Variation in the type I interferon gene cluster on 9p21 influences susceptibility to asthma and atopy

A genome-wide screen for asthma and atopy susceptibility alleles conducted in the Hutterites, a founder population of European descent, reported evidence of linkage with a short tandem repeat polymorphism (STRP) within the type I interferon (IFN) gene cluster on chromosome 9p21. The goal of this study was to identify variation within the IFN gene cluster that influences susceptibility to asthma and atopic phenotypes. We screened approximately 25 kb of sequence, including the flanking sequence of all 15 functional genes and the single coding exon in 12, in Hutterites representing different IFNA-STRP genotypes. We identified 78 polymorphisms, and genotyped 40 of these (in 14 genes) in a large Hutterite pedigree. Modest associations (0.003相似文献   

Genome screen for asthma and bronchial hyperresponsiveness: interactions with passive smoke exposure

BACKGROUND: Asthma is a common respiratory disease caused by the interaction of genetic susceptibility and exposure to various environmental factors. Passive smoke exposure, characterized by parental smoking, has been shown to be a risk factor for the development of atopy and asthma. OBJECTIVE: We sought to perform a genome-wide linkage screen for asthma and bronchial hyperresponsiveness (BHR) and to determine the influence of passive tobacco smoke exposure during childhood on the results of genetic linkage studies to investigate gene-environment interactions. METHODS: A genome-wide linkage screen for asthma and BHR was performed in 200 families ascertained through a parent with asthma. Analyses were performed separately for the entire sample and for the smoking-exposed and nonexposed families. RESULTS: For asthma and BHR, the strongest evidence for linkage was observed for chromosomes 3p and 5q. The families in which the children were exposed to passive smoking accounted for the evidence for linkage of BHR to 5q ( P < .001), but evidence for linkage to 3p was found in both sets of families. Similar results were observed for asthma. However, there was no observed difference in the frequency of asthma or BHR in the offspring from the smoke-exposed compared with the nonexposed families. CONCLUSION: The results from this study demonstrate that the influence of susceptibility genes for a common disease such as asthma might not be apparent unless there is the appropriate exposure to environmental stimuli, such as passive exposure to cigarette smoke. This approach should be useful for identification of asthma susceptibility genes.     

Genome-wide search for asthma susceptibility loci in a founder population. The Collaborative Study on the Genetics of Asthma

Founder populations offer many advantages for mapping genetic traits, particularly complex traits that are likely to be genetically heterogeneous. To identify genes that influence asthma and asthma- associated phenotypes, we conducted a genome-wide screen in the Hutterites, a religious isolate of European ancestry. A primary sample of 361 individuals and a replication sample of 292 individuals were evaluated for asthma phenotypes according to a standardized protocol. A genome-wide screen has been completed using 292 autosomal and three X-Y pseudoautosomal markers. Using the semi-parametric likelihood ratio chi2 test and the transmission-disequilibrium test, we identified 12 markers in 10 regions that showed possible linkage to asthma or an associated phenotype (likelihood ratio P < 0.01). Markers in four regions (5q23-31, 12q15-24.1, 19q13 and 21q21) showed possible linkage in both the primary and replication samples and have also shown linkage to asthma phenotypes in other samples; two adjacent markers in one additional region (3p24.2-22) showing possible linkage is reported for the first time in the Hutterites. The results suggest that even in founder populations with a relatively small number of independent genomes, susceptibility alleles at many loci may influence asthma phenotypes and that these susceptibility alleles are likely to be common polymorphisms in the population.      

Lack of linkage between chromosome 5q23–33 markers and IgE/bronchial hyperreactivity in 67 Scottish families

BACKGROUND: Raised serum immunoglobulin E (IgE) and bronchial hyperreactivity (BHR) are risk factors for the expression of the asthma phenotype. Previous studies have reported evidence for linkage between these traits and markers on the 5q23-33 cytokine gene cluster. OBJECTIVE: To test for linkage between total serum IgE/BHR and microsatellite markers which map to the 5q23-33 region in an ethnically distinct cohort of families from Aberdeen, Scotland. METHODS: We performed a linkage study between five polymorphic markers (spanning the chromosome 5q23-33 region) and total serum IgE and BHR traits. A cohort of 67 families, who were recruited originally to study the natural history of wheeze, were clinically characterized and genotyped for D5S404, IL4, IRF-1, IL9, D5S436 markers. Linkage analyses were performed using the nonparametric Haseman-Elston algorithm for the quantitative trait log IgE, and the nonparametric LOD score (NPL-score) of the GENEHUNTER package for the qualitative traits serum IgE and BHR. RESULTS: The results of the nonparametric linkage analysis using either the Haseman-Elston algorithm or NPL-score were consistent and showed no evidence for linkage with IgE. There was also no evidence for linkage between the BHR traits (at cut-off values of PD20FEV1 < 8 mmol and 16 mmol) and any of the tested five microsatellite markers. CONCLUSIONS: This study presents evidence against the presence of a gene with a major effect on total serum IgE or BHR in the 5q23-33 region, in this ethnic group.     

Chromosome 14 linkage analysis and mutation study of 2 serpin genes in allergic asthmatic families

BACKGROUND: Genome and chromosome screens reported DNA markers on chromosome 14 linked to allergic asthma or intermediate phenotypes in several populations. OBJECTIVE: We sought to perform a linkage study on chromosome 14 and a further association study on candidate genes mapped in the region found to be linked to allergic asthma or intermediate phenotypes. METHODS: The study consisted of a sample of 189 families (847 genotyped individuals) from a restricted geographic area in northeastern Italy. The subjects were characterized for the following phenotypes: allergic asthma, total serum IgE levels, skin prick test responses, and bronchial hyperresponsiveness (BHR) to methacholine. Genotyping was done with 14 DNA markers and 4 polymorphisms in the genes encoding alpha(1)-anti-trypsin and alpha(1)-antichymotrypsin (ACT). RESULTS: Multipoint analysis indicated a potential linkage of BHR with marker D14S617 (nonparametric linkage z score = 2.32, P =.01). Transmission disequilibrium of Thr -15Ala in the gene encoding ACT was observed with all the phenotypes investigated: allergic asthma, BHR, total IgE levels, or skin prick test responses (P =.041,.02,.0053, or.026, respectively). CONCLUSION: Chromosome 14 screening and transmission disequilibrium testing on the gene encoding ACT suggest that it or a closely located gene may be involved in susceptibility to allergic asthma in the Italian population.     

Are common disease susceptibility alleles the same in outbred and founder populations?

Founder populations have been the subjects of complex disease studies because of their decreased genetic heterogeneity, increased linkage disequilibrium and more homogeneous environmental exposures. However, it is possible that disease alleles identified in founder populations may not contribute significantly to susceptibility in outbred populations. In this study we examine the Hutterites, a founder population of European descent, for 103 polymorphisms in 66 genes that are candidates for cardiovascular or inflammatory diseases. We compare the frequencies of alleles at these loci in the Hutterites to their frequencies in outbred European-American populations and test for associations with cardiovascular disease-associated phenotypes in the Hutterites. We show that alleles at these loci are found at similar frequencies in the Hutterites and in outbred populations. In addition, we report associations between 39 alleles or haplotypes and cardiovascular disease phenotypes (P<0.05), with five loci remaining significant after adjusting for multiple comparisons. These data indicate that this founder population is informative and offers considerable advantages for genetic studies of common complex diseases.     

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 IL4R gene polymorphisms with asthma in Chinese populations

Cytokines, having central functions in immunological and inflammatory processes, are expected to play important roles in the pathogenesis of various diseases, such as asthma. Genetic polymorphisms of those cytokine and cytokine receptor genes are the focus of genetic association studies. In an effort to identify gene(s) whose variant(s) are associated with asthma, we screened all exons and their flanking regions, as well as the promoter region (1.5kb) of eight genes, including IL4, IL13, IL12B, IL5, IL3, IL9, CD14 and IL4R. We identified 42 single nucleotide polymorphisms, 15 of which were novel. Then, we examined the genetic effects of 30 single nucleotide polymorphisms in eight cytokine and cytokine receptor genes on asthma in a Chinese asthma cohort (n = 537). Genetic association analysis of polymorphisms revealed that six polymorphisms (c.899-2C>A, c.1199A>C, c.1242G>T, c.1291T>C, c.1299T>C, c.1507T>C) in the IL4R gene, three of which resulted in an amino-acid change, showed significant association with the risk of asthma (P = 0.00023). Further analysis indicates that these six polymorphisms segregated in strong linkage disequilibrium. The genetic association of IL4R with asthma might provide valuable insights into the pathogenesis of asthma.     

Identifying genes predisposing to atopic eczema.

BACKGROUND: Genetic and environmental factors are known to play a role in the development of atopic diseases, such as asthma, eczema, and rhinitis. However, the atopy gene (or genes) has yet to be defined. Studies of familial asthma have identified several regions that may contain genes predisposing to atopy, but the data for candidate regions do not show agreement, which may be due to heterogeneity, ascertainment bias, or stochastic factors. Factors such as an early age of onset, a positive family history, and a clearly defined phenotype favor a genetic origin and improve the chance of identifying genes that predispose to atopy. OBJECTIVE: We sought to define genes that predispose to the development of atopic eczema. METHODS: We have studied nuclear families with multiple cases of early-onset atopic eczema for involvement of the candidate regions on chromosomes 5q31 (IL gene cluster), 11q13 (high-affinity FCepsilon receptor), 14q11.2 (mast cell chymase), and 16p12 (IL-4 receptor alpha-chain, IL4RA gene). RESULTS: Using a recessive model, we find a maximum parametric log of the odds of linkage score of 2. 25 and nonparametric score of 2.54 (P =.006) for a region on chromosome 5q31, which we postulate contains a gene predisposing to atopic eczema, but lack of support for linkage to 11q13. Transmission disequilibrium tests do not support an association with candidate polymorphisms in the mast cell chymase and IL4RA genes. CONCLUSION: We have identified a clinically homogeneous cohort of patients with atopic eczema to identify genetic factors predisposing to the development of atopy. We postulate that there are certain loci that predispose to atopy in general and other loci that determine which of the atopic phenotypes is expressed.     

Genetic control of serum IgE levels and asthma: linkage and linkage disequilibrium studies in an isolated population

Immunoglobulin E (IgE) concentration in serum is elevated in atopic diseases such as asthma. A large genomic region on chromosome 5 has previously been implicated in the control of IgE levels and bronchial hyperreactivity and may, therefore, harbor genes predisposing to asthma. In an effort to confirm this linkage and to delimit the critical region, we took advantage of an isolated founder subpopulation in Finland to study genetic linkage and haplotype associations. Sixteen polymorphic markers, including the Interleukin-4 and -9 genes (IL4, IL9), were physically ordered and genotyped in 157 nuclear families. Genetic linkage studies involving sib- and cousin-pair analyses found no evidence of genetic linkage between markers in 5q and either serum IgE levels or asthma. Haplotype association studies were also performed. Although initial inspection suggested the possibility of linkage disequilibrium in the region of IL9, we developed a rigorous permutation test for assessing association and determined that the association was no greater than would be expected by chance. Sequence analysis of the IL9 gene in three patients sharing a possibly conserved haplotype revealed a T113M coding polymorphism, but this variant showed no association with either serum IgE levels or asthma. We conclude that allelic variation at chromosome 5q31 is not likely to contribute to inheritance of serum IgE levels or the development of asthma in this Finnish subpopulation.      

Evidence for gene x smoking exposure interactions in a genome-wide linkage screen of asthma and bronchial hyper-responsiveness in EGEA families

Asthma and bronchial hyper-responsiveness (BHR), an asthma-related phenotype, result from many genetic (G) and environmental (E) factors. Passive exposure to tobacco smoke (ETS) in early life is one of these risk factors. Following a genome scan for asthma and associated phenotypes conducted in 295 French Epidemiological study on the Genetics and Environment of Asthma, our present aim was to investigate interactions between genetic susceptibility to asthma and to BHR with passive ETS using two different methods: the predivided sample test (PST) and the mean interaction test (MIT). PST and MIT consider the identical by descent (identity by descent) distribution at all markers in affected sib-pairs with 2, 1 or 0 sib(s) exposed to ETS. While the PST allows detection of both linkage and G x E interaction, the MIT tests for linkage by taking into account a possible interaction. Among the six regions detected at P相似文献   

Fine mapping of an IgE-controlling gene on chromosome 2q: Analysis of CTLA4 and CD28

BACKGROUND: Several genomic regions have been identified that might contain genes contributing to the development of asthma and atopy. These include chromosome 2q33, where we have observed evidence for linkage for variation in total serum IgE levels in a Dutch asthma population. Two candidate genes, CTLA4 and CD28, important homeostatic regulators of T-cell activation and subsequent IgE production, map within this candidate region. OBJECTIVE: We sought to fine-map the chromosome 2q33 region and evaluate CTLA4 and CD28 as candidate genes for the regulation of total serum IgE levels and related phenotypes. METHODS: The coding regions of CTLA4 and CD28 were resequenced in 96 individuals; 4 novel SNPs in CTLA4 and 10 in CD28 were identified. Polymorphisms in both genes were analyzed in 200 asthmatic probands and their spouses (n = 201). RESULTS: Subsequent fine- mapping in this region has resulted in an increased log of the odds (lod) score (1.96 to 3.16) for total serum IgE levels. For CTLA4, the +49 A/G single nucleotide polymorphism (SNP) in exon 1 and the 3 ' untranslated region microsatellite were significantly associated with total serum IgE levels (P =.0005 and.006, respectively). For the combined +49 A/G and 3 'untranslated region genotypes, individuals homozygous for the risk allele for both polymorphisms (AA and 86/86) had the highest total serum IgE values (87.1 IU/mL), whereas those individuals with the GG and XX/XX genotypes (anything but the 86-bp allele) had the lowest IgE values (29.3 IU/mL). Significant association was also observed for the CTLA4 -1147 C/T SNP with bronchial hyperresponsiveness (BHR) and asthma (P =.008 and.012, respectively), but not for allergy-related phenotypes. Promoter luciferase assays examining the -1147 polymorphism suggested that the T allele, which was associated with increased BHR susceptibility, was expressed at half the level of the C allele. Individuals with the risk genotypes for both BHR (-1147 CT or TT) and elevated IgE levels (+49 AA) were 4.5 times more likely to have asthma than individuals with both nonrisk genotypes (P =.0009). No significant associations were observed for SNPs in CD28. CONCLUSION: These data suggest that the costimulatory pathway, specifically CTLA4, is important in the development of atopy and asthma.     

Corticosteroid resistance in mild asthma: markers of persistent inflammation.

BACKGROUND: Bronchial hyperresponsiveness (BHR) is an important feature of asthma. Glucocorticosteroids (GCS) reduce BHR, probably by suppressing allergic inflammation. There are, however, two groups of asthmatics with either GCS-responsive or non-responsive BHR to methacholine. We investigated the mechanism of non-GCS-responsive BHR in mild asthma. METHODS: Non-GCS-responsive BHR asthma was defined as failure of reduction of BHR to methacholine after a 2-week course of oral prednisolone (30 mg/day). The expression of interleukin (IL)-4, IL-5, IFN-gamma mRNA in peripheral blood mononuclear cells, eosinophil count, serum cortisol, eosinophilic cationic protein (ECP), and spirometry were measured in five non-GCS-responsive BHR asthmatics and six patients with GCS-responsive BHR asthma before and after prednisolone therapy. RESULTS: With the exception of serum ECP and expression of IL-5 mRNA, no significant differences were observed between GCS-responsive BHR and non-GCS-responsive BHR asthma. The mean ECP level was significantly higher in non-GCS-responsive BHR than in GCS-responsive BHR asthma before and after prednisolone therapy. Interleukin-5 mRNA was detected in all asthmatics before prednisolone therapy; however, after prednisolone therapy, IL-5 mRNA was only detected in non-GCS-responsive BHR asthmatics. CONCLUSIONS: Our findings suggest that activation of eosinophils appears to persist in some asthmatics with non-GCS-responsive BHR due to continuous IL-5 production by lymphocytes.     

A genome-wide search for linkage to asthma phenotypes in the genetics of asthma international network families: evidence for a major susceptibility locus on chromosome 2p

Asthma is a complex disease and the intricate interplay between genetic and environmental factors underlies the overall phenotype of the disease. Families with at least two siblings with asthma were collected from Europe, Australia and the US. A genome scan using a set of 364 families with a panel of 396 microsatellite markers was conducted. Nonparametric linkage analyses were conducted for asthma and three asthma-related phenotypes: bronchial hyper-reactivity (BHR), strict definition of asthma and atopic asthma. Nine chromosomal regions with LOD scores greater than 1.5 were identified (chromosomes 1q, 2p, 3q, 4p, 4q, 6q, 12q, 20p and 21). Linkage refinement analysis was performed for three BHR loci by genotyping single nucleotide polymorphisms at an average marker density of 1 cM. The LOD scores increased to 3.07 at chromosome 4p and 4.58 at chromosome 2p, while the chromosome 6p locus did not refine. The LOD score at the chromosome 2p locus is highly significant on a genome-wide basis. The refined locus covers a region with a physical size of 12.2 Mb. Taken together, these results provide evidence for a major asthma susceptibility locus on chromosome 2p.     

Genetic susceptibility to asthma and atopy among Chinese in Singapore--linkage to markers on chromosome 5q31-33

BACKGROUND: Asthma and atopy are complex genetic traits, influenced by the interaction of multiple genes and environmental factors. Linkage of these traits to chromosome 5q31-33 has been shown in other populations, but has not been well studied in the Chinese. We studied linkage between asthma and atopy with markers on chromosome 5q31-33 in the Singapore Chinese. This region contains many candidate genes, including the cytokine gene cluster. METHODS: We recruited 88 Chinese families with at least two affected offspring, totaling 373 subjects, with 125 and 119 sib-pairs for atopy and asthma, respectively. All individuals were genotyped with 19 polymorphic microsatellite markers spanning a distance of 41 cM along chromosome 5q31-33. Affected sib-pair and multipoint linkage analysis was performed. RESULTS: There was evidence for linkage of the asthma and atopy phenotypes with three markers, D5S2110, D5S2011, and D5S412 (P values of 0.001 to 0.00001). Multipoint analysis further substantiated this (nonparametric linkage scores of 1.8-2.9). These findings suggest that susceptibility genes for asthma and atopy are found in this region in the Chinese. CONCLUSION: This study has shown linkage of atopy and asthma to chromosome 5q31-33 in a heterogeneous Chinese population. These findings further substantiate the notion that chromosome 5q31-33 contains "universally" important susceptibility genes for these traits.     

Combined effect of tumour necrosis factor-α and interleukin-13 polymorphisms on bronchial hyperresponsiveness in Korean children with asthma

Background TNF‐α and IL‐13, two pivotal pro‐inflammatory cytokines, are increased in asthmatic airways and may be linked to asthma susceptibility and/or bronchial hyperresponsiveness (BHR). Objective We investigated the association between the TNF‐α?308G/A polymorphism and asthma susceptibility or asthma‐related phenotypes in Korean children with asthma, and tested for a combined effect with IL‐13 polymorphisms. Methods Asthmatic children (n=719) and non‐atopic healthy control children (n=243) were evaluated for asthma phenotypes including total serum IgE and BHR to methacholine. Genotypes were determined by PCR‐restriction fragment length polymorphism analysis. Results The allele frequency of TNF‐α?308A in asthmatics (14.1%) was higher than that in control children [8.7%, odds ratio (OR) 1.72, 95% confidence interval (CI) 1.05–2.82]. Significantly lower PC₂₀ values were found in asthmatic children carrying one or two copies of the TNF‐α risk allele (?308A) vs. those homozygous for the common allele (P=0.026). Combined analysis revealed that atopic asthmatic children co‐inherited the risk alleles of TNF‐α?308G/A and IL‐13 +2044G/A more frequently than control children (aOR 1.91, 95% CI 1.00–3.65), and asthmatic children co‐inheriting both risk alleles had significantly lower PC₂₀ values vs. asthmatic children homozygous for the common alleles (P=0.024). Conclusion The TNF‐α promoter polymorphism (?308G/A) may be associated with asthma susceptibility and BHR in Korean children with asthma. In addition, there appears to be a synergistic effect between the TNF‐α promoter polymorphism and an IL‐13 coding region polymorphism in terms of asthma susceptibility and BHR in this population.     

Involvement of IL-9 in the bronchial phenotype of patients with nasal polyposis

BACKGROUND: Nasal polyposis (NP) is frequently associated with asthma. In this disease, asymptomatic bronchial hyperresponsiveness (BHR) is thought to precede the development of asthma. IL-9 and its receptor have been reported as candidate genes for asthma and to be associated with BHR. OBJECTIVE: The objective of this study was to assess the contribution of 11-9 to the pathogenesis of BHR in NP by comparing the expression of IL-9 and its receptor in bronchial biopsy specimens from three groups of patients with NP: NP without BHR, NP with asymptomatic BHR, and NP with BHR and asthma. METHODS: Bronchial biopsy specimens were examined in terms of cellular infiltration and in terms of expression of IL-9 protein and mRNA as well as of its receptor by using immunohistochemistry and in situ hybridization. RESULTS: Patients with NP with asthma as compared with the two other groups exhibited an increased bronchial infiltration of basophils, eosinophils, and T cells that correlated with the asthma score. The two groups of patients with NP with BHR showed an increased expression in IL-9 protein and mRNA as well as an increase in the expression of IL-9R mRNA at the epithelial level. These modifications were inversely correlated with the airway responsiveness to methacholine, producing a 20% fall in FEV1. There was a close association between IL-9+ cells, IL-5 mRNA expression, and eosinophil infiltration that correlated with each other. CONCLUSIONS: These results suggest an important role for IL-9 in the pathogenesis of BHR and a causal relation between IL-9 and the development of bronchial eosinophilia in asthma.     

The combination of a genome-wide association study of lymphocyte count and analysis of gene expression data reveals novel asthma candidate genes

Recent genome-wide association studies (GWAS) have identified a number of novel genetic associations with complex human diseases. In spite of these successes, results from GWAS generally explain only a small proportion of disease heritability, an observation termed the 'missing heritability problem'. Several sources for the missing heritability have been proposed, including the contribution of many common variants with small individual effect sizes, which cannot be reliably found using the standard GWAS approach. The goal of our study was to explore a complimentary approach, which combines GWAS results with functional data in order to identify novel genetic associations with small effect sizes. To do so, we conducted a GWAS for lymphocyte count, a physiologic quantitative trait associated with asthma, in 462 Hutterites. In parallel, we performed a genome-wide gene expression study in lymphoblastoid cell lines from 96 Hutterites. We found significant support for genetic associations using the GWAS data when we considered variants near the 193 genes whose expression levels across individuals were most correlated with lymphocyte counts. Interestingly, these variants are also enriched with signatures of an association with asthma susceptibility, an observation we were able to replicate. The associated loci include genes previously implicated in asthma susceptibility as well as novel candidate genes enriched for functions related to T cell receptor signaling and adenosine triphosphate synthesis. Our results, therefore, establish a new set of asthma susceptibility candidate genes. More generally, our observations support the notion that many loci of small effects influence variation in lymphocyte count and asthma susceptibility.     

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.