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

Abstract

Alpha‐subunit of the IL‐2 receptor (IL‐2Rα) 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‐2Rα (sIL‐2Rα) 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‐2Rα. 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‐2Rα 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, Pc = 0.00102]. The allele A of rs41295061 and allele A of rs11594656 constitute a higher risk haplotype AA (OR = 1.47, Pc = 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‐2Rα 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‐2Rα in GD.

Non-HLA autoimmunity genetic factors contributing to Autoimmune Polyglandular Syndrome type II in Tunisian patients

“…This receptor regulates lymphocytes through controlling T reg activity [33]. This gene could be considered as a general autoimmunity gene whose variants showed association with susceptibility to numerous autoimmune diseases especially T1D [33,34,7,25,11] and Grave's disease [35]. It was also shown that rs rs2104286 of IL2RA gene variants was correlated with decreased serum level of S-IL2RA in healthy subjects and patients affected with T1D and Multiple Sclerosis [36].…”

TSHR intronic polymorphisms (rs179247 and rs12885526) and their role in the susceptibility of the Brazilian population to Graves’ disease and Graves’ ophthalmopathy

“…About 25-50 % of GD patients have clinical signs of Graves' ophthalmopathy (GO), most having mild disease [2,3]. Genome-wide screens conducted in GD have identified a number of putative susceptibility genes in GD [4] and several gene loci have been reported to be associated with a risk of developing GD, including HLA [4,5], CTLA4 [6], PTPN22 [7], CD40 [8], IL2RA [9], IL21 [10], and TG [11]. About 20 identified genetic polymorphisms, including both thyroid-specific genes and those regulating the autoimmune response were already investigated.…”

Genetic Profiling in Graves' Disease: Further Evidence for Lack of a Distinct Genetic Contribution to Graves' Ophthalmopathy

“…The first group is those genes common to many autoimmune diseases and involving immune regulatory and response genes. These include HLA-DR3 (7,8), CTLA4 (9,10), PTPN22 (11,12), CD40 (13,14), IL2RA (CD25) (15,16), FCRL3 (17,18), and the IL23R (19). The second group includes genes that are specific to the thyroid gland: the TSHR (20-24) and thyroglobulin (TG) (25,26).…”