Jonathan Edwards
Senior Member (Voting Rights)
I like that idea @jnmaciuch . I am boating again but will add some thorts later.
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Genetics: OLFM4
- Thread starter Hutan
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Very interesting! How would we test the hypothesis that type I interferons are involved in ME/CFS?Looking through the candidate list again, I think there's an interesting thread that ties several of the top genes together, which is regulation of type I (alpha/beta) interferon signaling.
OLFM4
No directionality info from eQTLs.
PEBP1
TRIM38 (type I interferons are one of the main products of TLR and cGAS-STRING/viral RNA sensing)
KLHL20
E3-ubiquitin ligases are typically associated with degradation of interferon, but it might not be so cut and dry.
ZNFX1
I'll note that though this is an interferon-stimulated gene, it's activity as a dsRNA sensory would also trigger interferon.
And interestingly, PRDX6, a cousin of PRDX5--which is inhibited by itaconate to allow type I interferon production in macrophages
Itaconate modulates immune responses via inhibition of peroxiredoxin 5 - Nature Metabolism
Itaconate is shown to non-covalently inhibit the antioxidant enzyme peroxiredoxin 5 in macrophages, thereby modulating the production of mitochondrial peroxide and enhancing the type I interferon production.www.nature.com
The BTNs could also be part of the story via their regulatory effect on TLRs. Plus TLR/type I interferon signaling utilizes MAPK signaling, which potentially implicates ZNF322 (increased) and SUDS3 (increased).Plus PTGIS (decreased expression), since prostaglandins are known to inhibit interferon signaling in some contexts.
Just throwing things at a wall to see what sticks based on the assumption that at least some of these genes are actually affected by the identified SNPs. The directionality of most of these (where eQTL data is provided) seems to generally be in the direction of enhanced interferon in ME/CFS (either increased expression in genes that are positive regulators or decreased in genes that are negative regulators), so that would be some weak evidence against the idea that these SNPs are driven by [edit: poorer protection in ME/CFS cases] against viral infections.
[Edit: and acknowledging that I’m probably biased here since I already think there’s a good case for type I interferons in ME/CFS]
jnmaciuch
Senior Member (Voting Rights)
I unfortunately can't give details about projects involving data from another research group, but I can say that I'm already on the case and have reasons to be encouraged so far
(I know, the most annoying response to hear from a researcher!) Speaking in generalities, there are a couple ways this could be assessed depending on the specific hypothesis. Measurements in the blood have turned up nil so far, so if type I interferon is involved, that negative finding at baseline has to be explained.
The options for type I interferon are basically:
1) Interferon only reaches detectable levels in the blood transiently, i.e. during active PEM.
2) Interferon production is limited to certain tissues and does not reach the bloodstream.
It could potentially be a combination of both as well, if interferon production starts from a trigger in the tissue and eventually increases in concentration until it reaches the blood during PEM. One option is to run high-sensitivity assays for interferon on blood samples from pwME in active PEM, which probably would probably be quite difficult to arrange but is potentially doable for a team of able-bodied researchers who can drive around for home visits.
The second option, which could potentially provide more mechanistic insight but would be much more technically involved, is to collect (and possibly culture) cells from the tissues you think are affected and measure interferon before and after some stimulation. Measuring interferon directly can sometimes get difficult depending on your experimental setup, so initial screens might look at the expression of interferon-stimulated genes, which tend to give a more robust signal.
Kitty
Senior Member (Voting Rights)
If they're standard assays, it might not be unsurmountable for moderately affected people with access to a general hospital.
I have to have bloods taken every fortnight at the moment, so I drive 15 minutes to the hospital, park next to it, wheel in to the phlebotomy dept next to the reception desk, take a ticket and wait for my number to come up. The whole thing (waiting included) never takes more than 10 minutes.
It's so streamlined I could do it in pretty nasty PEM. You don't even have to talk to anyone except for giving your DoB; I swear they get paid by the number of vials they fill, they never even look up from what they're doing.
jnmaciuch
Senior Member (Voting Rights)
They’re not standard assays, unfortunately, though if it’s possible to find enough people that can travel while in PEM then sample collection could just happen as normal. If it gets funded by one of the charities maybe they could be convinced to include funds to pay for a driver to make the trek as painless as possible. Or at least one could dream.
This makes intuitive sense to me but that is probably meaningless.
Two thoughts and you've probably already had both of them but just in case you havent:
Chris Armstrong's team are/were doing a study that involved sampling people in active PEM with home visits iirc, so he might be a good person to consult on the logistics of that.
I know LIINC have a lot of tissue samples from pwLC, perhaps they have some of the tissues you theorise are affected? But of course access is a problem and probably not possible to know which test subjects experience PEM.
Anyway glad you're on the case and encouraged that you're encouraged. I look forward to hearing more when you can share it!
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chillier
Senior Member (Voting Rights)
Looking through the candidate list again, I think there's an interesting thread that ties several of the top genes together, which is regulation of type I (alpha/beta) interferon signaling.
OLFM4
No directionality info from eQTLs.
PEBP1
TRIM38 (type I interferons are one of the main products of TLR and cGAS-STRING/viral RNA sensing)
KLHL20
E3-ubiquitin ligases are typically associated with degradation of interferon, but it might not be so cut and dry.
ZNFX1
I'll note that though this is an interferon-stimulated gene, it's activity as a dsRNA sensory would also trigger interferon.
And interestingly, PRDX6, a cousin of PRDX5--which is inhibited by itaconate to allow type I interferon production in macrophages
Itaconate modulates immune responses via inhibition of peroxiredoxin 5 - Nature Metabolism
Itaconate is shown to non-covalently inhibit the antioxidant enzyme peroxiredoxin 5 in macrophages, thereby modulating the production of mitochondrial peroxide and enhancing the type I interferon production.
The BTNs could also be part of the story via their regulatory effect on TLRs. Plus TLR/type I interferon signaling utilizes MAPK signaling, which potentially implicates ZNF322 (increased) and SUDS3 (increased).Plus PTGIS (decreased expression), since prostaglandins are known to inhibit interferon signaling in some contexts.
Just throwing things at a wall to see what sticks based on the assumption that at least some of these genes are actually affected by the identified SNPs. The directionality of most of these (where eQTL data is provided) seems to generally be in the direction of enhanced interferon in ME/CFS (either increased expression in genes that are positive regulators or decreased in genes that are negative regulators), so that would be some weak evidence against the idea that these SNPs are driven by [edit: poorer protection in ME/CFS cases] against viral infections.
[Edit: and acknowledging that I’m probably biased here since I already think there’s a good case for type I interferons in ME/CFS]
One thing I'm trying to get my head around is to what extent the 'immunological' and 'neurological' parts of the genetics story are compartmentalised. For example is there a inteferon response happening within the neurons (or glia) themselves or would something like that be happening elsewhere and affecting neurons through cell interactions etc.
None of these genes here have particular neuron specificity as far as I can tell. However, PEBP1 can supposedly be degraded into ' hippocampal cholinergic neurostimulating peptide (HCNP)'
and KLHL20, much like RABGAP1L and ARFGEF2 regulates vesicle trafficking between in the region between golgi and membrane - and is supposedly involved in neurite development.
Maybe it is significant that the decode genes may moonlight with roles both in neurite development and immunological responses