Context: IL-23 and its receptor (IL-23R) guide T cells toward the Th17 phenotype. IL-23R single nucleotide polymorphisms (SNPs) have been shown to be associated with several autoimmune diseases, including Crohn's disease and rheumatoid arthritis.

Objectives: To determine whether variants in the IL-23R gene are associated with Graves' disease (GD) and Graves' ophthalmopathy (GO).

Design and Participants: 216 North American Caucasian GD patients and 368 healthy controls were genotyped for 4 SNPs spanning the IL-23R gene. SNPs rs11209026 and rs7530511 were genotyped using the TaqMan allelic discrimination assays and SNPs rs2201841 and rs10889677 were genotyped using a fluorescent-based restriction fragment length polymorphism (RFLP) method.

Results: The A-allele of rs2201841 was present in 78.8% of GD patients with GO and in 64.7% of controls (p = 1.1 x 10^-4, OR = 2.04); the AA genotype was also significantly increased in GO patients compared to controls (62.5% and 41%, respectively; p = 1.0 x 10^-4, OR = 2.4). The C-allele of rs10889677 was present in 78.6% of GO patients and in 64.5% of controls (p = 1.3 x 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 x 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 in 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 dataset.

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.