Association of the IL2RA/CD25 gene with juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA), the most common chronic rheumatic disease in children (1), is an umbrella term for diseases that start before the age of 16 years and are characterized by arthritis that persists for more than 6 weeks. JIA can be subdivided into 7 clinically more homogeneous subtypes, using the International League of Associations for Rheumatology (ILAR) classification system (2). The genetic basis of JIA is complex, but it has been estimated that the sibling recurrence risk (λs) is 15 (3). The most well-established genetic factor for JIA is HLA, and associations with HLA class I and class II genes exist, although both the strength of the associations and the associated alleles vary between subtypes (4). Recently, a variant in the coding region of the PTPN22 gene, which has been found to be associated with a number of autoimmune diseases, including rheumatoid arthritis (RA), type 1 diabetes mellitus (DM), autoimmune thyroid disease (AITD), and systemic lupus erythematosus (SLE) (5), was identified as a second susceptibility locus for JIA (6). The effect size for PTPN22 varies between subtypes but, in general, is smaller than that for HLA, and it has been hypothesized that there are additional genetic risk factors for JIA that remain to be discovered. Another gene that is emerging as a potential “autoimmune gene” is IL2RA/CD25. It was initially identified as a candidate gene for type 1 DM and AITD (7). Further support has come from recently conducted genome-wide association studies of RA (8) and multiple sclerosis (MS) (9) showing that the same SNP, rs2104286, which lies within intron 1 of the IL2RA/CD25 gene (8), is associated with both diseases. The study in MS patients also identified an association of an additional SNP, rs12722489, in linkage disequilibrium with it (9). More recently, the IL2RA/CD25 region has been intensely studied in type 1 DM, where large-scale fine-mapping across the IL2RA/CD25 gene found strong statistical evidence of association with 2 independent groups of SNPs (10). In that study, the presence of the susceptibility alleles was also shown to be correlated with lower concentrations of soluble interleukin-2 receptor α (IL-2Rα)/CD25. The IL2RA/CD25 gene encodes 1 of the subunits of the IL-2 receptor that binds IL-2 and is vital in the regulation of T cell function. IL2RA/CD25–knockout mice develop severe systemic autoimmune disease, a paradoxical finding suggesting that the gene is needed for down-regulation of immune responses in order to prevent autoimmunity. IL-2Rα/CD25 is the hallmark antigen of regulatory T cells (11–14), which play a vital role in the suppression of autoreactive T cells that escape other methods of tolerance. Depletion of these cells in mouse models results in the spontaneous development of autoimmune diseases (11). Thus, the evidence is building in support of a critical role of the IL-2/IL-2Rα–dependent regulatory pathway in the development of autoimmunity. Given the evidence of a role of variation in the IL2RA/CD25 gene in autoimmune disease susceptibility provided by the genome-wide association studies of MS and RA and the fine-mapping of the IL2RA/CD25 region in type 1 DM, we hypothesized that IL2RA/CD25 may also play a role in JIA. The aim of this study, therefore, was to determine whether IL2RA/CD25 SNPs previously found to be associated with RA, MS, and type 1 DM are also associated with JIA.