Killer immunoglobulin-like receptor interactions with human leukocyte antigen ligands are associated with ankylosing spondylitis — ASN Events
  1. Schedule
  2. Poster Session One & Burnet Oration Cocktail Function
  3. Killer immunoglobulin-like receptor interactions with human leukocyte antigen ligands are associated with ankylosing spondylitis

Killer immunoglobulin-like receptor interactions with human leukocyte antigen ligands are associated with ankylosing spondylitis (#237)

Aimee L Hanson 1 , Kim-Anh Le Cao 2 , Tony J Kenna 3 , Matt A Brown 3
  1. Diamantina Institute, University of Queensland, Brisbane, QLD, Australia
  2. School of Mathematics and Statistics, University of Melbourne, Melbourne, VIC, Australia
  3. Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia

Killer immunoglobulin-like receptors (KIRs) found predominantly on natural killer (NK) cells have both activating and inhibitory functionality. HLA subtypes are KIR ligands, and the inherited repertoire of HLA and KIR alleles can alter risk for autoimmune or infectious diseases. Certain HLA presented peptides can perturb or facilitate KIR ligand recognition, and may play a role in modulation of KIR signaling. We interrogated statistical interactions between KIR genes and HLA alleles inherited in individuals with ankylosing spondylitis (AS), an inflammatory arthritis in which HLA-B*27 contributes substantially to disease risk and the HLA class I peptide presentation pathway is strongly implicated in disease. KIR and HLA dosages were imputed from Immunochip genotype data for 8888 AS cases and 13306 healthy controls using KIR*IMP and HLA*IMP03. We identified a statistical interaction between KIR2DL5 and HLA-B*27 (Pint=0.01); with HLA-B*27+KIR2DL5+ genotype increasing disease risk (OR=1.14, P=0.04) over HLA-B*27+KIR2DL5-, however KIR2DL5 did not influence risk in those lacking HLA-B*27 (OR=0.96, P=0.14). KIR2DL5+ controls had a significantly lower frequency of HLA-B*27 (8%) than KIR2DL5- controls (9.5%, P=0.004), suggesting evolutionary pressure acting against the co-occurrence of these factors. The inhibitory receptor KIR3DL1 that engages HLA-Bw4 subtypes (including HLA-B*27) interacted with disease-associated amino acids in the peptide binding grove of HLA-B, including Lys70 (Pint=0.004) and Asn97 (Pint=0.007). Individuals with disease predisposing HLA-B alleles were at a decreased risk of disease if also carrying KIR3DL1. KIR3DL1 also interacted with the AS-associated polymorphism rs30187 in the aminopeptidase ERAP1, an enzyme that processes peptides for HLA class I presentation. In individuals lacking KIR3DL1, the rs30187 risk allele had no effect on disease risk (Pint=0.02). Interactions between HLA and specific KIR genes may contribute to AS by altering the inflammatory activity of KIR expressing cells, and may provide an explanation for the involvement of HLA-B*27 and ERAP1 in disease.

#ASI2017QLD