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Significant association of DNA variants with self-reported ME/CFS (Chris Ponting blog)

Discussion in 'BioMedical ME/CFS News' started by Simon M, Aug 28, 2018.

  1. Trish

    Trish Moderator Staff Member

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    I suspect the idea that it's different in children partly stems from people like Crawley who diagnoses lots of tired, depressed and anxious kids and ones with temporary post viral fatigue as having ME/CFS and gets her 'recovery' rates looking good as a result. Just defining diagnosis in kids as starting at 3 months from onset instead of 6 months that is usually used for adults means they will inevitably include more with time-limited post viral fatigue.
     
  2. Sasha

    Sasha Senior Member (Voting Rights)

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    Does this male/female split also occur in other diseases? (As well as different underlying causes producing the same pattern of symptoms?)
     
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  3. adambeyoncelowe

    adambeyoncelowe Senior Member (Voting Rights)

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    This is what I've thought, too, although it's not just Crawley who says this. Though she's certainly the first person I saw who says this.
     
  4. Amw66

    Amw66 Senior Member (Voting Rights)

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    It can actually be difficult to get a paediatrics appointment within 3 months from onset- GPs tend to suggest PVFS first and refer on afterwards if nothing is improving.
    It is paediatricians who generally diagnose, not GPs
     
  5. Trish

    Trish Moderator Staff Member

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    Good point, thank you.

    I was thinking particularly of Crawley's epidemiological papers where she uses self diagnosed fatigue as a proxy for ME/CFS, and the fact that some definitions specify 3 months for children and 6 months for adults. But I agree, taking time to get a referral will weed out most of the temporary PVFS cases from paediatric clinic statistics.
     
  6. adambeyoncelowe

    adambeyoncelowe Senior Member (Voting Rights)

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    I think that the approach of diagnosing PVFS early, and then ME later, is the right one and strikes the balance between immediate care and waiting to see how the illness develops. This is what Charles Shepherd advocates, for instance.

    But what that means is that the way you 'treat' PVFS shouldn't be contradictory if the illness later turns out to be ME. I.e., no GET/CBT.
     
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  7. Trish

    Trish Moderator Staff Member

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    Apologies for diverting the discussion on this thread onto paediatric diagnosis.

    To get back to the article, thank you to Chris Ponting and team for the article. And to @Simon M for hosting it on your blog.

    Trying to get my head around it from a patient's perspective. I understand that this research suggests that if I have the particular (common) genetic marker found in females with ME in this study, I would have a slightly higher probability of getting ME than other women. However, at this stage, there would be no point getting myself tested for it, since we don't yet know what the implications would be in terms of treatment, and it is such a common variation that it is in no way diagnostic.

    The interesting bit, if this is replicated, is that it might suggest a useful direction for better unpicking at least part of the cellular biochemistry - specifically the urea cycle and mitochondrial function in some organs. And that ultimately this might give pointers to subgrouping, diagnostics, and treatments, but all that is probably decades away, since there is no large GWAS for ME currently funded anywhere in the world, and even if a strong genetic marker were found, it would not immediately lead to treatment.

    Also the fact that all the small genetic studies done so far, and this large one have not found any clear and obvious genetic basis for ME suggests to me that this route may not be the most fruitful for spending on ME research.

    Edited to add last 2 sentences.
     
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  8. Londinium

    Londinium Senior Member (Voting Rights)

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    At the risk of putting the cat amongst the pigeons, is this tentative finding a good case for resurrecting MEGA or an MEGA-like programme? I know MEGA has been controversial (I think I'm one of the few who was tentatively for it) but a large-scale patient repository to allow better-powered GWAS would seem to be a positive thing.

    Side semi-related question: my other half took part in the 100,000 Genomes Project due to her rare(ish) type of epilepsy* - is/was there any kind of attempt to have ME/CFS included as a covered condition in this project or were they focussed on rarer diseases only?



    *also misdiagnosed and treated, unsurprisingly to a total lack of effect, by CBT for a couple of years
     
    Last edited: Aug 29, 2018
  9. Andy

    Andy Committee Member & Outreach

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    With the likes of Crawley off of the scene and Chris Ponting more directly involved with the CMRC then I would have thought there would be far less opposition to the general concept. The challenge, as always, would be to collect enough well-defined samples.

    The list of conditions can be found here, https://www.genomicsengland.co.uk/?wpdmdl=5207 (PDF document) - ME isn't one of them.

    They do say though
    https://www.genomicsengland.co.uk/taking-part/intro/
     
  10. Trish

    Trish Moderator Staff Member

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    Sorry to nitpick. The project was called MEGA. OMEGA was the petition opposing MEGA!

    With Chris Ponting in charge rather than Esther Crawley, I think there would be much more support for a project like MEGA, especially if it could be done in conjunction with the existing UK ME Biobank.
     
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  11. Londinium

    Londinium Senior Member (Voting Rights)

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    Thanks for that! As I was typing it I was thinking 'was it OMEGA?' but was too bone-idle (can't blame my fatigue this time) to check... now fixed.
     
  12. Londinium

    Londinium Senior Member (Voting Rights)

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    Cheers. I think this would be the sticking point:

     
  13. arewenearlythereyet

    arewenearlythereyet Senior Member (Voting Rights)

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    I think for me I’m a bit more optimistic. What I find interesting is that mitochondrial dysfunction and the urea cycle seems to keep cropping up from various angles. Genetic predisposition is interesting but not really the issue here as you point out.

    The genetic testing would be good to screen a more precise sample of test subjects that would benefit from any treatment (which I presume would be based on “known science”) so not necessarily as far off as all that. I’m thinking 5-10 years rather than decades?

    I may be wrong but I feel more optimistic about this than anything else I’ve seen since rituximab
     
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  14. Simon M

    Simon M Senior Member (Voting Rights)

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    I don’t know if this, from the blog, is relevant:
    "Another of the Neale results is that women that have G at this position tend to have very slightly lower lymphocyte count (rs7337312; p = 4.6×10-7; other variants in LD have p < 5×10-8)."

    they recruited people aged 40 to 69 to increase the chances of getting informative outcomes (such as developing a disease or having a heart attack).

    I think it is a relatively unusual variant., But yes, currently there would be no point in getting tested.

    my understanding is that one of the major benefits of GWAS is that they highlight particular biochemical processes (for instance) that might always also be affected by non-genetic triggers. So that even in diseases with a relatively low genetic component, the studies can still be very revealing about overall pathology.

    see above.

    agreed.
    hopefully the CMRC will betaking a properly collaborative approach and bringing in the likes of the ME/CFS bio bank for such work. Louis Nacul was an observer at the last CMRC meeting, though the biobank has not yet joined the organisation.
     
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  15. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    This seems pessimistic to me. Repeating the result does not require GWAS, just a repeat analysis of this gene in another cohort. A tiny cohort should do if this gene variant is relevant to a substantial number of PWME.

    When we got a piece of information of this sort in RA the whole story unravelled within months without doing any further experimental work. Thinking in a new direction can make you realise that lots of relevant data are already published. We already have quite a lot of data on mitochondria in lymphocyte subsets from Fane Mensah and Jo cambridge, for instance. An immediate question would be how many of the cases they have studied have this variant.

    And if a plausible story emerges, backed up by some simple data, like all the B cells with small mitochondrial mass turn out to be in PWME with the gene variant, thenSimon Wessely has to eat his hat at last.

    Leading to treatment might well take longer, but of course in the RA case I discovered that exactly the right drug was being licensed for another disease by Christmas.

    We will have to see if this is replicable and maybe it isn't, but if it is I think things may change fast. Finding genetic risk is 100 times more powerful than most other evidence for causal pathways.
     
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  16. Trish

    Trish Moderator Staff Member

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    Thanks for the reassurance, @Jonathan Edwards. It's good to know that for once I'm being too pessimistic!
     
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  17. Sasha

    Sasha Senior Member (Voting Rights)

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    How quickly can a replication be attempted? Is there anything we can do to speed that up?
     
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  18. arewenearlythereyet

    arewenearlythereyet Senior Member (Voting Rights)

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  19. mariovitali

    mariovitali Senior Member (Voting Rights)

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  20. sea

    sea Senior Member (Voting Rights)

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    dbSNP has the frequency for the minor allele at around 43%, so it is a common variant.

    That doesn’t make it irrelevant though. In Celiac disease for example, 98% of people with the disease have the predisposing variants. Around 55% of the general population without Celiac Disease carry these variants too.
     

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