Killer cell immunoglobulin-like receptor (KIR) alleles suggested to be associated with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating disease with unknown cause. Involvement of infection and immune dysregulation has been suggested, including changes in immune cell subsets and abnormal functions of natural killer (NK) cells. The regulatory NK cell receptors, killer cell immunoglobulin-like receptors (KIR) have previously been investigated in small cohorts of ME/CFS patients with conflicting results regarding gene content. Here, we studied KIR genes also at the allelic level using high-resolution sequencing, in 418 ME/CFS patients and 473 healthy controls. Human leukocyte antigen (HLA) class I genotype data were included for KIR ligand annotation. Our healthy control data represent KIR frequencies for a Norwegian population, which have not previously been reported. We found no association between ME/CFS and KIR gene content or copy number variations. However, our data suggested that specific KIR alleles at loci encoding inhibitory receptors were associated with ME/CFS, which was further supported by allelic haplotype analyses. Three alleles were more frequent in patients, i.e. KIR3DL3*002 (OR = 1.43, 95 % CI (1.09-1.86), p = 0.009), KIR3DL1*020 (OR = 2.20, 95 % CI (1.19-4.06), p = 0.01) and KIR3DL2*009 (OR = 1.56, 95 % CI (1.09-2.23), p = 0.01), while two alleles had a reduced patient frequency, i.e. KIR3DL3*013 (OR = 0.60, 95 % CI (0.42-0.86), p = 0.005) and KIR3DL2*010 (OR = 0.46, 95 % CI (0.30-0.71), p = 0.0005). Our data support an involvement of NK cells in ME/CFS.