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.     

Genetic variants of the IL13 and IL4 genes and atopic diseases in at-risk children

We studied a cohort containing 368 children at high risk of developing atopy and atopic disorders and 540 parents of those children to investigate whether the IL13 Arg130Gln and C-1112 T polymorphisms were associated with these outcomes. We also investigated whether haplotypes consisting of any two polymorphisms of IL13 Arg130Gln, IL13 C-1112 T and IL4 C-589 T were associated with these phenotypes. In 288 white children, the IL13 130Gln allele was associated with atopy (RR=1.9, P=0.047), and with atopic dermatitis (RR=2.5, P=0.014). The associations were confirmed using a family-based test of association (P=0.027 and 0.030, respectively) in all subjects. In white subjects there were associations of haplotypes consisting of IL13 Arg130Gln and IL4 C-589 T with atopic dermatitis (P=0.006) and with atopy (P=0.009). Our data suggest that the IL13 Arg130Gln polymorphism and haplotypes consisting of IL13 Arg130Gln and IL4 C-589 T were associated with the development of atopy and atopic dermatitis at 24 months of age.     

Impact of interleukin 13 (IL13) genetic polymorphism Arg130Gln on total serum immunoglobulin (IgE) levels and interferon (IFN)‐γ gene expression

This cross‐sectional study was designed to investigate the extent of genetic susceptibility by targeting variants in interleukin (IL)?4/IL‐13 signalling pathways leading to atopic disease in early childhood. We evaluated involvement of five single nucleotide polymorphisms IL4 C‐590T, IL13 C‐1055T, IL13 Arg130Gln, IL4RA Ile50Val and IL4RA Gln576Arg, in the control of serum total and antigen‐specific immunoglobulin (Ig)E levels. Furthermore, we analysed their association with changes in gene expression of five cytokines having key roles in inflammatory and anti‐inflammatory immune response [IL‐4, IL‐13, interferon (IFN)‐γ, IL‐8 and IL‐10]. Total and antigen‐specific IgE levels in serum and gene expression of selected cytokines in peripheral blood were measured in 386 children aged 1–8 years. TaqMan allelic discrimination, amplification refractory mutation system–polymerase chain reaction (ARMS–PCR) and restriction fragment length polymorphisms (RFLP) methods validated by sequencing were used for genotyping. All genotypes for children with total and antigen‐specific IgE levels in the normal range were in Hardy–Weinberg equilibrium. Gene expression analyses were carried out using TaqMan gene expression assays. We found elevated total IgE levels in carriers of IL13 Arg130Gln variant allele [odds ratio (OR) = 1·84; 95% confidence interval (CI) = 1·16‐2·93]. This effect was more apparent for boys (OR = 2·31; 95% CI = 1·25‐4·28). However, no significant association was observed for the other four variants examined. We found up‐regulation of IFN‐γ in children with elevated serum total IgE levels carrying the Arg130 allele (P = 0·005). No differences were found for IL4, IL8 or IL10, while IL13 gene expression was under the detection limit. IL13 Arg130Gln genotypes can play a role in genetic susceptibility to allergy via regulation of serum total IgE levels and affecting IFN‐γ gene expression.     

A complete screening of the IL4 gene: novel polymorphisms and their association with asthma and IgE in childhood

BACKGROUND: IL-4, a cytokine with immunomodulatory functions, is involved in the upregulation of IgE production characteristic of asthma and allergy. Thus far, 2 single nucleotide polymorphisms (SNPs) in the promoter (C-589T) and 5' untranslated region (C-33T) of the IL4 gene have been identified. Polymorphism C-589T was reported to influence total serum IgE levels and bronchial hyperresponsiveness. However, no study has investigated the putative existence of further SNPs in exons, introns, and flanking regions of the IL4 gene. OBJECTIVE: A complete screening of the IL4 gene and its flanking regions for new polymorphisms was performed. Large-scale association studies in 1120 German schoolchildren were conducted to determine the effect of all polymorphisms present in the IL4 gene on the phenotypic expression of atopic diseases. METHODS: Denaturing HPLC and standard sequencing techniques were performed to detect novel polymorphisms in 33 unrelated subjects unselected for atopic diseases. Linkage disequilibrium was assessed for all polymorphisms in the IL4 gene, and association studies were performed. RESULTS: A total of 16 polymorphisms were identified in the IL4 gene, 14 of which were not reported previously. The pattern of linkage disequilibrium observed in IL4 could not be explained by physical distance. A significant association between a cluster of polymorphisms in strong linkage disequilibrium with each other and a physician's diagnosis of asthma and total serum IgE levels was found. CONCLUSION: These results indicate a possible involvement of SNPs in the IL4 gene in the development of asthma and the regulation of total serum IgE.     

Lack of association between the IL13 variant Arg110Gln and susceptibility to cedar pollinosis in a Japanese population

BACKGROUND: Interleukin (IL)-13 has come to be appreciated as a molecule critically involved in allergic inflammatory responses. Recent studies revealed that a common variant in the coding region of the IL13 gene, Arg110Gln, has been implicated in the development of asthma and atopy. METHODS: To assess whether the IL13 variant Arg110Gln is associated with cedar pollinosis, one of the most common atopic diseases in the Japanese population, we examined the Arg110Gln variant using PCR-RFLP to compare the genotype and allele frequencies between 95 patients with cedar pollinosis and 95 healthy control subjects. Relationships between the Arg110Gln variant and the pollinosis-related traits, e.g. rhinitis severity, eosinophil counts in nasal secretion and serum total and allergen-specific IgE levels, were also investigated. RESULTS: The frequencies of the minor allele Gln110 were 25.8% in patients with cedar pollinosis and 30.9% in healthy control subjects (p > 0.05). There was also no significant difference in the genotype frequencies between cases and controls (p > 0.05). In addition, we found no significant association of the Arg110Gln variant with any of the pollinosis-related phenotypes (p > 0.05). CONCLUSIONS: Our data suggest lack of evidence for identifying the variant Arg110Glnat the IL13 locus as a genetic risk factor involved in the development of Japanese cedar pollinosis.     

Association study of the IL13 variant Arg110Gln in atopic diseases and juvenile idiopathic arthritis

BACKGROUND: It has previously been shown that various inflammatory diseases, such as diabetes mellitus, bronchial asthma, chronic inflammatory bowel diseases, and rheumatoid arthritis, are in some circumstances genetically linked to the same chromosomal regions. Consequently, common genes underlying the pathogenetics of these diseases have been proposed. Chronic inflammatory disorders can be subdivided by their predominant immune response, either TH1 or TH2. For example, juvenile idiopathic arthritis (JIA) is a TH1 disease, and bronchial asthma is a TH2 disease. OBJECTIVES: The present study investigated the polymorphism Arg110Gln within the IL13 gene, a strong TH2 cytokine. We attempted to determine whether it is associated with these 2 diseases and whether this would reflect the TH1/TH2 paradigm. METHODS: Arg110Gln was typed in 4 different populations: asthmatic children, atopic children, children with JIA, and a control population. Statistical analysis was performed by using logistic and linear regression analysis of serum IgE levels and the Armitage trend test. RESULTS: The variant Gln110 was shown to be associated with increased total serum IgE levels in our atopic population (P =.006) and was weakly associated with bronchial asthma (P =.04). There was no association of the variant with JIA when compared with the control population. However, the variant Gln110 was significantly less frequent in children with JIA compared with its presence in children with bronchial asthma (P =.007). CONCLUSION: This is the first study to compare the same gene variant in TH1 and TH2 chronic inflammatory diseases. The results suggest that the same gene variant might protect from one disease and make an individual susceptible to the other.     

A cluster of seven tightly linked polymorphisms in the IL-13 gene is associated with total serum IgE levels in three populations of white children

BACKGROUND: Increased levels of total serum IgE are a strong risk factor for the development of asthma. IgE is also involved in host defenses against parasites and fungi. Linkage of total serum IgE with markers located close to the 3 Mb cluster of cytokine genes in chromosome 5q31 has been reported. IL-4 or IL-13 are regarded as essential for IgE synthesis. OBJECTIVE: We tested whether polymorphisms in the IL-13 gene might explain the linkage between chromosome 5q31 and total serum IgE levels. METHODS: We used denaturing HPLC to detect polymorphisms in overlapping PCR fragments of the IL-13 gene including promoter and 3' untranslated regions. After sequencing was performed to identify the locations of the polymorphisms, PCR and primer-induced restriction site assays were used to genotype subjects in 3 unselected populations. RESULTS: We report here 7 polymorphisms (6 novel) in IL-13. Four of these polymorphisms are tightly linked to a variant in the terminal portion of the coding region of the gene that results in a predicted amino acid change in residue 130 (Arg130Gln). The Gln form is strongly associated (P =.000002) with increased serum IgE levels in 3 different populations comprising a total of 1399 children. Two additional polymorphisms in the promoter region of IL-13 are more loosely linked to Arg130Gln and are also less significantly associated with total serum IgE levels. CONCLUSION: These data suggest that the Arg130Gln polymorphism in IL-13, or others in close linkage with it, is associated with the development of the elevated serum IgE phenotype.     

Association of IL13 with total IgE: evidence against an inverse association of atopy and diabetes

BACKGROUND: Atopic illnesses, related to high circulating IgE levels, and the autoimmune disease type 1 diabetes, have been reported to be inversely associated. One possible explanation is that susceptibility alleles for one disease provide protection for the other. OBJECTIVE: Using the largest sample sizes reported so far for the identification of genetic determinants of circulating IgE levels, we investigated associations between total serum IgE (log-transformed) and single nucleotide polymorphisms in 8 genes that are candidate susceptibility loci for IgE levels/atopic illness (IL13, IL4, IL4RA, FCER1B, IL12B, TBET) and/or type 1 diabetes (CTLA4, PTPN22, IL2RA). METHODS: As many as 4570 DNA samples obtained from members of the British 1958 Birth Cohort were genotyped for 51 candidate variants, and the associations of alleles and genotypes with log-transformed serum IgE levels were evaluated by regression modeling. RESULTS: We obtained evidence of association between IL13 variants and total serum IgE levels (P = .00002, explaining 0.59% of phenotypic variance). However, there was no evidence of association of the confirmed type 1 diabetes susceptibility genes CTLA4 and PTPN22 and the candidate gene IL2RA with IgE levels. CONCLUSION: Allelic variation in the IL-13 gene is robustly confirmed as a contributor to the variance of IgE levels but has no detectable effect in type 1 diabetes. CLINICAL IMPLICATIONS: Although the allelic variation at the confirmed IL-13 locus explains too little of the between-individual variation of circulating IgE to be of use for clinical prediction on its own, the discovery of additional susceptibility loci in the future may aid in the stratification of atopic subjects and improve risk assessment.     

Lack of association between atopic eczema and the genetic variants of interleukin-4 and the interleukin-4 receptor α chain gene: heterogeneity of genetic backgrounds on immunoglobulin E production in atopic eczema patients

BACKGROUND: The genetic background of atopic eczema might be heterogeneous and there is a possibility that immunoglobulin (Ig)E responsiveness in patients with atopic eczema is controlled separately from the development of atopic eczema. Although both interleukin (IL)-4 and the IL-4 receptor alpha chain have an important role for IgE production and are therefore possible candidate genes for atopy, it has not been clarified whether these genes play any roles in atopic eczema patients who have normal IgE productivity. OBJECTIVE: We aimed to assess whether the polymorphisms of the IL-4 gene and the IL-4 receptor alpha chain gene play any roles in atopic eczema patients, particularly in patients who have normal IgE productivity. METHOD: We determined the genotype with regard to polymorphisms in the genes for IL-4 and the IL-4 receptor alpha chain (- 589C/T of IL-4; Ile50Val, Ala375Glu and Arg551Gln of IL-4 receptor alpha chain) in patients with atopic eczema using the fluorogenic 5' nuclease assay. RESULTS: IL-4 and the IL-4 receptor alpha chain genotypes were not significantly associated with either total patients with atopic eczema or atopic eczema patients who had normal IgE productivity. The distribution of genotypes of IL-4-589C/T differed by the serum IgE levels in patients with atopic eczema. CONCLUSION: These results suggest that the polymorphisms in the IL-4 gene and the IL-4 receptor alpha chain gene play no role in the development of atopic eczema in patients who have normal IgE productivity.     

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.     

Association between a new polymorphism in the activation-induced cytidine deaminase gene and atopic asthma and the regulation of total serum IgE levels.

BACKGROUND: Activation-induced cytidine deaminase (AICDA) is a recently identified RNA-editing deaminase that plays an important role in class-switching. Defects in AICDA result in a hyper-IgM phenotype and lack of IgG, IgA, and IgE in both human beings and mice. OBJECTIVE: The aim of this study was to determine whether the AICDA gene is related to regulation of total serum IgE and development of atopic asthma. METHODS: We screened for polymorphisms in the 5;-flanking and coding regions of the AICDA gene in subjects with atopic asthma and analyzed the effect of these polymorphisms on the development of atopic asthma and on total serum IgE levels in Japanese asthmatic families. RESULTS: We identified 3 novel polymorphisms (5923A/G, 7888C/T, and 8578A/C) and 1 rare variant (Arg25Cys) in the AICDA gene. Transmission disequilibrium testing showed that the 7888C allele was transmitted preferentially to asthma-affected children (P =.007). Mean log [total serum IgE] levels of parents with the 7888C/7888C, 7888C/7888T, and 7888T/7888T genotypes were 2.12, 1.99, and 1.77, respectively, and a significant association was observed between the genotypes (P =.02). In RT-PCR experiments, we found 2 novel splice variants of AICDA, one lacking all of exon 4 (variant 1; 367 base pairs) and the other lacking the first 30 base pairs of exon 4 (variant 2; 453 base pairs). These variants were not associated with the 7888C/T polymorphism. CONCLUSION: The 7888C/T polymorphism might be associated with the pathogenesis of atopic asthma and the regulation of total serum IgE levels.     

A comprehensive evaluation of IL4 variants in ethnically diverse populations: association of total serum IgE levels and asthma in white subjects

BACKGROUND: The role of variation in the IL4 gene in asthma and allergy susceptibility is controversial. This cytokine is important in IgE isotype switching and the regulation of allergic inflammation; however, published studies have not delineated the specific role of variation in this gene in allergic disorders. OBJECTIVE: We sought to identify single nucleotide polymorphisms (SNPs) in IL4 and to evaluate the association of SNPs and haplotypes with asthma and allergic phenotypes (total serum IgE) in white, African American, and Hispanic asthmatic populations. METHODS: Sixteen individuals were resequenced, and 19 SNPs were identified; 2 novel and 17 SNPs were previously reported. Eleven of the SNPs were used to evaluate association in the 3 groups. RESULTS: Nine polymorphisms were associated with total serum IgE levels in white subjects (.0012 < or = P < or =.034), and 5 of these were also associated with asthma in this population (.010 < or = P < or =.031). Three common haplotypes were observed, and all were associated with either high or low serum IgE levels in white subjects (.00008 < or = P < or =.004). Inspection of the haplotypes revealed that 3017 G/T in intron 2 was the only SNP concordant with serum IgE levels (G allele with lower levels and T allele with higher levels). CONCLUSIONS: After a comprehensive genetic evaluation, our data suggest that the 3017 G/T variant or the haplotype it identifies influences IL4's ability to modulate total serum IgE levels. Inconsistencies with previously reported IL4 associations might be due to population differences in allele frequencies, the extent of linkage disequilibrium with this SNP or haplotype, or both.     

Allelic polymorphisms in the interleukin-4 promoter regions and their association with bronchial asthma among the Russian population

BACKGROUND: Susceptibility to the development of bronchial asthma (BA) and other atopic diseases is known to be associated with genetic components. OBJECTIVE: To evaluate the possible role of the polymorphisms in IL-4 gene promoters (C-33T, C-590T and G-1098T) in modulating allergic response and asthma in the Russian population. METHODS: The polymorphism analysis was carried out by PCR-RFLP; IL-4 and total IgE concentrations were determined by ELISA. RESULTS: In the case group, the T allele was found at frequencies of 74% (C-33T), 51% (C-590T) and 5% (G-1098T); in the control group the frequencies were 22, 42 and 8%, respectively. Only the C-33T polymorphism was associated with BA. The concentrations of total IgE and serum IL-4 were raised in the case group, while in the control group they were normal. Serum IL-4 level depended on C-33T polymorphism both in the case and control groups, the mutant T allele promoting its increase. The dependence on C-590T polymorphism was detected only in the case group. As for the total IgE level, in both cases it depended on the polymorphism in the case group rather than the control. G-1098T polymorphism did not demonstrate any correlations with total IgE or serum IL-4 levels. All 3 polymorphisms did not affect the severity of BA in the case group. On the basis of the computer analysis, we propose that the T-33C region is the CREB-binding site. CONCLUSIONS: Our data suggest that IL-4 promoter polymorphism in the Russian population might play a role both conferring susceptibility to BA and modulating the levels of serum IL-4 and total IgE.     

A promoter polymorphism in the CD14 gene is associated with elevated levels of soluble CD14 but not with IgE or atopic diseases

BACKGROUND: A polymorphism in the promoter region of the CD14 gene, C-159T, has been shown to be associated with increased levels of soluble CD14 (sCD14) and decreased serum immunoglobulin E (IgE) and the expression of a more severe atopic phenotype in previous studies. METHODS: To test if these associations are consistently found in different populations and different age groups, we genotyped 2048 children of different age groups as well as 888 adults from different regions of Germany for the CD14 C-159T polymorphism. RESULTS: While an association between this promoter polymorphism and levels of sCD14 could be confirmed in our study population (CC: 1017 ng/ml vs TT: 1370 ng/ml, P = 0.03), no association between CD14 C-159T genotypes and IgE levels or the prevalence of atopic diseases was seen. CONCLUSIONS: The lack of association between CD14 genotypes and IgE as well as atopic outcomes in this large German study population seems to indicate that CD14 genotypes may not directly be involved in the development of allergies during childhood.     

Lack of association between a polymorphism in the interleukin-13 gene and total serum immunoglobulin E level among nuclear families in Costa Rica

BACKGROUND: IL-13 has been implicated in the pathogenesis of asthma and in the regulation of IgE synthesis in humans. Single nucleotide polymorphisms (SNPs) in the IL-13 gene have been associated with asthma and total serum IgE level in Caucasian populations. OBJECTIVE: To test for genetic association between an SNP in exon 4 of the IL-13 gene (IL-13 + 2044 or Arg130Gln) and total serum IgE level and asthma-related phenotypes in a population with high prevalence of asthma living in Costa Rica. METHODS: Family-based association study. RESULTS: Among 83 Costa Rican school children with asthma and their parents (249 individuals), there was no evidence of linkage disequilibrium between the IL-13 + 2044 SNP and any of the outcomes of interest (total serum IgE level on a logarithmic scale, number of positive skin tests to aeroallergens, and asthma). These results were not significantly changed after adjustment for age and gender. CONCLUSIONS: No significant evidence of linkage disequilibrium between an SNP in exon 4 of the IL-13 gene and total serum IgE level, sensitization to allergens or asthma was found in a family-based association study in Costa Rica.     

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

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

A comprehensive analysis of interleukin-4 receptor polymorphisms and their association with atopy and IgE regulation in childhood

BACKGROUND: The interleukin (IL) 4/IL13 pathway is involved in the regulation of IgE production associated with atopic diseases. Numerous polymorphisms have been identified in the coding region of the IL4 receptor alpha chain (IL4Ra) and previous association studies have shown conflicting results. Based on their putative functional role, polymorphisms A148G, T1432C and A1652G, located in the coding region of IL4Ra, were selected for association and haplotype studies in a large German population sample (n = 1,120). METHODS: Genotyping was performed using allele-specific PCR and restriction-enzyme-based assays. Haplotypes were estimated, and population-derived IgE percentiles (50% IgE >60 IU/ml, 66% IgE >115 IU/ml and 90% IgE >457 IU/ml) were calculated as outcome variables in a haplotype trend regression analysis. RESULTS: In our population, only polymorphism T1432C showed a trend for a protective effect against atopic rhinitis (odds ratio, OR: 0.52, 95% confidence interval, CI: 0.26-1.02, p = 0.05). When haplotypes were calculated, one haplotype was significantly associated with elevated serum IgE levels at the 50th percentile (OR 1.60, 95% CI 1.08-2.37, p = 0.02). CONCLUSIONS: These data indicate that IL4Ra polymorphisms, although suggested to be functionally relevant by in vitro studies, have only a minor influence on IgE regulation in our large population sample.     

Polymorphisms in the IL 18 gene are associated with specific sensitization to common allergens and allergic rhinitis

BACKGROUND: Atopy has been linked to chromosome 11q22, a region that harbors the IL18 gene. IL-18 enhances IL-4/IL-13 production and induces IgE production that is directly associated with the pathogenesis of atopic disorders. OBJECTIVE: We sought to investigate whether genetic abnormalities in the regulatory regions of the IL18 gene predispose, in part, to susceptibility to atopy. METHODS: Among a white population of 105 families, the oldest child was examined with regard to atopic phenotypes and single-nucleotide polymorphisms (SNPs) within the IL18 gene. RESULTS: We have identified 5 novel SNPs in the IL18 gene (-920[t/c], -133[c/g], and -132[a/g] in promoter 2 [upstream of exon 2]; +179[c/a; Ser35Ser] in exon 4; and +486[c/t; Phe137Phe] in exon 6). Three SNPs are located in promoter 2, and one (-133[c/g]; nuclear factor 1 site) was significantly associated with high serum IgE levels (P =.001; odds ratio, 3.96) and specific sensitization to common allergens (P =.005; OR, 4.12). In addition, previously identified SNPs in exon 1 (+113[t/g] and +127[c/t]) and in promoter 1 (-137[g/c], GATA3 site) of the IL18 gene were significantly associated with high IgE levels (P < or =.005; OR, 3.27-3.90) and specific sensitization (P =.02 to.008; OR, 3.27-3.83). The SNP +127(g/t) in exon 1 was also a susceptibility locus for seasonal allergic rhinitis (P =.008; OR, 3.22). CONCLUSION: IL18 might be responsible for the linkage effects seen in the chromosomal region 11q22, which has been found previously with the phenotype "sensitization to mite allergen." Thus a suspected direct role of IL18 in the pathogenesis of atopy has been strengthened by the presence of 8 common SNPs in the promoter regions of IL18.     

Involvement of interleukin (IL)-13, but not IL-4, in spontaneous IgE and IgG4 production in nephrotic syndrome

Nephrotic syndrome (NS) is a renal disease characterized by proteinuria and hypoalbuminemia. In NS patients without any allergic disease, serum IgE and IgG4 levels were selectively increased, and peripheral blood mononuclear cells (MNC) spontaneously produced IgE and IgG4. T cells produced interleukin (IL)-13 spontaneously, and B cells constitutively expressed IL-13 receptors (IL-13R). In addition, T cells stimulated surface IgE-negative (sIgE^?) and sIgG4^? B cells to produce IgE and IgG4, respectively, and IgE and IgG4 production was specifically blocked by anti-IL-13 antibody (Ab). MNC from atopic dermatitis (AD) patients also produced IgE and IgG4 spontaneously. However, in AD patients, T cells spontaneously produced IL-4, but not IL-13, and B cells constitutively expressed IL-4R, but not IL-13R. T cells stimulated sIgE^? and sIgG4^? B cells to produce IgE and IgG4, respectively, and the production was specifically blocked by anti-IL-4 Ab. On the other hand, sIgE⁺ and sIgG4⁺ B cells from both NS and AD patients spontaneously produced IgE and IgG4, respectively, and this production was not affected by T cells, anti-IL-4 Ab, or anti-IL-13 Ab. These results indicate that IL-13 is involved in the enhanced production of IgE and IgG4 in NS, while IL-4 is involved in these responses in AD.     

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.