Association between interleukin-1 receptor antagonist gene and asthma-related traits in a German adult population

Background:  A recent study in German and Italian families associated variants in the interleukin-1 receptor antagonist (IL1RA) gene with asthma. The aim of the present study was to further investigate the role of single nucleotide polymorphisms (SNPs) in the IL1RA gene in the development of atopy and lifelong asthma in a population-based study.
Methods:  DNA samples from the German centres of the European Community Respiratory Health Survey were analysed for genetic variants in the IL1RA gene and the development of asthma, atopy and bronchial hyperreactivity.
Results:  Carriers of the rare G allele of SNP rs447713 had a significantly increased risk of developing asthma ( P  = 0.0013) and allergic sensitization ( P  = 0.0119). Carriers of the rare C allele of SNP rs3087271 had an increased risk of asthma ( P  = 0.0227) and high immunoglobulin E (IgE) levels ( P  = 0.0232). A haplotype built from eight SNPs in the IL1RA gene (A-C-A-G-A-C-G-A) was associated with a higher prevalence of asthma ( P  = 0.007) and high total IgE ( P  = 0.02). Bronchial hyperreactivity was positively associated with the haplotype A-C-G-G-A-C-G-C ( P  = 0.02) and negatively with the A-C-G-G-A-C-T-C ( P  = 0.03).
Conclusion:  A previously described association between IL1RA and asthma in families could be reproduced in a population-based sample. The genetic variants of IL1RA gene do not to seem to affect asthma alone, but to act as modulators of asthma-related traits as well, where different haplotypes drive the development of different phenotypes.     

Haplotypes of the interleukin-4 receptor α chain gene associate with susceptibility to and severity of atopic asthma

BACKGROUND: 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. OBJECTIVE: We chose to analyse IL4R gene haplotypes and assess their possible relevance in susceptibility to asthma and to certain clinical phenotypes. METHODS: 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. RESULTS: Our data showed significantly higher levels of soluble IL-4R (sIL-4R) in asthma patients compared with controls (P<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<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<0.05) and showed less severe asthma according to lung function test (P<0.05). Analysis of single markers showed the T-3223 IL4R allele to associate with lower serum levels of sIL-4 receptor (P<0.0001) and patients carrying the T allele also had more symptoms of active asthma (wheezing, P<0.01; coughing, P<0.05 and breathing difficulties, P<0.01). CONCLUSION: 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.     

Case–Control Study of Eczema in Relation to IL4Rα Genetic Polymorphisms in Japanese Women: The Kyushu Okinawa Maternal and Child Health Study

Epidemiological research on the relationship between single nucleotide polymorphisms (SNPs) in the IL4Rα gene and eczema is sparse. We investigated the associations between IL4Rα SNPs rs1805011, rs1805015 and rs1801275 and risk of eczema in young adult Japanese women. Included were 188 women who met the criteria of the International Study of Asthma and Allergies in Childhood (ISAAC) for eczema. Controls were 635 women without eczema according to the ISAAC criteria who also had not been diagnosed with asthma, atopic eczema and/or allergic rhinitis by a doctor. Adjustment was made for age, region of residence, number of children, smoking and education. Under the additive model, SNP rs1805011 was significantly related to eczema: the adjusted OR was 0.55 (95% CI: 0.31?0.99). SNP rs1805015 was significantly associated with eczema in the additive and dominant models: the adjusted ORs were 0.55 (95% CI: 0.30?0.98) and 0.55 (95% CI: 0.30?0.997), respectively. There was no significant association between SNP rs1801275 and eczema. None of the haplotypes were significantly related to eczema. Significant associations between SNPs rs1805011 and rs1805015 and eczema were reported in women who had never smoked, but not in those who had ever smoked; the multiplicative interactions, however, were not significant. This is the first study to demonstrate significant associations between IL4Rα SNPs rs1805011 and rs1805015 and eczema. We do not find evidence for interactions affecting eczema between IL4Rα SNPs and smoking.     

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.     

Associations between specific serum IgE response and 6 variants within the genes IL4, IL13, and IL4RA in German children: the German Multicenter Atopy Study

BACKGROUND: Among many published studies of specific IgE response or atopy, only a few showed positive marginal effects for 6 potentially functional single nucleotide polymorphisms (SNPs; C-590T in the IL4 gene, C-1055T and Arg130Gln in the IL13 gene, and Ile50Val, Ser478Pro, and Gln551Arg in the IL4RA gene). SNPs were commonly considered individually, and therefore the true effect could be masked by other genes or environmental factors. OBJECTIVE: We tested the relationship between these 6 SNPs and sensitization to food, mite, cat, and outdoor allergens in unrelated German children drawn from the Multicenter Atopy Study. Gene-gene and gene-environment interactions were also evaluated. METHODS: Multiple logistic regression models were used for the analyses of 4 sensitization outcomes. RESULTS: The variant C-1055T was significantly associated with increased risk of sensitization to food and outdoor allergens, with odds ratios of 3.49 (95% CI, 1.52-8.02) and 2.27 (95% CI, 1.04-4.94), respectively. The effects of the TT genotype on food sensitization appear to depend on variants in the IL4RA gene, in which marginally significant interaction terms were observed. Significant evidence supported an interaction between exposure to maternal smoking and variant Gln551Arg on risk of cat sensitization. In addition, we found that the effect of variant C-590T on sensitization to mite depended on Der p 1 allergen levels in carpet dust samples. CONCLUSIONS: These findings not only suggested that variants in the IL4, IL13, and IL4RA genes play an important role in controlling specific IgE response but also strengthened our understanding of gene-gene and gene-environment interaction on the development of specific sensitization in this study population.     

Investigation of the IL23R gene in a Spanish rheumatoid arthritis cohort

Recently, a genome-wide association study identified the interleukin-23 receptor gene (IL23R) as an inflammatory bowel disease (IBD) associated gene. Given the involvement of IL23R in T-cell regulation, we decided to test whether this gene is associated with rheumatoid arthritis (RA). Eight IL23R gene polymorphisms (rs1,004,819, rs7,517,847, rs10,489,629, rs11,209,026, rs1,343,151, rs10,889,677, rs11,209,032, and rs1,495,965) were selected among the 10 most associated SNPs from the IBD study. A total of 322 RA patients and 342 healthy controls were genotyped for the selected SNPs using a Taqman 5' allelic discrimination assay. We did not find statistically significant differences when we compared allele and genotype frequencies between RA patients and controls for none of the IL23R gene polymorphisms under study. We did not observe significant differences when RA patients were stratified according to their clinical and demographic features. We conclude that the IL23R gene does not seem to be associated with RA predisposition in a Spanish population.     

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   

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.     

IL-5 and IL-5 receptor alpha polymorphisms are associated with atopic dermatitis in Koreans

BACKGROUND: Eosinophils are recruited into the affected tissue of asthma and atopic dermatitis (AD) patients. IL-5 and IL-5R are highly expressed in the AD skin lesions, yet the reported levels of IL-8 are controversial. METHOD: We genotyped 17 singlenucleotide polymorphisms (SNPs) from five genes of the 1120 case-control samples (646 AD and 474 controls). We measured the serum IL-5 concentrations in 87 individuals [36 ADe (AD extrinsic), 18 ADi (AD intrinsic) and 33 controls] by ELISA, and compared the results among these groups. RESULT: The rs2522411SNP and haplotype T-A in the IL-5 gene were significantly associated with the ADe. The serum IL-5 concentration was higher in the ADe than that in the ADi patients without any correlation with the rs2522411SNP. In the IL-5RA gene, the rs334809SNP showed a weak association with AD, and the rs6771148SNP and the haplotype T-C-T of the three adjacent tagged SNPs had an effect on the blood eosinophil counts and the serum ECP levels in the AD patients. However, we could not detect any relationship between AD and the SNPs in the IL-8 and IL-8R genes. CONCLUSION: We found that the rs2522411SNP and the haplotype T-A in the IL-5 gene and the serum IL-5 levels were strongly associated with the allergic type of AD, but not with the nonallergic type of AD. The association of the rs6771148SNP and the haplotype T-C-T in the IL5RA gene with the blood eosinophil counts and the serum ECP levels indicates that the IL5RA gene has a role for controlling eosinophils in the peripheral blood.     

Association of interleukin 23 receptor gene with sarcoidosis

Interleukin 23 receptor (IL23R) gene has been reported as a genetic factor strongly associated with inflammatory bowel disease, psoriasis, and ankylosing spondylitis. We investigated the association between IL23R gene single nucleotide polymorphisms (SNPs) and susceptibility to sarcoidosis, including the clinical manifestation of uveitis. Ninety-one sarcoidosis subjects (58 with and 33 without uveitis) and 104 healthy controls were genotyped for eleven IL23R SNPs. DNA was amplified using specific PCR primers and genotyped by denaturing HPLC and/or direct DNA sequencing. Case-control frequency comparisons were analyzed using Chi square test. Three IL23R SNPs, rs7517847 (intron 6), rs11465804 (intron 8), and rs11209026 (exon 9, c.1142G>A, p.Arg381Gln) were associated with sarcoidosis in our population (p<0.05): rs7517847 showed increased frequencies in sarcoidosis compared to controls, but rs11465804 and rs11209026 were decreased. Two of these SNPs were associated with the uveitis subgroup compared to controls: rs11465804 (0.9% vs. 7.2%, OR=0.11, P=0.013) and rs11209026 (1.8% vs. 7.3%, OR=0.23, P=0.038). This finding indicates the association of IL23R polymorphism with sarcoidosis, especially with sarcoid uveitis. IL23R may be a common susceptibility gene shared by several autoimmune disorders including inflammatory bowel disease, psoriasis, and ankylosing spondylitis and sarcoid uveitis.     

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.     

Polymorphisms in the interleukin 17F gene (IL17F) and asthma

Interleukin17F (IL17F) is a regulatory cytokine for T-cell-mediated immune responses. The gene coding for IL17F (IL17F) is located on chromosome 6p, a genomic region linked to asthma and asthma-related phenotypes in multiple genome scans. IL17F is expressed in lung tissue, in bronchoalveolar lavage fluid from asthmatic subjects, and in activated CD4+ cells. We were thus interested in testing for association between single-nucleotide polymorphisms (SNPs) and haplotypes in IL17F and asthma. To characterize polymorphisms in IL17F, we sequenced this gene in a group of African Americans and a group of European Americans. A total of 50 SNPs (30 not previously reported in a public database (dbSNP build 118)) and two insertions/deletions were detected in IL17F; five of these polymorphisms were genotyped in participants of the Nurses' Health Study. We then tested for association between SNPs and haplotypes in IL17F and physician-diagnosed asthma in subjects with (cases) and without (control subjects) physician-diagnosed asthma. None of the SNPs or haplotypes tested in IL17F were associated with asthma. The polymorphisms identified in this study may be used in future studies of association between IL17F and phenotypes related to immune responses.     

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.     

Contribution of functional variation in the IL13 gene to allergy, hay fever and asthma in the NSHD longitudinal 1946 birth cohort

Background:  Genetic variants of the two adjacent genes, IL13 and IL4 have frequently been reported as being associated with susceptibility to atopy and asthma, both in adults and children, and some studies also suggest association with lung function and chronic obstructive pulmonary disease.
Methods:  In this study, we examined for the first time the effect of these variants in 2918 adults in a longitudinal birth cohort, the British National Survey of Health and Development, where there are extensive life style, developmental and environmental data. We examine two IL13 single nucleotide polymorphisms (SNPs) IL13 rs20541 (R110Q) and rs1800925 (−1024C>T) and one IL4 SNP, rs2070874 (−33C>T) with likely function.
Results:  We show that IL13 rs20541 and rs1800925 are each significantly associated with self-reported asthma and allergy, and that this association is not confounded by any of the known developmental and environmental risk factors for asthma and atopy, including in particular place of birth. IL13 rs20541 does however act as a confounder for the IL13 rs1800925 associations, meaning that there is no statistical support for rs1800925 having an independent effect. There is nevertheless evidence for interaction between smoking and rs1800925, with allergy as outcome. None of the SNPs showed association with measures of lung function, nor any interaction with the effect of smoking on lung function.
Conclusion:  In a longitudinal population cohort we have established a role for polymorphism of IL13 in determining susceptibility to both atopy and asthma.     

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.     

Lack of association between genetic variation in G-protein-coupled receptor for asthma susceptibility and childhood asthma and atopy

G-protein-coupled receptor for asthma susceptibility (GPRA or GPR154) was identified as an asthma and atopy candidate gene by positional cloning. Some subsequent studies suggest associations of GPRA single nucleotide polymorphisms (SNPs) and haplotypes with asthma or atopy susceptibility. However, the associated SNPs or haplotypes vary among studies. The role of GPRA genetic variation in asthma and atopy remains unsolved. Published data on GRPA variants and asthma come exclusively from Caucasian and Asian populations. We examined whether GPRA SNPs and haplotypes are associated with asthma and atopy in a Mexican population. We genotyped and analyzed 27 GPRA SNPs in 589 nuclear families consisting of asthmatic children aged 4-17 years of age and their parents in Mexico City. Atopy was determined by skin prick tests to 25 aeroallergens. The 27 SNPs examined provided excellent coverage of the GPRA gene. GPRA SNPs and haplotypes were not associated with childhood asthma and the degree of atopy to aeroallergens in a Mexican population. Our review of studies of GPRA variants in relation to asthma phenotypes shows considerable heterogeneity. Accordingly, our results suggest that GPRA variants are not an important contributor to childhood asthma and atopy susceptibility in a Mexican population.     

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.     

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.     

Association of interleukin-8 receptor alpha polymorphisms with chronic obstructive pulmonary disease and asthma

Chronic obstructive pulmonary disease (COPD) and asthma are common complex diseases characterized by airflow obstruction and inflammatory processes in the small airways. lnterleukin 8 (IL-8) is a potent proinflammatory cytokine which interacts with the IL-8 receptor alpha (IL8RA, CXCR1) and beta (IL8RB, CXCR2), leading to activation and migration of leukocytes. In order to evaluate the role of the IL8RA gene in the pathogenesis of COPD and asthma, we screened the coding region of IL8RA for mutations by means of single-strand conformation polymorphism analysis in 50 COPD patients and identified three exchanges (M31R, S276T and R335C). These three polymorphisms were subsequently genotyped in 182 adult patients with COPD, 68 adult patients and 130 children with asthma as well as 454 healthy controls. The frequencies of the IL8RA 31R and 335C alleles were significantly increased in patients with COPD and in children with asthma compared to healthy controls (P=0.0073 and 0.023, respectively). Thus, these polymorphisms may play a role in the pathogenesis of COPD and asthma.