Original Research Article
Polymorphisms in the interleukin 4, interleukin 4 receptor and interleukin 13 genes and allergic phenotype: A case control study

https://doi.org/10.1016/j.advms.2015.07.003Get rights and content

Abstract

Purpose

Interleukin 4 (IL4), interleukin 4 receptor (IL4R) and interleukin 13 (IL13) play a key role in the pathogenesis of allergy and asthma development. IL4 and IL13 strongly influence bronchial hyperreactivity in response to allergen, airway remodeling, airway inflammation and airway smooth muscle proliferation. Both IL4 and IL13 exert biologic effect via interleukin 4 receptor. The aim of this study was to evaluate the impact of the polymorphisms within interleukin 4 (rs2243250, rs2227284), interleukin 4 receptor α chain (rs1805010, rs1805011) and interleukin 13 (rs20541) genes on the incidence of allergic phenotype in Polish pediatric population.

Material/methods

We compared 177 asthmatic pediatric patients with 194 healthy children. Five polymorphisms within IL4, IL13 and IL4Rα genes were analyzed. Genotypes of four polymorphisms (rs2243250, rs2227284, rs1805011, rs20541) were assigned by TaqMan SNP Genotyping Assays (Applied Biosystems), whereas rs18050100 polymorphism was established using PCR-RFLP method.

Results

We observed an association of rs1805011 polymorphism of IL4Rα gene with allergy (p = 0.021), mild asthma (p = 0.00005) and atopic dermatitis (p = 0.0056). Significant correlation was found between rs20541 in IL-13 gene and the positive skin prick test results (p = 0.029), along with rs2243250 polymorphism with clinical atopy (p = 0.033) and rs2227284 with total IgE levels (p = 0.00047). No associations were found for rs1805010.

Conclusions

Our results indicate that rs1805011 polymorphism of IL4Rα gene seems to influence allergy risk, especially mild asthma and atopic dermatitis predisposition in Polish children. Subgroup analysis of three other SNPs revealed possible influence on allergy development.

Introduction

Both interleukin 4 (IL4) and interleukin 13 (IL13) are cytokines produced mainly by T-helper 2 (Th2) cells and they play a crucial role in the pathogenesis of allergic inflammation including allergic asthma [1], [2]. Interleukin 4 and interleukin 13 recruit mast cells and eosinophils, induce isotype class-switching of B-cells for IgE synthesis and regulate expression of MHC II, CD23 and VCAM-1 [3], [4], [5]. Interleukin 4 is also responsible for regulating differentiation of naive T cells into Th2 subtype.

Interleukin 4 and IL13 strongly influence bronchial hyperreactivity in response to allergen, airway inflammation, mucus hypersecretion and airway remodeling [4], [6]. Interleukin 13 also affects goblet cell hyperplasia and epithelial damage.

IL13 and IL4 genes are clustered in a 160 kb region on the long arm of chromosome 5 [7]. Two subunits compose the IL4 receptor (IL4R): α chain (IL4Rα), which is also present in IL13R, and γ chain, shared among other cytokine receptors [8]. IL4Rα chain gene is located on chromosome 16p [9].

Previous studies have shown that SNPs in the IL4 promoter may influence the response of mast cells to IgE-mediated signaling [10]. Polymorphism rs2243250 was associated with IgE levels, asthma, allergic rhinitis and atopic dermatitis [11], [12], [13], [14]. Other SNPs in the IL4 gene were associated with allergy in different populations. A significant correlation with total IgE levels, and asthma has been also observed for rs2227284 polymorphism [15], [16]. In regard to interleukin 4 receptor α chain gene, two functional polymorphisms were reported: rs1805010, observed to cause up-regulation of IL4Rα response to IL4 [17], and rs1805011, which function remains unknown. The former genetic variant was found to be associated with asthma [2], [18] and the latter with asthma [14] and atopic dermatitis [19].

In interleukin 13 gene, a functional SNP contributing to aminoacid substitution R110Q (rs20541) was described to change the binding strength of IL13 to its receptor, causing higher activity of Gln110 variant [20]. Numerous studies showed that this polymorphism correlated significantly with higher total IgE levels, atopic dermatitis and asthma [1], [21], [22].

The aim of this study was to evaluate genetic association of five polymorphisms within interleukin 4, interleukin 4 receptor α chain and interleukin 13 genes with allergic phenotype in Polish pediatric population.

Section snippets

Patients and controls

Our study included 371 Polish children of Caucasian origin, aged from 6 to 18 years old (mean 11.84; SD = 3.48); 177 were asthmatic patients, diagnosed at least six months before the inclusion in the study, and 194 healthy children formed a control group. Participants and their legal guardians gave written informed consent. The project received acceptance from the local ethics committee. The description of the patients and controls was presented in Table 1.

Patients were recruited from inpatients

Results

All genotypes were in Hardy–Weinberg equilibrium, as presented in Fig. 1, Fig. 2, Fig. 3, Fig. 4, Fig. 5. Genotype distributions and allele frequencies of all analyzed polymorphisms for the patients and control group were shown in Table 3.

We observed significant differences in genotype distribution and allele frequencies between patients and controls for rs1805011 polymorphism. We identified C allele as a risk variant for asthma development (p = 0.024; OR = 1.673; 95%CI = 1.070–2.16). For four other

Discussion

Our main finding is the association of rs1805011 polymorphism in IL4R gene with asthma and lack of association with other polymorphisms.

Previous studies have shown that rs2243250 polymorphism within IL4 gene may enhance IL4 activity, resulting in higher total serum IgE levels [24]. Previously, this variant showed associations with asthma, lower FEV1 values and allergic rhinitis [14], [25], [26]. We observed a relationship between rs2243250 polymorphism and the risk of clinical atopy, which

Conclusions

We discovered a strong association of rs1805011 functional polymorphism with asthma, mild asthma and atopic dermatitis in Polish population. Furthermore, associations of another three polymorphisms (rs2243250, rs2227284, rs20541) may influence the risk of allergy development. Only rs1805010 polymorphism showed no association in our study group. Careful interpretation of results is required, due to ethnic differences and limited sample size of analyzed populations.

Conflict of interests

Authors of this paper have no conflict of interest to report.

Financial disclosure

This study was supported by the Polish National Science Centre, Grant 2011/01/D/NZ5/02771.

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