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.

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.