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. — CFSMEATLAS
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.
Hajdarevic, Riad, Lande, Asgeir, Rekeland, Ingrid et al. · Brain, behavior, and immunity · 2021 · DOI
Quick Summary
This study looked at genes related to the immune system in people with ME/CFS to understand why some people develop the condition. Researchers compared genetic markers in 427 Norwegian ME/CFS patients with 480 healthy controls and found two specific genetic regions associated with ME/CFS—one involving immune system genes that present antigens to cells, and another in a different immune region. These findings suggest the immune system's ability to recognize and respond to threats may play a role in ME/CFS.
Why It Matters
This is one of the first studies to systematically identify specific genetic regions associated with ME/CFS susceptibility, providing evidence for an immune-mediated component of the disease. If replicated, these findings could lead to better understanding of disease mechanisms, improved diagnostic approaches, and potentially targeted treatments based on immune system biology.
Observed Findings
Two independent ME/CFS-associated SNPs identified: rs4711249 (HLA class I region) and rs9275582 (HLA class II region)
HLA-DQB1 gene implicated in class II signal, particularly amino acid position 57 polymorphisms in the peptide-binding groove
HLA class I signal spans five genes (DDR1, GTF2H4, VARS2, SFTA2, DPCR1) with expression levels influenced by the associated SNP
Association signals remain distinct and independent after fine-mapping analysis
Inferred Conclusions
The MHC region, particularly HLA-DQB1, is involved in ME/CFS susceptibility
Both HLA class I and class II immune pathways may contribute to disease mechanisms
HLA-DQB1's role in antigen presentation suggests potential autoimmune or immune recognition components in ME/CFS pathogenesis
The HLA class I signal may involve regulatory variants affecting multiple genes rather than classical HLA proteins alone
Remaining Questions
Do the identified HLA variants increase ME/CFS susceptibility in non-Scandinavian populations, or is this a population-specific association?
Which of the five genes in the HLA class I region (DDR1, GTF2H4, VARS2, SFTA2, DPCR1) is causally responsible for the association signal?
What This Study Does Not Prove
This study does not prove that HLA variants cause ME/CFS—it demonstrates association only, not causation. The findings are specific to a Norwegian population and must be confirmed in other populations before broader conclusions can be drawn. The study also does not establish which genes in the identified regions are actually responsible for disease susceptibility, as multiple genes show associations.