysfunction (↑ infections, autoimmunity, allergies, asthma).

Recommendations: Ensure optimal vitamin D levels with regular testing, sun exposure, food sources (e.g., mushrooms, oily fish, eggs) and supplementation.

Question 20

What gene can be affected by a SNP for EFAs?

What recommendation if you have that SNP?

Answer 20

Genes: Fatty acid desaturases are involved in EFA conversion. FADS 1 codes for Delta 5 Desaturase and FADS2 Delta 6 Desaturase.

FADS1 rs174537 GG genotype may increase conversion of high dietary omega-6 to inflammatory AA, more so in African Americans (pro inflammatory activity).

FADS2 rs174570 T allele is associated with lower GLA, AA, and EPA levels.

Consider EPA / DHA / ALA from fish oils / algae / flaxseed oils. Keep a good balance of omega fat in the diet.

Question 21

What gene can be affected by a SNP for TNF?

What recommendation if you have that SNP?

Answer 21

The TNF gene codes for the production of the pro-inflammatory cytokine (protein).

SNP: At rs1800629 the A allele is associated with ↑ TNF and is associated with an ↑ risk of asthma, RA, psoriasis and cancer.

Recommendations:
* Extra focus on ↓ pro-inflammatory foods (e.g., sugar, dairy, fried foods, high omega-6 foods), processed meats, alcohol.
* Increase anti-inflammatory foods / herbs ― turmeric, catechins (green tea), echinacea, omega-3 rich foods (‘SMASH’, flax).

Question 22

What other consideration with patient with a vit C SNP?

Answer 22

Consider that the vitamin C SNP could also impair iron absorption (reducing conversion from the Fe3+ to Fe2+ state).

Question 23

What is Methylation?

Answer 23

Methylation is a biochemical process within the body. Process of adding a methyl group (CH3) to a substrate to modify a function:
It is involved in almost every metabolic process in the body and contributes to crucial functions

Question 24

For what processes is methylation involved?

Answer 24

It is involved in almost every metabolic process in the body and contributes to crucial functions, including:
* Gene regulation (turning genes on and off) We can add methyl group to genes to modify them (on/off)
* DNA RNA synthesis (e.g., growth, repair, cancer prevention is dependant on the function of methylation) helps us make DNA and RNA => help us make new cells.
* Detoxification (e.g., hormones such as oestrogen). Help us balance oestrogen
* Energy production (CoQ10, carnitine and ATP) help us synthesise those molecules
* Myelination and neurotransmitter production (e.g., dopamine and serotonin  melatonin) - choline and bile production
* Immune function (e.g., immune cell synthesis, inflammation) – helps with histamine production

Question 25

What are the dietary co-factor of methylation?

Answer 25

Folate, B12, B6, B2, choline, betaine (TMG - trimethylglycine) and zinc.

Question 26

Why are Folate and B12 important for methylation?

Answer 26

Dietary Folate ends up as methyl folate

Dietary B12 help us make SAMe => body major methyl donor

Question 27

What is SAMe and what is it’s role? From which amino acid is it formed?
What nutrients are key for SAMe production?

Answer 27

Methyl (CH3) is provided to the body by the methyl donor known as SAMe (S-adenosylmethionine).

SAMe is formed from the amino acid methionine.

The system that produces SAMe is reliant on the active form of folate ― methylfolate.

NUTRIENTS:
Dietary Folate ends up as methyl folate

Dietary B12 help us make SAMe => body major methyl donor

Question 28

What are the key methylation disruptors?

Answer 28

• Insufficient substrates (folate, methionine).
• Lack of essential co-factors (B2, B12, B6, zinc) / malabsorption (vegetarian, vegan, compromised digestion, elderly people, drugs like OCP, metformin, ultra-processed diet, stress, over training, raised inflammation, toxins exposure increase the need for methylation and can create a depletion)
• SNPs affecting enzyme activity (involved in methylation).
• Specific nutrients depleting methyl groups (niacin).
• Drugs (e.g., contraceptive pill, metformin = ↓ B vits).
• Increased demand on processes described previously e.g., stress, imbalanced hormones, inflammation, need for repair etc.
• Toxin exposure ― aflatoxin (fungi on crops), air pollution, BPA (e.g., food packaging), phthalates (e.g., beauty products), heavy metals etc.

Question 29

What disease can impaired methylation contribute to?

Answer 29

Impaired methylation can contribute to:
* Cardiovascular disease.
* Cancer (e.g., breast cancer).
* Infertility and unexplained miscarriages.
* Chronic fatigue and mood disorders.
* Neurological disease (e.g., MS, Alzheimer’s).

Question 30

What are impaired methylation signs and symptoms?

Answer 30

Impaired methylation signs/symptoms: Hormone imbalance, miscarriage, CVD, infertility (woman / man possibly), energy/fatigue problem, mood issues, depression, low motivation, chronic inflammation, neurodegeneration

Question 31

How to assess for indicators of poor methylation?

Answer 31

• Genetic testing ― for methylation SNPs.
• Homocysteine testing ― if methylation is poor, homocysteine levels generally rise. Ideal levels: 5–8 μmol / L.
• SAMe / SAH ratio in some tests may be more accurate.

Question 32

Which nutrient can deplete methyl group?

Answer 32

Niacin - B3

Question 33

Explain the methylation cycles and links (TEST) => folate cycle, methionine cycle, biopterin cycle and urea cycle

Answer 33

Folate cycle = Dietary folate and via several steps turn it to methyl folate (5-MTHF)
Methionine cycle = 5-MTFH is used in the methionine cycle as converted to SAMe as thanks to B12 (SAMe does multiple things) => the waste product of this methionine cycle is homocysteine and using B12 and Folate turns it back to 5-MTFH and SAMe.

Folate + methionine cycles create methylation cycles.

The biopterin cycle recycles BH2 by remethylating it (with methyl folate) and produces BH4 => BH4 is used to synthesise neurotransmitters and hormones from some of the amino acids => affects motivation, mood and stress response

The biopterin cycle BH4 feeds into the Urea cycle which turns ammonia into urea and creates NOS => NOS is key for vasodilation

If we have a problem with the folate cycle it will not only affect methylation but also our mood and circulation and PB at the very end.

Question 34

when is low homocysteine not a good indication of good methionine ?

Answer 34

When we use up SAMe it turns into SAH and AHCY enzymes turns SAH into homocysteine. Homocysteine is either remethylating it (need B12 and folate) or we push it down the sulphation pathway transsulphuration pathway – if this pathway works too fast then we can easily drain off homocysteine and low homocysteine levels is then not a good indicator of good methylation!

Question 35

What gene can be affected by a SNP for MTHFR - folate cycle enzyme ?
explain the role of the enzymes

What recommendation if you have that SNP?

Answer 35

Gene: MTHFR codes for the enzyme ‘methylenetetrahydrofolate reductase’ ― converting folate into a methylated form.

Key SNP: The C667T (cytosine replaced by thymine) SNP at rs1801133 is associated with reduced activity of MTHFR enzyme.

Recommendations:
* Optimise dietary folate
* Consider a methylated folate supplement – not folic acid because of all the step we go through and the inefficiency in conversion – 800mg to 1000mg
* Optimise vitamin B2 (riboflavin) ― supporting the MTHFR gene.

Question 36

which drug used for inflammation and cancer is a folate antagonist ?

Answer 36

‒ Note: The drug methotrexate is a folate antagonist – used for inflammation and cancer to slow down cell replication

Question 37

What gene can be affected by a SNP for MTR / MTRR - folate cycle enzyme ? explain the role of the enzymes

What recommendation if you have that SNP?

Answer 37

Genes: MTR / MTRR = code for the enzyme methionine synthase (MS), which ↑ the conversion of homocysteine to methionine.

• MTR SNP: The A allele of rs1805087 in the MTR gene is associated with decreased MS activity. => we are less able to get the B12 into the process to create the methionine
• MTRR SNP: The A66G SNP at rs1801394 = ↓ conversion of vitamin B12 to its methylated form => less able to recycle the B12

Recommendations: Vitamin B12 and folate foods are co-factors in the conversion of homocysteine to methionine. Consider supplementation of their methylated forms.

Question 38

What heavy metal can hinder the methionine cycle?

Answer 38

mercury / lead toxicity

Question 39

What happens to homocysteine on the transsulphuration pathway? What is the main enzyme involved?
What is the issue for client with a SNP on this enzyme?

Answer 39

Homocysteine not remethylated can be used down the transsulphuration pathway. When the homocysteine go down this pathway it gets converted via the enzyme CBS into Cystathionine (some polymorphism make the CBS faster pulling more homocysteine down the transsulphuratioon pathway creating a potential problem of not enough homocysteine for remethylating).
Cysteine can turn into sulphate (good – to promote sulphation detox pathway for heavy metals and oestrogen detox)
Cysteine is used to synthetise glutathione

BUT Cystathionine can be turned into ammonia and sulphite (bad) – having too much cystathionine and a SNP on CBS enzyme making it faster can lead to an overload of ammonia or sulphites when the other processes are not functioning well.

Question 40

What nutrient can be used to moderate sulphite production with a client presenting with a SNP on CBS in the transsulphuration cycle? How can it present in clinic?

Answer 40

Moderating cysteine with this client and use Mo Molybdenum in the nutrition plan!

Some clients with sulphite sensitivities (red wine, dried fruit, salad bar vegetables) because they are not able through the pathway to turn sulphite into sulphate…

Question 41

What gene can be affected by a SNP for CBS - transsulphuration cycle enzyme ? explain the role of the enzymes

What recommendation if you have that SNP?

Question 42

What gene can be affected by a SNP for CBS - transsulphuration cycle enzyme ? explain the role of the enzymes

What recommendation if you have that SNP?

Answer 42

Genes: CBS converts homocysteine to cystathionine.

SNP: C669T SNP at rs234706 ↑ CBS activity = less homocysteine converted and potential ↓ SAMe. Faster conversion to ammonia (pressure on urea cycle) increasing the need for glutathione.

Recommendations: Increase zinc, choline and TMG (e.g., beetroot). Neutralise the ammonia (↓ animal protein, probiotics to ↓ bacterial production, supplement activated charcoal.
Limit sulphur-containing foods, e.g., eggs, garlic, brassica, Cysteine, sulphur containing supplements

Question 43

What gene can be affected by a SNP for COMT enzyme - Biopterin cycle ? explain the role of the enzyme

What recommendation if you have that SNP?

Answer 43

Genes: MTHFR essential for 5-MTHF, thus biopterin and
synthesis of serotonin, dopamine, adrenaline etc. SAMe-dependent COMT enzyme breaks down dopamine, adrenaline, and noradrenaline. COMT also converts active oestrogen to less active oestrogen. COMT is a balancing enzyme => for neurotransmitters (stress response) and hormones balance (oestrogen).

SNPs: rs4680 ― the A allele is associated with ↓ COMT activity:
* AA = excessive catecholamines (excessive stress response) ― also associated ↑ oestrogen (and hence breast cancer, etc.).
* GG = fast metabolism of catecholamines  drain neurotransmitter away too quickly making the client feel depressed

Recommendations: Choline, betaine, folate and B12-rich foods support the production of SAMe. Avoid exogenous oestrogens (e.g., avoid plastic, anti-perspirants, dairy products, HRT, OCP, etc.). Manage stress to take the pressure off COMT. People struggling with methylated nutrients because it can make people high as it can create too much dopamine and serotonin. Manage stress with magnesium. Gentle methylation support and stress support but watch for excessive catecholamines.