STAT4 and IL23R loci represent common susceptibility genetic factors in autoimmunity. We decided to investigate for the first time the possible role of different STAT4/IL23R autoimmune disease-associated polymorphisms on the susceptibility to develop non-anterior uveitis and its main clinical phenotypes.
Four functional polymorphisms (rs3821236, rs7574865, rs7574070, and rs897200) located within STAT4 gene as well as three independent polymorphisms (rs7517847, rs11209026, and rs1495965) located within IL23R were genotyped using TaqMan® allelic discrimination in a total of 206 patients with non-anterior uveitis and 1553 healthy controls from Spain.
No statistically significant differences were found when allele and genotype distributions were compared between non-anterior uveitis patients and controls for any STAT4 (rs3821236: P=0.39, OR=1.12, CI 95%=0.87-1.43; rs7574865: P=0.59 OR=1.07, CI 95%=0.84-1.37; rs7574070: P=0.26, OR=0.89, CI 95%=0.72-1.10; rs897200: P=0.22, OR=0.88, CI 95%=0.71-1.08;) or IL23R polymorphisms (rs7517847: P=0.49, OR=1.08, CI 95%=0.87-1.33; rs11209026: P=0.26, OR=0.78, CI 95%=0.51-1.21; rs1495965: P=0.51, OR=0.93, CI 95%=0.76-1.15).
Citation: Cénit MC, Márquez A, Cordero-Coma M, Gorroño-Echebarría MB, Fonollosa A, Adán A, et al. (2013) No Evidence of Association between Common Autoimmunity STAT4 and IL23R Risk Polymorphisms and Non-Anterior Uveitis. PLoS ONE 8(11): e72892. https://doi.org/10.1371/journal.pone.0072892
Editor: Graham R. Wallace, University of Birmingham, United Kingdom
Received: April 5, 2013; Accepted: July 15, 2013; Published: November 29, 2013
Copyright: © 2013 Cénit et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The authors have no support or funding to report.
Competing interests: The authors have declared that no competing interests exist.
Uveitis can be defined as any inflammation affecting the uveal tract, the middle vascular layer of the eye, although in the clinical practice this term includes any intraocular inflammatory process . The prevalence of uveitis is estimated at 38 cases per 100,000 people, although it depends on the geographic area . This condition is considered a major source of visual impairment as well as an important socio-economic problem, being the fourth cause of blindness on the worldwide . There are different forms of uveitis, including either uveitis triggered by a wide range of exogenous (infectious and traumatism) or endogenous agents (non-infectious uveitis related with inflammatory or autoimmune processes) . In addition, uveitis patients are frequently classified according to the anatomical location of the inflammation into anterior uveitis (AU), the most common form which represents 60% of cases, intermediate uveitis (IU) (5-13%), posterior uveitis (PU) (15%) and panuveitis or also called diffuse uveitis (PAN) (20%) .
Endogenous uveitis is an inflammatory response triggered by certain environmental factors in individuals with a particular genetic component and it is mainly mediated by immune system driven for a loss of tolerance against self antigens . So far, certain HLA alleles have been strongly associated with the uveitis predisposition [5,6,7,8]. However, the effect of these alleles just explains a small part of the uveitis heritability and different studies have recently highlighted the implication of non-HLA genetic factors in the susceptibility to this condition [9,10,11].
There is a well established knowledge that most autoimmune diseases share a certain percentage of their genetic component, showing that some pathologies may be influenced by common pathways [12,13]. Genes encoding signal transducer and activator of transcription 4 (STAT4) and interleukin 23 receptor (IL23R) belong to the well established group of risk factors shared by different conditions that influence the breakdown of self-tolerance . STAT4 and IL23R are strongly involved in the control of the immune system through of the development and perpetuation of Th17 immune responses , which display a dominant role in autoimmunity-associated inflammation .
Different studies have identified IL23R as a susceptibility factor associated to multiple inflammatory conditions [16,17,18]. In these studies several independent signals located within IL23R locus were suggested; however, only the R381Q (rs11209026) polymorphism, whose minor allele plays a protective role for several autoimmune disease, appear to have a functional involvement [19,20]. Additionally, the rs1495965 polymorphism has been reported as the stronger IL23R association with Behçet’s disease (BD), a systemic autoimmune disease involving uveitis, in a previous combined meta-analysis of two genome-wide association studies (GWASs) [21,22]. On the other hand, STAT4 has been also identified as another shared susceptibility locus [23,24]. Interestingly, the presence of two STAT4 independent functional genetic variants associated with systemic lupus erythematosus (SLE), both affecting the STAT4 levels, has been recently evidenced by fine mapping . Furthermore, two functional polymorphisms located at STAT4 gene have been recently implicated in BD susceptibility by GWASs [26,27].
Recent data have suggested that autoimmune uveitis also seems to share common genetic factors with other autoimmune disorders although these remain unknown yet . Taking into account all of the above, we herein aimed to investigate whether the STAT4 and IL23R autoimmune disease-associated polymorphisms are involved in the genetic predisposition to autoimmune uveitis.
A subject’s written consent was obtained according to the declaration of Helsinki, and the design of the work was approved by the Ethics Committee of Granada (Spain). The Ethics Committees of the Hospital de León (León), Hospital Universitario Príncipe de Asturias (Alcalá de Henares), Hospital de Cruces (Bilbao), Hospital Clinic (Barcelona), Hospital Clínico San Carlos (Madrid), Hospital Marqués de Valdecilla (Santander), Hospital Universitario La Fe (Valencia), Hospital Clínico San Cecilio (Granada) and Hospital Carlos Haya (Málaga) also approved the study.
A total of 206 patients with endogenous non anterior uveitis, excluding the uveitis forms associated with systemic immune-mediated diseases except the Vogt-Koyanagi-Harada syndrome, and 1553 ethnically matched healthy controls, all of them of Caucasian origin, were included in the present study. The main clinical and demographic characteristics of uveitis patients included in the present study are described in Table 1. The intraocular inflammation seen in patients included intermediate uveitis (24.8%), posterior uveitis (50.0%), and panuveitis (25.2%).
|General characteristics of uveitis patients||All patients n=206|
|Female (%)||126 (61.2)|
|Age (mean ± SD)||47.3 ± 16.9|
|Intermediate Uveitis (%)||51 (24.8)|
|Posterior Uveitis (%)||103 (50.0)|
|Panuveitis (%)||52 (25.2)|
|Bilateral affection (%)||153 (74.3)|
|Vitritis (%)||135 (65.5)|
|Macular edema (%)||92 (44.7)|
|Retinal vasculitis (%)||87 (42.2)|
|Choroidal neovascularization (%)||16 (7.8)|
Genomic DNA was extracted from peripheral white blood cells and saliva following standard procedures. The single-nucleotide polymorphisms (SNPs) were genotyped using pre-designed TaqMan® allelic discrimination assays in a 7900HT Real-Time polymerase chain reaction (PCR) System from Applied Biosystems under conditions recommended by the manufacturer (Foster City, CA, USA).
Since the aim of this study was to investigate whether different STAT4/IL23R autoimmune disease-associated polymorphisms were also implicated in the susceptibility to develop non-anterior uveitis, the IL23R and STAT4 polymorphisms most robustly associated with autoimmunity were selected. Following this criterion, we studied the IL23R rs11209026 genetic variant, encoding the functional amino-acid change Arg381Gln [16,17,18,19,20], and two independent STAT4 SNPs (rs3821236 and rs7574865), influencing levels of the protein [23,24,25]. Additionally, two IL23R polymorphisms were analyzed; rs7517847, strongly associated with Crohn’s disease and whose association seems to be independent on rs11209026 , and, rs1495965, previously associated with BD by GWASs [21,22]. On the other hand, two STAT4 genetic variants, rs7574070 and rs897200, recently associated with BD, were included in the study [26,27]. Both polymorphisms seem to have functional consequences and are located in a different linkage disequilibrium block from the SNPs rs3821236 and rs7574865.
The overall statistical power of the analysis, according to Power Calculator for Genetic Studies 2006 software (http://www.sph.umich.edu/csg/abecasis/CaTS/), is shown in Table S1. The genotype, allele and carrier frequencies were compared between patients, subgroup of patients and controls applying χ2 test and/or Fisher’s exact test. The Linux software plink (v1.07) (http://pngu.mgh.harvard.edu/purcell/plink/) was used to perform 2 × 2 contingency tables and χ2 test and/or Fisher’s exact test when it was necessary. Odds ratios (OR) and 95% confidence intervals (CI) were obtained according to Woolf’s method. Hardy-Weinberg equilibrium (HWE) was tested for all SNPs at significance level=0.01. P-values below 0.05 were considered as statistically significant.
Furthermore, the effect of the analyzed genetic variants was analyzed either in isolation or in allelic combination analysis. The allelic combination frequencies were estimated using plink (v1.07) and Haploview (V. 4.2).
Possible interactions between genes were evaluated following two different approaches: using logistic regression and by analyzing the distribution of genotypes for one SNP in cases conditioned by genotypes for the other SNP located in different gene.
Genotypic and allelic frequencies in cases and controls are shown in Table 2. No statistically significant deviation from Hardy-Weinberg equilibrium (P≤0.01) was observed for all the studied SNPs in the control set and the frequencies of the analyzed SNPs were in agreement with the data of the HapMap project. Genotyping success rate was higher than 99% for all analyzed SNPs. In addition, randomly selected samples were genotyped twice to verify the genotyping accuracy and 99% of the genotypes were identical.
|Genotype, N (%)||Allele test|
|SNP||1/2||Subgroup (n)||1/1||1/2||2/2||MAF (%)||P -value*||OR [CI 95%]**|
|rs7517847||G/T||Controls (n=1547)||267 (17.26)||732 (47.32)||548 (35.42)||40.92|
|Non anterior Uveitis (n=206)||41 (19.90)||94 (45.63)||71 (34.47)||42.72||0.49||1.08 (0.87-1.33)|
|rs11209026||A/G||Controls (n=1547)||8 (0.52)||211 (13.64)||1328 (85.84)||7.34|
|Non anterior Uveitis (n=206)||0 (0.00)||24 (11.65)||182 (88.35)||5.83||0.26||0.78 (0.51-1.21)|
|rs1495965||C/T||Controls (n=1547)||326 (21.07)||738 (47.71)||483 (31.22)||44.93|
|Non anterior Uveitis (n=206)||44 (21.36)||90 (43.69)||72 (34.95)||43.20||0.51||0.93 (0.76-1.15)|
|rs3821236||A/G||Controls (n=1547)||65 (4.20)||504 (32.58)||978 (63.22)||20.49|
|Non anterior Uveitis (n=206)||10 (4.85)||72 (34.95)||124 (60.19)||22.33||0.39||1.12 (0.87-1.43)|
|rs7574865||T/G||Controls (n=1547)||72 (4.65)||533 (34.45)||942 (60.89)||21.88|
|Non anterior Uveitis (n=206)||8 (3.88)||79 (38.35)||119 (57.77)||23.06||0.59||1.07 (0.84-1.37)|
|rs7574070||A/C||Controls (n=1547)||247 (15.97)||754 (48.74)||546 (35.29)||40.34|
|Non anterior Uveitis (n=203)||29 (14.29)||94 (46.31)||80 (39.41)||37.44||0.26||0.89 (0.72-1.10)|
|rs897200||T/C||Controls (n=1547)||277 (17.91)||759 (49.06)||511 (33.03)||42.44|
|Non anterior Uveitis (n=205)||33 (16.10)||95 (46.34)||77 (37.56)||39.27||0.22||0.88 (0.71-1.08)|
As shown in Table 2, when genotype, allele and carriers frequencies for the analyzed STAT4 and IL23R SNPs were compared between non-anterior uveitis patients and controls, no association with the global disease susceptibility was observed for any of the analyzed polymorphisms. Similarly, when we compared the different subgroups of non-anterior uveitis patients stratified according to the different clinical features showed in Table 1 no statistically significant differences were detected (data not shown).
On the other hand, the allelic combination analysis of the studied polymorphisms located within the IL23R locus as well as within the STAT4 gene did not provide further information (data not shown).
Furthermore, since STAT4 and IL23R are molecules of the same pathway, we decided to study the possible interaction between the analyzed IL23R and STAT4 genetic variants; however, no interaction between them was observed (data not shown).
No large-scale genome-wide association studies in uveitis have been published to date, and only few genetic studies, focused mainly on anterior uveitis, have been conducted to identify the uveitis genetic component [9,10,11]. Indeed, only some HLA alleles have been strongly associated with uveitis predisposition [5,6,7,8], and genetic factors outside HLA region influencing uveitis susceptibility remain unknown.
Autoimmune uveitis pathogenesis seems to be mainly mediated by a T cell-driven cellular immune response . Uveitis condition was traditionally considered as a Th1 mediated trait ; however, cumulating knowledge suggests that IL-23, rather than IL-12, is necessary for experimental autoimmune uveitis (EAU) induction . Indeed, Th17 cells, whose development in human is mainly induced in response to IL-23 and IL-1β , release interleukin-17A that exhibits potent proinflammatory properties in animal models of autoimmunity, including EAU . In this IL-23/IL-17 axis, STAT4 is required for the signal transduction of IL-23 and, consequently is involved in the development of Th17 cells .
Considering the shared genetic component among the different immune-mediated diseases, including the autoimmune uveitis [12,13,28], and the key role that Th17 responses play in the uveitis pathogenesis, we speculated that STAT4 and IL23R, two general autoimmunity loci, may contribute to the non-anterior uveitis susceptibility.
However, our results evidenced no association of any analyzed STAT4 and IL23R genetic variants with either the non-anterior uveitis or with the studied clinical subphenotypes. Regarding IL23R, the statistical power of our study to detect the described odds ratios in previous GWASs on different autoimmune diseases [16,34,35] was higher than 80%, considering the strong effect sizes observed in those studies for the analyzed IL23R variants (Table 3). It could be speculated that the effect size of the analyzed IL23R polymorphisms was similar in non-anterior uveitis than in other autoimmune diseases. In this case, it is not likely that the lack of association was due to a type II error. Likewise, based on the statistical power of our study, an effect of the STAT4 rs897200 and rs7574070 genetic variants similar to that described for BD [26,27] could be discarded in non-anterior uveitis (Table 3). In relation to the STAT4 rs3821236 and rs7574865 polymorphisms, there was a higher heterogeneity in the reported ORs [36,37,38,39,40] (Table 3), with some autoimmune diseases showing considerably stronger signals than others (e.g. OR > 1.40 for SLE and 1.16 for RA). Therefore, no definitive conclusions on these STAT4 variants can be drawn.
|rs7574070||BD||1.40 /1.27 ||0.88/0.61|
On the other hand, associations of these IL23R and STAT4 polymorphisms with systemic autoimmune diseases involving uveitis, such as Behçet’s disease, Vogt-Koyanagi-Harada disease or sarcoidosis, have been described in Asian populations [21,22,26,27,41,42,43,44] but not in Europeans. The allele frequencies of controls in our study are similar to those described in Asian populations. Therefore, the lack of association of these polymorphisms with non-anterior uveitis in the Spanish population may be due to a differential genetic background of this disease among ethnicities rather than differences in allele frequencies. Hence, these genes may not be uveitis risk factors in populations of European ancestry.
In conclusion, our data do not support a relevant role of IL23R and STAT4 polymorphisms in the genetic susceptibility to develop non-anterior uveitis. As limitation, our study presents a moderate statistical power due to the low prevalence of endogenous non-anterior uveitis in Caucasian population. Hence, a possible weak effect of the studied variants in disease predisposition or phenotype expression may not be discarded and, hence, additional studies in larger independent cohorts would be desirable.
The authors thank Sofía Vargas, Sonia García and Gema Robledo (from Instituto de Parasitología y Biomedicina ‘López-Neyra’, CSIC, Spain) for their excellent technical assistance, and all the patients and healthy controls for kindly accepting their essential collaboration. Banco Nacional de ADN (University of Salamanca, Spain) and Biobanco Vasco para la Investigación (Fundación Vasca de Innovación e Investigación Sanitarias, Bizkaia, Spain) are thanked for supplying part of the samples.
Conceived and designed the experiments: JM MCC AM. Performed the experiments: MCC AM. Analyzed the data: MCC AM MC-C MBG-E AF AA AM-B DDV EP RB JC MD-L JLGS ER MJR JMM-V BM NO-C JM. Contributed reagents/materials/analysis tools: MC-C MBG-E AF AA AM-B DDV EP RB JC MD-L JLGS ER MJR JMM-V BM NO-C JM. Wrote the manuscript: MCC AM.
- 1. Wakefield D, Chang JH (2005) Epidemiology of uveitis. Int Ophthalmol Clin 45: 1-13. doi:https://doi.org/10.1097/01.iio.0000155938.83083.94. PubMed: 15791154.
- 2. Rothova A, Suttorp-van Schulten MS, Frits Treffers W, Kijlstra A (1996) Causes and frequency of blindness in patients with intraocular inflammatory disease. Br J Ophthalmol 80: 332-336. doi:https://doi.org/10.1136/bjo.80.4.332. PubMed: 8703885.
- 3. Levy RA, de Andrade FA, Foeldvari I (2011) Cutting-edge issues in autoimmune uveitis. Clin Rev Allergy Immunol 41: 214-223. doi:https://doi.org/10.1007/s12016-011-8267-x. PubMed: 21913066.
- 4. Deschenes J, Murray PI, Rao NA, Nussenblatt RB (2008) International Uveitis Study Group (IUSG): clinical classification of uveitis. Ocul Immunol Inflamm 16: 1-2. doi:https://doi.org/10.1080/09273940801899822. PubMed: 18379933.
- 5. Brewerton DA, Caffrey M, Nicholls A, Walters D, James DC (1973) Acute anterior uveitis and HL-A 27. Lancet 302: 994-996. doi:https://doi.org/10.1016/S0140-6736(73)91090-8. PubMed: 4127279.
- 6. LeHoang P, Ozdemir N, Benhamou A, Tabary T, Edelson C et al. (1992) HLA-A29.2 subtype associated with birdshot retinochoroidopathy. Am J Ophthalmol 113: 33-35. PubMed: 1728143.
- 7. Shindo Y, Ohno S, Yamamoto T, Nakamura S, Inoko H (1994) Complete association of the HLA-DRB1*04 and -DQB1*04 alleles with Vogt-Koyanagi-Harada's disease. Hum Immunol 39: 169-176. doi:https://doi.org/10.1016/0198-8859(94)90257-7. PubMed: 8026985.
- 8. Oruc S, Duffy BF, Mohanakumar T, Kaplan HJ (2001) The association of HLA class II with pars planitis. Am J Ophthalmol 131: 657-659. doi:https://doi.org/10.1016/S0002-9394(00)00863-1. PubMed: 11336946.
- 9. Chen Y, Vaughan RW, Kondeatis E, Fortune F, Graham EM et al. (2004) Chemokine gene polymorphisms associate with gender in patients with uveitis. Tissue Antigens 63: 41-45. doi:https://doi.org/10.1111/j.1399-0039.2004.00150.x. PubMed: 14651522.
- 10. Wallace GR, Kondeatis E, Vaughan RW, Verity DH, Chen Y et al. (2007) IL-10 genotype analysis in patients with Behcet's disease. Hum Immunol 68: 122-127. doi:https://doi.org/10.1016/j.humimm.2006.11.010. PubMed: 17321902.
- 11. Atan D, Fraser-Bell S, Plskova J, Kuffova L, Hogan A et al. (2010) Cytokine polymorphism in noninfectious uveitis. Invest Ophthalmol Vis Sci 51: 4133-4142. doi:https://doi.org/10.1167/iovs.09-4583. PubMed: 20335604.
- 12. Zhernakova A, van Diemen CC, Wijmenga C (2009) Detecting shared pathogenesis from the shared genetics of immune-related diseases. Nat Rev Genet 10: 43-55. doi:https://doi.org/10.1038/nrg2489. PubMed: 19092835.
- 13. Cho JH, Gregersen PK (2011) Genomics and the multifactorial nature of human autoimmune disease. N Engl J Med 365: 1612-1623. doi:https://doi.org/10.1056/NEJMra1100030. PubMed: 22029983.
- 14. Wilson NJ, Boniface K, Chan JR, McKenzie BS, Blumenschein WM et al. (2007) Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol 8: 950-957. doi:https://doi.org/10.1038/nrg2199. PubMed: 17676044.
- 15. Bettelli E, Oukka M, Kuchroo VK (2007) T(H)-17 cells in the circle of immunity and autoimmunity. Nat Immunol 8: 345-350. doi:https://doi.org/10.1038/nrm2164. PubMed: 17375096.
- 16. Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS et al. (2006) A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314: 1461-1463. doi:https://doi.org/10.1126/science.1135245. PubMed: 17068223.
- 17. Burton PR, Clayton DG, Cardon LR, Craddock N, Deloukas P et al. (2007) Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet 39: 1329-1337. doi:https://doi.org/10.1038/ng.2007.17. PubMed: 17952073.
- 18. Cargill M, Schrodi SJ, Chang M, Garcia VE, Brandon R et al. (2007) A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet 80: 273-290. doi:https://doi.org/10.1086/511051. PubMed: 17236132.
- 19. Di Meglio P, Di Cesare A, Laggner U, Chu CC, Napolitano L et al. (2011) The IL23R R381Q gene variant protects against immune-mediated diseases by impairing IL-23-induced Th17 effector response in humans. PLOS ONE 6: e17160. doi:https://doi.org/10.1371/journal.pone.0017160. PubMed: 21364948.
- 20. Pidasheva S, Trifari S, Phillips A, Hackney JA, Ma Y et al. (2011) Functional studies on the IBD susceptibility gene IL23R implicate reduced receptor function in the protective genetic variant R381Q. PLOS ONE 6: e25038. doi:https://doi.org/10.1371/journal.pone.0025038. PubMed: 22022372.
- 21. Mizuki N, Meguro A, Ota M, Ohno S, Shiota T et al. (2010) Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behcet's disease susceptibility loci. Nat Genet 42: 703-706. doi:https://doi.org/10.1038/ng.624. PubMed: 20622879.
- 22. Remmers EF, Cosan F, Kirino Y, Ombrello MJ, Abaci N et al. (2010) Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behcet's disease. Nat Genet 42: 698-702. doi:https://doi.org/10.1038/ng.625. PubMed: 20622878.
- 23. Remmers EF, Plenge RM, Lee AT, Graham RR, Hom G et al. (2007) STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med 357: 977-986. doi:https://doi.org/10.1056/NEJMoa073003. PubMed: 17804842.
- 24. Palomino-Morales RJ, Diaz-Gallo LM, Witte T, Anaya JM, Martín J (2010) Influence of STAT4 polymorphism in primary Sjogren's syndrome. J Rheumatol 37: 1016-1019. doi:https://doi.org/10.3899/jrheum.091007. PubMed: 20360187.
- 25. Abelson AK, Delgado-Vega AM, Kozyrev SV, Sánchez E, Velázquez-Cruz R et al. (2009) STAT4 associates with systemic lupus erythematosus through two independent effects that correlate with gene expression and act additively with IRF5 to increase risk. Ann Rheum Dis 68: 1746-1753. doi:https://doi.org/10.1136/ard.2008.097642. PubMed: 19019891.
- 26. Hou S, Yang Z, Du L, Jiang Z, Shu Q et al. (2012) Identification of a susceptibility locus in STAT4 for Behcet's disease in Han Chinese in a genome-wide association study. Arthritis Rheum 64: 4104-4113. doi:https://doi.org/10.1002/art.37708. PubMed: 23001997.
- 27. Kirino Y, Bertsias G, Ishigatsubo Y, Mizuki N, Tugal-Tutkun I et al. (2013) Genome-wide association analysis identifies new susceptibility loci for Behcet's disease and epistasis between HLA-B*51 and ERAP1. Nat Genet 45: 202-207. doi:https://doi.org/10.1038/ng.2520. PubMed: 23291587.
- 28. Mattapallil MJ, Sahin A, Silver PB, Sun SH, Chan CC et al. (2008) Common genetic determinants of uveitis shared with other autoimmune disorders. J Immunol 180: 6751-6759. PubMed: 18453595.
- 29. Horai R, Caspi RR (2011) Cytokines in autoimmune uveitis. J Interferon Cytokine Res 31: 733-744. doi:https://doi.org/10.1089/jir.2011.0042. PubMed: 21787221.
- 30. Xu H, Rizzo LV, Silver PB, Caspi RR (1997) Uveitogenicity is associated with a Th1-like lymphokine profile: cytokine-dependent modulation of early and committed effector T cells in experimental autoimmune uveitis. Cell Immunol 178: 69-78. doi:https://doi.org/10.1006/cimm.1997.1121. PubMed: 9184700.
- 31. Luger D, Silver PB, Tang J, Cua D, Chen Z et al. (2008) Either a Th17 or a Th1 effector response can drive autoimmunity: conditions of disease induction affect dominant effector category. J Exp Med 205: 799-810. doi:https://doi.org/10.1084/jem.20071258. PubMed: 18391061.
- 32. Amadi-Obi A, Yu CR, Liu X, Mahdi RM, Clarke GL et al. (2007) TH17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27/STAT1. Nat Med 13: 711-718. doi:https://doi.org/10.1038/nm1585. PubMed: 17496900.
- 33. Mathur AN, Chang HC, Zisoulis DG, Stritesky GL, Yu Q et al. (2007) Stat3 and Stat4 direct development of IL-17-secreting Th cells. J Immunol 178: 4901-4907. PubMed: 17404271.
- 34. Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH et al. (2008) Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet 40: 955-962. doi:https://doi.org/10.1038/ng.175. PubMed: 18587394.
- 35. Anderson CA, Boucher G, Lees CW, Franke A, D'Amato M et al. (2011) Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet 43: 246-252. doi:https://doi.org/10.1038/ng.764. PubMed: 21297633.
- 36. Allanore Y, Saad M, Dieudé P, Avouac J, Distler JH et al. (2011) Genome-wide scan identifies TNIP1, PSORS1C1, and RHOB as novel risk loci for systemic sclerosis. PLoS Genet 7: e1002091. PubMed: 21750679.
- 37. Chung SA, Taylor KE, Graham RR, Nititham J, Lee AT et al. (2011) Differential genetic associations for systemic lupus erythematosus based on anti-dsDNA autoantibody production. PLoS Genet 7: e1001323. PubMed: 21408207.
- 38. Graham RR, Cotsapas C, Davies L, Hackett R, Lessard CJ et al. (2008) Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus. Nat Genet 40: 1059-1061. doi:https://doi.org/10.1038/ng.200. PubMed: 19165918.
- 39. Radstake TR, Gorlova O, Rueda B, Martin JE, Alizadeh BZ et al. (2010) Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus. Nat Genet 42: 426-429. doi:https://doi.org/10.1038/ng.565. PubMed: 20383147.
- 40. Stahl EA, Raychaudhuri S, Remmers EF, Xie G, Eyre S et al. (2010) Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet 42: 508-514. doi:https://doi.org/10.1038/ng.582. PubMed: 20453842.
- 41. Hu K, Yang P, Jiang Z, Hou S, Du L et al. (2010) STAT4 polymorphism in a Chinese Han population with Vogt-Koyanagi-Harada syndrome and Behcet's disease. Hum Immunol 71: 723-726. doi:https://doi.org/10.1016/j.humimm.2010.04.007. PubMed: 20438790.
- 42. Jiang Z, Yang P, Hou S, Du L, Xie L et al. (2010) IL-23R gene confers susceptibility to Behcet's disease in a Chinese Han population. Ann Rheum Dis 69: 1325-1328. doi:https://doi.org/10.1136/ard.2009.119420. PubMed: 20375120.
- 43. Kim HS, Choi D, Lim LL, Allada G, Smith JR et al. (2011) Association of interleukin 23 receptor gene with sarcoidosis. Dis Markers 31: 17-24. doi:https://doi.org/10.1155/2011/185106. PubMed: 21846945.
- 44. Xavier JM, Shahram F, Davatchi F, Rosa A, Crespo J et al. (2012) Association study of IL10 and IL23R-IL12RB2 in Iranian patients with Behcet's disease. Arthritis Rheum 64: 2761-2772. doi:https://doi.org/10.1002/art.34437. PubMed: 22378604.
- 45. Reveille JD, Sims AM, Danoy P, Evans DM, Leo P et al. (2010) Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nat Genet 42: 123-127. doi:https://doi.org/10.1038/ng.513. PubMed: 20062062.