A total of 1873 articles were identified through the systematic literature search of databases. After excluding 219 duplicate studies and removing 1496 irrelevant publications based on titles/abstracts, 158 studies went under full-text screening. Of which, 134 paper were excluded. Finally, twenty-four studies qualified for quantitative analysis Figure 1. All included studies were performed between 2000 to 2016 and had good methodological score ranging 5 to 8. Case-control design was common between eligible studies and different genotyping method were used by included studies. Table 1 and 2 summarized the characteristics and allele distribution, genotype frequency of the eligible studies.
Meta-analysis of IL-4 C33T polymorphism and the risk of asthma
Twenty-four studies with 6587 cases and 8408 healthy controls were included in final meta-analysis of overall population. Of them, 15 publications were carried out in Asian countries, 5 publications were in American countries and 4 publications were in Europe. The pooled OR indicated that IL-4 C33T polymorphism increase risk of asthma across all genotype models including dominant model (OR= 1.15, 95% CI= 1.04-1.26, P= ≤0.001, FEM), recessive model (OR= 1.16, 95% CI= 1.06- 1.28, P= ≤0.001, FEM), allelic model (OR= 1.14, 95% CI= 1.07-1.21, P= ≤0.001, FEM), CC vs. TT model (OR= 1.21, 95% CI= 1.02-1.43, P= 0.02, FEM) and CT vs. TT model (OR= 1.10, 95% CI= 1-1.22, P= 0.05, FEM) Figure2. The detailed findings for different analysis models are shown in Table 3.
We categorized studies into different subgroups on the basis of age, continent and ethnicity. The results of pooled ORs, heterogeneity tests and publication bias tests for different analysis models are reported in Table 3.
Subgroup analysis by age
In this group, we stratified included publications into three groups including: adult (8 articles), children (7 articles) and mixed (cover both ranges; 9 articles). Overall, the results rejected significant association between IL-4 C33T polymorphism and risk of asthma in different age group except for allelic model [adults (OR= 1.14, 95% CI= 1.02-1.26, P= 0.02, FEM), mixed (OR= 1.14, 95% CI= 1.01-1.29, P= 0.03, REM), children (OR= 1.13, 95% CI= 1.04-1.24, P= ≤0.001, FEM)] and recessive model (just in children (OR= 1.18, 95% CI= 1.03-1.35, P= 0.01, REM)) Figure 3.
Subgroup analysis by continent
Our included studies performed in Asia (15 articles), Europe (4 articles), America (4 articles), and Oceania (1 article). Since there was only one study for Oceania, we exclude it. The final findings indicated strong significant association between IL-4 C33T polymorphism and asthma risk in European population across dominant model (OR= 1.23, 95% CI= 1.01- 1.50, P= 0.03, FEM), recessive model (OR= 2.94, 95% CI= 1.54- 5.62, P= ≤0.001, FEM), allelic model (OR= 1.30, 95% CI= 1.10-1.54, P= ≤0.001, FEM) and CC vs. TT (OR= 3, 95% CI= 1.56- 5.76, P= ≤0.001, FEM). Moreover, there was a significant association between IL-4 C33T polymorphism and risk of asthma in American population under dominant model (OR= 1.26, 95% CI= 1.05 -1.51, P= ≤0.001, FEM), allelic model (OR= 1.17, 95% CI= 1.03- 1.33, P= 0.01, FEM), and CT vs. TT model (OR= 1.23, 95% CI= 1.02-1.49, P= 0.03, FEM). Eventually, Significant positive association was revealed in Asians just in recessive model (OR= 1.14, 95% CI= 1.02- 1.26, P= 0.01, FEM), and allelic model (OR= 1.12, 95% CI= 1.03-1.21, P= ≤0.001, FEM) Figure 3.
Subgroup analysis by ethnicity
Finally, we stratified eligible articles according ethnicity including Caucasians (20 articles), and African-Americans (4 articles). The results showed significant association between IL-4 SNP (C33T) and asthma risk in Caucasians under dominant model (OR= 1.15, 95% CI= 1.04- 1.28, P= 0.008, FEM), recessive model (OR= 1.17, 95% CI= 1.06- 1.30, P= 0.002, FEM), allelic model (OR= 1.14, 95% CI= 1.07-1.22, P= ≤0.001, FEM),and CC vs. TT model (OR= 1.23, 95% CI= 1.01-1.49, P= 0.03, FEM) but not CT vs. TT model (OR= 1.1, 95% CI= 0.98 -1.22, P= 0.09, FEM). However, there was no significant association between IL-4 C33T polymorphism and risk of asthma in American-African population across all genotype models Figure 3.
Evaluation of heterogeneity
No significant heterogeneity was detected for IL-4 C33T polymorphism neither in overall population nor subgroup analysis, therefore we did not perform mete-regression analysis for possible parameters (Table 3).
Sensitivity analysis and publication bias
Begg’s and Egger’s tests were performed to estimate the publication biases of studies. As showed in Table 3 no evidence of publication bias was detected in overall populations and subgroup analysis. Also, symmetric shape of Begg’s funnel plot confirm this finding Figure 4. Moreover, the impact of individual study on pooled OR was evaluated by sensitivity analysis, which confirmed stability of our results Figure 5.