GENE X NUTRIENT

Question 1

What is a multifactorial disease?

Answer 1

When a disease is influenced by both genes and environment (diet) - follows non-mendelian inheritance

Question 2

What are the two main dietary component groups?

Answer 2

Nutrients (essential) - Macro and Micro
Non-nutrients (not essential, but provide benefits) - e.g. dietary flavonoids (plants - antioxidant - tumour inhibition) and phytoestrogens (soy beans - reduce cancer risk)

Question 3

What is the relationship between Age and Chronic diseases risk?

Answer 3

Share common metabolic pathways - both influenced by genetics and environment - if we can delay ageing can we delay disease onset

Lifelong accumulation of damage to proteins, lipids, nucleic acids

85% of deaths in the UK as a result of age

Question 4

What is the ageing rate?

Answer 4

Rate of accumulation of damage - malleable - affected by environment, genes and lifestyle acting on repair and damage mechanisms

Question 5

Why does ageing influence chronic disease?

Answer 5

Reduced response to oxidative stress
Increased inflammation
Reduced repair mechanisms
Reduced immune response

Question 6

What are SNPS?

Answer 6

Single Nucleotide Polymorphisms - occur in >1% of population - non mendelian inheritance - 85 Million SNPs in the human genome

Question 7

What regions can SNPS affect?

Answer 7

Promoter (TF binding)
Exon (Synonyous - does not affect AA, Non-synonymous - sense/missense)
Intron (splice site)
5’/3’ UTR

Question 8

What is a functional SNP?

Answer 8

A SNP that affects key regulatory regions

Gene expression
mRNA stability
Protein expression/degradation/activity/PTMs

Question 9

What effect do SNPs have?

Answer 9

Genetic variation
Suscpetibility to disease
Dietary requirements
Medication

Question 10

What is linkage disequilibrium?

Answer 10

When SNPs are located close on the homologous chromosome, they are transmitted together in a haplotype block

Question 11

What are the two branches of Nutritional Genomics?

Answer 11

Nutrigenetics - study of how a SNP interacts with diet to influence disease - identification of SNPs involved in disease - Genomics

Nutrigenomics - How diet affects gene expression, metabolic pathways and homeostasis in disease - Transcriptomics, metabolics, proteomics

Question 12

What is genetic association studies?

Answer 12

Aim to identify statistically significant correlations between disease and increased allele frequency of SNP

Question 13

What are the 3 approaches to association studies?

Answer 13

1) Candidate SNP - known SNP functionality
2) Metabolic Pathway - known gene functionality (SNP not necessarily known)
3) GWAS - fishing

Question 14

What is the candidate approach?

Answer 14

Identification of novel associations between functional SNP and disease

Comparison of allele frequency between cases and controls

Small population

Identify SNP x SNP and SNP x Nutient interactions

:) - cheap, matching, SNP functionality known
:( - might not be representative of population, might be difficult to find matching controls, limited number of SNPs

Question 15

What is the statistical power of a study influenced by?

Answer 15

Population Size
Effect size of SNP with disease
Number of tests being performed

Question 16

How do we calculated the corrected p-value?

Answer 16

0.05/N

Question 17

What are TagSNPs?

Answer 17

Limit the number of SNPs needed in pathway and GWAS studies - group SNPs in haplotypes

:) - reduce cost, able to use lower p-value and thus identify SNPs with smaller effects (beneficial because in many multifactorial diseases, there are lots of SNPs with small effect sizes

:( - functionality of SNP not known

Question 18

What is the metabolic pathway approach?

Answer 18

Hypothesis driven - identification of novel genes within a disease metabolic pathway

Test for association with ALL SNPs (Tag and functional) in ALL GENES in a metabolic pathway

Medium Sized

Question 19

What is GWAS?

Answer 19

Genome Wide Association Studies - hypothesis free

Genotype all cases and controls

Need around 1000 TagSNPs for 1-1.5 million SNPs

VERY large sample size - expensive, cannot match, cannot test for SNP x SNP or SNPxNutient interactions due to lack of statistical power.

Question 20

What is an example of a candidate SNP approach for studying SNPxNutrient interactions?

Answer 20

APOA1 x PUFA - Corella and Ordovas - group of women

APOA1 - efflux of cholesterol from cells and transport of HDL-C to the liver

PUFA - Polyunsaturated Fatty Acids - Oily Fish (Omega3)

Functional SNP known - -75G/A upstream from the APOA1 promoter

Individually no effect on HDL-C (CVD risk)

When studied together, found LOW PUFA (<4%) showed an increase in HDL-C for women with GG SNP. HIGH PUFA (>8%) showed increase in HDL-C for women with GA/AA genotype.

Question 21

What is example of micronutrient metabolism in SNP x nutrient interactions?

Answer 21

B-carotene x BCMO1 - Leung et al.

Rare SNP in BCMO1 (267Serine and 379Valine) confers 57% reduction in BCMO1 activity (enzyme crucial in first step of metabolising B-carotine into Vit.A). Study in women compared reaction velocity between rare variant and common variant (Argninine267 and Alananine379).

Question 22

Why is VitA crucial?

Answer 22

Visual cycle - night blindness. Cellular differentiation. Deficiency can lead to increase mortality from infection (T Killer cells require retinoids to proliferate). Supplementation can cause miscarriage, birth defects. Beta carotene often only source of Vit. A for vegans (Active VitA comes from animal source such as Eggs and Meat)

Question 23

What is example of micronutrient metabolism in SNP x nutrient interactions?

Answer 23

Folate x MTHFR

Folate needs to be converted to the active form which is 5-Methyl THF by MTHFR - this allows Homocysteine to be converted to Met which can play a role in DNA methylation. Low folate levels reduce 5-Methyl THF and increase Hcy (increase CVD) and reduce methyl group availability for DNA methylation.

SNP in MTHFR (C677T) affects the activity of the enzyme. TT genotype confers a 30% activity of the enzyme and as a result low folate diet results in increase plasma Hcy and increased CVD. High folate diet compensates for the low activity of the enzyme and restores 5-methyl THF.

HOWEVER if high folate diet given to CC (100% activity) we get an excess of methyl group and DNA synthesis and increased cancer.

NEED for personalised medicine to ensure we give correct dietary advice to correct people.