A Variant of the Il2ra/Cd25 Gene Predisposing to Graves' Disease is Associated with Increased Levels of Soluble Interleukin-2 Receptor

Alpha-subunit of the IL-2 receptor (IL-2R alpha) encoded by the IL2RA/CD25 gene binds IL-2 that plays a pivotal role in the regulation of T cell function. Levels of a soluble form of IL-2R alpha (sIL-2R alpha) lacking the transmembrane and cytoplasmic domains were shown to be increased in several autoimmune diseases including Graves' disease (GD). Recent studies showed association between the IL2RA/CD25 gene variants and several autoimmune diseases including GD. In this study, we analyzed whether polymorphic markers rs2104286, rs41295061, and rs11594656 located at the IL2RA/CD25 locus confer susceptibility to GD and are related to increased concentrations of sIL-2R alpha. A total of 1474 Russian GD patients and 1609 control subjects were genotyped for rs2104286, rs41295061, and rs11594656 using a Taqman assay. Concentrations of sIL-2R alpha in sera of affected and non-affected individuals were measured using an ELISA test. A minor allele A of rs41295061 showed significant association with increased risk of GD [odds ratio (OR) = 1.43, P-c = 0.00102]. The allele A of rs41295061 and allele A of rs11594656 constitute a higher risk haplotype AA (OR = 1.47, P-c = 0.0477). Compared to carriers of the protective haplogenotype GT/GT, the carriage of two copies of the haplogenotype AA/AA was associated with elevated levels of sIL-2R alpha in both GD patients (AA/AA versus GT/GT: 1.35 +/- 0.47 ng/ml versus 1.12 +/- 0.45 ng/ml, P = 0.0065) and healthy controls (AA/AA versus GT/GT: 0.67 +/- 0.28 ng/ml versus 0.51 +/- 0.33 ng/ml, P = 0.0098). This is the first report presenting correlation between the carriage of disease-associated variants of IL2RA/CD25 with increased levels of sIL-2R alpha in GD.