Interleukin (IL)-23 receptor is a major susceptibility gene for Graves' ophthalmopathy: The IL-23/T-helper 17 axis extends to thyroid autoimmunity

Context: IL-23 and its receptor (IL-23R) guide T cells toward the T-helper 17 phenotype. IL-23R single nucleotide polymorphisms (SNPs) have been associated with several autoimmune diseases, including Crohn's disease and rheumatoid arthritis. Objective: Our objective was to determine whether variants in the IL-23R gene are associated with Graves' disease (GD) and Graves' ophthalmopathy (GO). Design and Participants: A total of 216 North American Caucasian GD patients and 368 healthy controls were genotyped for four SNPs spanning the IL-23R gene. SNPs rs11209026 and rs7530511 were genotyped using the TaqMan allelic discrimination assays (Applied Biosystems, Foster City, CA), and SNPs rs2201841 and rs10889677 were genotyped using a fluorescent-based restriction fragment length polymorphism method. Results: The A allele of rs2201841 was present in 78.8% of GD patients with GO and 64.7% of controls [P = 1.1 × 10^-4; odds ratio (OR) = 2.04]; the AA genotype was also significantly increased in GO patients compared with controls (62.5 and 41%, respectively; P = 1.0 × 10^-4; OR = 2.4). The C allele of rs10889677 was present in 78.6% of GO patients and 64.5% of controls (P = 1.3 × 10^-4; OR = 2.03), and the CC genotype was also significantly increased in GO patients vs. controls (62.1 and 41.0%, respectively; P = 1.4 × 10^-4;OR = 2.36). The TT genotype of rs7530511 was significantly associated with GD, but not specifically with GO; it was present in 2.5% of GD patients and 0.3% of controls (P = 0.02; OR = 9.4). The rs11209026 SNP, which is the most strongly associated with Crohn's disease, was not associated with GD or GO in our data set. Conclusions: Variants in the IL-23R gene are strongly associated with GO. These variants may predispose to GO by changing the expression and/or function of IL-23R, thereby promoting a proinflammatory signaling cascade.