Week 9.15: Environmental effects Flashcards
Environmental effects
Topic; Genomic x Environment interactions, diet, toxic environments, personal genetic risk modifiers
Reading: EPG ch8
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Learning outcomes
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· <!--[endif]-->Define what is meant by gene by environment (GxE) interactions.
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· <!--[endif]-->Give examples of GxE interactions (e.g relating to nutrition, toxins)
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· <!--[endif]-->Find information about GxE interactions in online databases
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· <!--[endif]-->Appreciate the difficulties in discovering GxE interactions
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· <!--[endif]-->Demonstrate an awareness of the statistical methods used to characterise GxE interactions
You’ve probably noticed that most findings from personal genomics personal genomics are quite vague – no definite answers, just modest changes in the chance of developing particular diseases.
All of this fancy information but all they can really tell you might have a slightly higher risk of developing something.
Penetrance – probability of developing the disease – is low for most disease-related alleles.
Why can’t we be more certain?
All of these studies tend to try to associated the genotype to a particular factor that is monitored in a population
If you try to do a GWAS to detect SNPs associated with type 2 diabetes – you find a group of people with diabetes and try to compare the genotype between them and identify the SNP. But there are a lot of factors that you don’t collect
Mathematically you are trying to identify disease risk based on only the genotype – you are implying that disease risk is a function of the genotype. But in reality we know that people are more complicated than that. Actually, disease risk is a function of many other things.
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Mathematically speaking, disease risk calculations generally assume the following:
Disease risk = f(genotype)
** But in reality there are many other variables:**
Disease risk = f(genotype, diet, location, occupation,…)
Or more generally:
Disease risk = f(genotype, environment)
What do we mean by “environment”?
Essentially, all the non-genetic factors that may affect biological state these are many:
- *Things ingested**: Food, toxins, pharmaceuticals, recreational drugs (anything you consume and metabolise)
- *Exposure to biological agents**: Bacteria, viruses, parasites
- *Behaviour:** activities, lack of activities, occupational hazards
- *Psychological effects**: stress poverty, religion mental illness
- *Physical phenomena**: heat, cold, radiation (UV or other)
A whole load of different things that we need to consider, the point is we can actually change a lot of these things – if we see that somebody has an increase in risk because of their genotype – and it is also linked to the environment we can do something about their environment. Changing is so that you can mitigate the problem.
So what?
These environmental factors are clinically important, because you cannot change your genome (yet ;) ), but you can modify your environment.
Unpicking genetics, environment and disease
Some areas – Deep South of the US, some of the East coast, maybe there is some sort of geographical factor?
Various studies have been done.
Is there a genetic trait why certain geographical regions have higher rates of obesity – turns out that there isn’t a case as far as genetic case relating to obesity.
“Although the genetic variation in genes associated with susceptibility to obesity DO NOT vary significantly across the US, disparities are likely due to environmental factors”
Some areas – Deep South of the US, some of the East coast, maybe there is some sort of ancestral factor
But, ancestry pattern shows similarities;
But poverty is an even better match:
Perhaps social factors are more important
Turns out you have high pesticide leaching from farms
There is a whole load of factors to consider, even with statistical analysis you can find strong correlations (this doesn’t mean causation)
And probably a whole load of other factors that you could map
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1. ** <!--[endif]-->Some specific edible examples of GxE interactions:**
Examples of things we ingest – has different effects on different people;
Phenylketonuria (PKU)
Is a problem where by people who suffer from this struggle to break down phenylalanine. PKU is a rare (1 in 10,000 in UK) genetic condition. Defects in the coding sequence of phenylalanine hydroxylase (PAH) mean that the body struggles to break down phenylalanine.
During development the resulting build-up of phenylalanine in the brain causes irreversible brain damage, leading to severe learning difficulties.
Timely diagnosis: identify the problem at birth, currently done by checking phenylalanine levels in newborn babies as part of the Guthrie heel prick test. Genetic test also possible.
Modified diet: Avoid sources of phenylalanine, i.e proteins, and the artificial sweetener aspartame during childhood.
For more details check out OMIM: From OMIM you can look up the record for genetic basis
The view from Ensembl:
The protein that is effected by this genotype – in this case PAH, it is relatively easy to make the link from mutations to physiology (low PA) and disease (PKU)
The little lines show this
Easy case at looking at genotype and finding out mechanism
Lactose intolerance
Lactase, produced by the LCT gene, is an enzyme that digests lactose, a sugar found primarily in dairy products. In most people, this enzyme is expressed in infancy and not in adulthood, leading to adults to suffer from lactose intolerance – digestive problems as their bodies try to deal with lactose.
However, a certain European lineage has an allele (SNP rs4988235) that ensures persistent production of lactase into adulthood.
You can see this in Ensembl – LTC gene which codes for lactase enzyme but what is strange about this is that the SNP that is related in actually in black (in MCM gene) Strange that the SNP is in that gene
This variant actually occurs in the 13th INTRON of the MCM6 gene. This is 14kb upstream of the LCT, but prevent transcription factor AP-2 binding to the DNA as this point. AP-2 is known to be involved in development, which makes sense.
The rs4988235 variant is very rare outside of Europe, but lactose persistence can be found in non-Europeans due to other mutations.
Lactose intolerance
Treatments:
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· <!--[endif]-->Again, no cure but modification of diet to reduce consumption of milk and milk-derived products.
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· <!--[endif]-->Replace dairy milk with vegetable-derived “milk” that doesn’t contain lactose.
Allergies
Unlike the other examples, an allergy is a reaction produced by the body in response to an environment stimulus, rather than an inability to break something down.
Strong association found between functionally disruptive variants of the filaggrin gene FLG an alleric responses in people of European decent.
Non-synonymous and deletion variants of FLG have been found that increase the odds of peanut allergy by a factor of three.
When you are trying to eat something, if they body is not processing those they way that you should then that is going to cause trouble – genetic effects
Action you can take from that is that if you have a particular genotype….
Pubmed: 21377035
Toxins
Naturally occurring: e.g heavy metals, mineral oil, alfatoxins produced by fungi growing on foodstuffs
Synthetic: e.g synthetic pesticides, industrial pollution. Main danger of toxins is of course ingestion, but skin contact an also be a problem
In the industrialised world, workplace toxins are of particular concern (due to threat of ligation) as are environmental pollutants
Linking specific toxins to health is a major challenge:
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· <!--[endif]-->There’s almost no limit to the number of exotic chemicals that can be synthesised.
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· <!--[endif]-->Even for natural toxins like mineral oil, there are many distinct variants with different compositions.
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· <!--[endif]-->Very difficult to accurately determine which toxins an individual has been exposed to, in what quantity and when. However, there can be some traces (e.g in fatty tissue).
It is basically impossible to have a study that you can collect all the toxins present, difficult to do study
