Association between Q551R IL4R genetic variants and atopic asthma risk demonstrated by meta-analysis

BACKGROUND: IL4R, the gene encoding the alpha chain of the IL-4 and IL-13 receptors, has received extensive attention as a candidate gene for asthma risk. However, the results from studies testing for associations of the I50V and Q551R IL4R genetic variants are conflicting. OBJECTIVE: We sought to determine the average risk of asthma associated with the I50V and Q551R IL4R variants based on the results of case-control studies reported in the literature. METHODS: Meta-analyses were performed with data from case-control association studies that met specified inclusion criteria (9 and 8 studies for I50V and Q551R, respectively). Random-effects models were used to calculate combined odds ratios (ORs) and significance of associations. Analyses were performed for asthma in general and for subgroups based on the atopy status of the asthma population. RESULTS: The R551 IL4R variant was significantly associated with increased risk of asthma, most notably atopic asthma (combined OR, 1.6; P = .004). Exclusion of the outlier study reporting an OR of less than 1 greatly increased the significance of association (OR, 1.8; P = 3 x 10(-9)). I50V variants were not significantly associated with asthma. CONCLUSIONS: A meta-analysis of results from case-control studies strongly supports the conclusion that the R551 IL4R variant imparts a modest yet significant risk for atopic asthma. CLINICAL IMPLICATIONS: Knowledge that the R551 IL4R variant is associated with increased asthma risk should provide a basis for understanding the heterogeneity of asthma pathogenesis and for pharmacogenetic approaches to treat individuals carrying this variant.     

No linkage or association of five polymorphisms in the interleukin‐4 receptor α gene with atopic asthma in Italian families

The literature contains conflicting reports on the association of common variants of the interleukin (IL)‐4 receptor alpha (IL4RA) gene with atopic asthma. The purpose of the present study was to investigate the linkage and association of several gene polymorphisms with atopic asthma in a large series of well‐characterized individuals. Analysis of five polymorphisms (I50V, E375A, C406R, S478P and Q551R) of the IL4RA gene was performed in 823 individuals from 182 families with atopic asthmatic children from north‐east Italy. The subjects were tested for clinical asthma, total serum IgE level, skin prick test positivity to common aeroallergens, and bronchial hyperresponsiveness to methacholine. The frequency of the polymorphisms was similar to that reported for other populations. The 375, 406, 478 and 551 polymorphisms were in linkage disequilibrium, as previously reported. No linkage or transmission disequilibrium was observed in the families between any mutation and any of the phenotypes investigated. No multipoint haplotype was associated with any phenotype. In conclusion, the IL4RA gene does not seem to play an important role in genetic predisposition to atopic asthma in the population tested.     

No linkage or association of five polymorphisms in the interleukin-4 receptor alpha gene with atopic asthma in Italian families.

The literature contains conflicting reports on the association of common variants of the interleukin (IL)-4 receptor alpha (IL4RA) gene with atopic asthma. The purpose of the present study was to investigate the linkage and association of several gene polymorphisms with atopic asthma in a large series of well-characterized individuals. Analysis of five polymorphisms (I50V, E375A, C406R, S478P and Q551R) of the IL4RA gene was performed in 823 individuals from 182 families with atopic asthmatic children from north-east Italy. The subjects were tested for clinical asthma, total serum IgE level, skin prick test positivity to common aeroallergens, and bronchial hyperresponsiveness to methacholine. The frequency of the polymorphisms was similar to that reported for other populations. The 375, 406, 478 and 551 polymorphisms were in linkage disequilibrium, as previously reported. No linkage or transmission disequilibrium was observed in the families between any mutation and any of the phenotypes investigated. No multipoint haplotype was associated with any phenotype. In conclusion, the IL4RA gene does not seem to play an important role in genetic predisposition to atopic asthma in the population tested.     

Polymorphisms in the interleukin-4 and interleukin-4 receptor α chain genes confer susceptibility to asthma and atopy in a Caucasian population

BACKGROUND : IL-4 by binding to its receptor (IL-4R) is essential for the development of airway inflammation present in asthma, through the induction of IgE synthesis in B cells and differentiation of T cells to a Th2 phenotype. OBJECTIVE : To investigate the role of four common polymorphisms in the IL-4 (IL4-34CT and IL4-589CT) and IL-4Ralpha chain (IL4RAI50V and IL4RAQ576R) genes in conferring susceptibility to the development of atopy and/or asthma. METHODS : Two polymorphisms in the IL-4 gene promoter, IL4-34CT and IL4-589CT, and two polymorphisms in the IL-4Ralpha chain gene, IL4RAI50V and IL4RAQ576R, have been genotyped using PCR-based methods in 341 asthmatic families and in 184 non-asthmatic adults recruited from the south of England. RESULTS : Case-control analysis did not reveal differences in the distribution of the four polymorphisms between asthmatics and controls. However, the transmission disequilibrium test showed that the IL4-589 T allele was preferentially transmitted to asthmatic children (P=0.036) and that the IL4RAQ576 was preferentially transmitted to children with atopic asthma (P=0.018). Haplotype analysis showed a strong association between the IL4-34T/-589T haplotype and asthma per se (P=0.041), and a strong association between the IL4RA I50/Q576 haplotype and atopic asthma (P=0.006). CONCLUSION : Our data suggest that polymorphisms in the IL-4 and IL-4Ralpha chain genes might play a role both conferring susceptibility to and modulating severity of atopy and asthma.     

Asthma and IL‐4 receptor alpha gene variants

Linkage of allergy to chromosome 16 has been described in several studies, together with a positive association with interleukin 4 receptor α gene variants. Our aim was to replicate these findings in a sample of German and Swedish families recruited through sib‐pairs affected by bronchial asthma. None of the markers showed linkage with the main phenotype of asthma or with total serum IgE. Seropositivity to D. pteronyssinus showed borderline significance in a region flanking the IL4Rα location. Single nucleotide polymorphisms (SNPs) leading to the protein exchanges I50V, E375A, C406R, S478P and Q551R in the IL‐4 receptor α were examined for allele sharing in sibs with asthma. Multiple regression analysis was performed for association with total serum IgE and specific IgE. Allele sharing of IL4Rα SNPs in asthmatic children was not significantly increased for any of the examined SNPs except for the intracytoplasmatic polymorphism 551R (0.79 vs. 0.84 expected, P = 0.044). The variants 50V, 478P and 551R were associated with slightly increased, and 375A and 406R with decreased total IgE levels, all at a non‐significant level. None of the examined IL4Rα variants were correlated to asthma severity. In summary, a single gene effect of IL4Rα variants or any other gene on chromosome 16 could not be shown in this selected population of children with asthma. As there could be interactions with multiple genetic and environmental factors, IL4Rα could still be involved in asthma pathogenesis.     

IL-4 receptor alpha chain genetic polymorphism and total IgE levels in the English population: two-locus haplotypes are more informative than individual SNPs

The IL-4RA locus encodes for the alpha chain of the IL-4 receptor, and is both a functional and positional candidate gene for atopy and allergic disease. Recently Ober et al. have shown that the study of haplotypes at multiple loci in the IL-4RA gene could be more informative than the separate study of single nucleotide polymorphisms (SNPs). One hundred and fifty subjects affected by atopic asthma and 150 healthy control subjects were studied in the English population (Oxford district). Subjects and controls were genotyped for the Ile50Val, Ser478Pro and Gln551Arg polymorphism of the IL-4 receptor alpha chain. The distribution of haplotypes 50-478 shows a highly significant association with IgE levels. In particular, the haplotype Val50/Pro478 is much less frequent in subjects with IgE levels > 100 U mL-1 than in those with IgE levels < 100 U mL-1. Furthermore, the distribution of haplotype 50-551 shows a weak association with IgE levels that is lacking for 478-551 haplotypes. A lower frequency of the Val50/Pro478 haplotype is also observed among asthmatic subjects as compared to healthy controls. With regard to individual SNPs (50 478 and 551), no significant association has been observed with IgE levels or with asthma, thus confirming the higher informative value of the haplotype analysis as compared to separate study on SNPs.     

Asthma and IL-4 receptor alpha gene variants.

Linkage of allergy to chromosome 16 has been described in several studies, together with a positive association with interleukin 4 receptor alpha gene variants. Our aim was to replicate these findings in a sample of German and Swedish families recruited through sib-pairs affected by bronchial asthma. None of the markers showed linkage with the main phenotype of asthma or with total serum IgE. Seropositivity to D. pteronyssinus showed borderline significance in a region flanking the IL4Ralpha location. Single nucleotide polymorphisms (SNPs) leading to the protein exchanges I50V, E375A, C406R, S478P and Q551R in the IL-4 receptor alpha were examined for allele sharing in sibs with asthma. Multiple regression analysis was performed for association with total serum IgE and specific IgE. Allele sharing of IL4Ralpha SNPs in asthmatic children was not significantly increased for any of the examined SNPs except for the intracytoplasmatic polymorphism 551R (0.79 vs. 0.84 expected, P = 0.044). The variants 50V, 478P and 551R were associated with slightly increased, and 375A and 406R with decreased total IgE levels, all at a non-significant level. None of the examined IL4Ralpha variants were correlated to asthma severity. In summary, a single gene effect of IL4Ralpha variants or any other gene on chromosome 16 could not be shown in this selected population of children with asthma. As there could be interactions with multiple genetic and environmental factors, IL4Ralpha could still be involved in asthma pathogenesis.     

Interleukin 18 receptor 1 gene polymorphisms are associated with asthma

The interleukin 18 receptor (IL18R1) gene is a strong candidate gene for asthma. It has been implicated in the pathophysiology of asthma and maps to an asthma susceptibility locus on chromosome 2q12. The possibility of association between polymorphisms in IL18R1 and asthma was examined by genotyping seven SNPs in 294, 342 and 100 families from Denmark, United Kingdom and Norway and conducting family-based association analyses for asthma, atopic asthma and bronchial hyper-reactivity (BHR) phenotypes. Three SNPs in IL18R1 were associated with asthma (0.01131相似文献   

Gene–gene interaction between IL-13 and IL-13Rα1 is associated with total IgE in Korean children with atopic asthma

Interleukin (IL)-13, which is essential for IgE synthesis, mediates its effects by binding with a receptor composed of IL-4Rα and IL-13Rα1. We investigated the effects of IL-13 and IL-13Rα1 polymorphisms in Korean children with asthma, and whether these have been associated with IgE production. We enrolled 358 atopic asthmatic, 111 non-atopic asthmatic, and 146 non-atopic healthy children. IL-13 and IL-13Rα1 genotypes were identified using the PCR-RFLP method. There was an association between the asthma susceptibility and homozygosity for risk allele of IL-13 G+2044A. In children with atopic asthma, risk alleles in IL-13 (A−1512C and C−1112T) and IL-13Rα1 (A+1398G) showed increased total IgE (P=0.012, 0.015 and 0.017, respectively). Three-loci haplotype analysis for IL-13 showed that the haplotype composed of −1512C, −1112T and +2044A was associated with higher total IgE than other tested haplotypes in children with atopic asthma (P=0.003). The gene–gene interaction between risk alleles of each IL-13 promoter polymorphism and IL-13Rα1 polymorphism was associated with higher total IgE in children with atopic asthma (P=0.002, 0.010). These findings indicate that the IL-13 G+2044A is associated with asthma development and the IL-13 and IL-13Rα1 polymorphisms may interact to enhance IgE production.Hyo-Bin Kim, and Yong-Chul Lee contributed equally to this work. This work was supported by grants from the Asan Institute for Life Science (2005-091) and the National Research Laboratory Program, Korea Science and Engineering Foundation and by Korea Research Foundation Grants funded by the Korean Government (MOEHRD, Basic Research Promotion Fund) (KRF-2005-201-E00014), Republic of Korea.     

Analysis of IL4R haplotypes in predisposition to multiple sclerosis

We have investigated the association of multiple sclerosis (MS) with polymorphisms in the IL4R gene in 332 single-case MS families. IL4R encodes a subunit of the interleukin-4 receptor, a molecule important for T-cell development and differentiation, and is a gene shown to be associated with immune-related diseases such as asthma and type I diabetes. By genotyping two promoter and eight coding IL4R SNPs and identifying haplotypes (complex alleles) in the MS families, stratified for HLA genotype, we have observed evidence of the association of the IL4R gene to MS. In particular, we have identified a specific susceptibility haplotype, and observe that the risk is conferred primarily to individuals not carrying the high MS-risk HLA DR2 (DRB1(*)1501-DQB1(*)0602) haplotype (nominal P=0.009). These findings suggest a potentially important role for the IL4R gene in predisposition to MS, and provide further evidence of its relevance as a candidate gene for immune-related diseases.     

哮喘患者外周血淋巴细胞IL-4Rα链的表达及其意义

为了解过敏性哮喘患者外周血淋巴细胞IL 4受体 (IL 4R )的变化规律及其影响因素。本工作将研究对象分为正常对照组 (n =12 )、过敏性哮喘患者缓解期组 (n =14 )和急性发作期组 (n =16 ) ,分离外周血单个核细胞 (PBMC ) ,取 1× 10 6个细胞加入或不加入 10ng/mlIL 3、IL 5及GM CSF培育 2 4h ,利用流式细胞仪测量PBMC中淋巴细胞亚群膜IL 4Rα的表达。结果显示 :哮喘患者缓解期B细胞IL 4Rα表达阳性率明显低于正常人及哮喘急性发作期 ,而哮喘患者急性发作期CD3+ 细胞、CD4 + 细胞和CD8+ 细胞IL 4Rα表达阳性率则较哮喘缓解期和正常人明显升高 ,差异有显著性 (P均 <0 0 5 )。经IL 3、IL 5及GM CSF刺激后 ,正常组仅见B细胞携带IL 4Rα的比例显著下降 (P <0 0 5 ) ,T细胞携带IL 4Rα的比例则无变化 ;而哮喘患者缓解期T、Th细胞携带IL 4Rα的比例有明显上升 (P均 <0 0 5 ) ,B细胞携带IL 4Rα的比例则无变化 ;哮喘患者急性发作期T细胞和B细胞携带IL 4Rα的比例均无变化。这提示CD4 + 细胞携带IL 4R比例的升高可能在过敏性哮喘发病过程中起重要作用 ,而IL 3、IL 5及GM CSF则有助于Th细胞携带IL 4R比例的上调     

Childhood atopic asthma: positive association with a polymorphism of IL-4 receptor alpha gene but not with that of IL-4 promoter or Fc epsilon receptor I beta gene

We examined the relative contributions of three representative candidate genes for atopy (Fc epsilon receptor I beta, IL-4, and IL-4 receptor alpha) to the development of atopic asthma. Four polymorphisms of the three candidate genes including Ile50Val and Gln551Arg of IL-4 receptor alpha, -590C/T of IL-4 promoter and Glu237Gly of Fc epsilon receptor I beta were studied in 100 patients with atopic asthma and 100 nonatopic controls in the northern Kyushu area in Japan. Among the four polymorphisms of the three candidate genes, the Ile50 allele of the IL-4 receptor alpha chain gene demonstrated an association with atopic asthma subjects (p = 0.044), especially in patients with onset at 2 years of age or earlier (p = 0.034) and in patients with moderate to severe atopic asthma (p = 0. 031). Gln551Arg of IL-4 receptor alpha, -590C/T of IL-4 promoter and Glu237Gly of Fc epsilon receptor I beta showed no association with atopic asthma. A slight linkage disequilibrium between Ile50Val and Gln551Arg polymorphisms of the IL-4 receptor alpha chain gene was observed in both patients and nonatopic controls. The identification of additional atopy genes in areas with a certain genetic background is essential for genetic diagnosis and to establish new therapeutic modalities for atopic asthma.     

IL4 gene polymorphisms and their relation to periodontal disease in a Macedonian population

Genetic polymorphisms in the interleukin-4 (IL4) gene have been reported to influence the host response to microbial challenge by altering levels of cytokine expression. We analyzed nucleotide polymorphisms in the promoter region of the IL4 gene and its relation with periodontal disease in a Macedonian population. The study population consisted of 92 unrelated subjects with chronic periodontitis and 286 healthy controls. DNA was isolated and IL4 genotyping performed by polymerase chain reaction-single-strand polymorphism (Heidelberg kit) for the alleles and genotypes of IL4 -1098, IL4 -590, and IL4 -33. Frequencies of IL4 haplotypes and the haplotype zygotes were also examined. Comparisons between groups were tested using the Pearson's p value. After Bonferroni adjustment, significant associations were detected between subjects with periodontitis and the following: (1) cytokine alleles IL4 -1098 and IL4 -33; (2) cytokine genotypes IL4 -1098/G:T; IL4 -1098/T:T, and IL4 -33/T:T, (3) cytokine haplotypes IL4/GCC, IL4/TCC, and IL4/TTC; and (4) cytokine haplotype zygotes IL4/TTC: TCC, IL4/TCT:TTT, and IL4/GCC:TTC. Cytokine polymorphism on the IL4 gene appears to be associated with susceptibility to chronic periodontitis in Macedonians.     

Gene–gene interaction between interleukin-4 and interleukin-4 receptor α in Korean children with asthma

BACKGROUND: Interleukin-4 receptor alpha (IL-4Ralpha), which binds IL-4 and IL-13, is involved in signal transduction of those cytokines that lead to IgE production, and is also a key functional component of the Th2 lymphocyte phenotype. OBJECTIVE: To determine whether IL-4 and IL-4Ralpha polymorphisms are associated with susceptibility to asthma and whether there are gene-gene interactions between IL-4 and IL-4Ralpha polymorphisms. METHODS: We genotyped three groups of Korean children, consisting of 196 atopic asthmatics, 60 non-atopic asthmatics, and 100 healthy children, for an IL-4 promoter polymorphism (C-590T) and three IL-4Ralpha polymorphisms (Ile50Val, Pro478Ser, and Arg551Gln) using PCR-RFLP (restriction fragment length polymorphism) assays. RESULTS: The allele frequencies of the IL-4 (C/T) polymorphism and the Ile50Val and Pro478Ser polymorphisms of IL-4Ralpha did not differ statistically among the three groups of children. For the Arg551Gln polymorphism, the combined genotype frequency of the Arg/Gln heterozygote and the Arg/Arg homozygote was significantly higher in atopic asthmatics (27.6%) than in healthy children (16.0%) (odds ratio (OR) = 1.97, 95% CI (confidence interval) = 1.07-3.71). The eosinophil fraction (%) and bronchial responsiveness were higher in children with the Arg/Gln and Arg/Arg genotype than in those with the Gln/Gln genotype (P = 0.036 and 0.024, respectively). In asthmatic children, combinations of the IL-4 CT/TT genotype and the IL-4Ralpha Arg/Gln and Arg/Arg genotypes were associated with significantly increased risk for development of asthma (OR = 3.70, 95% CI = 1.07-12.78, P = 0.038). CONCLUSIONS: In Korean children, the IL-4Ralpha Arg551 allele may play a role in susceptibility to atopic asthma and correlate with markers of asthma pathogenesis, including increased eosinophil fraction and enhanced bronchial hyper-responsiveness. In addition, a significant gene-gene interaction between the IL-4-590C and the IL-4Ralpha Arg551 allele significantly increases an individual's susceptibility to asthma.     

T cell and eosinophil activation in mild and moderate atopic and nonatopic children's asthma in remission

BACKGROUND: Inflammation in the pathogenesis of asthma is associated with products of activated T cells and eosinophils. The aim of this study was to determine whether ongoing inflammation persists in children with different phenotypes of asthma despite the disease in remission. METHODS: Serum samples were collected from 68 children with atopic or nonatopic asthma in remission and from 15 healthy children. Soluble interleukin-2 receptor (sIL-2R), IL-2 and IL-4 were examined by using an enzyme-linked immunosorbent assay. Total and specific immunoglobulin E, and eosinophil cationic protein (ECP) were analysed by fluoroimmunoassay (Pharmacia CAP System). RESULTS: In patients with moderate persistent atopic asthma, sIL-2R was increased significantly when compared with mild persistent atopic asthma (P < 0.05). No changes of sIL-2R were seen in nonatopic asthmatics compared with atopics and controls. The level of IL-2 was elevated in moderate persistent atopic and nonatopic asthmatic children compared with controls (P < 0.05 and P < 0.05 respectively) and compared with mild persistent atopic asthmatics and mild persistent nonatopic asthmatics (P < 0.05 in both cases). The levels of IL-4 in most patients and controls remained below the sensitivity of the assay. Eosinophil cationic protein levels in moderate persistent atopic and nonatopic asthmatics were significantly higher than in mild persistent asthma severity cases (P < 0.001 and P < 0.01 respectively) and in healthy children (P < 0.01 in both cases). CONCLUSION: Changes in the concentration of sIL-2R, IL-2 and ECP reflect increased T cell and eosinophil activity in relation to the level of severity of asthma in atopic and nonatopic children, thereby proving the presence of persistent inflammation despite the absence of disease symptoms.     

Multifactor‐dimensionality reduction reveals interaction of important gene variants involved in allergy

Elevated IgE levels in the atopic triad of asthma, allergic rhinitis and atopic dermatitis is a multifactorial condition whose genetic component involves interaction of several gene loci. One hundred and two matched pairs of allergic and nonallergic individuals were phenotyped for total serum IgE level using enzyme‐linked immunosorbent assay (ELISA). Atopic status was defined by serum IgE concentration ≥100 IU mL^?1. SNPs genotyped include the IL4 ‐590C>T (rs2243250), FCER1B E237G (rs569108), CD14 ‐159C>T (rs2569190), IL4RA Q551R (rs1801275) and ADRB2 R16G (rs1042713). Gene–gene interaction was analysed using multifactor‐dimensionality reduction (MDR). Significant association between atopic allergy and the IL4 ‐590C>T polymorphism was confirmed in three genetic models. Interaction among the 5 gene variants was validated by MDR. The five‐locus model was chosen as the best to describe the interaction of the SNPs within the context of atopy. The strongest interaction was between IL4 ‐590C>T and IL4RA Q551R and between FCER1B E237G and ADRB2 R16G. The IL4 variant also interacts synergistically with the FCER1B and ADRB2 coding variants. CD14 ‐159C>T, in general, interacts antagonistically with the rest of the SNPs. In conclusion, a five‐locus interaction exists among IL4 ‐590C>T, FCER1B E237G, CD14 ‐159C>T, IL4RA Q551R and ADRB2 R16G in Filipino cases of atopic allergy.     

Testing the possible negative association of type 1 diabetes and atopic disease by analysis of the interleukin 4 receptor gene

Variations in the interleukin 4 receptor A (IL4RA) gene have been reported to be associated with atopy, asthma, and allergy, which may occur less frequently in subjects with type 1 diabetes (T1D). Since atopy shows a humoral immune reactivity pattern, and T1D results from a cellular (T lymphocyte) response, we hypothesised that alleles predisposing to atopy could be protective for T1D and transmitted less often than the expected 50% from heterozygous parents to offspring with T1D. We genotyped seven exonic single nucleotide polymorphisms (SNPs) and the -3223 C>T SNP in the putative promoter region of IL4RA in up to 3475 T1D families, including 1244 Finnish T1D families. Only the -3223 C>T SNP showed evidence of negative association (P=0.014). There was some evidence for an interaction between -3233 C>T and the T1D locus IDDM2 in the insulin gene region (P=0.001 in the combined and P=0.02 in the Finnish data set). We, therefore, cannot rule out a genetic effect of IL4RA in T1D, but it is not a major one.     

Serum levels of soluble IL-2 receptor, IL-4 and IgE-binding factors in childhood allergic diseases.

The serum levels of soluble IL-2 receptor (sIL-2R), IL-4 and IgE-binding factors were examined in children with allergic diseases, and compared with those in non-allergic controls of the same age and sex. The results showed age-related decreases in the serum levels of sIL-2R and IgE-binding factors, but not in that of IL-4 in both allergic and non-allergic individuals. Significant elevation of sIL-2R was observed in sera from children with atopic eczema or history of an anaphylactic reaction to food, as compared with that in non-allergic controls. The serum concentration of IL-4 was elevated in all allergic groups, including cases of atopic eczema, bronchial asthma and anaphylaxis to food, compared with non-allergic controls, and was correlated significantly with the serum level of IgE (r = 0.59). The IgE-binding factor levels in sera from patients aged 6-10 years with bronchial asthma, or patients aged 1-5 years with a history of food anaphylaxis were elevated as compared with those in non-allergic controls of same age. There was no significant correlation between the serum levels of IgE-binding factors and IgE. Since sIL-2R is released by activated T cells, the present study is in favour of T cell activation causing allergic skin disorders. The serum levels of IL-4 as well as IgE did not differ among allergic patients of different clinical categories. The role of IgE in atopic eczema and other allergic diseases is not clearly established; however, it seems likely that IL-4 is deeply involved in the increased production of IgE seen in allergic individuals. The possible involvement of IgE-binding factors in the age-related changes of clinical manifestations in childhood allergic diseases was also discussed.     

IL-5 and thromboxane A2 receptor gene polymorphisms are associated with decreased pulmonary function in Korean children with atopic asthma

BACKGROUND: Asthmatic airways undergo chronic inflammatory cell infiltration by T cells and eosinophils, which results in sustained airway hyperresponsiveness. IL-5 is important for eosinophil-induced airway inflammation and airway hyperresponsiveness. Thromboxane A2 and its receptor, TBXA2R, are involved in constriction of respiratory smooth muscles and may play a role in thickening and remodeling of airways, which contributes to the severity of asthma. The relationship between IL-5 and TBXA2R gene polymorphisms and pulmonary function in children with asthma has rarely been examined. OBJECTIVE: To determine whether IL-5 (T-746C) and TBXA2R (T924C) gene polymorphisms are associated with asthma phenotype and pulmonary function in Korean children with atopic and nonatopic asthma. METHODS: We conducted an association study between known polymorphisms of IL-5 (T-746C) and TBXA2R (T924C) and asthma phenotype and the parameters of atopy and pulmonary function in atopic and nonatopic Korean children with asthma. The subjects were 240 atopic children with asthma, 70 nonatopic children with asthma, and 106 nonatopic healthy children. Asthma phenotypes and bronchial responsiveness to methacholine were determined by a physician. IL-5 and TBXA2R gene polymorphisms were determined by genotyping by using PCR-RFLP assays. RESULTS: The genotype frequencies of IL-5 and TBXA2R polymorphisms did not differ between healthy controls and atopic or nonatopic children with asthma. A significant association was observed between the IL-5 polymorphism and forced expiratory flow at 25% to 75% of forced vital capacity (FEF 25-75% ; %; P = .002), and between the TBXA2R polymorphism and FEV 1 (%; P = .035) and FEF 25-75% (%; P = .042) in children with atopic asthma, whereas no such association between the polymorphisms and lung function was observed in nonatopic or control children. In atopic children with asthma, we identified a significant gene-gene interaction in that the combination of the IL-5 (T-746C) and TBXA2R (T924C) mutant alleles was shown to be associated with reduced pulmonary function as determined by FEF 25-75% (%) measurement. CONCLUSION: The current study indicates that IL-5 (T-746C) and TBXA2R (T924C) polymorphisms alone are associated with spirometric markers of asthma severity, whereas they are not associated with presence of asthma per se. In addition, the data suggest that an interaction between IL-5 and TBXA2R genes may contribute to the severity of asthma, especially atopic asthma. These results suggest that IL-5 and TBXA2R genes may be disease-modifying genes in Korean children with atopic asthma.     

Monitoring of disease activity by measurement of inflammatory markers in atopic dermatitis in childhood

Serum levels of soluble interleukin-2 receptor (sIL-2R), intercellular adhesion molecule-1 (ICAM-1), endothelial leukocyte adhesion molecule (ELAM-1), and eosinophil cationic protein (ECP) were measured in 20 patients with atopic dermatitis before and after 4 days'treatment with prednisolone p.o. as well as in 16 healthy, nonatopic controls. Before steroid treatment, patients with atopic dermatitis demonstrated significantly higher serum levels of sIL-2R, ICAM-1, and ECP than healthy controls (P<0.001), whereas ELAM-1 levels were not different between the groups. After 4 days of steroid treatment, clinical improvement was associated with a decrease of sIL-2R (P<0.003), ICAM-1 (P<0.004), and ECP serum levels (P<0.003), but ELAM-1 levels remained unchanged. Both serum ECP and slL-2R levels were significantly correlated with disease severity before as well as after steroid treatment. Changes of sIL-2R concentrations were strongly related to the changes of ECP levels. In addition, changes of serum sIL-2R and ECP levels in percentage were correlated with clinical improvement. These results indicate that the determination of sIL-2R and ECP serum levels may be useful in monitoring disease activity in atopic dermatitis in childhood, especially in treatment trials.