The cytokine IL-4 act as a key player in the development and pathogenesis of allergic inflammation  and atopy  through the induction of the heavy chain isotype switching, secretion of IgE antibody (IgE synthesis) by B cells, functioning as a growth factor for Th2 cells . The IL-4 promotes IgE-dependent immune responses as it induces overexpression of IgE receptors on the surface of various immune cells: FcεRI on basophils and mast cells; and FcεRII (CD23) on mononuclear phagocytic cells and B lymphocytes . Thee IL-4 tilts the immune response to anti-inflammatory, inhibiting macrophages pro-inflammatory effect and downregulating secretion of pro-inflammatory cytokines . The IL-4 critically, initiate immediate allergic responses by triggering IgE-mediated mast cell activation. The IL-4 plays a pivotal role in the priming of naïve T cell towards Th2 differentiation as well as exacerbate allergic inflammation through induction of vascular adhesion molecule 1 (VCAM-1) that recruit leukocytes and promote their survival . The IL-4 induce airway remodeling encountered in asthma by its role in the proliferation of bronchial fibroblasts, myofibroblasts, and airway smooth muscles .
At the turn of the millennium genetic polymorphisms of the IL-4 gene in the development and maintenance of asthma have drawn increasing consideration. Modulation of the immune system is the common denominator in IL-4 polymorphisms . Suzuki and coworkers found a single nucleotide polymorphism of C replacement of T at position 33 bp of exon 1 (C + 33T) of the IL-4 proximal promoter region . Asthmatic patients with C + 33T have higher serum level of IL-4 and IgE . Anovazzi and colleagues studied IL-4 haplotypes and reported that the studied haplotypes induce an opposing immune response, as well they recorded minimal functional activity in polymorphisms involving the promoter region . An increasing body of evidence has demonstrated that C + 33T of the IL-4 gene untranslated region (UTR) of chromosome 5q was associated with elevated serum IgE levels and the risk of asthma [44, 45]. However, this association remains inconclusive. If this is indeed the case, a meta-analysis with big sample size, sufficient statistical power, and subgroup analysis was needed.
Our current meta-analysis composed of 24 studies involving 6587 cases and 8408 controls, we systematically assessed the relationship between IL-4 C33T polymorphism and asthma susceptibility. Cumulatively, the result illustrated IL-4 C33T polymorphism as a risk factor in the pathogenesis of asthma. The result indicated that the presence of T allele across different genetic models increased asthma risk by 10–21%. In the subgroup analysis by age, the results rejected the significant association between IL-4 SNP (C33T) and risk of asthma in different age groups except for allelic model, which highlighted the predisposing role of the T allele for the asthma risk in all three age groups. Subgroup analysis by continent revealed a significant association between IL-4 SNP (C33T) and asthma risk in the European population. In the Asian population, there was a significant association between IL-4 SNP (C33T) and the risk of asthma under recessive and allelic models. In contrast, the American population showed a significant association under dominant and allelic models.
Additionally, Subgroup analysis was conducted according to ethnicity; the results showed a significant association between IL-4 SNP (C33T) and asthma risk in Caucasians under the recessive model and allelic model. On the other hand, there was a significant association between IL-4 SNP (C33T) and the risk of asthma in the American-African population under the dominant model, allelic model, and CT vs. TT model.
It should be noted that our results are not in agreement with those of Liu et al.  meta-analysis on the role of IL-4 − C33T variation and asthma. They suggested a significant association between whites and Asians but not among African Americans. While they reported a significant association between the IL-4-C33T polymorphism and asthma risk in the overall population, they did not found a significant association among atopic and non-atopic asthma patients in subgroup analysis. Furthermore, in contrast to our meta-analysis, in the subgroup analysis by age, they reported an increased risk of asthma among children but not in the adult. Finally, while they reported evidence of publication bias, we identified no evidence of publication bias for the overall population and subgroup analysis under all genetic models.
The main reason for these discrepancies raised could be from the fact that Liu and colleagues included 18 studies with 5523 cases and 5618 controls. However, our meta-analysis encompasses 28 studies including 6587 cases and 8408 controls from different ethnicities and continents.
The C33T single nucleotide polymorphism is detected on the 5’ untranslated regions (UTR) of the IL-4 gene . The 5′ UTRs region of mRNA may contain many gene regulatory elements (GRE) that regulate the localization, translation and degradation of transcripts . In the eukaryotic mRNAs, the 5’ UTRs regulate both cap-dependent and cap-independent translation initiation of mRNA . Researchers revealed a relationship between IL-4 C33T polymorphism and elevated serum IgE levels in a group of the Japanese population . While the exact mechanisms by which the IL-4 C33T allele modulates the gene expression of the IL-4 remain elusive, it has been suggested that this variation may influence the stability of mRNA, as well as transcriptional or translational efficiency of the IL-4 gene, highlighting that the 5’ UTR may involve many cis-acting elements [46, 49, 50].
Heterogeneity and publication bias, which may affect the results of meta-analyses, should always be considered. The result of this study did not show significant heterogeneity. Moreover, there was no significant publication bias in the overall population and subgroup analysis under all genetic models. Consequently, heterogeneity and publication bias did not appear to have inclined the results. Sensitivity analyses were also performed. There was a little variation of the estimates after exclusion of a single study and the significance of the pooled ORs was not affected proposing the consistency of this result.
The current study had some limitations. First, most included articles were from the Asia continent with Caucasian race and there was no study from Africans; accordingly, the results of this meta-analysis may not be appropriate to Africans. Second, in some studies, the diagnostic criteria and asthma phenotype were not clearly determined; while the asthma diagnostic criteria were primarily based on physical examination, clinical history, and pulmonary function tests (PFT), there did exist a little dissimilarity among studies. Third, the overall results were based on unadjusted estimates; a more precise evaluation should be accompanied when all singular raw data are accessible, which would facilitate the adjustment by other potential co-variants such as; age, gender, obesity, environmental factors, smoking status, and other lifestyles. Fourth, due to a lack of extractable data, we failed to address gene-environment and gene-gene interactions. In contrast to these limitations, two main strengths of our meta-analysis include; Firstly, a large number of patients and the healthy individuals were pooled from various studies, which considerably augment the statistical power of the meta-analysis. Secondly, no evidence of publication biases was identified, representing that the whole collected data may be unbiased.