Background/Purpose: Killer immunoglobulin-like receptors (KIRs) are expressed predominantly on the surface of natural killer (NK) cells and some T-cells and are important in regulating the inflammatory phenotype of these cell types. The 17 known KIR genes are arranged in variable content haplotypes that differ substantially in composition across the human population. Specific HLA subtypes act as KIR ligands, and the repertoire of HLA and KIR alleles carried has been shown to alter risk for autoimmune or infectious diseases by shifting activation thresholds of cytotoxic NK cells. We aimed to interrogate patterns in, and statistical interactions between, KIR genes and HLA alleles in a large population of individuals with ankylosing spondylitis (AS), in which HLA-B*27 in particular exerts a substantial genetic contribution to disease.

Methods: Gene dosages across KIR loci were imputed from Immunochip genotype data for 10464 AS cases and 15239 control HLA-typed individuals using the statistical package KIR*IMP. Differences in KIR gene content and haplotype composition were assessed, with additional consideration of HLA type used to investigate gene-gene interactions and co-occurrence patterns in cases and controls.

Results: We identified a statistical interaction between the HLA-Bw4 recognising KIR genes KIR3DL1 and KIR3DS1 and HLA-B*27 (a Bw4 type allele). Presence of the NK cell activating receptor KIR3DS1 increased risk of AS in HLA-B*27 positive individuals, but was protective in HLA-B*27 negative individuals (P interaction = 0.007). In contrast, inhibitory receptor KIR3DL1 exhibited the opposite pattern of association, with presence of the gene being protective in HLA-B27 positive individuals but risk predisposing in HLA-B*27 negative individuals (P interaction = 0.002). We observed a suggestive disease association with KIR locus variant rs775859 (P=2×10^-5) and a significant interaction between the variant used to tag the presence of the KIR2DL5 gene and HLA-B*27 (P=3×10^-4), with carriage of both KIR2DL5 and HLA-B27 increasing disease risk. Intriguingly, a significantly lower frequency of KIR2DL5 was also seen in HLA-B*27 positive controls relative to HLA-B27-ve controls (P=0.001, OR=0.81), indicative of evolutionary pressure against this co-occurrence. In HLA-B*27 negative individuals there was a strong interaction between the KIR2DL3 gene and HLA-C*12 (P interaction = 7.1×10^-5).

Conclusion: Interactions between HLA-B*27 and specific KIR receptors may contribute to AS by altering the inflammatory activity of NK cells.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/killer-immunoglobulin-like-receptors-are-associated-with-ankylosing-spondylitis/