Genetics and Pain Flashcards
Why should the risks of environmental factors be approached with caution?
Making inferences about individuals from the population is unreliable.
Individual risk should not be conflated with population risks.
Also, most population means between two environmental ‘groups’ do not differ that much - they have small effect size. Therefore even though the population means for a disease risk differ, individuals fall into an indefinable middle space where no predictions can be made on the basis of the group status.
The majority of influences on chronic pain have small effect sizes.
What are shared and non shared environments?
Shared environments refer to measurable similaries in an individuals environment, such as parental upbringing.
Non-shared environments are the myriad of influences encountered in your life, e.g., random stochaistic unmeasurable factors that cannot be quantified by epidemiology.
Shared environments are insignificant in accounting for disease. Non-shared envionrments contribute signficantly.
What is linkage analysis?
This involves analysing the DNA from affected and non-affected members of a family carrying a familial disease and identifying overrepresentation of regions of DNA in the affected members relative to the non-affected members.
- Easiest to carry out on monogenetic disorders
- It uses inheritance of non-disease genes (as measured by phenotypes) close together with other regions. They closer they are together, the more likely they are to be inherited together due to random recombination during meiosis. It can be used to identify disease genes whose approximate loci is known .
- However it turns out very large sections of B.P. which need to be honed in.
What are the three main factors that limit GWAS studies in pain?
- Pain phenotyping. This includes both the type of pain e.g. neuropathy can be diabetic, post herpatic, HIV-induced etc. Another type of phenotyping regards qualitiative features of the type of pain experienced.
- Population stratification. Some populations may contain stratified ethnic groups, which are very genetically distinct from one another - therefore results are not generalisable, and studies using a mix of ethnic groups may be confounded.
- Power. Power is the probability of correctly rejecting the null hypothesis. It is a composition of effect size (e.g. effect of the SNP) and sample size. Larger = more power for both.
What must be considered regarding epigenetic studies?
Epigenetics are required for normal development. This is how cells differentiate from embryonic stem cells to form specific cell types. Therefore, epigenetic modifications are cell-type specific. This means it is important to look at the relevant tissue types when examining epigenetics.
The majority of epigenetics are stable over time - epigenetic changes tend to occur during adolescence. Nonethless, adults may be able to go subtle modifcations that could convert a normal nocioceptor to a hypersensitive nocioceptor, for example. There is evidence that variance in histone 4 acetylation increases with age, and that variance in DNA methylation between twins is best explained by non-shared envionmental factors.
An example of inappropriate inferences from epigenetics: recent media claimed that epigenetic modifcations from blood cells revealed heritability in the epigenome for genes relating to anxiety for the offspring of holocaust survivors. Whilst there may be some correlation between epigenetics of blood and neurons, neurons would need to be looked at to make this kind of inference - or even more specifically, neurons in circuitry relevant to anxiety/fear.
On top of this, the blood contains around 50 cell types - all would need to be examined to make any inferences.
What is the epigenetic model of chronic pain?
The epigenetic model essentially states that we inherit our genome and a complete set of epigenetics, which are the modified during development to give rise to various cell lineages, and may potentially be modified throughout adult lifetime.
Many small adverse events may lead to epigenetic modifications that serve as a memory of previous adverse events, conferring enhanced pain vulnerability to future injuries.
This may then give rise to the long term sensitisation of the nervous system that gives rise to chronic pain states.
What is the early tentative evidence for epigenetic alterations in pain from Denk’s lab?
Microglia are known to be crucial players in regulating pain - for example, mice knocked out for the primary chemokine attractant of microglia do not show any hypersensitivity to pain.
There is evidence that the epigenome of macrophages (microglial cousins) changes in response to stimulation - particulation in a methlyation of enhancers. TNFalpha leads to a methylation in a small signifcant number of enhancers being methylated and becoming more accessbile. Washing out TNFa leads macrophages to return to a state of quiescence - yet the enhancers remain accessible for at least 48hrs. This implies a fundamental change to the potential of how the macrophage will respond to future TNFa.
Denks lab wanted to see if this occurs in pain. The model is ligation of the sciatic of a mouse leading to a pain state. Isolation of microglia reveals regions of newly accessible enhancers upstream of CCL12. This is a chemokine known to be upregulated in microglia. A number of novel enhancers correlated with genes known to be upregulated by microglia. This suggests novel enhancers are changing expression of these genes, and also retain a memory for the adverse experience - perhaps representing a priming mechanism. The time course of this gene expression is temporary and returns to baseline by 14 days. However, the enhancer region remains more accessible for 28 days after.
