University of Queensland Diamantina Institute, University of Queensland, Brisbane, Queensland, Australia.
Melbourne Integrative Genomics, School of Mathematics and Statistics, University of Melbourne, Parkville, Victoria, Australia.
PLoS Genet. 2020 Aug 17;16(8):e1008906. doi: 10.1371/journal.pgen.1008906. eCollection 2020 Aug.
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-B27-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-B27 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.
杀伤细胞免疫球蛋白样受体（KIRs）主要存在于自然杀伤（NK）细胞和一些 T 细胞表面，是一组高度多态性的激活和抑制受体，对人类白细胞抗原（HLA）I 类配体具有可变的特异性。15 个 KIR 基因以不同基因组成的单倍型遗传，独立遗传的 KIR 和 HLA 等位基因的组合已知通过改变淋巴细胞激活的阈值来改变免疫介导和传染病的风险。我们进行了迄今为止最大的 KIR-HLA 上位性疾病关联研究，这得益于对 12214 名健康对照者和 8107 名 HLA-B27 相关免疫介导性关节炎、强直性脊柱炎（AS）个体的基因型数据进行 KIR 基因和 HLA 等位基因剂量的推断。我们确定了 KIR 基因与其配体（在 HLA 亚型和等位基因分辨率上）之间的上位性相互作用，这些相互作用增加了疾病的风险，在一个由 3497 例病例和 14844 例对照组成的半独立队列中复制了分析。我们进一步证实，内质网氨肽酶基因 ERAP1 的致病性变异与 AS 强烈相关，该基因已知会改变 HLA-B27 呈递的肽组，而经典 HLA-B 受体 KIR3DL1/S1 的携带并不改变其相关性。总的来说，我们的数据表明，AS 风险除了 HLA-B*27 的影响外，还受到遗传的 KIR 和 HLA 配体的影响，这共同改变了表达 KIR 的淋巴细胞的促炎能力，从而导致疾病的免疫发病机制。
