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Genetics: HLA-DQA*05:01
- Thread starter forestglip
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Yann04
Senior Member (Voting Rights)
Interesting given they didn’t actually measure DQA1*05:01
As far as I understand they inferred its value by imputation (using linkage disequilibrium) which is ever more interesting and confusing given it didn’t return the expected associations with other linkages.
I hope we will get some higher resolution data from SequenceME to clear this up.
jnmaciuch
Senior Member (Voting Rights)
Also interesting that the allele is protective—if it was a risk allele you could feel more comfortable assuming that the gene is involved in the disease somehow, either as mediator or part of a trigger.
But a protective allele for HLA doesn’t lend itself to easy interpretation. Coupled with some of the other hits, the most straightforward interpretation seems to say that a couple genes that enhance viral protection across different facets of the immune system make it slightly less likely to develop ME/CFS. It’s certainly a different story than what HLA hits usually indicate in other diseases, at the very least.
But a protective allele for HLA doesn’t lend itself to easy interpretation. Coupled with some of the other hits, the most straightforward interpretation seems to say that a couple genes that enhance viral protection across different facets of the immune system make it slightly less likely to develop ME/CFS. It’s certainly a different story than what HLA hits usually indicate in other diseases, at the very least.
ME/CFS Science Blog
Senior Member (Voting Rights)
Apologies if this is a stupid question but how do you know which SNPs are measured and which ones are imputed? Do they mention this somewhere in the text or is it somewhere in the data?
Just in case there's a connection, this other study found other suggestive (not significant after correction) protective HLA alleles (one of which, interestingly, it says, is protective against rheumatoid arthritis):
Human Leukocyte Antigen alleles associated with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Fluge, Mella et al 2020
Paper said:
Paper said:
Yann04
Senior Member (Voting Rights)
I have no idea sorry. That comment was the very limit of my blurry understanding.
Utsikt
Senior Member (Voting Rights)
If I’ve found the correct gene here, I’ve got a few thoughts.
If you couple that with some genes that makes T cells behave a bit differently, it might be the foundation of @Jonathan Edwards hypothesis.
I suppose a reduced ability to fight viruses also could fit with a viral persistence hypothesis.
If the proteins that are supposed to pick up foreign proteins and present them to T cells, actually function worse in ME/CFS, could it be that this makes them more prone to pick up junk and try to present the junk to T cells?
If you couple that with some genes that makes T cells behave a bit differently, it might be the foundation of @Jonathan Edwards hypothesis.
I suppose a reduced ability to fight viruses also could fit with a viral persistence hypothesis.
Well this specific allele from the study seems to protect against getting ME/CFS, which I don't think would fit with that. Maybe it's more like it's good at presenting a specific virus to T cells that is a common cause of ME/CFS and this fights the infection more quickly?
Yann04
Senior Member (Voting Rights)
Does Decode ME have the data of what infection agent people report triggered ME? Stratifying by that vis à vis this allele could be interesting.
Yeah, that could be good. They just have EBV, COVID, or other (columns are females, males, total, and total percent)
Hoopoe
Senior Member (Voting Rights)
The genetic findings and the lack of autoantibodies seem to say that roughly the following might be occurring:
An immune response against pathogens leads to the side effect of a non-antibody mediated immune attack against the brain.
Presumably parts of the brain that are especially involved in regulating the various processes that are affected in ME, handling upright posture, fatigue, recovering from exertion, processing sensory stimuli, etc. Presumably the immune attack is mild but enough to cause persistent problems and dysregulation.
An immune response against pathogens leads to the side effect of a non-antibody mediated immune attack against the brain.
Presumably parts of the brain that are especially involved in regulating the various processes that are affected in ME, handling upright posture, fatigue, recovering from exertion, processing sensory stimuli, etc. Presumably the immune attack is mild but enough to cause persistent problems and dysregulation.
Utsikt
Senior Member (Voting Rights)
I might have misunderstood something then.
I thought the gene that’s protective against ME/CFS is also associated with a more effective response to viruses and bacteria?
So not having a better ability to pick up the right peptides, makes you more likely to have ME/CFS.
Have I got it all backwards?
Are you referring to a different gene in the main part of the study? This HLA part was looked at separately and they found another protective gene here (though they say they'll need to verify the association is correct).
Jonathan Edwards
Senior Member (Voting Rights)
I am not sure that a protective effect of an MHC allelle is particularly puzzling. After all, the whole idea of having polymorphic MHC genes with lots of different alleles is that each one in preserved in evolution because it lowers risk of some infection or other.
B27 lowers risk of AIDS and some other infections. Interesting to see that Fluge and Mella picked up on a potential protective effect of HLA A1,B8, C7.01, DR3, DQB1 0201. Judging by discussions with Chris at advisory board meetings there are complications to the interpretation here that would be worth laying out in detail. It sounds pretty certain that the Fluge and Mella findings are compatible with the DecodeME findings on the basis the for DQ risk with one allele inherently implies protection from others (they mean the same thing).
Something that I realised looking at diseases associated with DQ is that although some of them appear to involve antibody and B cells they do so in a way that is not typical of autoimmunity. In MS B cells seem to be important and there are oligoclonal CSF IgG bands but no obvious single autoantibody specificity has emerged. In coeliac, uniquely, the T cell response appears to be against a specific foreign antigen, gluten, with antibodies to self tansglutaminase. In narcolepsy it is still rather unclear where DQ fits in. Even in type 1 diabetes the story remains rather unclear.
ME/CFS might involve some similarly atypical 'auto-responsive' process but, as said, a weak protective role for a DQ allele is very unlike the very strong risk roles for speific alleles in the above diseases.
I am tempted to think that if anything a DQ signal is nudging things towards the more innate side of T cell recognition, which can use DQ, as seen with MAIT cells and gamma delta cells. It may just indicate a non-specific threshold effect due to perhaps binding outside of the traditional active site but even if it just does that it maybe should not be ignored.
B27 lowers risk of AIDS and some other infections. Interesting to see that Fluge and Mella picked up on a potential protective effect of HLA A1,B8, C7.01, DR3, DQB1 0201. Judging by discussions with Chris at advisory board meetings there are complications to the interpretation here that would be worth laying out in detail. It sounds pretty certain that the Fluge and Mella findings are compatible with the DecodeME findings on the basis the for DQ risk with one allele inherently implies protection from others (they mean the same thing).
Something that I realised looking at diseases associated with DQ is that although some of them appear to involve antibody and B cells they do so in a way that is not typical of autoimmunity. In MS B cells seem to be important and there are oligoclonal CSF IgG bands but no obvious single autoantibody specificity has emerged. In coeliac, uniquely, the T cell response appears to be against a specific foreign antigen, gluten, with antibodies to self tansglutaminase. In narcolepsy it is still rather unclear where DQ fits in. Even in type 1 diabetes the story remains rather unclear.
ME/CFS might involve some similarly atypical 'auto-responsive' process but, as said, a weak protective role for a DQ allele is very unlike the very strong risk roles for speific alleles in the above diseases.
I am tempted to think that if anything a DQ signal is nudging things towards the more innate side of T cell recognition, which can use DQ, as seen with MAIT cells and gamma delta cells. It may just indicate a non-specific threshold effect due to perhaps binding outside of the traditional active site but even if it just does that it maybe should not be ignored.
jnmaciuch
Senior Member (Voting Rights)
I don't think they really suggest that, they just say that having some alleles that generally have been linked to neuronal or immune cell functioning make one slightly more likely to develop ME/CFS for reasons unknown. On their own, they don't give hints to pathophysiology. Disappointing, I know, but caution is warranted in over-interpreting evidence
jnmaciuch
Senior Member (Voting Rights)
That would be my guess. Combined with the RABGAP1L finding as well, it seems like we have a set of genes that generally have to do with susceptibility to the trigger. Which may be more or less separate from the actual disease process
Utsikt
Senior Member (Voting Rights)
I’m referring to the one in the title, based on the link in the first comment I wrote.
@jnmaciuch said that the allele is protective. And the page I linked said that the HØA-DQA1 genes are involved in getting MHC class II cells to pick up and present the right proteins to the other immune cells, especially related to viruses and bacteria.
If you have more of that gene, you’re better at picking up the right proteins and you have a lower chance of getting ME/CFS. Which I took to mean that if you have less of that gene, you’re worse at picking up and presenting the right proteins. And I thought that maybe the way you’re worse at it, is that you more often pick up the wrong proteins, i.e. junk (can’t pick up virus proteins if you’ve already got something else).
If this junk then gets presented to T cells (or some other immune cells), and they also have a slight inclination to react more often to junk, you might end up with JE’s hypothesis.
Maybe. In theory this could mean people with ME/CFS have other HLA alleles that are good at presenting junk. But HLA alleles are different from regular DNA since there are very many possible HLA alleles, plus each person has several different alleles. So not having this gene doesn't necessarily mean they do have a specific other gene that is presenting junk.
If there was a specific junk allele, it should be significant on its own, as opposed to the protective allele being significant.
I'm not positive I've got that right though.
Jonathan Edwards
Senior Member (Voting Rights)
I think the accepted rationale for having lots of MHC alleles in a gene pool is that being good at presenting one lot of peptides is inevitably going to come with being not so good at other peptides, just as Yale keys are good for Yale locks but by the same token no good for Ingersoll.
Immunologists spend a lot of time trying to track down individual 'bad peptides' - as in the putative 'arthritogenic peptide' that probably does not exist in ank spond. What needs to be considered is that MHC alleles may differ in quite a broad way in presentation repertoire. They may be very good, or no good, at presenting peptides whose arginines have been citrullinated, for instance. Alleles like B27 may just be a bit gluier generally, so protect against loads of things but also risk overstepping a threshold with autoinflammatory disease.
In other words just about any variation in DQ could link to a story of protection or risk for ME/CFS.
Immunologists spend a lot of time trying to track down individual 'bad peptides' - as in the putative 'arthritogenic peptide' that probably does not exist in ank spond. What needs to be considered is that MHC alleles may differ in quite a broad way in presentation repertoire. They may be very good, or no good, at presenting peptides whose arginines have been citrullinated, for instance. Alleles like B27 may just be a bit gluier generally, so protect against loads of things but also risk overstepping a threshold with autoinflammatory disease.
In other words just about any variation in DQ could link to a story of protection or risk for ME/CFS.
Hoopoe
Senior Member (Voting Rights)
That strikes me as unintuitive.
ME/CFS is triggered by a variety of pathogens and my intuition tells me that while specific genetic vulnerabilities for ME/CFS would certainly exist for each of these pathogens, they wouldn't be among the top hits in a GWAS. Variants related to disease process would dominate because these are what ME/CFS patients tend to have in common.
Maybe my mental model is wrong. I'm just an amateur that can't stop thinking about these things.