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


METHODS
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=1.1x10(-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=1.0x10(-4); OR=2.4). The C allele of rs10889677 was present in 78.6% of GO patients and 64.5% of controls (P=1.3x10(-4); OR=2.03), and the CC genotype was also significantly increased in GO patients vs. controls (62.1 and 41.0%, respectively; P=1.4x10(-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.
Huber
Amanda K
AK
Division of Endocrinology, The Vontz Center, ML 0547, University of Cincinnati College of Medicine, 3125 Eden Avenue, Cincinnati, Ohio 45267, USA. huberak@uc.edu
Jacobson
Eric M
EM
Jazdzewski
Krystian
K
Concepcion
Erlinda S
ES
Tomer
Yaron
Y
D015551:Autoimmunity; D005260:Female; D020022:Genetic Predisposition to Disease; D049970:Graves Ophthalmopathy / Q000235:genetics*; D006801:Humans; D053759:Interleukin-23 / Q000502:physiology*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D018123:Receptors, Interleukin / Q000235:genetics*; D050797:STAT4 Transcription Factor / Q000502:physiology; D018417:Th1 Cells / Q000145:classification / Q000276:immunology*; D013961:Thyroid Gland / Q000276:immunology*
C515500:IL23R protein, human; D053759:Interleukin-23; D018123:Receptors, Interleukin; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human