Genetics: HLA-DQA*05:01

Of the 8 hits, only 1 was measured, but the others have a high INFO_SCORE suggestion that their distributions follow Hardy-Weinberg Equilibrium.

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Jonathan Edwards said:
Yes, I don't understand how that works.
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I suppose it's based on the strong correlations between SNPs that you only need to know a few to be pretty certain what the others are. But I was quite surprised that the actually measured SNPs are so low (around 5% of the total, apparently).
 
Jonathan Edwards said:
Yes, I don't understand how that works.
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The actual machine that reads the participants' DNA, to make it more afforadable and practical, only actually physically observes a subset of locations on the DNA. In DecodeME, that's 800,000 locations where the output could tell you the actual letter that all the participants' had at these locations. (Though 400,000 were discarded during quality control.)

They then use algorithms and a reference dataset of European individuals who have had many more actual locations/SNPs actually accurately read. It's possible to predict what a DecodeME participant would have at a non-measured location because of LD.

If you only measured SNP1 in DecodeME, and if the reference dataset shows that individuals with SNP1 also almost always have SNP2, you can predict what SNP2 in DecodeME probably is. That's the "imputation" and how you get to around 8,000,000 SNPs in DecodeME.

Then they look at which of these SNPs in the full dataset are related to various genes. Do they cause increased expression of a certain gene? Are they near a gene?

Imputation on Wikipedia:
Genotyping arrays used for genome-wide association studies (GWAS) are based on tagging SNPs and therefore do not directly genotype all variation in the genome. Imputation of the genotypes to a reference panel that has been genotyped for a greater number of variants boosts the coverage of genomic variation beyond the original genotypes. As a consequence, one can assess the effect of more SNPs than those on the original micro-array.
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Jonathan Edwards said:
I am still puzzled.maybe it means that the string of dots up and down for a skyscraper on the Manhattan plot are mostly 'filled in'. But I fail to see how you can fill in a skyscraper unless you have at least one high dot, which, if it is way above background, seems likely to be real.
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How the actual math works, I don't know. But somehow it returns SNPs that are a different significance from the actual measured SNPs.
 
Hoopoe said:
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.
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Sarcoid was for years considered autoimmune and autoimmunity is a feature in some patients. I has now been broadly reclassified as autoinflammatory but with several established HLA predispositions (though I would not be surprised if it was reclassified again one way or another int he future). Generally speaking unknown pathogens are invoked of organic or inorganic nature causing disease in genetically predisposed, there are granulomatous lesions and in some cases fibrosis. The lesionsa and fibrosis is what the doctors concentrate on Biopsy for sarcoid lesions is gold standard but I am not lying when I say that that many, many sarcoid patients suffer from the complaints you list and the source of this phenomenon is elusive. Some may be undiscovered sarcoid involvement disturbing affected organs and inhibiting system wide function e.g. heart, nervous system. However, prediction of function from lesions is not linear. It makes me wonder if there is such aninitiating immune attack on the brain in sarc too. Whether it would have to be persistent or whether on big shock at the start would "derail" the brain I don't know. Maybe a mix. I write as a layperson, I accept sarcoid is not ME, I may over time have (had) both + multiple infections.
 
richie said:
I am not lying when I say that that many, many sarcoid patients suffer from the complaints you list and the source of this phenomenon is elusive.
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I believe you because I've been trying for years to find other diseases that resemble ME/CFS and sarcoidosis was one of the diseases with a PEM-like phenomenon.

The idea is that this information could be useful for differential diagnosis and for narrowing down the cause of PEM. If all these disease are associated with PEM then the cause of PEM must be in something they all have in common (unless the PEM is caused by comorbid ME/CFS that is going undiagnosed, but in this case, it could still be interesting to know what diseases are comorbid with ME/CFS).
 
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Hoopoe said:
I believe you because I've been trying for years to find other diseases that resemble ME/CFS and sarcoidosis was one of the diseases with a PEM-like phenomenon.

The idea is that this information could be useful for differential diagnosis and for narrowing down the cause of PEM. If all these disease are associated with PEM then the cause of PEM must be in something they all have in common (unless the PEM is caused by comorbid ME/CFS that is going undiagnosed, but in this case, it could still be interesting to know what diseases are comorbid with ME/CFS).
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Possibly there are overlaps in mechanism. One thing to note is that among very few (perhaps only ) one trials sarcoid patients showed no worsening on 2 day CPET. Presence of poor 1st day CPET in context of normal PFT has been attributed to heart involvement in sarcoid (if PFT is "normal")
 
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