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

Autor: Stephen Leslie, Matthew A. Brown, Jessica Harris, Damjan Vukcevic, Tony J. Kenna, Aimee L. Hanson, Kim-Anh Lê Cao
Rok vydání: 2020
Předmět:
Cancer Research
Heredity
Epidemiology
Ankylosing Spondylitis
Single Nucleotide Polymorphisms
QH426-470
Aminopeptidases
Homozygosity
0302 clinical medicine
Receptors
KIR
HLA Antigens
Genotype
Medicine and Health Sciences
Receptor
Genetics (clinical)
0303 health sciences
education.field_of_study
Genetic Mapping
KIR3DL1
Research Article
Population
Immunology
Single-nucleotide polymorphism
chemical and pharmacologic phenomena
Variant Genotypes
Human leukocyte antigen
Biology
Polymorphism
Single Nucleotide
Autoimmune Diseases
Minor Histocompatibility Antigens
03 medical and health sciences
Genetics
Humans
Spondylitis
Ankylosing
Allele
education
Molecular Biology
Ecology
Evolution
Behavior and Systematics
Alleles
030304 developmental biology
Haplotype
Biology and Life Sciences
Epistasis
Genetic
Haplotypes
Genetic Loci
Medical Risk Factors
Clinical Immunology
Clinical Medicine
030217 neurology & neurosurgery
Zdroj: PLoS Genetics
PLoS Genetics, Vol 16, Iss 8, p e1008906 (2020)
ISSN: 1553-7404
Popis: 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.
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.
Databáze: OpenAIRE
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