IL4Rα Mutations Are Associated with Asthma Exacerbations and Mast Cell/IgE Expression (original) (raw)
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IL4Rα Mutations Are Associated with Asthma Exacerbations and Mast Cell/IgE Expression
American Journal of Respiratory and Critical Care Medicine, 2007
Background: Severe asthma has been associated with severe exacerbations, lower lung function and greater tissue inflammation. Previous studies have suggested that mutations in interleukin-4 receptor ␣ (IL4R␣) are associated with lower lung function, higher IgE, and a gain in receptor function. However, an effect on exacerbations and tissue inflammation has not been shown. Hypothesis: Allelic substitutions in IL4R␣ are associated with asthma exacerbations, lower lung function, and tissue inflammation, in particular to mast cells and IgE. Methods: Two well-characterized cohorts of subjects with severe asthma were analyzed for five single nucleotide polymorphisms (SNPs) in IL4R␣. These polymorphisms were compared with the history of severe asthma exacerbations and lung function. In the primary (National Jewish) cohort, these polymorphisms were also compared with endobronchial tissue inflammatory cells and local IgE. Results: In both cohorts, the presence of the minor alleles at E375A and Q551R, which were more common in African Americans, was associated with a history of severe exacerbations and lower lung function. In the National Jewish cohort, the C allele at E375A was associated with higher tissue mast cells and higher levels of IgE bound to mast cells. The significance for most of these associations remained when whites (the larger racial subgroup) were analyzed separately. Conclusions: SNPs in IL4R␣, which are more common in African Americans, are associated with severe asthma exacerbations, lower lung function, and increased mast cell-related tissue inflammation. Further studies of the impact of these mutations in African Americans and on receptor function are indicated.
IL4R Mutations Are Associated with Asthma Exacerbations and Mast Cell/IgE Expression
American Journal of Respiratory and Critical Care Medicine, 2007
Background: Severe asthma has been associated with severe exacerbations, lower lung function and greater tissue inflammation. Previous studies have suggested that mutations in interleukin-4 receptor ␣ (IL4R␣) are associated with lower lung function, higher IgE, and a gain in receptor function. However, an effect on exacerbations and tissue inflammation has not been shown. Hypothesis: Allelic substitutions in IL4R␣ are associated with asthma exacerbations, lower lung function, and tissue inflammation, in particular to mast cells and IgE. Methods: Two well-characterized cohorts of subjects with severe asthma were analyzed for five single nucleotide polymorphisms (SNPs) in IL4R␣. These polymorphisms were compared with the history of severe asthma exacerbations and lung function. In the primary (National Jewish) cohort, these polymorphisms were also compared with endobronchial tissue inflammatory cells and local IgE. Results: In both cohorts, the presence of the minor alleles at E375A and Q551R, which were more common in African Americans, was associated with a history of severe exacerbations and lower lung function. In the National Jewish cohort, the C allele at E375A was associated with higher tissue mast cells and higher levels of IgE bound to mast cells. The significance for most of these associations remained when whites (the larger racial subgroup) were analyzed separately. Conclusions: SNPs in IL4R␣, which are more common in African Americans, are associated with severe asthma exacerbations, lower lung function, and increased mast cell-related tissue inflammation. Further studies of the impact of these mutations in African Americans and on receptor function are indicated.
Journal of human …, 2005
The gene for mast cell chymase (CMA1) is an ideal candidate for investigating genetic predisposition to atopic asthma, as it is an important mediator of inflammation and remodeling in the asthmatic lung. Various studies have examined the association between -1903 G/A polymorphism and allergic phenotypes, but inconsistent results have been obtained. We investigated the association of this SNP and a novel (TG)(n)(GA)(m) repeat polymorphism (accession no. BV210164) 254 bp downstream of the gene with asthma and its associated traits in a case-control study in two independent cohorts recruited from the Indian population. A significant association was observed for the (TG)(n)(GA)(m) repeat with asthma (p<0.05) in both the cohorts. Although no association was observed for the -1903 G/A SNP with asthma, a significant association was observed between the genotypes and serum IgE levels (p=0.003 and 0.0004 for cohort A and B). When haplotypes were compared between patients and controls, the...
Genetic Variation Determines Mast Cell Functions in Experimental Asthma
The Journal of …, 2011
Mast cell-deficient mice are a key for investigating the function of mast cells in health and disease. Allergic airway disease induced as a Th2-type immune response in mice is employed as a model to unravel the mechanisms underlying inception and progression of human allergic asthma. Previous work done in mast cell-deficient mouse strains that otherwise typically mount Th1-dominated immune responses revealed contradictory results as to whether mast cells contribute to the development of airway hyperresponsiveness and airway inflammation. However, a major contribution of mast cells was shown using adjuvant-free protocols to achieve sensitization. The identification of a traceable genetic polymorphism closely linked to the Kit W-sh allele allowed us to generate congenic mast cell-deficient mice on a Th2-prone BALB/c background, termed C.B6-Kit W-sh. In accordance with the expectations, C.B6-Kit W-sh mice do not develop IgE-and mast cell-dependent passive cutaneous anaphylaxis. Yet, unexpectedly, C.B6-Kit W-sh mice develop full-blown airway inflammation, airway hyperresponsiveness, and mucus production despite the absence of mast cells. Thus, our findings demonstrate a major influence of genetic background on the contribution of mast cells in an important disease model and introduce a novel strain of mast cell-deficient mice.
American Journal of Human Genetics, 2000
After a genomewide screen in the Hutterites was completed, the IL4RA gene was examined as the 16p-linked susceptibility locus for asthma and atopy. Seven known variants and one novel variant, representing all nonsynonymous substitutions in the mature protein, were examined in the Hutterites; on the basis of studies in the Hutterites, outbred white, black, and Hispanic families were genotyped for selected markers. All population samples showed evidence of association to atopy or to asthma (P values .039-.0044 for atopy and .029-.0000061 for asthma), but the alleles or haplotypes showing the strongest evidence differed between the groups. Overall, these data suggest that the IL4RA gene is an atopy-and asthma-susceptibility locus but that variation outside the coding region of the gene influences susceptibility.
Cellular and molecular biology (Noisy-le-Grand, France), 2003
Single nucleotide polymorphisms (SNPs) in the gene encoding the interleukin-4 receptor alpha chain (IL-4R alpha) have been associated with IgE levels or clinical atopy in some populations. Two SNPs that encode S503P and Q576R in the intracytoplasmic domain of the receptor are associated with loss or gain of function, respectively. We investigated the frequency of these SNPs and their association with traits of allergic asthma in 36 unrelated subjects selected from a racially admixed, clinically ascertained study population with family histories of asthma. The frequency of the 1682 T to C substitution that encodes S503P was 0.11 (70 alleles analyzed, from 29 TT homozygotes and 6 TC heterozygotes). The frequency of the 1902 A to G substitution that encodes Q576R was 0.26 (68 alleles analyzed, from 20 AA homozygotes, 10 AG heterozygotes and 4 GG homozygotes). In this atopic admixed sample, no significant association was detected between the variant genotypes and serum IgE levels, perce...
Association of STR polymorphisms in CMA1 and IL-4 with asthma and atopy: The SAPALDIA Cohort
Human Immunology, 2010
Asthma is a chronic pulmonary disorder that is characterized by airway inflammation and bronchial hyperreactivity. Several genetic loci have been associated with asthma, and some of these associations have been replicated in independent studies. However, larger population-based replication studies for the association of short tandem repeat (STR) polymorphisms with asthma are limited. In this study, we investigated the association of STR polymorphisms in genes encoding mast cell chymase (CMA1), uteroglobin (UGB), tumor necrosis factor-␣ (TNF-␣) and interleukin-4 (IL-4) with asthma and atopic phenotypes in the large populationbased Swiss Cohort Study SAPALDIA. Our results show that the STR polymorphism in the CMA1 gene is associated with asthma and that this association is even stronger with atopic asthma. Similarly, we observed a weak association of the IL-4 2-allele with asthma that tended to be stronger for atopic asthma than for nonatopic asthma. This minor IL-4 2-allele was also associated with higher IgE levels, with a higher risk for a positive skin prick test and with a trend for a higher risk for bronchial hyperresponsivenes. These results support previous findings suggesting a role for CMA1 and IL-4 in atopic asthma and for IL-4 in atopy in general. ᭧
Clinical <html_ent glyph="@amp;" ascii="&"/> Experimental Allergy, 2004
Development of asthma is likely to depend on a complex interaction between environmental and genetic factors. Several groups have suggested the gene of the IL-4 receptor alpha chain (IL4R) as a candidate gene for the development of asthma, although association with single polymorphisms has shown contradicting results. We chose to analyse IL4R gene haplotypes and assess their possible relevance in susceptibility to asthma and to certain clinical phenotypes. IL4R gene haplotypes were analysed, based on the three markers C-3223T, Q551R and I50V, using the expectation-maximization algorithm, in 170 atopic asthma patients and 350 controls, all adult Swedish Caucasians. Our data showed significantly higher levels of soluble IL-4R (sIL-4R) in asthma patients compared with controls (P&amp;lt;0.0001). Furthermore, we showed a significant association between the IL4R haplotype containing the alleles T-3223, V50 and R551 (TVR) of the IL4R gene, and susceptibility to atopic asthma, with a frequency of 6.5% in the patients compared with 1% in the controls (P&amp;lt;0.0005). A subgroup of patients with heterozygous or homozygous state for the T-3223, V50 and R551 alleles, also had lower levels of sIL-4R in their circulation compared with patients with homozygous state in the C-3223, I50 and Q551 alleles (P&amp;lt;0.05) and showed less severe asthma according to lung function test (P&amp;lt;0.05). Analysis of single markers showed the T-3223 IL4R allele to associate with lower serum levels of sIL-4 receptor (P&amp;lt;0.0001) and patients carrying the T allele also had more symptoms of active asthma (wheezing, P&amp;lt;0.01; coughing, P&amp;lt;0.05 and breathing difficulties, P&amp;lt;0.01). Our data suggest that asthmatic patients with low levels of sIL-4 receptor may represent a genetically distinct subgroup of atopic asthma. TVR haplotype analyses confirm the importance of IL4R as a candidate gene for susceptibility to asthma. This finding may have implications for the understanding of the pathogenesis of asthma and possibly for the development of more specific therapies.
Journal of investigational allergology & clinical immunology, 2008
BACKGROUND Mast cell chymase is a mediator of inflammation and remodeling in the asthmatic lung. Although various studies have examined the association between the -1903 G/A single nucleotide polymorphism (SNP)in the mast cell chymase gene (CMA1) and allergic phenotypes, the results have been inconsistent. A (TG)n(GA)m repeat polymorphism 254 base pairs downstream of CMA1 has been reported in adult asthmatics. We investigated the relationship between these CMA1 genetic variants and childhood asthma in Egyptian children. METHODS A case-control study was undertaken in 15 children (6-10 years old) with bronchial asthma enrolled consecutively during exacerbation and 15 age-matched and sex-matched nonasthmatic control subjects. Genotyping was performed by polymerase chain reaction (PCR) restriction fragment length polymorphism to search for polymorphisms in the CMA1 gene promoter region (-1903 G/A) and PCR amplification followed by sequencing to detect the (TG)n(GA)m repeat 254 base pair...