Thursday, 10 February 2011

Genetics and Pain

Last year there was a post on Body in Mind in response to an article published on the genetics of chronic pain. With refreshing honesty the author admitted he “was going to write a blog-post on it and then I read it and I was too intimidated by it.”

I had a look at the paper, with my molecular biology background, it wasn’t too scary. I was interested in the original blog post as it intersects many parts of my life. First my original training as a biochemist, second my current kiddie friendly employment as a movement teacher (which is why I follow Body in Mind) and third the long term nerve pain I have suffered since the birth of my first child.

So here is a non-geneticists run through the paper, plus some thoughts on the implications of knowing about the genetics of chronic pain.

The researchers (an international collaboration from Israel, Canada, Germany and Sweden) first studied mice. Nerves were removed from the paw of the animals in order to model the type of pain that follows nerve damage. Some mice seem to be annoyed by the numb paw which they scratch and bite. This behaviour is used as a measure of their pain.

Individual mice and mice within a strain vary in how much pain they feel, suggesting there may be a genetic component to their response. The behaviour of many mice was compared using standard genetic techniques involving inbreeding and database searches which lead to the identification of a clutch of potentially influential genes.

The researchers also looked at expression of genes in mouse paw ganglions from different strains, either from those having undergone nerve removal or a sham operation, and narrowed down the search to a gene called CACNG2. The expression of CACNG2 was turned down in mice that seemed to have more pain, and mice with mutated CACNG2 genes were shown to have different responses to nerve removal.

The corresponding gene in humans was investigated by using a group of mastectomy patients, some of whom suffered chronic pain following their operations. The researchers looked at naturally occurring differences in gene sequence in the women and found statistically significant associations between changes in two areas of the gene and chronic pain.

CACNG2 turns out to code for a protein of just the type you might expect to be involved in the control of pain response. The protein modulates AMPA receptors (ion channels gated by the neurotransmitter glutamate) by influencing their transport and probably by effecting channel gating. CACNG2 is already known to play a role in epilepsy.

The authors say their finding may be of immediate social benefit – “patients who report more pain than might be expected given the extent of their injuries are frequently stigmatised, with the suspicion that they are exaggerating their symptoms in the hope of obtaining secondary gains....knowledge of the existence of genetic factors controlling pain susceptibility....ought to reduce unwarranted stigmatization of patients with severe pain due to no fault of their own”.

I will finish with some of my thoughts on the implications of the role of genetics in chronic pain.

It doesn’t surprise me that genetics plays some part in susceptibility to long term pain, so the results in themselves do not make me feel any better about my pain. But could these findings reassure sufferers who are unaware of possible genetic vulnerabilities or even help shift the views of those who don’t believe the pain of others?

I am afraid to say that am not hopeful. Education about genetics tends to come through care providers, and I suspect only doctors who are already doing a good job communicating chronic pain knowledge would pass on new genetic findings such as these. Nothing is likely to change for patients who are currently given the impression the pain is their own fault.

Longer term, what if our DNA sequences were stored in a hospital database and we could learn of our personal genetic liabilities? Would it be helpful to know that you had a higher than average likelihood of suffering chronic pain? Or would this just create a self fulfilling prophecy?

As with genetic knowledge in other disease areas it partly depends on the type of treatment available. If stratified care for your particular genotype was offered, then you would want to know. If nothing different could be done then perhaps you wouldn’t.

And what if the genetic basis of long term pain were understood, what form would it take? It’s a fairly safe bet to say that it wouldn’t be neat and tidy. Because of the role of the sufferers’ attitudes and beliefs, their social environment and their pain escape behaviours, the genetics of chronic pain is likely to be a hodgepodge of small gene effects interwoven with environmental influences. Chronic pain also casts a wide etiological net (there are many many different causes of pain) so the underlying genetic backgrounds are likely to be similarly disparate across the population.

To my knowledge, no genome wide association studies (GWAS  - large scale systematic genetic study of hundreds or thousands of individuals) have been carried out to look at chronic pain, but many psychiatric disorders have been studied this way and the results have been disappointing. Because of the shared role of the mind in both mental illness and pain any patterns emerging from GWAS of long term pain are likely to be deeply hidden too.

I’m sure in the future we will know more about the genetic basis of chronic pain and I suspect that the inherent complexity revealed will be a little intimidating to everyone.

Nissenbaum J, Devor M, Seltzer Z, Gebauer M, Michaelis M, Tal M, Dorfman R, Abitbul-Yarkoni M, Lu Y, Elahipanah T, delCanho S, Minert A, Fried K, Persson AK, Shpigler H, Shabo E, Yakir B, Pisanté A, & Darvasi A (2010). Susceptibility to chronic pain following nerve injury is genetically affected by CACNG2. Genome research, 20 (9), 1180-90 PMID: 20688780

For further information on genetics

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