Sasha
Senior Member (Voting Rights)
All our evidence seems so feeble that I don't have a sense that we even have many definite negatives, let alone definite positives.
Is the key pathology of ME/CFS in bone marrow?
- Thread starter Jonathan Edwards
- Start date
Kitty
Senior Member (Voting Rights)
Do we know if anyone studying lupus has looked at this gene and/or the Xist? Or might be interested in doing so?
Might RBCs be involved, perhaps linked also to ideas of RBC deformability/morphology/volume?
Jonathan Edwards
Senior Member (Voting Rights)
Yes, but if you are looking for an increased risk from a double dose of X genes that is cheating because you are not comparing against an equal number of controls with one dose (men), so you have written the risk ratio out of your study.
I think it is interesting that this is clearly not obvious to everyone. I was surprised by some of the wording from the DecodeME team about this. To me this is obvious. If I am wrong that would be interesting, but I don't think I am.
No, we already know the result. Two XXs confer risk. It might be the absence of Y but the TLR7 type story is much more plausible. There is nothing further to discover.
What we do not know is exactly which genes on X are important - whether TLR7, TLR8 or whatever, but the answer is not going to be in looking for gene variants. The effect is not due to gene variants but chromosome variants, otherwise known as sex.
What a WGS might show is a link to a variant of TLR7. There is a rare variant of TLR7 that links strongly to lupus. That would tell us that TLR7 is relevant but it still does not tell us directly that it is the normal TLR7 on women's XXs that is the major risk for them.
Jonathan Edwards
Senior Member (Voting Rights)
I doubt it. There are likely to be all sorts of confounding factors and collecting material that way is extremely difficult in practical terms.
Something that might be more realistic is imaging along the lines of the study looking for macrophage activation with PET presented at OMF.
Jonathan Edwards
Senior Member (Voting Rights)
We have loads of definite negatives. It is just that people hate to talk about them because they refute hypotheses. They forget that that is the whole point of doing experiments - proving oneself wrong.
Jonathan Edwards
Senior Member (Voting Rights)
Which might be exactly what is relevant, but unquantifiable. "Quite a few red mullet on offer in aisle six today"
Sasha
Senior Member (Voting Rights)
I don't understand - if the sex ratio is the same in both cases and controls, you're not comparing equal numbers (because controls vastly outnumber cases in a GWAS) but you'll be comparing males and females in the same ratio. So if you've got 7,500 female and 2,500 male cases and 75,000 female and 25,000 controls...? What am I missing? You'd compare the Fs with the Fs and the Ms with the Ms, surely?
Wouldn't a repeat of TLR7 be indicative, rather than just a rare variant?
Jonathan Edwards
Senior Member (Voting Rights)
I don't. The fact that these people did controls looking specifically for an X dose effect makes me think this has been done before and lupus would be the obvious one to do.
My guess is that it is the TLR7 that is interesting. Xist is involved in controlling the dose effect of XX. I suspect it is just doing what it would always do and that includes letting TLR7 levels reflect XX double dose. The more relevant question would be whether TLR7 is just one of a whole casette of genes that can benefit from a double dose and the important one is something else. Maybe the data inform that but I have yet to wade through the whole paper.
Sasha
Senior Member (Voting Rights)
Just picked up the latest copy of MERUK's Breakthrough magazine and there's what seems a very relevant study by a Dr Manousaki starting up:
Chromosomes carry our genetic information and, typically, females have two X chromosomes while males have one X and one Y chromosome. In females, one of the X chromosomes is inactivated in each cell in order to avoid a double-dose of X-linked genes.
X chromosome inactivation (XCI) therefore needs to be maintained throughout life, and disruption of this can lead to developmental problems and diseases, including those affecting the immune system, such as systemic lupus erythematosus. There is also reason to suspect that dysregulation of XCI could affect the function of the mitochondria, the powerhouses of the cell.
Objectives
Dr Manousaki’s research will test the idea that, in ME/CFS, XCI is not being maintained correctly. This could lead to abnormal levels of certain X-linked genes, disrupting immune balance and energy production in cells.
This mechanism could therefore explain the higher prevalence of ME/CFS in females than in males. Dr Manousaki plans to investigate this using super-resolution microscopy and gene expression analysis.
She will first assess whether XCI is dysregulated in women with ME/CFS, specifically looking at genetic factors which regulate XCI and may therefore have value as a diagnostic biomarker.
She will also investigate whether cells from men and women with ME/CFS struggle to generate and use energy efficiently, analysing mitochondrial structure and its interactions with associated endoplasmic reticulum contact sites which have been implicated in other diseases such as Alzheimer’s and Parkinson’s diseases.
Finally, linking these two areas, Dr Manousaki will test whether XCI disruption can directly cause mitochondrial dysfunction, linking the genetic findings with cellular energy problems and exploring whether these effects differ between men and women.
Jonathan Edwards
Senior Member (Voting Rights)
The basic point I think. Maybe someone else can explain.
But you are wanting to compare females with males because you are wanting to explain the difference in ME/CFS incidence in those two groups.
You can repeat the TLR7 just by asking the subjects to tick the M/F box on a questionnaire. No need even to take a sample. The girls have two and the boys have one, and that explains why the girls are more at risk.
Jonathan Edwards
Senior Member (Voting Rights)
I don't see RBCs as relevant to this line of thought, no. They may contribute nuclear debris to innate immune scavenging mechanisms in bone marrow but otherwise they don't really have an immune role.
Jonathan Edwards
Senior Member (Voting Rights)
We have a thread on that study.
I am sceptical that there is any need to talk about 'disruption' of X silencing. I suspect that certain genes, like TLR7, may just not be silenced all the time or possibly any of the time. If diseases like lupus or ME/CFS are shown to be linked to variants of Xist then that might be true, but again, that would explain a different question (assuming that 90% of women have a usual Xist and are still more likely to get ME/CFS).
I wasn't thinking about any immune role RBCs might have. I was more thinking if RBC deformability/etc has some merit in explaining ME/PEM, might bone marrow problems play into that.
Sasha
Senior Member (Voting Rights)
But is anything stopping you from comparing females with males?
Jonathan Edwards
Senior Member (Voting Rights)
No, but you said that you had to compare females with females. You do to look for effects of gene variants but not for effects of X chromosomes.
Utsikt
Senior Member (Voting Rights)
How do you even do a study on the effects of X chromosomes? Can you just compare the rates between equal groups of men and women?
Jonathan Edwards
Senior Member (Voting Rights)
Yes, it is that simple, if you ignore the rare cases of testicular feminisation etc.
Interesting.
General musculoskeletal pain, often very serious, has always been a major and almost constant feature for me. It has what feels like a very deep component, like it is underneath the muscle, and the bones themselves are hurting.
Would bone marrow experiencing altered pressure dynamics be consistent with that?