Human Leukocyte Antigen C12:02:02 and Killer Immunoglobulin-Like Receptor 2DL5 are Distinctly Associated with Ankylosing Spondylitis in the Taiwanese

• Published in: International journal of molecular sciences 2017-08, Vol.18 (8), p.1775
• Main Authors: Wang, Chin-Man, Wang, Sheng-Hung, Jan Wu, Yeong-Jian, Lin, Jing-Chi, Wu, Jianming, Chen, Ji-Yih
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Alleles; Ankylosing spondylitis; Antigens; Asian People; Clonal deletion; Computer simulation; Confidence intervals; Cytolytic activity; Female; Gene deletion; Gene frequency; Genetic Predisposition to Disease; Genotyping; Haplotypes; Histocompatibility antigen HLA; HLA-C Antigens - genetics; HLA-C Antigens - immunology; human leukocyte antigen C (HLA-C); Humans; Immunoglobulin-like receptors; Immunoglobulins; Killer cell immunoglobulin-like receptors; killer immunoglobulin-like receptor (KIR); Leukocytes; Ligands; Lymphocytes; Lymphocytes T; Male; Modelling; natural killer cell; Natural killer cells; Patients; Polymorphism, Genetic; Potassium channels (inwardly-rectifying); Protein Domains; Receptors, KIR2DL5 - genetics; Receptors, KIR2DL5 - immunology; Risk; Spondylitis; Spondylitis, Ankylosing - genetics; Spondylitis, Ankylosing - immunology; Taiwan
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms18081775

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%; < 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 ( = 0.0047; = 0.0423) and the KIR Bx haplotype ( = 0.0000275) were protective against Taiwanese AS, while KIR 2DS4/1D (22 base pair truncated deletion; = 0.0044; = 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%; = 0.002; = 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%; = 0.002; = 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.