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.
Highlights
Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) is a disease of unknown etiology and pathogenesis resulting in a variety of symptoms like post exertional malaise (PEM), brain fog, fatigue and pain
Given the complex and extensive linkage disequilibrium (LD) structure of the Major Histocompatibility complex (MHC), we investigated the dependencies between the five tag SNPs of which one is located in the extended human leukocyte antigen (HLA) class I region, three in the HLA class I region, and one in the HLA class II region
We have previously reported that the HLA risk alleles DQB1*03:03 and C*07:04 are associated with response to cyclophosphamide treat ment in ME/CFS patients (Rekeland et al, 2020)
Summary
Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) is a disease of unknown etiology and pathogenesis resulting in a variety of symptoms like post exertional malaise (PEM), brain fog, fatigue and pain. The major genetic determinants for most autoim mune diseases are the human leukocyte antigen (HLA) genes within the Major Histocompatibility complex (MHC) (Trowsdale and Knight, 2013). The extended MHC (7.5 Mb) is typically divided into the extended class I, class I, class III, class II and extended class II subregions, with the classical HLA genes encoding for antigen presenting molecules located in the class I and II subregions These genes harbor variants associated with both susceptibility and protection for numerous auto immune diseases (Trowsdale and Knight, 2013), the hyperpolymorphic properties and extensive linkage disequilibrium (LD) in the region can make it difficult to pinpoint causal genetic variants (Thorsby and Lie, 2005)
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