Nutrient X Gene interactions and age-related disorders Flashcards
What are the main characteristic of a monogenic disease?
1 gene
Early onset
RARE
Mendelian pattern of inheritance
What are the main characteristics of multifactorial disorders?
Multiple genes
Other factors
Late onset
Common and complex
Non-mendelian pattern of inheritance.
What is the risk of developing a multifactorial disease based on?
The equilibrium between disease mechanisms and the prevention mechanisms.
What is SNP?
Single base change in DNA sequence.
What factors affect multifactorial disease risk?
Genetic factors
Environmental and lifestyle factors.
What are some examples of environmental and life style factors?
Pathogens
Mediation
Diet
Medication conditions
Socioeconomic factors
Why is diet so important?
Key factor in development as you need it from the day you are born to the day you die.
What are macronutrients?
Carbohydrate, protein & fat, provide energy and building blocks for growth and maintenance of a healthy body.
What are micronutrients?
Vitamins & minerals needed in small amounts, essential to keep us healthy.
What are non-nutrient bioactive foods?
Not vital to human health (non-nutritive), but has been shown to affect it.
How does lactose intolerance come about in individuals?
A child can consume lactose from 1-4 because the lactase gene is switched on.
Sometimes later in life lactase is switched off.
This leads to lactose intolerance.
This is due to evolution, human migration and famine (survival of the best adapted).
Why is ageing a huge risk for chronic disease?
The ageing process and chronic diseases share common molecular
pathways/ mechanisms
What is the ageing process?
Progressive and random accumulation of unrepaired molecular damage (in nucleic acids, proteins, and lipids) over time
What are the consequences of the ageing process?
More susceptible to succumbing to addition stress and developing a disease.
What is the ageing rate?
Rate of accumulation of damage.
What is intrinsic stress?
ROS and reactions inside the body?
What is extrinsic stress?
Lifestyle and environmental stress
What is a common misconception with lifestyle factors affecting multifactorial disease?
Only limited control over environmental factors, comes down to so much more than just diet and lifestyle choices.
What does the accumulation of cellular damage lead to?
Mutagenic lesions which lead to cancer
Cytotoxic or cytostatic lesions which lead to cellular defects and death, and therefore ageing.
Previously mentioned increase ageing leads to a decline in DNA repair quality and therefore a higher accumulation of cellular stress.
Which mechanisms are often found to be effected in chronic disease and ageing?
Response to oxidative stress
Cellular maintenance mechanisms
Immune response
Inflammatory response
Which inter-individual genetic variations affect chronic disease risk and suseptability?
Genetic variations
Origin of SNP
Functionality of SNP
Inheritance pattern
Linkage disequilibrium
Why are SNPs important?
Because they represent 90% of the variations between individuals.
What are the components of the SNP?
Single base change
Minor (rare) allele frequency
How is an SNP different to a mutation?
SNP are present in the whole population, mutations are only in less than 1%.
Difference is the frequency in population.
Where can SNPs happen?
Anywhere along the DNA from the promoter to the 3’UTR
What is a functional SNP?
Affects a key regulatory region, for example expression.
They have functional consequences.
What ate SNPs associated with?
Genetic diversity
Inter-individual variations in dietary requirements
Individual susceptibility to chronic disease
Individual response to medicine
How are functional SNPs involved in chronic disease?
Likely to be located in genes in molecular pathways which are involved in maintaining the homeostasis of the disease mechanism and the prevention mechanism.
How can SNPs be transmitted if on the same homologous chromosomes?
Independent, not due to crossing over
Together as a haplotype due to geographical closeness on the gametes.
What is linkage disequilibrium (LD)?
A measure of how often two alleles or specific sequences are inherited together
Alleles that are always co-inherited said to be in linkage disequilibrium
What is a haplotype?
A haplotype is a set of alleles at multiple loci located on the same
homologous chromosome and inherited together from a single parent because of genetic linkage.
What is a haplotype block?
Haplotype that is transferred down the family due to persistence of an ancestral association.
Previously good adaptations lead to disease?
Several gene variants (alleles) that arose through positive selection are modern-day candidates for disease risk alleles.
Storing fat would have saved lives when food was scares however now it leads to obesity.
What are nutrigenetics?
Our genes affect how our body responds to food and dietary requirements
What are nutrigenomics?
Our diet affects how our genes are expressed
What are the applications of nutrigenetics?
Identification of SNP and genes involved in gene processes
Identification of those at risk due to genetic + dietary factors.
What are the applications of Nutrigenomics?
Identification of metabolic pathways of genes involved in disease
Understanding mechanisms leading to disease.
What is personalised nutrition?
Aimed at providing advice for nutritionists and physicians to personalised dietary recommendations based on genetic makeup to match individual requirements to prevent disease.
How do we study gene x nutrient
interactions and their impact on age-related chronic disease risk?
Genetic association studies
What is sequencing?
When you collect information at every single base.
What is genotyping?
Identify the genetic variant present at a given locus, this is more relative to nutrient interactions.
What is the aim of genetic association?
Identifying a statistically significant correlation between presence of the disease and increase or decrease in allele frequency for a SNP in disease cases.
What are case-control genetic association studies?
Compare the genotype frequency at each locus between the:
The control - No disease trait at the time of the study
And
Cases - Patients at the disease trait
When is a genetic variant considered genetically associated with disease?
If allele frequency in cases increases significantly an allele can be considered a risk allele.
If an allele frequency in cases decreases significantly the allele can be considered protective.
What is the issue with the case control genetic association study?
Because the controls only don’t have the disease at the time doesn’t mean they don’t have an increase risk of developing the disease in the future.
Matching the case/control for other risk factors.
What are the 3 approaches when conduction a case-control genetic association study?
Candidate SNP approach
Molecular pathway approach
GWAS (genome wide association studies)
When is the candidate SNP approach used?
When the gene is KNOWN to be involved in disease/normal function and is a KNOWN functional SNP.
When are pathways approaches used?
When the gene is KNOWN to be involved in disease/normal function but its functionality is KNOWN or UNKNOWN.
When are GWAs approached used?
When the gene is NOT KNOWN to be associated with disease no matter whether the functionality is KNOWN or UNKNOWN.
What affects statistical power?
Population size
Magnitude of effect of SNP on disease risk
Number of tests run.
How do we correct the statistical power for multiple testing?
If only one test is done significant p-value must be less that 0.05.
If n test are done significant p-value must be less that 0.05/n.
What is the candidate SNP approach to genetic association testing aimed at?
Aimed at identifying new associations between functional SNPs and a disease trait
How is the candidate SNP approach to genetic association conducted?
Select SNPs of known functionality in genes known to be involved in disease pathway
Compare allele frequency between cases and controls
What is the study population for candidate SNP approach to genetic association?
Generally well defined
Small-medium (100s-1000)
What are the advantages of candidate SNP approach to genetic association?
Studies both SNP x nutrient and SNP x SNP interactions.
SNP functionality is known, hypothesis driven
Can match case/controls for other factors
Relatively cheap
Define hypothesis driven?
Problem solving methods where you start with the answer and work back to prove or disprove that answer.
What are the limitations of the candidate SNP approach to genetic association?
Selected SNPs may not be involved in disease mechanism
Only a limited number of SNPs can be studied at once
May be difficult to replicate .
What are the similarities of the pathway approach and the GWA approach to genetic association testing?
The functionality of SNPs can be known or unknown
The number of SNPs is large which may lead to false positive and need for correction through multiple testing.
The number of genetic associations tested is high thus statistical power is limiting
Require the use of Tag SNPs
What is a Tag SNP?
A tag SNP is a representative single nucleotide polymorphism (SNP) in a region of the genome with high linkage disequilibrium that represents a group of SNPs called a haplotype.
What are the advantages of Tag SNP over genotyping all SNPs in a genome?
Decrease in cost
Cut-off for statistical significance
SNP with smaller effect can be found
Finding clinically relevant SNP even if the functionality is not known by looking at the whole genome.
What is the aim of the pathway approach towards genome association testing?
Aimed at identifying variants (alleles) in the SNPs in gene within a molecular pathway associated with that disease trait.
How is a pathway approach genome association test conducted?
Test association disease with all SNPs (TagSNP and functional SNP) in all genes in a molecular pathway.
What is the study population for the pathway approach towards genome association studies?
Medium size (few 1000s)
What are the advantages of the pathway approach towards gene association studies?
Can test both SNP x nutrient and SNP x SNP interactions
Include functional SNP to test their impact
Can use matching for case/controls
Relatively cheap
What are the limitations of the pathway approach to gene association studies?
The pathway studied may not be involved in the disease trait.
SNPs used are of a known and unknown functionality.
May be difficult to replicate in another population
What is the aim of Genome Wide association studies?
Identify all SNPs associated with a disease or trait
In contrast to pathway and candidate it is hypothesis free and therefore unbias
What is the hypothesis of genome wide association studies?
Common disease are in part because of allelic variants present in mor than 1-5% of the population.
What is the principle of genome wide association studies?
Simultaneously genotype all TagSNP.
Case/Control association study
Statistical test for each locu to determine if locus is associated with disease.
What size population do genome wide association studies require?
Very large, thousands.
What are the advantages of
genome wide association studies?
Identification of novel associations
Information on potential molecular pathways involved in disease
What are the limitations of genome wide association studies?
Very expensive
Very large population required to account for high volume of statistical test.
Due to high population matching isn’t possible
Cant test for SNP x SNP or SNP x nutrient interactions
SNP functionality is unknown due to the use of TagSNPs
Describe the example of CVD in SNP x Diet interactions.
HDLC is inversely correlated with the risk of cardiovascular disease.
SNP located in the promoter of the apolipoprotein A1 gene promoter, which promotes the efflux of cholesterol from cells and transports HDLC to the liver.
There was an association between this SNP and increased cholesterol levels but not replicated in every population
PUFA, polyunsaturated fatty acids intake decreased cholesterol for GG individuals but increased it for any individual with an A allele.
What is beta-carotene?
Found in vegetables converted to Vitamin A.
How if beta-carotene converted to Vitamin A?
Cleavage in the centre to give two molecules of glutamate due to enzyme BCMO1.
What were the two SNPs associated with reduced ability to covert beta-carotene?
Arg267Ser
and
Ala379Val
How was the Vitamin A problem solved?
BCMO1 was cloned and used in woman with reduced Vitamin A production.
Anyone with a double variant experienced a further reduction.
Why is Vitamin A important?
Involved visual cycle
Maintaining cell growth and differentiation
Why is Vitamin A overdose dangerous?
Can be harmful, miscarriage or cancer.
Means direct supplementation should be done carefully in an individual which is deficient.
Important to genotype to ensure enzyme function.
