Identification and Association of Polymorphisms in the Interleukin-13 Gene with Asthma and Atopy in a Dutch Population (original) (raw)
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BioMed Research International, 2013
Asthma susceptibility genes are mapped to a region on human chromosome 5q31-q33, which contains a cluster of proinflammatory cytokine genes such as interleukin-13 (IL-13), which is associated with asthma. This study investigated the allele frequencies of two single nucleotide polymorphisms (SNPs) (−1111C>T and 4257C>A) in the IL-13 gene between asthmatics and healthy volunteers as well as the relationship between these SNPs and IL-13 production. DNA extracted from buffy coat of asthmatic and control subjects was genotyped using the PCR-RFLP method. Amount of IL-13 produced by mitogen-stimulated peripheral blood leucocytes PBLs (PBLs) was determined by ELISA. The frequencies of the −1111C and 4257G wild-type alleles were 0.52 and 0.55 in asthmatics and were 0.67 and 0.56 in controls. A significant ( < 0.05) association was found between genotype and allele frequencies of SNP at position −1111C>T between asthmatic and control groups (OR, 1.810; 95% CI = 1.184 to 2.767; < 0.05). The mitogenstimulated PBLs from asthmatics produced higher amounts of IL-13 production ( < 0.001). The 4257GA heterozygous and 4257AA homozygous mutant alleles were associated with higher IL-13 production in asthmatics ( < 0.05). Our results show that the −1111T mutant allele are associated with asthma and the 4257A mutant alleles are associated with elevated IL-13 production.
The gene encoding interleukin-13: a susceptibility locus for asthma and related traits
Respiratory Research, 2000
Asthma is a complex inflammatory disorder controlled by both genetic and environmental influences. Multiple genetic analyses have identified the T helper type 2 (Th2) cytokine gene cluster on chromosome 5q as a susceptibility locus for asthma. Recently, the Th2 cytokine interleukin-13 has been shown to be a critical mediator of the asthma phenotype in murine models. In this commentary we discuss several recent studies that have identified polymorphisms in the gene encoding interleukin-13. The consistent genetic associations of interleukin-13 with asthma and related traits across diverse ethnic populations in these studies provides strong support for the candidacy of this cytokine as a susceptibility locus for asthma and atopy on chromosome 5q31.
Genetic variants of IL-13 signalling and human asthma and atopy
Human Molecular Genetics, 2000
Asthma and atopy show epidemiological association and are biologically linked by T-helper type 2 (T h 2) cytokine-driven inflammatory mechanisms. IL-4 operates through the IL-4 receptor (IL-4R, a heterodimer of IL-4Rα and either γc or IL-13Rα1) and IL-13 operates through IL-13R (a heterodimer of IL-4Rα and IL-13Rα1) to promote IgE synthesis and IgE-based mucosal inflammation which typify atopy. Recent animal model data suggest that IL-13 is a central cytokine in promoting asthma, through the stimulation of bronchial epithelial mucus secretion and smooth muscle hyper-reactivity. We investigated the role of common genetic variants of IL-13 and IL-13Rα1 in human asthma, considering IgE levels. A novel variant of human IL-13, Gln110Arg, on chromosome 5q31, associated with asthma rather than IgE levels in casecontrol populations from Britain and Japan [peak odds ratio (OR) = 2.31, 95% CI 1.33-4.00]; the variant also predicted asthma and higher serum IL-13 levels in a general, Japanese paediatric population. Immunohistochemistry demonstrated that both subunits of IL-13R are prominently expressed in bronchial epithelium and smooth muscle from asthmatic subjects. Detailed molecular modelling analyses indicate that residue 110 of IL-13, the site of the charge-modifying variants Arg and Gln, is important in the internal constitution of the ligand and crucial in ligand-receptor interaction. A non-coding variant of IL-13Rα1, A1398G, on chromosome Xq13, associated primarily with high IgE levels (OR = 3.38 in males, 1.10 in females) rather than asthma. Thus, certain variants of IL-13 signalling are likely to be important promoters of human asthma; detailed functional analysis of their actions is needed.
Clinical Medicine and Diagnostics, 2014
Background: Asthma is a chronic, inflammatory disease of the respiratory tract, which is characterized by bronchial hyperreactivity and respiratory obstruction in which many cells and cellular elements play a role. Interleukin 13 (IL-13) is a type 2 helper T cells (Th2) cytokine that has been shown to be pivotal in the induction of allergic inflammation of the airways. Moreover, Several IL-13 genetic polymorphisms have been linked with susceptibility to bronchial asthma. Aim: The aim of this study was to evaluate the association of IL-13 + 2044G/A polymorphism with bronchial asthma development, severity and total serum immunoglobulin E (IgE) levels in Egyptian patients with bronchial asthma. Subjects and methods: This study included 50 asthmatic patients and 30 controls. Restriction Fragment Length Polymorphism (RFLP) PCR was used for the analysis of the studied polymorphism. Also, the serum was analyzed for total IgE levels by enzyme-linked immunosorbent assay (ELISA). Results: The frequency of the A allele was significantly higher in asthmatic patients as compared to control subjects. On the contrary, the G allele was less frequent in the asthmatic patients as compared to control subjects. In addition the A allele was more frequent in severe asthmatic patients and on the other hand the G allele was less frequent in severe asthmatic patients. Moreover, the presence of the A allele was significantly associated with higher total serum IgE levels whether in homozygous or heterozygous state. Conclusions: The results showed that the IL-13 +2044 A allele is a risk factor for bronchial asthma. There is a significant association between the A allele and more severe asthma, however the G allele is significantly associated with less severe asthma. In addition, the A allele is significantly associated with higher total serum IgE levels.
Polymorphisms in IL13 pathway genes in asthma and chronic obstructive pulmonary disease
Allergy, 2010
Background: Asthma and chronic obstructive pulmonary disease (COPD) are chronic respiratory diseases involving an interaction between genetic and environmental factors. Interleukin-13 (IL13) has been suggested to have a role in both asthma and COPD. We investigated whether single nucleotide polymorphisms (SNPs) in the IL13 pathway may contribute to the susceptibility and severity of asthma and COPD in adults. Methods: Twelve SNPs in IL13 pathway genes -IL4, IL13, IL4RA, IL13RA1, IL13RA2 and STAT6 -were genotyped in subjects with asthma (n = 299) and in subjects with COPD or healthy smokers (n = 992). Genetic association was evaluated using genotype and allele models for asthma severity, atopy phenotypes and COPD susceptibility. Linear regression was used to determine the effects of polymorphism on baseline lung function (FEV 1 , FEV 1 /FVC). Results: In asthmatics, three IL13 SNPs -rs1881457(-1512), rs1800925(-1111) and rs20541(R130Q) -were associated with atopy risk. One SNP in IL4RA1 [rs1805010(I75V)] was associated with asthma severity, and several IL13 SNPs showed borderline significance. IL13 SNPs rs1881457(-1512) and rs1800925 (-1111) were associated with better FEV 1 and FEV 1 /FVC in asthmatics. IL13 SNPs rs2066960(intron 1), rs20541(R130Q) and rs1295685(exon 4) were associated with COPD risk and lower baseline lung function in the recessive model. In females, but not in males, rs2250747 of the IL13RA1 gene was associated with COPD and lower FEV 1 . Conclusion: These data suggest that IL13 SNPs (promoter and coding region) and, to a lesser extent, IL4RA SNPs may contribute to atopy and asthma. We also provide tentative evidence that IL13 SNPs in the coding region may be of significance in COPD susceptibility.
Interleukin-13 gene polymorphism G4257A is associated with atopic dermatitis in Japanese patients
Journal of Dermatological Science, 2002
Interleukin (IL)-13 plays an important role in the induction of immunoglobulin E (IgE) and in the pathogenesis of atopic dermatitis (AD). We investigated the allele and genotype frequencies of three IL-13 single nucleotide polymorphisms (SNPs) (A704C and C1103T in the promoter region and G4257A in exon 4) in Japanese patients with AD. For A704C and C1103T SNPs, there were no significant differences in allele or genotype frequencies between AD patients and controls. For G4257A SNP, A allele was significantly increased in AD patients (39.5%) compared with controls (29.4%) (P0/0.016). The same proportion of each genotype and allele was observed in the patient subgroup with and without asthma. Serum IgE levels and peripheral eosinophil counts were not significantly different among genotypes in G4257A SNP. There was also no significant difference in allele or genotype frequencies between AD patients with mild disease and those with severe disease, between those with family history of AD and those without it, or between those with family history of atopic disorders and those without it. This result suggests that 4257A allele is associated with susceptibility to AD and that it may function in the pathogenesis of AD itself, presumably by other mechanisms than inducing IgE production. #
Interleukin 13 and Interleukin 4 Receptor-α Polymorphisms in Rhinitis and Asthma
International Archives of Allergy and Immunology, 2010
consistently associated with asthma and serum IgE in both asthma populations. IL4R Glu375Ala (rs1805011) and Ser411Leu (rs1805013) were associated with asthma in the asthma case-control population. Combining risk genotypes of IL13 Arg130Gln with IL4R Glu375Ala, and IL13 C-1111T with IL4R Ser478Pro yielded increased risks for asthma compared to their separate effects. Conclusion: IL13 polymorphisms were associated with asthma and rhinitis without clinical asthma; thus, these polymorphisms may constitute a common etiologic pathway for their development. In addition, the study replicates a previously reported interaction of IL13 and IL4R polymorphisms in asthma.