PMID- 34403736
OWN - NLM
STAT- MEDLINE
DCOM- 20211210
LR  - 20211214
IS  - 1090-2139 (Electronic)
IS  - 0889-1591 (Linking)
VI  - 98
DP  - 2021 Nov
TI  - 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.
PG  - 101-109
LID - S0889-1591(21)00509-2 [pii]
LID - 10.1016/j.bbi.2021.08.219 [doi]
AB  - 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.
CI  - Copyright (c) 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
FAU - Hajdarevic, Riad
AU  - Hajdarevic R
AD  - Department of Medical Genetics, University of Oslo and Oslo University Hospital, 
      Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway. 
      Electronic address: riad.hajdarevic@medisin.uio.no.
FAU - Lande, Asgeir
AU  - Lande A
AD  - Department of Medical Genetics, University of Oslo and Oslo University Hospital, 
      Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
FAU - Rekeland, Ingrid
AU  - Rekeland I
AD  - Department of Oncology and Medical Physics, Haukeland University Hospital, 
      Bergen, Norway.
FAU - Rydland, Anne
AU  - Rydland A
AD  - Department of Medical Genetics, University of Oslo and Oslo University Hospital, 
      Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
FAU - Strand, Elin B
AU  - Strand EB
AD  - CFS/ME Center, Oslo University Hospital, Oslo, Norway; Faculty of Health, VID 
      Specialized University, Stavanger, Norway.
FAU - Sosa, Daisy D
AU  - Sosa DD
AD  - CFS/ME Center, Oslo University Hospital, Oslo, Norway; National Advisory Unit on 
      CFS/ME, Oslo, Norway.
FAU - Creary, Lisa E
AU  - Creary LE
AD  - Department of Pathology, Stanford University, School of Medicine, Palo Alto, CA, 
      USA; Histocompatibility and Immunogenetics Laboratory, Stanford Blood Center, 
      Palo Alto, CA, USA.
FAU - Mella, Olav
AU  - Mella O
AD  - Department of Oncology and Medical Physics, Haukeland University Hospital, 
      Bergen, Norway; Department of Clinical Science, University of Bergen, Norway.
FAU - Egeland, Torstein
AU  - Egeland T
AD  - Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of 
      Immunology, Oslo University Hospital, Oslo, Norway.
FAU - Saugstad, Ola D
AU  - Saugstad OD
AD  - Department of Pediatric Research, Oslo University Hospital, University of Oslo, 
      Oslo, Norway.
FAU - Fluge, Oystein
AU  - Fluge O
AD  - Department of Oncology and Medical Physics, Haukeland University Hospital, 
      Bergen, Norway; Department of Clinical Science, University of Bergen, Norway.
FAU - Lie, Benedicte A
AU  - Lie BA
AD  - 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.
FAU - Viken, Marte K
AU  - Viken MK
AD  - Department of Medical Genetics, University of Oslo and Oslo University Hospital, 
      Oslo, Norway; Department of Immunology, Oslo University Hospital, Oslo, Norway. 
      Electronic address: m.k.viken@ous-research.no.
LA  - eng
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20210814
PL  - Netherlands
TA  - Brain Behav Immun
JT  - Brain, behavior, and immunity
JID - 8800478
RN  - 0 (HLA Antigens)
RN  - 0 (HLA-DQ Antigens)
RN  - 144515-61-7 (VARS2 protein, human)
RN  - EC 6.1.1.9 (Valine-tRNA Ligase)
SB  - IM
MH  - Alleles
MH  - Canada
MH  - *Fatigue Syndrome, Chronic/genetics
MH  - HLA Antigens
MH  - HLA-DQ Antigens/genetics
MH  - Humans
MH  - Major Histocompatibility Complex
MH  - Valine-tRNA Ligase
OTO - NOTNLM
OT  - HLA fine-mapping
OT  - Human leukocyte antigen
OT  - ME/CFS
EDAT- 2021/08/18 06:00
MHDA- 2021/12/15 06:00
CRDT- 2021/08/17 20:14
PHST- 2021/06/23 00:00 [received]
PHST- 2021/08/04 00:00 [revised]
PHST- 2021/08/09 00:00 [accepted]
PHST- 2021/08/18 06:00 [pubmed]
PHST- 2021/12/15 06:00 [medline]
PHST- 2021/08/17 20:14 [entrez]
AID - S0889-1591(21)00509-2 [pii]
AID - 10.1016/j.bbi.2021.08.219 [doi]
PST - ppublish
SO  - Brain Behav Immun. 2021 Nov;98:101-109. doi: 10.1016/j.bbi.2021.08.219. Epub 2021 
      Aug 14.