Genetic variation in ORM1-like 3 (ORMDL3) and gasdermin-like (GSDML) and childhood asthma

Background:  A genome-wide association study identified ORM1-like 3 (orosomucoid 1-like 3, ORMDL3 ) as an asthma candidate gene. Single nucleotide polymorphisms (SNPs) in the region including ORMDL3 on chromosome 17q21 were related to childhood asthma risk and ORMDL3 expression levels in Europeans.
Objective:  We examined whether polymorphisms in ORMDL3 and the adjacent gasdermin-like ( GSDML ) gene associated with asthma in the genome-wide association study are related to childhood asthma and atopy in a Mexico City population.
Methods:  We genotyped rs4378650 in ORMDL3 and rs7216389 in GSDML in 615 nuclear families consisting of asthmatic children aged 4–17 years and their parents. Atopy was determined by skin prick tests to 25 aeroallergens.
Results:  Individuals carrying the C allele of rs4378650 or the T allele of rs7216389 had increased risk of asthma [relative risk (RR) = 1.73, 95% confidence interval (CI) 1.19–2.53, P  = 0.003 for one or two copies of rs4378650 C, and RR = 1.64, 95% CI 1.12–2.38, P  = 0.009 for one or two copies of rs7216389 T). Linkage disequilibrium between the two SNPs was high ( r ² = 0.92). Neither of the SNPs was associated with the degree of atopy. A meta-analysis of five published studies on rs7216389 in nine populations gave an odds ratio for asthma of 1.44 (95% CI, 1.35–1.54, P  < 0.00001).
Conclusions:  Our results and the meta-analysis provide evidence to confirm the finding from a recent genome-wide association study that polymorphisms in ORMDL3 and the adjacent GSDML may contribute to childhood asthma.     

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.     

Association of STAT6 variants with asthma risk: A systematic review and meta-analysis

A large number of studies have reported that the genetic variants in STAT6 gene may be implicated in susceptibility to asthma, but with inconsistent results. Therefore, the aim of this meta-analysis was to determine the likelihood of developing asthma for the individuals with different STAT6 variants. The database including Pubmed, Embase and CNKI (Chinese National Knowledge Infrastructure) were searched to find the relevant papers. Data were extracted by two independent reviewers and the odds radios (ORs) were pooled with 95% confidence intervals (CIs), using random effect or fixed effect models as appropriate, to indicate the risk of asthma for different STAT6 variants. The heterogeneity and bias were tested for each pooled result. Data from 19 studies were pooled that reported associations of rs324015, rs71802646 and rs324011 in STAT6 gene with asthma risk. The results demonstrated that 13GT and short GT in rs71802646 were both associated with increased risk of asthma in overall analysis (OR = 1.26 for 13GT and 1.30 for short GT). Further, subgroup analysis showed an increased risk of asthma in Asian population with 13GT (OR = 1.21), 14GT (OR = 1.97) and short GT (OR = 1.27). Besides, 13GT, 14GT and short GT all contributed to higher risk of atopic asthma, with OR 1.50, 2.21 and 1.65 respectively. However, rs324015 (G>A) appeared to be associated with decreased risk for atopic asthma (with OR = 0.83, 0.68 and 0.79 for A, AA and AA+AG respectively). Both overall and subgroup analyses indicated no effect of rs324011 on asthma risk. In conclusion, our meta-analyses suggest that short GT repeats of rs71802646 in STAT6 contribute to higher risk for asthma, while rs324015 may have a protective effect on atopic asthma.     

Polymorphisms in IL13, total IgE, eosinophilia, and asthma exacerbations in childhood

BACKGROUND: It is unclear whether single nucleotide polymorphisms (SNPs) in the gene for IL-13 (IL13) influence asthma severity and/or asthma morbidity. OBJECTIVES: To examine the relation between IL13 SNPs and asthma-related phenotypes in 2 independent populations. METHODS: We used family-based methods to test for association between SNPs in IL13 and asthma-related phenotypes in Costa Rican children with asthma. We attempted to reproduce significant findings in white (non-Hispanic) children with asthma in the Childhood Asthma Management Program (CAMP). RESULTS: In Costa Rica and in CAMP, the A allele (Gln) of IL13 coding SNP (rs20541) was significantly associated with increased eosinophil count (P < .011 in both studies) and increased serum total IgE (P < .054 in both studies). The T allele of IL13 promoter SNP (rs1800925) was inversely associated with asthma exacerbations in Costa Rica (P = .069). Although this SNP (rs1800925) was not associated with asthma exacerbations among all white children in CAMP, it was associated with increased risk of asthma exacerbations among children on inhaled corticosteroids (P = .02). CONCLUSION: Polymorphisms in IL13 were significantly associated with serum total IgE and eosinophil count in 2 populations. IL13 polymorphisms may also be associated with asthma exacerbations, and this effect may be dependent on medication use. Our study is the first to report a potential negative interaction between a genetic polymorphism and response to inhaled corticosteroids. CLINICAL IMPLICATIONS: Polymorphisms in IL13 are associated with serum total IgE and eosinophil count and may be associated with asthma exacerbations.     

Effects of a 17q21 chromosome gene variant, tobacco smoke and furred pets on infant wheeze

The first common genetic factor identified for pediatric asthma by genome-wide association is the chromosome 17q21 locus, harbouring the ORMDL3 gene. ORMDL3 is involved in facilitation of endoplasmic reticulum-mediated inflammatory responses, believed to underlie its asthma association. We investigated associations between the rs7216389 polymorphism in the 17q21 locus affecting ORMDL3 expression and the risk for recurrent wheeze and interactions with exposure to tobacco smoke and furred pets during pregnancy and infancy using a birth cohort of 101,042 infants. Rs7216389 was significantly associated with recurrent wheeze risk among 18-month-old infants. There was a 1.35-fold higher risk of recurrent wheeze among homozygous variant allele carriers compared with homozygous wild-type allele carriers. There was significant interaction between rs7216389 and domestic furred pets, with a positive association between pets and wheeze among homozygous wild-type carriers and a negative association among homozygous variant allele carriers. There was no interaction between rs7216389 and tobacco smoke exposure.     

Relationship between the 17q21 locus and adult asthma in a Czech population

Several whole-genome association studies have shown a significant link between childhood asthma and the 17q12 chromosome region. We selected tagging single nucleotide polymorphisms (SNPs) in the ORMDL3 gene (17q12) to investigate gene variability in relation to adult allergic asthma and asthma/atopy traits in a Czech Caucasian population of adults. We conducted a case-control association study comprising 668 unrelated subjects (337 asthmatic and 331 control subjects). Four selected SNPs (rs17608925, rs12603332, rs8076131, and rs3169572) were genotyped using the TaqMan SNP Genotyping Assays. The single locus analysis showed only a borderline association between rs3169572 variant and asthma (p = 0.030, p(corr) > 0.05). However, seven different haplotypes were identified; among them, the TTAA haplotype was marginally associated with asthma (p = 0.045, p(corr) > 0.05) and TCAG haplotype was significantly associated with asthma in males (p = 0.009, p(corr) < 0.05, odds ratio = 1.48, 95% confidence interval = 1.10-2.00). In addition, associations between the ORMDL3 genotypes and the total IgE level (p = 0.05, p(corr) > 0.05) and hypersensitivity to the pollen (p = 0.007, p(corr) < 0.05) were established. However, no relationship between ORMDL3 SNPs and the pulmonary functions was found (p > 0.05). These findings suggest that the genetic variability in the 17q21 region may be one of the risk factors also for adult asthma, especially in male individuals.     

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   

Association of ADAM33 gene polymorphisms with asthma in Indian children

Asthma is the most common chronic disorder in childhood, and asthma exacerbation is an important cause of childhood morbidity and hospitalization. In the present study, the relationship between single-nucleotide polymorphisms (SNPs) of the ADAM33 gene and asthma in Indian children has been examined using a case-control study. Five SNPs of the ADAM33 gene, F+1(rs511898) G/A, S2 (rs528557) G/C, ST+4 (rs44707) A/C, ST+5 (rs597980) C/T and V4 (rs2787094) C/G, were analyzed in 211 asthma cases and 137 controls aged 1-15 years using the PCR-restriction fragment length polymorphism method. Data were statistically analyzed using the χ(2)-test and logistic regression model. Haplotype estimation and linkage disequilibrium were conducted using the expectation-maximization algorithm. The genotypes and allele frequencies of SNPs S2 and ST+5 of the ADAM33 gene were significantly associated with asthma risk (P = 0.020 - < 0.001), whereas F+1, ST+4, V4 homozygous mutant genotypes and mutant alleles were significantly associated with increased asthma risk (P = 0.031 - < 0.001). A positive association was also found with haplotypes AGCCT, GGACT and AGCCC (P = < 0.001, odds ratio (OR) = 6.10-6.50), whereas ACAGT, AGCGC, AGCGT, GCAGC and GCCGT showed protective association with asthma (P = 0.019-0.000, OR = 0.50-0.20). Taken together, out results suggest that ADAM33 gene polymorphisms may modify individual susceptibility to develop childhood asthma in the Indian population.     

Association of the MMP9 gene with childhood cedar pollen sensitization and pollinosis

Matrix metalloproteinase 9 (MMP9) gene has been shown to be involved in the pathogenesis of allergic rhinitis (AR) and asthma. Previous studies suggested that single-nucleotide polymorphisms (SNPs) of the MMP9 gene conferred a risk for childhood asthma. However, whether the SNPs confer a risk for AR has not been previously investigated. The objective of this study was to investigate whether SNPs of the MMP9 gene are associated with risk of seasonal AR (pollinosis), perennial AR and allergen sensitization. A total of 670 school children were recruited in Japan and genotyped for functional polymorphism in the promoter (-1590C/T: rs3918242) and three amino-acid substitutions (R297Q: rs17576; P574R: rs2250889; R668Q: rs17577). Serum levels of total and specific IgE were determined. Disease status and other clinical characteristics of the subjects were investigated using a questionnaire. Associations between the MMP9 SNPs and both AR and serum IgE levels were evaluated. -1590C/T showed significant association with cedar pollinosis (corrected P (Pcor)=0.039). R668Q was in strong linkage disequilibrium (LD) with -1590C/T and showed significant association with cedar pollinosis (Pcor=0.023) and serum cedar pollen-specific IgE level (Pcor=0.022). A haplotype associated with -1590T and 668Q showed a significant association with cedar pollinosis, orchard grass pollinosis and cedar pollen-specific IgE (Pcor=0.0012, Pcor=0.0059 and Pcor=0.0041, respectively). R297Q and P574R were in weak LD with the rest of the SNPs and did not show significant association with disease. Compared with wild-type MMP9 protein (279R-574P-668R), a variant enzyme (279R-574P-668Q) that showed association with pollinosis had lower activity. However, lower enzyme activity was not associated with disease risk because another variant (279Q-574R-668R) showed lower enzyme activity but was not associated with pollinosis. The -1590T allele and its corresponding haplotype was associated with higher promoter activity and with pollen-specific IgE levels and pollinosis, suggesting that -1590C/T may have more impact on sensitization and disease development than R668Q. Our results suggest that the MMP9 gene confers susceptibility to cedar pollinosis in Japanese children. The MMP9 gene may be associated with pollinosis through sensitization processes.     

TBXA2R gene polymorphism and responsiveness to leukotriene receptor antagonist in children with asthma

Background Thromboxane A2 receptor (TBXA2R) gene polymorphism has been associated with atopy and asthma, but few studies have reported the effect of this gene polymorphism on asthma‐related phenotype or responsiveness to leukotriene receptor antagonist (LTRA) in asthmatic children. This study investigated associations between asthma‐related phenotypes and TBXA2R polymorphism, and also analysed whether the TBXA2R polymorphism has an effect on the efficacy of the LTRA, montelukast, in asthmatic children with exercise‐induced bronchoconstriction (EIB). Methods Asthmatic children (n=695) and control children (n=159) were evaluated for asthma‐related phenotypes including total IgE, pulmonary function test, and bronchial hyperresponsiveness to methacholine or exercise. Genotypes were detected by PCR‐RFLP. In the montelukast study, exercise challenge was performed before and after an 8‐week montelukast treatment. Results The TBXA2R polymorphism was not associated with asthma susceptibility and the clinical parameters of asthma. However, asthmatic children with combinations of the TBXA2R+795T>C and +924T>C risk alleles had significantly higher total IgE levels (P=0.01), total eosinophil counts (P<0.01) and lower forced expiratory volume in 1 s (FEV₁) (P=0.02) and forced expiratory rates at 25–75% of vital capacity (P=0.02) than those carrying the common alleles. When compared with individuals with the common alleles, patients with the TBXA2R+924T>C TT homozygote and TBXA2R+795T>C hetero‐ or homozygote (CT or CC) had a 3.67‐fold poor response to 8‐week montelukast treatment with respect to maximum percent fall in FEV₁ after exercise (odds ratio, 3.67; 95% confidence interval, 1.15–11.15). Conclusions A combined effect of TBXA2R+795T>C and +924T>C risk alleles may be linked to IgE production, eosinophilic inflammation, and severity of asthma. In addition, the TBXA2R+795T>C genotype may be a predictive marker of a clinical response to the LTRA in Korean asthmatic children with EIB.     

Polymorphisms and haplotypes of the chromosome locus 17q12-17q21.1 contribute to adult asthma susceptibility in Slovenian patients

One of the major asthma susceptibility loci is 17q12-17q21.1, but the relationship between this locus and adult asthma is unclear. Association analysis of 13 single nucleotide polymorphisms (SNPs) and haplotypes from 17q12-17q21.1 was performed in 418 adult patients with asthma and 288 controls from Slovenia. Single SNP analysis revealed only marginal associations with adult asthma for SNPs located in GSDMA, GSDMB, ORMDL3 and ZPBP2 genes, and rs7219080 was the most highly associated. Analyses of asthma phenotypes found no association with atopy or lung function, but rs2305480 and rs8066582 were associated with childhood asthma and rs9916279 was associated with asthma in smokers. Notably, haplotypes consisting of rs9916279, rs8066582, rs1042658, and rs2302777 harbouring PSMD3, CSF3 and MED24 genes were highly associated with asthma. The four most common haplotypes, TCCG, TTTA, CCCA and TTCA, were more frequent in patients with asthma, whereas TTCG, TCCA, TCTA and TTTG were more frequent in controls. Only 3% of asthma patients belonged to haplotypes TTCG, TCCA, TCTA and TTTG compared with nearly one-third (31%) of controls. Associations confirmed that the 17q12-17q21.1 locus harbours a genetic determinant for asthma risk in adults and suggest that in addition to the previously known ORMDL3-GSDM locus, CSF3-PSMD3-MED24 also plays a role in asthma pathogenesis.     

Investigation of JAK2, STAT3 and CCR6 polymorphisms and their gene-gene interactions in inflammatory bowel disease

Genome-wide association studies identified many loci associated with the two forms of inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC). Components of the interleukin-23 signalling pathway, such as IL23R, JAK2 and STAT3, have been implicated in both diseases. In addition, emerging evidence supports the role of IL23-driven Th17 cells in inflammation. Here, we studied the susceptibility nature of three components of IL23 signalling and Th17 cell differentiation: JAK2 rs10758669, STAT3 rs744166 and CCR6 rs2301436 initially associated with CD in Hungarian CD and UC patients. A total of 616 unrelated subjects with either form of IBD and 496 healthy controls were genotyped with PCR-RFLP methods. We also tested the genetic interactions of JAK2, STAT3 and CCR6 polymorphisms in a pairwise fashion with regard to disease risk. We could confirm the susceptibility of STAT3 rs744166 TT homozygotes for UC (OR: 1.483, 95% CI: 1.103-1.992, P = 0.009). Data on genetic interaction reveals that the above JAK2 and STAT3 risk alleles contribute to CD susceptibility in combination with each other (OR: 2.218; 95% CI: 1.097-4.487; P = 0.024), while the JAK2 variant shows a tendency to confer UC risk only on a wild-type STAT3 background (OR: 1.997, 95%CI: 0.994-4.009, P = 0.049). Our results may help in understanding how these natural variants contribute to development of IBD through their genetic association.     

Asthma and atopy are associated with chromosome 17q21 markers in Chinese children

Background:  Single-nucleotide polymorphism (SNP)-based genome-wide association study revealed that markers on chromosome 17q21 were linked to childhood asthma but not atopy in Caucasians, with the strongest signal being detected for the SNP rs7216389 in the ORMDL3 gene. Such association was unknown in Chinese. This study delineated the allele and genotype frequencies of 10 SNPs at chromosome 17q21, and investigated the relationship between these SNPs and asthma and plasma IgE in southern Chinese children.
Methods:  Asthmatic children and non-allergic controls were recruited from pediatric clinics. Their plasma total and aeroallergen-specific IgE concentrations were measured by immunoassay. Ten SNPs on 17q21 region were genotyped by multiplex SNaPshot™, and their genotype associations with asthma traits analyzed using multivariate regression.
Results:  315 patients and 192 controls were enrolled. The allele frequency for C allele of rs7216389 varied significantly from 0.232 in our controls, 0.389 in Han Chinese to 0.536 in Caucasians. Asthma diagnosis was associated with rs11650680 and five other SNPs including rs7216389 ( P  =   0.019–0.034), whereas atopy was associated only with rs11650680 ( P  =   0.0004). Linear regression revealed the covariates for plasma total IgE to be significant for rs11650680 ( P  =   0.008–0.0002). Haplotypic associations were found with atopy and increased plasma total IgE, with the respective odds ratios and 95% confidence intervals for TTTCCGTT haplotype to be 0.21 and 0.09–0.52 ( P  =   0.0002) and 0.41 and 0.18–0.90 ( P  =   0.025).
Conclusion:  Childhood asthma and atopy are associated with chromosome 17q21 in Chinese, but such association may involve genes other than ORMDL3 in this region.     

17q12-21 and asthma: interactions with early-life environmental exposures

Background17q12-21 polymorphisms are associated with asthma presence and severity across different populations.ObjectiveTo extensively investigate the genes in this region among Croatian schoolchildren in a case-control study, taking account of early-life environmental exposures.MethodsWe included 423 children with asthma and 414 controls aged 5 to 18 years. Fifty-one haplotype tagging single-nucleotide polymorphisms (SNPs) were genotyped (GSDMA, GSDMB, ORMDL3, IKZF3, ZPBP2, and TOP2). Data on exposure to smoking and furry pet ownership were collected using a validated questionnaire. Information on severe asthma exacerbations with hospital admission were retrieved from hospital notes. All patients underwent spirometry.ResultsWe found 2 SNPs (1 novel rs9635726 in IKZF3) to be associated with asthma. Among children with asthma, 4 SNPs (in ZPBP2, GSDMB, and GSDMA) were associated with hospital admissions and 8 SNPs with lung function. One SNP (rs9635726) remained significantly associated with a predicted forced expiratory volume in 1 second after false discovery rate correction. Nine markers across 5 genes showed interaction with early-life environmental tobacco smoke (ETS) exposure in relation to asthma and 2 with furry pet ownership. Among children with asthma, we observed significant interactions between early-life ETS exposure and 3 SNPs for lung function and among early-life ETS exposure, 3 SNPs (in ORMDL3 and GSDMA), and hospital admission with asthma exacerbation. Three SNPs (in ORMDL3) interacted with current furry pet ownership in relation to hospital admissions for asthma exacerbation.ConclusionOur results indicate that several genes in the 17q12-21 region may be associated with asthma. This study confirms that environmental exposures may need to be included into the genetic association studies.     

Genetic variation in ORMDL3 gene may contribute to the risk of asthma: A meta-analysis

Background

Since the first genome-wide association study report of an association between the ORMDL3 rs7216389 polymorphism and asthma, many studies have been carried out to establish its role in asthma susceptibility among different ethnic groups. However, results have not been consistent across all studies, compelling us to conduct the present meta-analysis.

Methods

A literature search for eligible studies published before January 20, 2014 was conducted in the MEDLINE, EMBASE, and CNKI databases. The association was assessed using pooled crude odds ratios (ORs) with their corresponding 95% confidence intervals (CIs).

Results

A total of 18 individual studies in 15 publications (total 7904 asthma patients and 10,874 healthy controls) were included in the meta-analysis. A meta-analysis of all included studies suggested that there was a highly significant risk effect conferred by the rs7216389*T allele on asthma susceptibility. In addition, we performed stratified analyses to evaluate ethnicity-specific and age-specific effects. Our subgroup analyses based on ethnicity and age-of-onset confirmed the role of the ORMDL3 rs7216389 polymorphism in conferring susceptibility to both childhood- and adult-onset asthma, especially in Caucasians and Asians.

Conclusions

The results of this meta-analysis firmly established that genetic variation at the rs7216389 locus, which controls the expression of the ORMDL3, may be a major, independent predisposing factor for asthma in ethnically diverse populations. However, further systematic studies are needed to determine the underlying mechanisms of this association.     

Interaction between variants in the interleukin-4 receptor α and interleukin-9 receptor genes in childhood wheezing: evidence from a birth cohort study

BACKGROUND: Several polymorphisms in the IL-4 receptor alpha (IL4RA) gene have been associated with asthma and atopy, but with variable success in different populations. Immunologic studies suggest that IL4RA may interact with other cytokines and receptors, and gene-gene interactions have also been observed with respect to asthma. Such interactions have been proposed to explain partly the difficulties in replicating association studies. METHODS: Using the prospective birth cohort BAMSE, we examined eight single nucleotide polymorphisms (SNPs) and corresponding haplotypes in the IL4RA gene in relation to wheezing and sensitization up to age 4. We also evaluated potential interaction effects (departure from a multiplicative interaction model) between the IL4RA SNPs and four SNPs in the IL-9 receptor (IL9R) gene previously associated with childhood wheezing. RESULTS: We found no main effect of the IL4RA SNPs alone and only weak associations to wheezing and sensitization when haplotypes were considered. Gene-gene interactions between several IL4RA and IL9R SNPs with regard to wheezing were observed (P=0.009), especially between IL4RA Q576R (rs1801275) and IL9R rs731476 (P=0.005). An interaction was also seen between IL4RA and IL9R haplotypes. CONCLUSION: Variants in the IL4RA gene alone may not exert any major influence on susceptibility to asthma-related diseases in childhood, but in combination with other genes, such as IL9R, IL4RA may be an important gene for disease susceptibility.