Evidence of a genetic background predisposing to complex regional pain syndrome type 1, 2023, Shaikh et al

Evidence of a genetic background predisposing to complex regional pain syndrome type 1

Samiha S Shaikh1, Andreas Goebel2,Michael C Lee3, Michael S Nahorski1,Nicholas Shenker4,Yunisa Pamela1,5,Ichrak Drissi1,Christopher Brown3,Gillian Ison3,Maliha F Shaikh4,Anoop Kuttikat4,William A Woods1,Abhishek Dixit3,Kaitlin Stouffer1,MurrayCH Clarke6,David K Menon7,C Geoffrey Woods1
Correspondence to Dr C Geoffrey Woods, Cambridge Institute for Medical Research, Cambridge, Cambridgeshire, UK

Abstract

Background
Complex regional pain syndrome type 1 (CRPS-1) is a rare, disabling and sometimes chronic disorder usually arising after a trauma. This exploratory study examined whether patients with chronic CRPS-1 have a different genetic profile compared with those who do not have the condition.

Methods
Exome sequencing was performed to seek altered non-synonymous SNP allele frequencies in a discovery cohort of well-characterised patients with chronic CRPS-1 (n=34) compared with population databases. Identified SNP alleles were confirmed by Sanger sequencing and sought in a replication cohort (n=50). Gene expression of peripheral blood macrophages was assessed.

Results
In the discovery cohort, the rare allele frequencies of four non-synonymous SNPs were statistically increased. The replication cohort confirmed this finding. In a chronic pain cohort, these alleles were not overexpressed. In total, 25 out of 84 (29.8%) patients with CRPS-1 expressed a rare allele. The SNPs were rs41289586 in ANO10, rs28360457 in P2RX7, rs1126930 in PRKAG1 and rs80308281 in SLC12A9. Males were more likely than females to have a rare SNP allele, 8 out of 14 (57.1%) vs 17 out of 70 (24.3%) (Fisher’s p=0.023). ANO10, P2RX7, PRKAG1 and SLC12A9 were all expressed in macrophages from healthy human controls.

Conclusion
A single SNP in each of the genes ANO10, P2RX7, PRKAG1 and SLC12A9 was associated with developing chronic CRPS-1, with more males than females expressing these rare alleles. Our work suggests the possibility that a permissive genetic background is an important factor in the development of CRPS-1.
 
This looks quite important. There was a confirmatory sample but it would be good to see further confirmation.

CRPS-1 as I understand it is 'spontaneous' in that there is no defined nerve injury beforehand. It can follow soft tissue trauma but need not. If you like it is a 'medically unexplained symptom'. The effects, however, show clear structural pathology. So it is a good example of how unexplained processes can generate major symptomatic problems such as pain.

Finding a range of uncommon gene associations suggests that CRPS-1 may involve some increased neural pathway sensitivity that can get out of control.
 
I asked my good buddy ChatGPT what those genes do:
The genes you mentioned, ANO10, P2RX7, PRKAG1, and SLC12A9, have various functions in the human body:
  1. ANO10 (Anoctamin 10): ANO10 is part of a family of proteins called Anoctamins or TMEM16 proteins. They are involved in chloride ion channel activity, which is essential for several physiological processes, including regulating the flow of ions across cell membranes.
  2. P2RX7 (Purinergic Receptor P2X, Ligand-Gated Ion Channel, 7): P2RX7 is a purinergic receptor that is activated by ATP (adenosine triphosphate). It plays a role in the immune response, specifically in the activation of immune cells, including macrophages and microglia. Activation of P2RX7 can lead to inflammation and immune system responses.
  3. PRKAG1 (Protein Kinase AMP-Activated Non-Catalytic Subunit Gamma 1): PRKAG1 is a subunit of the AMP-activated protein kinase (AMPK) complex. AMPK is an enzyme that plays a critical role in regulating cellular energy homeostasis. It is involved in the response to changes in energy levels, such as during exercise or glucose deprivation.
  4. SLC12A9 (Solute Carrier Family 12 Member 9): SLC12A9 is a member of the solute carrier family of proteins. These proteins are responsible for transporting various substances across cell membranes. The specific function of SLC12A9 may vary depending on the context in which it is expressed, but it likely plays a role in ion transport or other cellular processes.
These genes have diverse functions in the body, contributing to various physiological and cellular processes. The exact roles and significance of these genes may vary in different tissues and under different conditions. If you have specific questions about these genes or their relevance to a particular condition, feel free to ask for more information.
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Hoopoe said:
I don't know much about CRPS. Is this relevant to ME/CFS?
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Not that I can think of, but it is definitely in the same MUS/"I don't believe in this illness" category that psychosomatic ideology has captured.

Progress is achingly slow, but as more and more conditions falsely categorized as psychosomatic get figured out, it will diminish the validity of the "we don't know the cause = psychological" logical fallacy that the entire construct is made of.

By far the biggest threat to psychosomatic ideology is research. Hence why they always try to stop it. Oh, the irony. It burns. It burns so deep.
 
Hoopoe said:
I don't know much about CRPS. Is this relevant to ME/CFS?
Click to expand...

I don't know if there is much of an overlap/comorbities of those with CRPS having ME/CFS and I guess in a sense we don't know enough about the cohort of either to know if there are similarities

However, as I was reading through this, and having read the recent post that asked people what their gut instinct was on what ME/CFS might turn out to be (and of course other threads on similar lines - which by the way I do think are useful given there might be different types and those who have had this for a long time have been their own guineau pigs and read up a bit so can muse somewhat on their 'sense' of what might fit) it seemed 'of use'. Or might be of interest.

It also made me think of the question of what areas should/might be involved in looking into ME/CFS and where developments that might shed light on parts of what is involved and going wrong might come from ie which areas of specialism have a lot of developing to do and might end up describing parts that currently are little-known but eventually might be relevant for understanding. Or transferrable methodological approaches etc

But really the article struck me most because I think the approach and thinking is very interesting, having read the more summarised version:

One person in three with complex regional pain syndrome (CRPS) could have an underlying genetic susceptibility to the condition, according to an article published today (11 October) online in the Journal of Medical Genetics.

Because men are less likely that their female counterparts to have CRPS (by a ratio of three-four: one) – despite being more likely to have the four genetic variations implicated in a heightened risk – there may be gender-specific causes, say first author Samiha Shaikh from the Cambridge Institute for Medical Research and 16 co-authors.
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More men than women expressed these genetic variations: eight out of 14 (57 per cent) vs 17 out of 70 (24 per cent) women – although this discrepancy would need to be confirmed in a larger group, say the researchers. ‘This raises the possibility of different mechanisms of disease in males and females in [CRPS] and that therapeutic responses may also be influenced by sex,’ they write.

Dr Shaikh and her colleagues note: ‘We acknowledge that our genetic results may be only part of the [CRPS] story; autoimmune disease is more common in women than men, and recent studies strongly suggest it could be causative in some cases of [CRPS].’

There may be plausible biological explanations for their findings, they suggest, as ANO10, P2RX7and SLC12A9 are expressed in immune cells in the peripheral nervous system, both of which are involved in the types of symptoms seen in people with CRPS

And all four genes are normally expressed in macrophages – a type of white blood cell involved in the immune response – in healthy people, they note.
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and on the journal paper above I found the discussion, as a non-expert in the area, a fascinating introduction to a 'new world' watching someone hypothesise on how the different parts could come together. Particularly from the following paragraphs down fascinating to learn about how different areas can interact and link together (as we think about how complex the picture might be for ME/CFS and the various patterns and symptoms within it):


It is well known that tissue injury results in rapid early response by neutrophils, followed by macrophages which contribute to the acute phase of inflammation.33 This inflammatory response is a normal post-traumatic physiological event, but in CRPS it is exaggerated.34 Inflammatory mediators that are secreted are thought to contribute to trophic changes and peripheral sensitisation of neurons. The role of inflammation in the development and propagation of CRPS is not a novel concept and has been well documented.7 35 36

The unpicking of the pathophysiology of CRPS will not simplistically align to a single cell lineage, but the alleles identified are plausible clustered to have a biological response that would align with the clinical presentation of sensory, motor and autonomic changes. Macrophage-cell lineage (tissue resident macrophages, microglia, osteoclasts) are well placed to account for many of the changes seen, hence we confirmed that all four genes are expressed in human peripheral macrophages. In addition, recent mouse studies provide evidence that spinal macrophages can be actively anti-inflammatory after superficial injury—our SNPs may block this process.37 Or alternatively, as suggested by recent mice studies of the effects of plasma from humans with CRPS, is the inflammation local but the nociceptive signal is at the dorsal root ganglia and mediated by microglia?.38 39 Finally, the pathogenesis of CRPS-1 maybe complex, with the SNP alleles we have found (and autoantibodies found by others) acting in multiple cell types, in different cell processes (eg, ANO10 is seen in inhibitory nerves and has an important role in endolysosomal pathways and P2RX7 is seen in excitatory neurons), and in both peripheral and central locations. Carefully performed functional studies in a variety of cell types will be needed to fully understand the role that the rare alleles have in understanding the disease mechanisms of this enigmatic condition.
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I agree with @bobbler that there are reasons to think this is relevant to thinking about ME, @Hoopoe.

The higher rate of risk genes in men I think is easily explained. If having two X chromosomes (being a woman) is also a risk then women need fewer other genes to tip them into CRPS. For men the other genes are more relevant.

I actually doubt this is to do with autoimmunity or inflammation. The author's musings on mechanisms look a bit guided by fashion. In CRPS-1 the affected part is often reddish but cold. This is not inflammation. It is something we have seen for decades or centuries and never had an explanation for.


So, thinking about why women should have more CRPS-1 and also more ME, without much indication of autoimmunity I started thinking about pain interacting with tissues - which in CRPS is easy for all to see, but unexplained. In ME and fibromyalgia, if that can be usefully defined, there is nothing to see but still a major problem.

I also note that pain can interact with body tissues in anyone, men as well, including me, in remarkable ways. When I had renal colic, which is said to be the worst pain known, my hands became completely drained of blood because of some peculiar pattern of sympathetic nerve activity.

And of course women have Raynaud's much more than men, regardless of any autoimmune problems - constitutional Raynaud's is more common in women.

So what is it that is different about women that might affect interactions between pain and tissues and blood flow? If we forget antibodies, is there anything much different? Do women look different?

Well, yes, very different. The skeleton is a bit different but they mostly look different because in men adipose tissue is collected in the omentum of the gut - beer belly - whereas in women it is distributed evenly around the subcutaneous tissue to produce a more pleasing contour! And presumably this is all about thermoregulation.

In other words women are vastly different in the way peripheral nerves interact with tissue structure, blood flow and metabolism. You will very likely find nothing on blood samples because it is regulation in the body that is different. The cells are the same.
You will probably find nothing specific in any metabolic pathway because the problem is the way the volume knob is being turned and down during the day and night. You still get Radio 1,2,3 or 4.

CRPS may bee of use as a lesson because it shows what can happen if locally the regulatory system goes completely off the scale.
 
Couple of thigs struck me about this:
1) They had a "cohort of well-characterised patients with chronic CRPS-1 (n=34)" and the genes were evident [Note 1]. Highlights the problem in ME/CFS i.e. the population is heterogeneous. Larger GWAS studies, or rather combining studies, have been successfully used as a workaround in dementia.
2) On a lighter note - in the Introduction the authors state "---In 95% of cases, it [CRPS-1] occurs post-traumatically --". The study finds a strong genetic link, despite the small study size, yet the authors don't give up on the old Gods (trauma) - in the Conclusion they state "Our work suggests the possibility that a permissive genetic background is an important factor in the development of CRPS-1." OK they've added a new God -- your genes -- maybe the fact that it's published in the BMJ is relevant!


Note 1:
"
Methods Exome sequencing was performed to seek altered non-synonymous SNP allele frequencies in a discovery cohort of well-characterised patients with chronic CRPS-1 (n=34) compared with population databases. Identified SNP alleles were confirmed by Sanger sequencing and sought in a replication cohort (n=50). Gene expression of peripheral blood macrophages was assessed.

Results In the discovery cohort, the rare allele frequencies of four non-synonymous SNPs were statistically increased. The replication cohort confirmed this finding. In a chronic pain cohort, these alleles were not overexpressed. In total, 25 out of 84 (29.8%) patients with CRPS-1 expressed a rare allele. The SNPs were rs41289586 in ANO10, rs28360457 in P2RX7, rs1126930 in PRKAG1 and rs80308281 in SLC12A9. Males were more likely than females to have a rare SNP allele, 8 out of 14 (57.1%) vs 17 out of 70 (24.3%) (Fisher’s p=0.023). ANO10, P2RX7, PRKAG1 and SLC12A9 were all expressed in macrophages from healthy human controls.

"Conclusion A single SNP in each of the genes ANO10, P2RX7, PRKAG1 and SLC12A9 was associated with developing chronic CRPS-1, with more males than females expressing these rare alleles. Our work suggests the possibility that a permissive genetic background is an important factor in the development of CRPS-1."
 
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