Study on the Protective Effect of the KIR3DL1 Gene in Ankylosing Spondylitis

Abstract

Objective Ankylosing spondylitis (AS) is an autoimmune disease that mainly affects the sacroiliac joints and the spine of the lower back. The disease is strongly associated with HLA–B27. Additional genes, single‐nucleotide polymorphisms, and molecular components have been identified to be associated with AS, but the exact mechanism that drives disease development remains poorly understood. The killer cell immunoglobulin‐like receptors (KIRs) are regulators of cytotoxicity of natural killer cells and T cell subsets and may be relevant in binding to HLA–B27 and the development of AS. We undertook this study to identify possible associations of KIR genotype with susceptibility to AS and disease characteristics including the presence of the HLA–B27 allele, disease severity, and uveitis. Methods We performed complete genotyping of the KIR locus in 303 Caucasian AS patients, 119 randomly selected healthy Caucasian controls, and 50 HLA–B27–positive healthy Caucasian controls by multiplex ligation‐dependent probe amplification assay for detection of gene presence and copy number. Results We did not observe a significant association of any specific KIR gene or haplotype with susceptibility to AS or any other clinical manifestation. Disease severity, as measured by fulfilling the criteria for treatment with tumor necrosis factor blocking therapy, was linked to a lower number of genes for the functional variant of KIR3DL1 (P = 0.007). Conclusion Our exploratory study indicates that KIR genes are not a major risk factor for susceptibility to AS. However, the data do suggest a role for KIRs in progression of the disease, whereby KIR3DL1 has a protective effect against the more severe manifestations of AS.

Allele imputation for the Killer cell Immunoglobulin-like Receptor KIR3DL1/S1

“…Other genotype chips used for disease association studies have less dense sets of SNPs, including the Infinium Immunoarray, which targets markers associated with autoimmune disease and inflammatory disorders (78). Because KIR3DL1/S1 diversity is associated with development or severity of multiple autoimmune diseases (20, 22, 23, 25, 93), we tested the accuracy of imputation using results generated from this genotyping chip, and achieved similar imputation accuracy as achieved from the high-density array.…”

“…Sequence diversity of KIR3DL1/S1 and HLA class I allotypes diversifies human immune responses to specific infections, cancers, cancer treatment and transplantation (10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Accordingly, this genetically determined diversity also associates with differential susceptibility and severity for multiple immune-mediated diseases (20)(21)(22)(23)(24)(25)(26). Although these factors render it imperative to genotype KIR3DL1/S1 allotypes accurately for medical research and applications that include therapy decisions (27,28), the high complexity of the genomic region presents obstacles for standard ascertainment methods (29).…”

The Nonradiographic Axial Spondyloarthritis, the Radiographic Axial Spondyloarthritis, and Ankylosing Spondylitis: The Tangled Skein of Rheumatology

“…Recently, several additional genetic factors (e.g., ERAP-1, IL23R) [52] and certain protein biomarkers have been found to influence the disease progression and radiographic damage. Thus, the KIR3DL1, a receptor protein biomarker, seems to have a protective effect against the most severe manifestations of AS [53]. Pathologic bone formation in AS might be due to molecular dysfunction of certain other protein biomarkers, for example, Sclerostin and Dkk-1, at the cellular level [54].…”

The impact of KIR/HLA genes on the risk of developing multibacillary leprosy

“…The cytotoxic function of NK cells on target cells is regulated through the balance between activating and inhibitory signals that results from the interaction of KIRs and their HLA class I ligands [15,16]. Thus, it is possible that KIR molecules play a significant role in controlling the immune response during infections, which would explain the associations observed between certain KIR genes and ankylosing spondylitis [17], Chagas disease [18] and leprosy [19,20].…”