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

[forestglip]

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):

There were two alleles with a negative association with ME/CFS, suggesting a potential protection, namely B*08:01 (OR = 0.7 [95% CI 0.6–0.9], pnc = 0.01, pc = n.s.) and DPB1*02:01 (OR = 0.7 [95% CI 0.6–0.9], pnc = 0.02, pc = n.s.) (Table 2). These alleles were not in LD (D’ = −0.29), indicating that the associations are independent.

HLA-B*08:01 showed reduced frequency in ME/CFS compared to controls in our material. This allele most often occur on the haplotype C*07:01-B*08:01-DRB1*03:01-DQB1*02:01, which was also less prevalent among ME/CFS patients in our material. This ancestral haplotype, AH8.1, is a risk factor for a wide variety of AID, including myasthenia gravis, systemic lupus erythematosus and coeliac disease31, but protective against rheumatoid arthritis34,35. In the existing literature on HLA and CFS, HLA-DRB1 is the locus most frequently studied. In four out of five studies, the frequency of DR3/DRB1*03 was lower in the patient group23,24,25,28, while in the fifth study the frequency was similar in both groups22. Hence, this haplotype seems truly less prevalent among ME/CFS patients.

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.)

Materials and Methods
HLA classes were genotyped using a next-generation sequencing method in 2322 persons, including 2217 healthy hematopoietic stem cell potential donors and 105 patients with symptomatic COVID-19.

Results
Symptomatic course of SARS-CoV-2 infection appeared to be associated with the presence of HLA-A*30:01, B*44:02, B*52:01, C*05:01, C*17:01, and DRB1*11:02, while HLA-C*07:04 and DQB1*03:03 seem to play a protective role.

Moreover, we demonstrated that the severe symptomatic course of COVID-19 can be associated with the presence of HLA-B*08:01, C*04:01, DRB1*03:01, and DQB1*03:01, while HLA-DRB1*08:01 appeared to be protective against severe COVID-19 disease.

 

[Jonathan Edwards]

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.

 

[wigglethemouse]

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

 

[Simon M]

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.

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.

 

[Jonathan Edwards]

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.

 

[Sasha]

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

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.

 

[Jonathan Edwards]

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?

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.

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

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.

 

[Sasha]

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.

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?

 

[Jonathan Edwards]

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.

 

[hotblack]

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?

 

[Jonathan Edwards]

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.

 

[wigglethemouse]

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

Imputation of classical HLA alleles

The major histocompatibility complex (MHC) on chromosome six is the most polymorphic region of the human genome and contains the largest number of genetic associations to common diseases29. We imputed HLA types at two-field (also known as four-digit) resolution for 11 classical HLA genes (HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DRB3, HLA-DRB4, HLA-DRB5, HLA-DQA1, HLA-DQB1, HLA-DPA1 and HLA-DPB1) using the HLA*IMP:02 algorithm with a multi-population reference panel (Supplementary Tables 5 and 6)30 and validated the accuracy using a cross-validation experiment. In a typical use, case accuracy was estimated at better than 96% across all loci (see Methods and Supplementary Tables 7, 8).

 

[hotblack]

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.

 

[wigglethemouse]

You beat me to it @wigglethemouse

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.

 

[hotblack]

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.

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!

 

[DMissa]

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.

 

[DMissa]

There is this idea that cells in ME/CFS cells have entered a hypometabolic because they feel threatened by something (in the blood).

This is maybe not yet a cast iron fact but let's assume that it's true.

Is this a recognized response tied to the innate immune system? The adaptive immune system? Or a different response alltogether that doesn't have much to do with the immune system, perhaps because it's an evolutionary ancient response that predates the immune system?

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)

 

[Hutan]

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.

I am not yet convinced that the severity of SARS-CoV-2 has much to do with the risk of ME/CFS following it - I don't think we have seen very good evidence for it.

Long Covid is a vague and wide-reaching term. Severe acute illness can cause all sorts of problems that can result in persistent symptoms and therefore a label of Long Covid. Long Covid includes ME/CFS, but it is obviously not the same as it.

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

!

 

[DMissa]

I am not yet convinced that the severity of SARS-CoV-2 has much to do with the risk of ME/CFS following it - I don't think we have seen very good evidence for it.

Long Covid is a vague and wide-reaching term. Severe acute illness can cause all sorts of problems that can result in persistent symptoms and therefore a label of Long Covid. Long Covid includes ME/CFS, but it is obviously not the same as it.

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

 

[Utsikt]

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.

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?