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

Andy

Andy

Retired committee member
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.

The most pronounced association in the HLA class I region was with rs4711249. This SNP is most likely not reflecting an association with HLA-C. Interestingly, the association between HLA risk alleles for ME/CFS and cyclophosphamide response was maintained even if we replaced the HLA-C*07:04 allele with the risk allele at rs4711249. However, due to complex LD patterns, it is difficult to conclude that the association maps outside the classical HLA locus, however, the numerous associated SNPs tagged by rs4711249 spans several genes (DDR1, GTF2H4, VARS2, SFTA2 and DPCR1) being candidates for involvement in ME/CFS. Interestingly, rs4711249 genotype was associated with gene expression differences of these surrounding genes in both muscle, brain, blood and nervous tissue. Hence, the risk variant could be a regulatory variant that provide susceptibility to ME/CFS through altering gene expression levels. The VARS2 gene is implicated in several mitochondrial diseases with causative mutations reported for mitochondrial encephalopathy and putative pathogenic variants have been found for mitochondrial respiratory complex deficiencies. [32] [33] This is interesting given the clinical manifestations of ME/CFS and the proposed, but not yet established, alterations of mitochondrial respiratory function related to ME/CFS [34].
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What are they saying about the relationship between HLA class I, rs4711249 and the VARS2 gene?
 
Andy said:
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
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@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:

Hi Anil.
HLA genes are immunologically very important genes. The encoded molecules, besides other things, regulate the bodies recognition of itself. As ME/CFS is hypothesized to have, at least in part, autoimmune features we investigated to see if those genes are associated in ME/CFS patients. The association of those HLA genes is very strong in other autoimmune diseases. We observed association on the genetic level as well as on the amino acid level (since those genes code for certain amino acids). However, this needs to be replicated independently before any conclusion can be drawn from this. We had the largest cohort,so far, diagnosed by the CCC which is definitely good but similar studies in other autoimmune disorders have up to 10x the amount of patients.
We think that this is a good starting point for further larger, consortia type studies.
I am skipping some crucial points here due to limited space but all in all it is a very interesting finding which we will keep on working.
Regards
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Riad Hajdarevic Thank you for explaining. The Norwegian group found HLA genes associations before right? How do your findings add up to the the previous studies including the amino acids as this was found before as well? Sorry the paper is so densed I hope you don't mind me asking.

PS: Maybe you would be interested in joining the discussion on the Science for ME forum. Others scientists do this sometimes as well.

https://www.s4me.info/threads/fine-...ss-i-and-class-ii-loci-2021-hajdarevic.21926/
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Anil van der Zee Hi. Yes, this is a more into depth analysis of that work.
We expanded the analysis and dug deeper into the HLA genetic region.

I am now quite busy writing my second paper on ME so I won't be able to interact in the forum a lot but I will do my best to find some time.
The paper is , indeed, very technical.

I have to stress the point that no conclusion in regards to a clinical application can be made from this work. I think this is important for the patient population to know. However, we are trying to unravel the pathogenesis of ME/CFS through this kind of study.
Cheers
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Source: https://www.linkedin.com/feed/updat...vity:6833712592175935488,6833722337934794752)
 
strategist said:
What are they saying about the relationship between HLA class I, rs4711249 and the VARS2 gene?
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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
 
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
 
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Milo said:
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
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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.
 
Interestingly, HLA-C*07:04 was almost always carried together with the risk allele at rs4711249 on a high-risk haplotype (3.3% in cases vs 1.3 % in controls; p = 0.001). However, the SNP risk allele was also carried on other HLA-Calleles (Supplementary Table 4), and overall haplotypes comprising the rs4711249 risk allele together with non-C*07:04 is still predisposing (15.4% in cases vs 11.5% in controls; p = 0.01).
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It's a bit unclear to me what all this means. The authors note that they lacked statistical power, with samples not being big enough.
 
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