Fine mapping of the major histocompatibility complex (MHC) in (ME/CFS) suggests involvement of both HLA class I and class II loci, 2021, Hajdarevic

Full title: Fine mapping of the major histocompatibility complex (MHC) in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) suggests involvement of both HLA class I and class II loci

Abstract

The etiology of myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is unknown, but involvement of the immune system is one of the proposed underlying mechanisms. Human leukocyte antigen (HLA) associations are hallmarks of immune-mediated and autoimmune diseases. We have previously performed high resolution HLA genotyping and detected associations between ME/CFS and certain HLA class I and class II alleles. However, the HLA complex harbors numerous genes of immunological importance, and there is extensive and complex linkage disequilibrium across the region.

In the current study, we aimed to fine map the association signals in the HLA complex by genotyping five additional classical HLA loci and 5,342 SNPs in 427 Norwegian ME/CFS patients, diagnosed according to the Canadian Consensus Criteria, and 480 healthy Norwegian controls. SNP association analysis revealed two distinct and independent association signals (p≤0.001) tagged by rs4711249 in the HLA class I region and rs9275582 in the HLA class II region. Furthermore, the primary association signal in the HLA class II region was located within the HLA-DQ gene region, most likely due to HLA-DQB1, particularly the amino acid position 57 (aspartic acid/alanine) in the peptide binding groove, or an intergenic SNP upstream of HLA-DQB1. In the HLA class I region, the putative causal locus might map outside the classical HLA genes as the association signal spans several genes (DDR1, GTF2H4, VARS2, SFTA2 and DPCR1) with expression levels influenced by the ME/CFS associated SNP genotype.

Taken together, our results implicate the involvement of the MHC, and in particular the HLA-DQB1 gene, in ME/CFS. These findings should be replicated in larger cohorts, particularly to verify the putative involvement of HLA-DQB1, a gene important for antigen-presentation to T cells and known to harbor alleles providing the largest risk for well–established autoimmune diseases.

Open access, https://www.sciencedirect.com/science/article/pii/S0889159121005092

 

Difficult paper to understand.

What are they saying about the relationship between HLA class I, rs4711249 and the VARS2 gene?

 

@Simon M
can you provide a plain english version - no problem if it takes a while.

 

Just adding the highlights and a quote from the discussion:
• By far the largest genetic study in ME/CFS.

• Multi-level HLA and SNP analysis.

• Independent HLA class I and II associations.

• Positive association of HLA-DQB1 amino acid residue 57D.


In conclusion, we report, to the best of our knowledge, the first HLA fine mapping study in ME/CFS, in an attempt to address a putative immunologic component of the ME/CFS pathogenesis. We observed independent association signals from the HLA class I and class II regions, which encourage future genetic studies of the MHC in ME/CFS.

 

Comments from the author on LinkedIn which he allowed me to share with you:

Source: https://www.linkedin.com/feed/updat...vity:6833712592175935488,6833722337934794752)

 

https://twitter.com/user/status/1428014987583369225

 

Here's an attempt from a noob when it comes to genetic studies:

Because of linkage disequilibrium, it is difficult for the researchers to know what genes the association signals point to. So the authors discuss what the strongest signals their study found, could mean.

One of the clearest signals in the HLA class I region was rs4711249 but the numerous associated SNPs tagged by rs4711249 spans several genes (DDR1, GTF2H4, VARS2, SFTA2 and DPCR1) so it is unclear which of these the signal points to as being involved in ME/CFS.

They explain that the VARS2 gene is implicated in several mitochondrial diseases.

 

Hello I am the first author of the studies. I want to bring some clarity to the paper to you guys.
Our study was trying to see the involvement of HLA genes in ME/CFS. We observed some genetic changes (SNPs) to be associated with ME/CFS across the immunologically important HLA genes.

The patients we analyzed were diagnosed according to the CCC. As you know the CCC are more stringent than the Fukuda or similar criteria. Our patient population was 427 Norwegian ME/CFS patients. This is the largest ME/CFS cohort diagnosed according to the CCC however we need much more (up to 10 x) to definitely make a correlation between our findings and ME/CFS.

So far, no clinical implications can be made from this. However, it is indicative that those genetic changes (SNPs) influenced gene expression of some relevant genes for the observed ME/CFS clinical picture. Likewise, it seems (from this statistically limited data set) that some of those changes correlate with response to cyclophosphamide treatment in patients with ME/CFS. You have heard, I assume, about our collaborator's study form Bergen where they reported improved symptoms for some ME/CFS patients taking the drug.

I just have to emphasize that we need much more research with much, much more patients diagnosed with the CCC to make any deeper assumptions.
If you have any extra questions please let me know I am glad to explain the findings in detail to anyone who wants to know the details.

Thank you

 

Thank you so much for that useful summary @Riad_Hajdarevic and welcome to the forum!

 

Didn't OMF (Ron Davis?) get a NIH grant to sequence HLA? Could have been KIR sequencing of course. Perhaps @Ben H could provide an update?

@Jonathan Edwards views might be interesting re this paper

EDIT - added text - if we're back to proposing autoimmunity then this technique could potentially provide much better tests for autoimmunity or indeed a study to look for target proteins. It's a bit like providing a much better target protein (lure) for autoimmune antibodies - if there are any of course.
*https://www.s4me.info/threads/reap-...-the-human-exoproteome-2021-wang-et-al.20747/

**https://www.biorxiv.org/content/10.1101/2021.02.11.430703v1

 

Thank you so much for explaining, for entering the field of ME research and for coming to the forum. My question to you is, will the DecodeME study (N=20,000) represent an attempt of replication? Tagging @Simon M and @Andy

Best regards from Canada

 

Yea Ron Davis got (5 year) NIH grant back in 2018 - so maybe this is an early indication of where that it is going [Fluge, Mella --- are part of OMF].

Great explanation of HLA from @Simon M here:
https://s4me.info/threads/ron-davis...s-hla-wtf-here’s-the-story-simon-m-blog.4798/

Ron on study here

https://www.youtube.com/watch?v=eQR4zpiyE6I

 

Well, it's not an attempt at replication per se, but it does plan to test association for all HLA loci, so we will be able to see if our results do replicate these findings or not.

 

Hello everyone I wanted to share our latest publication on ME/CFS with you. Please have a look. Also, feel free to contact me if something is unclear. e-mail riad.hajdarevic@medisin.uio.no

https://www.sciencedirect.com/science/article/pii/S0889159122000782?via=ihub

Best Regards

Riad