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