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, by Riad Hajdarevic, Asgeir Lande, Ingrid Rekeland, Anne Rydland, Elin B Strand, Daisy D Sosa, Lisa E Creary, Olav Mella, Torstein Egeland, Ola D Saugstad, Øystein Fluge, Benedicte A Lie, Marte K Viken in Brain Behav Immun. 2021 Aug 14;S0889-1591(21)00509-2 [doi: 10.1016/j.bbi.2021.08.219]

 

Highlights:

  • 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.

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.

Crystallographic structure of HLA-DQA1 (cyan) complexed with HLA-DQB1 (green) & HCRT (magenta) based on PDB: 1uvq​.

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.

 

Riad Hajdarevic says:

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 from 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.

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