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PainOct 10, 2023

Genes may be responsible for one complex regional pain syndrome case in three, say researchers

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.

Most cases of CRPS are triggered by an injury, with the skin of the affected body part becoming hypersensitive to a slight touch or temperature change. CRPS is difficult to treat, and – though it often improves with time – some people experience intense pain for many years. 

Why some people develop CRPS after an injury of a type that leaves others without it, remains clear. A heritable component to CRPS has been suggested, sparking the theory that some people might be genetically predisposed to the condition.

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Men are more likely to have genetic variants, yet are less likely to be affected by CRPS

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The mechanisms of the disease may vary in males and females

To explore this conundrum further, the researchers looked for variations in genes, formally known as single nucleotide polymorphisms (SNPs), in DNA samples from 34 people diagnosed with CRPS (discovery group). 

These were then searched for in 39 people with chronic back pain (comparison group), and then in another 50 people with CRPS (confirmatory group). The average age was mid-40s to mid-50s across all three groups, with a range of 20 to 86.

Our data support an underlying genetic predisposition to [CRPS] in up to a third of cases … further study of these genes and SNPs may catalyse the generation of personalised precision diagnosis and treatments [Samiha Shaikh et al]

A single SNP in each of four genes (ANO10, P2RX7, PRKAG1 and SLC12A9) was more common in those with CRPS in both the discovery and confirmatory groups than it was in the back-pain group. In all, 25 out of 84 patients (30 per cent) who had had CRPS for more than a year expressed these variations in at least one of the four genes. None of these variations was evident in those with back pain. 

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.

'Personalised precision diagnosis and treatments' could ensue

As the study was observational in nature, definitive conclusions about cause and effect cannot be made. Dr Shaikh and her colleagues also acknowledge that the sample sizes were relatively small, which may well have precluded other SNPs from being detected. In addition, the participants were mostly White. 

The authors conclude: ‘Our data support an underlying genetic predisposition to [CRPS] in up to a third of cases, with this effect being most prominent in males … Further study of these genes and SNPs may catalyse the generation of personalised precision diagnosis and treatments for [the condition].’ 

To read the full version of the article – titled Evidence of a genetic background predisposing to complex regional pain syndrome type 1 doi 10.1136/jmg-2023-109236 – click 

Author: Ian A McMillan
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