Killer cell immunoglobulin-like receptor (KIR) alleles suggested to be associated with [ME/CFS], 2025, Ramadan et al

[Nightsong]

Abstract:
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.

Link (Brain, Behaviour & Immunity, August 2025)

 

[Utsikt]

Discussion​

Our results demonstrate that certain alleles of genes encoding inhibitory KIR (KIR3DL3, KIR3DL2and KIR3DL1) could be involved in the development of ME/CFS.

Our associations are reported with uncorrected P values. If considering the study specific Bonferroni corrected significance threshold of 0.0007, only KIR3DL2*010 remains significant (P = 0.0005). Replication in larger cohorts is necessary to validate our findings, as accumulating datasets is essential for establishing robust genetic …

It’s paywalled, so I don’t know what the rest of the discussion says.

 

[SNT Gatchaman]

It’s paywalled, so I don’t know what the rest of the discussion says.

Here's my quick-summary of passages I highlighted —

Spoiler: Summary quotes

- Alleles of KIR3DL3, KIR3DL2 and KIR3DL1 are associated with ME/CFS

- Associated alleles encode inhibitory KIRs

- NK cell functions are regulated by numerous receptors, including the inhibitory and activating killer cell immunoglobulin-like receptors (KIR), through their interactions with their specific human leukocyte antigen (HLA) class I ligands

- KIR-HLA interactions are also important for the education of NK cells,

- Several KIR genes have shown association with autoimmune diseases, e.g. KIR3DL2 in susceptibility to spondylarthritis

- KIR2DS1 and/or KIR2DS2 in susceptibility to psoriatic arthritis

- KIR genes are highly polymorphic, like the HLA loci

- Only two studies have investigated KIR genes in ME/CFS or CFS

- higher carrier frequency of KIR3DS1 in CFS

- lower carrier frequency of the telomeric KIR A/B haplotype motif combination in patients

- did not replicate the reduced carrier frequency of KIR3DS1

- Notably, several HLA variants have been suggested to be associated with ME/CFS

- HLAC*07:04, which is a C1 ligand for KIR

- Ours is the largest study, to date, of KIR genes in ME/CFS patients (N=418).

- 418 Norwegian ME/CFS patients and 473 healthy controls

- Canadian Consensus Criteria

- genotyped by next generation sequencing

- The Bw4 motif is encoded by the codons in position 77-83 of certain HLA-A and HLA-B alleles that function as a ligand for KIR3DL1

- mean age 39.5 years 72.5% being female

- significant skewed allelic distributions for the framework genes KIR3DL3 (p=0.01)

- Three alleles were more frequent in ME/CFS

- KIR3DL3*002 (OR=1.43, p=0.009), KIR3DL1*020 (OR=2.20, p=0.01) and KIR3DL2*009 (OR=1.56, p=0.01)

- Two alleles had a reduced frequency among patients; i.e. KIR3DL3*013 (OR=0.60, p=0.005) and KIR3DL2*010 (OR=0.46, p=0.0005).

- positively associated alleles are found on a haplotype: KIR2DL4*001~KIR3DL1*020~KIR2DS4*001~KIR3DL2*009 (OR=2.35, p= 0.008)

- did observe a significantly higher presence of Bw480I carriers in ME/CFS patients compared to controls (OR=1.54, p=0.02)

- carriers of Bw480I and KIR3DL1 were more frequent among patients than controls (OR=1.60, p=0.01

- no significant differences were observed for copy number variation of any KIR genes

- Our results demonstrate that certain alleles of genes encoding inhibitory KIR (KIR3DL3, KIR3DL2 and KIR3DL1) could be involved in the development of ME/CFS.

- associations are reported with uncorrected P values

- considering the study specific Bonferroni corrected significance threshold of 0.0007, only KIR3DL2*010 remains significant (P=0.0005)

- Our lack of associations with gene content and copy number variation are in agreement with the study by Huth et al.

- the higher carrier frequency of the KIR3DS1 gene among cases reported by Pasi et al. was not replicated by either Huth et al. or us.

- All three KIR loci with associated alleles in our study encode inhibitory receptors,

- Both KIR3DL3 and KIR3DL2 are framework genes and present in every individual

- the ME/CFS associated KIR3DL1*020 is known as a highly expressed KIR allele

- The Bw4 allotype is a ligand for KIR3DL1, one of the genes we found to be associated with ME/CFS.

- we observe a higher carrier frequency of both Bw4 80Iand KIR3DL1. This specific KIR-HLA interaction has previously been implicated in psoriasis and autoimmune hepatitis

- several KIRs are also expressed on subsets of T cells, even though they were first identified from NK cells

- KIR3DL3, which we found to be associated with ME/CFS, has recently been shown to be enriched in γδ and CD8+ T cells and not NK cells

- in contrast to KIR3DL1 and KIR3DL2 which have HLA class I variants as ligands

- KIR3DL3 has HHLA2 (Human endogenous retrovirus-H Long repeat-associating 2) as ligand

- common viruses like the human cytomegalovirus (HCMV) can shape the NK cell receptor repertoire, including KIRs, and lead to adaptive-like expansion of NK cells giving them distinct functional capabilities

- EBV), where NK cells also seem to have an important role, and where a recent study have shown that differentiated KIR-positive NK cells are those that respond better against cells with lytic EBV replication

- Covid studies: suggested that the activating receptor encoded by KIR2DS2 with its cognate HLA-C1 ligand may have a protective effect against severe infection

- could imply that KIRs have multiple and/or variable roles in different diseases' development and progression. Furthermore, our KIR and previous HLA associations with ME/CFS may support that common infections could trigger the disease.