GENE X NUTRIENT Flashcards
What is a multifactorial disease?
When a disease is influenced by both genes and environment (diet) - follows non-mendelian inheritance
What are the two main dietary component groups?
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)
What is the relationship between Age and Chronic diseases risk?
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
What is the ageing rate?
Rate of accumulation of damage - malleable - affected by environment, genes and lifestyle acting on repair and damage mechanisms
Why does ageing influence chronic disease?
Reduced response to oxidative stress
Increased inflammation
Reduced repair mechanisms
Reduced immune response
What are SNPS?
Single Nucleotide Polymorphisms - occur in >1% of population - non mendelian inheritance - 85 Million SNPs in the human genome
What regions can SNPS affect?
Promoter (TF binding)
Exon (Synonyous - does not affect AA, Non-synonymous - sense/missense)
Intron (splice site)
5’/3’ UTR
What is a functional SNP?
A SNP that affects key regulatory regions
Gene expression
mRNA stability
Protein expression/degradation/activity/PTMs
What effect do SNPs have?
Genetic variation
Suscpetibility to disease
Dietary requirements
Medication
What is linkage disequilibrium?
When SNPs are located close on the homologous chromosome, they are transmitted together in a haplotype block
What are the two branches of Nutritional Genomics?
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
What is genetic association studies?
Aim to identify statistically significant correlations between disease and increased allele frequency of SNP
What are the 3 approaches to association studies?
1) Candidate SNP - known SNP functionality
2) Metabolic Pathway - known gene functionality (SNP not necessarily known)
3) GWAS - fishing
What is the candidate approach?
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
What is the statistical power of a study influenced by?
Population Size
Effect size of SNP with disease
Number of tests being performed
How do we calculated the corrected p-value?
0.05/N
What are TagSNPs?
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
What is the metabolic pathway approach?
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
What is GWAS?
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.
What is an example of a candidate SNP approach for studying SNPxNutrient interactions?
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.
What is example of micronutrient metabolism in SNP x nutrient interactions?
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).
Why is VitA crucial?
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)
What is example of micronutrient metabolism in SNP x nutrient interactions?
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.
