KIR3DL1 and KIR3DL2 gene copy number variation in axial spondyloarthritis

Axial spondyloarthritis (axSpA), including the subgroup ankylosing spondylitis (AS) is strongly genetically determined. HLA-B27 is the strongest known risk factor (1) and in recent years genome-wide association studies (GWAS) based on single nucleotide polymorphisms (SNPs) have yielded new genetic risk factors for AS (2). However, it is thought that HLA-B27 and the SNPs discovered in GWAS only account for a small part of the total genetic risk for AS. In order to fully understand the origin of axSpA, a complete risk analysis is required. We therefore performed a pilot study to determine the genetic risk of known binding partners of HLA-B27. Human leukocyte antigen (HLA) class I molecules constitute natural ligands for a number of killer immunoglobulin-like receptors (KIRs), which are expressed by natural killer (NK) cells and a subset of T-cells. KIRs are involved in the regulation of the cytotoxic activity of these cells. The HLA-B27 molecule is known to be recognized by KIR3DL1 and KIR3DL2 (3), and binding of HLA-B27 to KIR3DL2 activates Th17 cells in AS (4). The KIR locus is subject to genetic variation, which is because of gene polymorphisms and gene copy number variation (CNV), as we have previously shown (5). Although KIR genes and polymorphisms have been studied in SpA, nothing is known of gene CNV in relation to this disease. In this study, we investigated the distribution of KIRs and their CNV in a panel of Caucasian AS and early axSpA patients [from the Leiden Early Arthritis cohort (EAC) and Spondyloarthritis Caught Early (SPACE) cohort, respectively] (6, 7) (Table 1). All patients fulfill the Assessment of Spondyloarthritis International Society (ASAS) axSpA criteria (8). An unusual characteristic of the AS patients in the EAC was the low percentage of inflammatory back pain (IBP) according to ASAS expert criteria. Information on IBP was retrieved from patient files and at the time of inclusion of patients in the EAC, the ASAS IBP criteria had not been published.We observed that the ‘pain at night’ feature was not commonly used in clinical practice which has likely led to a lower percentage of IBP-positive patients in the EAC cohort. Consistent with this explanation is that a much higher percentage of more than 80% of AS patients had IBP according to the Calin criteria, which is consistent with other cohorts (9).