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

Autoři: Aimee L. Hanson aff001;  ;  Damjan Vukcevic aff002;  Stephen Leslie aff002;  Jessica Harris aff005;  Kim-Anh Lê Cao aff002;  Tony J. Kenna aff005;  Matthew A. Brown aff005
Působiště autorů: University of Queensland Diamantina Institute, University of Queensland, Brisbane, Queensland, Australia aff001;  Melbourne Integrative Genomics, School of Mathematics and Statistics, University of Melbourne, Parkville, Victoria, Australia aff002;  Data Science, Murdoch Children’s Research Institute, Parkville, Victoria, Australia aff003;  School of Biosciences, University of Melbourne, Parkville, Victoria Australia aff004;  Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia aff005;  Translational Research Institute, Brisbane, Queensland, Australia aff006;  Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia aff006
Vyšlo v časopise: Epistatic interactions between killer immunoglobulin-like receptors and human leukocyte antigen ligands are associated with ankylosing spondylitis. PLoS Genet 16(8): e32767. doi:10.1371/journal.pgen.1008906
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008906


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. Fifteen KIR genes are inherited in haplotypes of diverse gene content across the human population, and the repertoire of independently inherited KIR and HLA alleles 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 of KIR-HLA epistasis to date, enabled by the imputation of KIR gene and HLA allele dosages from genotype data for 12,214 healthy controls and 8,107 individuals with the HLA-B*27-associated immune-mediated arthritis, ankylosing spondylitis (AS). We identified epistatic interactions between KIR genes and their ligands (at both HLA subtype 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 gene ERAP1, 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 of KIRs and HLA ligands inherited, beyond the influence of HLA-B*27 alone, which collectively alter the proinflammatory capacity of KIR-expressing lymphocytes to contribute to disease immunopathogenesis.

Klíčová slova:

Alleles – Ankylosing spondylitis – Genetic loci – Haplotypes – Homozygosity – Medical risk factors – Single nucleotide polymorphisms – Variant genotypes


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PLOS Genetics

2020 Číslo 8
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