The association between genetic polymorphisms of the interleukin-23 receptor gene and susceptibility to uveitis: a meta-analysis

We performed a search for studies that examined the associations between IL-23R polymorphisms and uveitis. Genetic association studies that determined the distributions of rs7517847, rs17375018, and rs11209032 polymorphisms in uveitis and in normal controls were included. The literature was searched using the PUBMED and EMBASE databases to identify available articles in which IL-23R polymorphisms were analyzed in uveitis patients (up to June 2016). We listed combinations of key words and subject terms such as “interleukin-23 receptor,” “IL23R,” “polymorphism,” and “uveitis.” Only papers written in the English language were included. References from the identified studies were also investigated to identify additional studies that were not indexed by PUBMED and EMBASE. The following information was extracted from each study: author, year of publication, ethnicity of the study population, demographics, number of cases and controls, Hardy-Weinberg equilibrium (HWE) P-value, and the allele and genotype frequencies for each of the polymorphisms (rs7517847, rs17375018, and rs11209032). This meta-analysis was reported based on the Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA) guidelines [9].

The allele counting method was used to determine the allele frequencies of the genetic polymorphisms. The Chi-squared test was used to detect if the controls in each study conformed to HWE. The associations between rs7517847, rs17375018, rs11209032 and uveitis were estimated using the crude odds ratio (OR) and 95% confidence interval (CI). We performed meta-analyses using the 1) allelic contrast, 2) homozygote contrast, 3) recessive, and 4) dominant models. Inter-study heterogeneity was assessed with the Cochran Q test (in which P-value < 0.10 was considered statistically significant heterogeneity) and I² statistics (I² < 25 = no heterogeneity; 25 ≤ I² < 50 = moderate heterogeneity; 50 ≤ I² < 75 = large heterogeneity; 75 ≤ I² < 100 = extreme heterogeneity) [10]. If there were no significance between the study heterogeneity, a fixed-effects model was used [11]. Otherwise, a random-effect model was used [12]. Forest plots were drawn to visualize the overall effect. Meta-analysis was performed using Review Manager software, version 5.3.

Funnel plots are often used to detect publication bias. However, they require a range of studies of varying sizes and subjective judgments. Therefore, we evaluated publication bias using Egger’s linear regression test [13], which measures funnel plot asymmetry on a natural logarithm scale of odds ratios (ORs).

Sixty two studies were identified by electronic and manual researches, and 16 were selected for a full-text review based on the title and abstract details. Nine studies were excluded because they did not contain genotype data or were the lack of suitable controls. Ultimately, seven studies met our inclusion criteria [2, 5‐8, 14]. A flow chart describing inclusion/exclusion of the individual studies is displayed as Fig. 1. Six of these studies involved the association between the IL-23R gene rs7517847 polymorphism and uveitis, five studies involved rs17375018, and five studies involved rs11209032. A total of seventeen separate comparisons were considered in this meta-analysis, involving 1309 uveitis patients and 2400 controls.

Uveitis in ankylosing spondylitis, Behçet’s disease, sarcoidosis, endogenous non anterior uveitis, VKH, and Fuchs’ syndrome were included in this meta-analysis. Among these diseases, the etiology of Fuchs’ syndrome is not fully understood. Some theories on the etiology of Fuchs’ syndrome have been suggested including infection, vascular abnormality and autoimmunity [5, 15]. Thus, we performed a meta-analysis with and without Fuchs’ syndrome. The details of the IL-23R polymorphism studies are summarized in Table 1.

Table 2 and Fig. 2 demonstrate the findings from our meta-analysis with regard to the association between IL-23R polymorphisms and overall uveitis. There were no differences concerning the genotype and allele of rs7517847 SNPs between patients with uveitis and controls (OR 1.01, 95% CI 0.92–1.12, P = 0.83). There was also no significant association between the rs17375018 A allele and uveitis (OR 0.68, 95% CI 0.47–0.99, P = 0.05; Fig. 3a). However, the frequency of the rs17375018 AA + AG genotype was significantly associated with uveitis (OR 0.59, 95% CI 0.35–0.99, P = 0.04). The allele frequencies of rs11209032 in patients and in controls were not significantly different (OR 1.20, 95% CI 0.87–1.64, P = 0.27). A meta-analysis of the AA genotype of the rs11209032 polymorphism was significantly associated with uveitis (OR 1.33, 95% CI 1.11–1.60, P = 0.002; Fig. 3b).

Table 3 and Fig. 4 demonstrate the findings from our meta-analysis with regard to the association between IL-23R polymorphisms and uveitis without Fuchs’ syndrome. There were no differences concerning the genotype and allele of rs7517847, rs17375018 and rs11209032 SNPs between patients with uveitis and controls (OR 0.99, 95% CI 0.84–1.16, P = 0.87; OR 0.64, 95% CI 0.40–1.04, P = 0.07; OR 1.13, 95% CI 0.76–1.69, P = 0.54, respectively).