Role of IL‐10 gene polymorphisms in intermediate and HLA‐B27‐associated uveitis

Abstract

Editor, Interleukin (IL)-10 is one of the most important cytokines for immune tolerance and its anti-inflammatory effects have been demonstrated in experimental autoimmune uveitis (Rizzo et al. 1998; Fang et al. 2005). In a recent study, Atan et al. (2010) reported an association of three haplotype tagging SNPs (rs6703630, rs2222202 and rs3024490) in the IL-10 gene with the occurrence of noninfectious uveitis. The patients in the study by Atan et al. (2010) suffered from six different uveitis entities. We, however, showed recently in case of the IL-2 receptor gene that, depending on the uveitis subtype, the role of gene polymorphisms may differ significantly, suggesting that different subtypes of uveitis follow different pathogenic pathways and need to be investigated separately (Lindner et al. 2011). Thus, to further investigate the results of the study by Atan et al., we looked at the aforementioned SNPs in larger patient groups suffering from either HLA-B27 associated uveitis or intermediate uveitis. Our study was composed as a ‘follow-up study’. One hundred fifty-nine patients with HLA-B27-associated anterior uveitis, 85 patients with intermediate uveitis, 138 HLA-B27-negative controls and 100 HLA-B27-positive controls were enrolled in the present case–control study. All participants were of Caucasian origin, living in the same geographical area in Southern Austria. In all patients’ chest X-ray, TPHA, FTA-ABS and ACE were taken to rule out other causes of uveitis. Where indicated further investigations including serology for Toxoplasma, Toxocara, Bartonella and Borrelia were performed. Patients with Fuchs′ heterochromic iridocyclitis, sarcoidosis or malignancy were not included. Controls were segregated into HLA-B27 positives and negatives when looking at the role of the aforementioned SNPs in case of HLA B27 associated uveitis, to rule out possible confounding effects of HLA-B27. Exclusion criteria for all controls were any history of ocular inflammation, arthritis, lower back pain, autoimmune diseases or malignancy. DNA extraction and genotype determination were performed as described elsewhere (Lindner et al. 2011). Statistical analysis was performed using spss for Windows (release 15.0; SPSS Inc., Chicago, IL, USA). Association between the selected SNPs and disease was tested using linear regression. The criterion for statistical significance was p ≤ 0.05. Hardy–Weinberg equilibrium has been calculated using HW Diagnostics-Version 1.beta (Fox Chase Cancer Center, Philadelphia, PA, USA). In HLA-B27-associated uveitis, 22 patients had an acute, 125 a recurrent and twelve a chronic course. In intermediate uveitis, 36 patients had an acute, 31 a recurrent and 18 a chronic course. Genotypes were successfully determined in all participants and did not deviate from the distribution predicted by the Hardy–Weinberg equilibrium. All SNPs were in strong linkage disequilibrium, with pairwise D′ values that were ≥0.82. No significant differences in genotype distribution of any of the investigated IL-10 polymorphisms were found between patients and controls (p > 0.05; Table 1). The present study has a statistical power of more than 0.80 to detect ORs ranging from 2.0 to 2.7 at a significance level of 0.05. In their study, Atan et al. (2010) included a large variety of uveitis entities, which most likely contributed unequally to their findings. In a follow-up evaluation, they were able to show, by restricting their analysis to patients with punctate inner choroidopathy (PIC) and multifocal choroiditis (MFC), that the uveitis risk increased from 2.4-fold for all patient groups combined in their first study to 11.4 fold for carriers of the rs2222202 gene polymorphism in the subgroup analysis (Atan et al. 2011). The findings presented in our study suggest that in the primary study by Atan et al. (2010) patients suffering from intermediate uveitis did most likely not contribute to the positive findings. This further supports the fact that PIC and MFC where the uveitis entities in whom these gene polymorphisms contributed the most to disease development. Our study recapitulates previous (Lindner et al. 2011) findings that, depending on the uveitis entity investigated, the role of gene polymorphisms in disease development may vary significantly, suggesting specific underlying pathomechanisms for most of the uveitis entities. Therefore, results of genetic investigations seen in one uveitis entity will frequently not be applicable in other uveitis diseases.