Epistatic interactions between killer immunoglobulin-like receptors and human leukocyte antigen ligands are associated with ankylosing spondylitis

Author summary Cells of the immune system utilise various cell-surface receptors to differentiate between healthy and infected or malignant cells, enabling targeted inflammatory responses while minimising damage to self-tissue. In instances where the immune system fails to correctly differentiate healthy from diseased tissue, or inflammatory activity is poorly regulated, autoimmune or autoinflammatory conditions can develop. Here we have investigated a possible role for a class of immune-cell activating and inhibitory receptors in the pathogenesis of ankylosing spondylitis (AS), a common but poorly understood inflammatory arthritis in which the immune system causes severe damage to the joints of the pelvis and spine. Using genetic information from 12,214 healthy controls and 8,107 individuals with AS we were able to identify combinations of independently inherited immune cell receptors and their ligands that increase or decrease an individual's risk of disease. This research provides new insight into the nature of co-inherited genetic factors that may collectively alter the proinflammatory capacity of immune cells, contributing to the immunopathogenesis of immune-mediated diseases. The killer immunoglobulin-like receptors (KIRs), found predominantly on the surface of natural killer (NK) cells and some T-cells, are a collection of highly polymorphic activating and inhibitory receptors with variable specificity for class I human leukocyte antigen (HLA) ligands. FifteenKIRgenes are inherited in haplotypes of diverse gene content across the human population, and the repertoire of independently inheritedKIRandHLAalleles is known to alter risk for immune-mediated and infectious disease by shifting the threshold of lymphocyte activation. We have conducted the largest disease-association study ofKIR-HLAepistasis to date, enabled by the imputation ofKIRgene andHLAallele dosages from genotype data for 12,214 healthy controls and 8,107 individuals with theHLA-B*27-associated immune-mediated arthritis, ankylosing spondylitis (AS). We identified epistatic interactions betweenKIRgenes and their ligands (at bothHLAsubtype and allele resolution) that increase risk of disease, replicating analyses in a semi-independent cohort of 3,497 cases and 14,844 controls. We further confirmed that the strong AS-association with a pathogenic variant in the endoplasmic reticulum aminopeptidase geneERAP1, known to alter the HLA-B*27 presented peptidome, is not modified by carriage of the canonical HLA-B receptor KIR3DL1/S1. Overall, our data suggests that AS risk is modified by the complement ofKIRs andHLAligands inherited, beyond the influence ofHLA-B*27alone, which collectively alter the proinflammatory capacity of KIR-expressing lymphocytes to contribute to disease immunopathogenesis.