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

Pyrrhus

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Fine mapping of the major histocompatibility complex (MHC) in ME/CFS suggests involvement of both HLA class I & class II loci (Hajdarevic et al, 2021)
https://pubmed.ncbi.nlm.nih.gov/34403736/
https://www.sciencedirect.com/science/article/pii/S0889159121005092

A genetic analysis from a Norwegian team including Olav Mella and Øystein Fluge, focusing on the Human Leukocyte Antigen (HLA) genes.

What are Human leukocyte antigen (HLA) genes?
  • Human Leukocyte Antigen (HLA) genes are a group of genes that determine how the adaptive immune system responds to threats.
  • There is a large diversity in the HLA genes found in the general population, which means that different people's immune systems respond differently to the same threat. Specifically, this diversity means that different people often have different versions ("alleles") of the same HLA gene.
  • The HLA group of genes is sometimes referred to as the Major Histocompatibility Complex (MHC). (The term "histocompatibility" relates to whether one person can safely donate an organ to another person. If the two people have similar HLA genes, their organs are said to be "histocompatible".)
  • Some HLA genes, called HLA Class I, are involved with intracellular threats, such as viruses.
  • Other HLA genes, called HLA Class II, are involved with extracellular threats, such as most bacteria.
Excerpt:
Hajdarevic et al 2021 said:
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.

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.
 

Pyrrhus

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