Human leukocyte antigen (HLA) class I ligands and Killer immunoglobulin-like receptors (KIRs) regulate the cytolytic activity of natural killer (NK) cells and certain T cells. We examined their genetic predisposition to disease susceptibility and clinical phenotypes in Taiwanese ankylosing spondylitis (AS) patients. KIR genotyping and Human Leucocyte Antigen C (HLA-C) sequencing were performed in 653 Taiwanese AS patients and 952 healthy controls. KIR genotype distributions and HLA-C allele frequencies were compared in patients and controls and among patients with and without HLA-B27 positivity, early age onset and spinal syndesmophytes. HLA-C alleles were functionally characterized using 3D structural modelling with peptide simulation. This study discovered that the HLA-C*12:02:02 allele (43.42% vs. 3.31%; p < 0.00001 odds ratio (OR), 16.88; 95% confidence intervals (CI): 11.27-25.28) confers a strong risk for Taiwanese AS development. The 3D modelling results identified four unique amino acid polymorphisms, Ala73, Trp156, Arg219 and Met304, that may affect the function of the HLA-C*12:02:02 allele. KIR2DL5 (p = 0.0047; pFDR = 0.0423) and the KIR Bx haplotype (p = 0.0000275) were protective against Taiwanese AS, while KIR 2DS4/1D (22 base pair truncated deletion; p = 0.0044; pFDR = 0.1998) appeared to be a risk factor for it. KIR2DL5 combined with the HLA-C1/C2 heterozygous genotype showed a protective effect (AS 5.97% vs. normal 11.66%; p = 0.002; pFDR = 0.0127, OR, 0.48 95% CI: 0.33-0.70); in contrast, KIR 2DS4/1D combined with the HLA-C1C1 homozygous genotype (AS 45.33% vs. normal 35.92%; p = 0.002; pFDR = 0.0127, OR, 1.48 95% CI: 1.21-1.81) represented a risk factor for AS development. Our data suggested that interactions between KIRs and their cognate HLA-C ligands may contribute to the pathogenesis of AS.
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Acknowledgments: We greatly appreciate the Shin Chu Blood Donor Centre for the collection of blood samples and Su-Wei Chang for statistical analysis. This study was supported by funding from the Chang Gung Memorial Hospital (CMRPG3C0063 and CMRPG3F0052) and the Ministry of Science and Technology, Taiwan (105-2314-B-068-MY3).
- Ankylosing spondylitis
- Human leukocyte antigen C (HLA-C)
- Killer immunoglobulin-like receptor (KIR)
- Natural killer cell