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[CFS-L] Histocompatibility complex (MHC) in ME/CFS

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Source: Brain, Behavior, and Immunity
        Preprint
Date:   August 14, 2021
URL:    
https://www.sciencedirect.com/science/article/pii/S0889159121005092


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
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Riad Hajdarevic(1), Asgeir Lande(2), Ingrid Rekeland(3), Anne Rydland
(2), Elin B Strand(4), Daisy D Sosa(5), Lisa E Creary(6), Olav Mella
(7), Torstein Egeland(8), Ola D Saugstad(9), Oystein Fluge(7),
Benedicte A Lie(10), Marte K Viken(11)
1 Department of Medical Genetics, University of Oslo and Oslo
  University Hospital, Oslo, Norway; Institute of Clinical Medicine,
  University of Oslo, Oslo, Norway.
2 Department of Medical Genetics, University of Oslo and Oslo
  University Hospital, Oslo, Norway; Institute of Clinical Medicine,
  University of Oslo, Oslo, Norway.
3 Department of Oncology and Medical Physics, Haukeland University
  Hospital, Bergen, Norway.
4 CFS/ME Center, Oslo University Hospital, Oslo, Norway; Faculty of
  Health, VID Specialized University, Stavanger, Norway.
5 CFS/ME Center, Oslo University Hospital, Oslo, Norway; National
  Advisory Unit on CFS/ME, Oslo, Norway.
6 Department of Pathology, Stanford University, School of Medicine,
  Palo Alto, CA, USA; Histocompatibility and Immunogenetics Laboratory,
  Stanford Blood Center, Palo Alto, CA, USA.
7 Department of Oncology and Medical Physics, Haukeland University
  Hospital, Bergen, Norway; Department of Clinical Science, University
  of Bergen, Norway.
8 Institute of Clinical Medicine, University of Oslo, Oslo, Norway;
  Department of Immunology, Oslo University Hospital, Oslo, Norway.
9 Department of Pediatric Research, Oslo University Hospital,
  University of Oslo, Oslo, Norway.
10 Department of Medical Genetics, University of Oslo and Oslo
  University Hospital, Oslo, Norway; Institute of Clinical Medicine,
  University of Oslo, Oslo, Norway; Department of Immunology, Oslo
  University Hospital, Oslo, Norway.
11 Department of Medical Genetics, University of Oslo and Oslo
  University Hospital, Oslo, Norway; Department of Immunology, Oslo
  University Hospital, Oslo, Norway.
* Corresponding authors. Email: riad.hajdarevic@medisin.uio.no and
  m.k.viken@ous-research.no

Received 23 June 2021
Revised 4 August 2021
Accepted 9 August 2021
Available online 14 August 2021.


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.

Keywords: ME/CFS, human leukocyte antigen, HLA fine-mapping

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(c) 2021 Elsevier B.V.

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[CFS-L] Histocompatibility complex (MHC)  in ME/CFS fluks@COMBIDOM.COM (Dr. Marc-Alexander Fluks) - 2021-08-18 03:44 -0700

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