Human Leukocyte Antigen alleles associated with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Fluge, Mella et al 2020

Apart from the HLA alleles associated with an increased risk of ME/CFS (mainly HLA-C*07:04 and HLA-DQB1*03:03), they discuss two that appear to have a protective effect (but not significant after multiple test correction):

Interestingly, both of the ME/CFS risk alleles were found to be associated with a decreased risk of symptomatic COVID, and one of the protective alleles for ME/CFS was found to be associated with an increased risk of severe COVID.

Associations Between Clinical Manifestations of SARS-CoV-2 Infection and HLA Alleles in a Caucasian Population: A Molecular HLA Typing Study (2024, J. Clin. Med.)

 

It will be interesting to see what further genetic studies show in the MHC.
We have tended to park the Fluge and Mella study on the 'maybe' shelf. Maybe it was telling us something important. The negative association with B8 would be very interesting if confirmed. HLA-C comes up for psoriasis but is otherwise a bit of a dark horse - so intriguing.

 

Just a reminder that there was a follow up to the 2020 MHC paper.
Fine mapping of the major histocompatibility complex (MHC) in (ME/CFS) suggests involvement of both HLA class I and class II loci, 2021, Hajdarevic

 

DecodeME is looking at HLA. For Technical reasons, it needs to run a different kind of analysis for HLA It’ll be interesting to see if the HLAs flagged by this paper show up when the results finally appear.

 

Exactly. All we need is an interpretable MHC result and we are home and dry - an immunologically mediated disease.

My memory is that the smaller Leeds Biobank cohort drew a blank but I think we are beginning to see how dilute that cohort might have been.

 

If that happens, will PwME who've got DNA data (for example, from 23&me) be able to check it to see if they have that disease? If a clear DNA signal emerges, I think everyone is going to be desperate to know whether they're inside the camp.

Is it likely that the NHS would start testing people's DNA to see if they fit?

I'm wondering what will happen to people who don't fit the pattern.

I don't know that we're ready for any of this.

 

No, absolutely not. RA is strongly associated with DR4 and that told us something about the mechanism but loads of people with RA are not DR4. It has nothing to do with individuals.

Being female is genetically associated with ME/CFS. That doesn't mean that all women have ME/CFS and no men do.

The question simply isn't relevant. But it is reasonable to raise it because the Zhang group paint the picture as if it is. That is one of my big worries about the way they have analysed their findings.

 

So it would be basically showing that PwME tend more than most to have genes that tend to allow Biological Mechanism X go wrong, but Mechanism X could go wrong in pretty much anybody if they get hit hard enough with a virus or other immune shock, or if they are malnourished or otherwise generally vulnerable?

 

Yes.

 

Oh this is exciting!

DecodeMe is looking at SNPs, these are if I understand common (as opposed to rare) variations of single nucleotides within the DNA. So it’s looking for patterns of common variants within the population of people with ME.

I guess since the MHC/HLA (the bit of the DNA that is involved in coding for the cellular self identification in the immune system) is deliberately so diverse, with us all practically having our own repertoire (like the B cell repertoire discussed in Audrey Ryback’s paper) we’re looking for or hoping for some common patterns to show up here? Is that right or have I butchered something in my understanding?

 

I think that is right. If ME/CFS has genetic links to MHC it is a problem with adaptive immunity, and if it doesn't it almost certainly isn't, I would say. As you say, the diversity of MHC genes makes it as close to a litmus test as could be. It is going to be either red or blue. If there is a link it may be modest but that doesn't matter. It might also be multiple - which the Fluge and Mella study suggests. A combination of Class I and Class II linkages, if confirmed, would be particularly intriguing. There are some autoimmune diseases with combined linkage but probably due to common haplotypes in linkage disequilibrium - the Class I genes may be along for the ride.

 

This sounds promising. Quote from The UK Biobank resource with deep phenotyping and genomic data, 2018, Bycroft et al

Imputation of classical HLA alleles

 

Great, thanks @Jonathan Edwards. I suppose that’s what this paper was doing too. It can take a while for the teeth in the cogs to click into place for me but it’s nice when they do.

When learning about the MHC I was interested that Class II crop up in endothelial cells, given the issues reported there in some papers. Do you think this could be relevant?

You beat me to it @wigglethemouse After @Simon M ’s post I wondered if this was new information about what DecodeME is looking at, turns out not at all, more a case of something I didn’t understand when first looking at their analysis plan. But thought the reference and paper may be of interest to others.

 

Thanks for posting that thread. I wondered how could a generic array sequencing chip used in GWAS accurately report on HLA and was somewhat reassured that they matched the patterns of their "imputed" HLA data to data from genetic studies in a number of diseases. DecodeME uses the exact same array technology I believe.

I wonder what happened to the 400 samples Dr Jose Montoya sequenced for HLA (with Mark Davis team I think) about 10 years ago. There were some write-ups on Health Rising about it.

There has been quite a bit written about a follow-up of the Montoya data by the Ron Davis team. I wonder if they ran out of funds as it might have been rather ambitious to run three major projects on one NIH grant during the height of the pandemic.

 

Glad you found it useful. It’s all a bit beyond me to be honest, but I find it interesting. It sounds as if this is a process for inferring information on most but perhaps not all HLA genes? So there’s some room for error and it may not be complete. I guess we’d need SequenceME for that.

This paper seems to describe the process
https://pmc.ncbi.nlm.nih.gov/articles/PMC8837514/
And this another with an alternative algorithm
https://www.nature.com/articles/s41467-021-21541-5
I’ll post them properly tomorrow. Time for bed now!

 

even if there is no ME-specific mechanism I am certain that HLA alleles would contribute towards ME/CFS susceptibility even if it is as little as increasing one's tendency towards experiencing more severe illness with eg viral infection.

My reasoning is that particular HLA alleles associated with different severity of (or even asymptomatic) SARS-CoV-2 infection have been identified and that LC is associated with more severe illness during the acute infection.

But yes the more interesting and less easily answered question is whether there is a more specific mechanism at play.

 

something seems to be going on with cell survival processes in circulating PBMC in both ME/CFS and LC - stay tuned

(and in pre-empting the Jonathan Edwards/Snow Leopard "PBMCs aren't doing anything" reply, I'm not saying that it's driving the disease but there is a detectable feature here. The cause or clinical relevance of it remain unknown. Comment is intentionally vague)

 

This is true. I didn't say it for whatever reason (I blame sleep) but my thinking also stems from the idea that being hit "hard enough" by whatever trigger or combination of triggers leads to ME/CFS would fit with having a more severe infection.

And trust me, I spend most days drilling it into anyone who will listen that the LC label is broadly encompassing different clinical pictures with likely different pathologies

 

What then about getting ME/CFS following a relatively mild infection, or even a gradual onset of ME/CFS without any discernible «trigger»?

And with the more serious infections - do we know that the severity of the symptoms is caused by the infection, or could it just be a lot of ME/CFS from the get go?

Is ME/CFS something that develops over time, or could you pick it up overnight?