Association between interleukin-18 gene polymorphism 105A/C and asthma

BACKGROUND: IL-18 has been shown to exert anti-allergic or allergy-promoting activities, but the existence of genetic polymorphisms in the coding regions of IL-18 gene has not been demonstrated. OBJECTIVE: The aim of this study was to investigate whether polymorphism is present in the coding regions of the IL-18 gene and, if so, to further analyse the association between polymorphism and asthma in a case-control study. METHODS: We screened the coding regions of the IL-18 gene for polymorphisms by using PCRsingle-stranded conformation polymorphism and direct sequencing of PCR products, followed by analysis of the association between polymorphism and asthma. RESULTS: We identified one polymorphism (105A/C) in the coding regions. The frequency of the 105A allele was significantly higher in asthmatic patients than in controls (P<0.01; odds ratio (OR)=1.83 (1.37-2.26)). Significant linkage disequilibrium was observed between the 105A/C and -137G/C polymorphisms in the 5' flanking region of the IL-18 gene (D=0.58, P<0.0001). However, in asthmatic patients the 105A allele was not associated with either total serum IgE or IL-18 levels. CONCLUSION: The 105A/C polymorphism of the IL-18 gene may be associated with the pathogenesis of asthma.     

Lack of association of atopy/asthma and the interleukin-4 receptor α gene in Japanese

BACKGROUND: Susceptibility to the development of atopic diseases is known to involve genetic factors. Several investigators have reported the interleukin-4 (IL-4) receptor alpha gene to be involved in the development of atopy. Recent study has shown that the R allele of a polymorphism in the IL-4 receptor alpha chain gene (Q576R) to be associated with atopy. OBJECTIVE: The objective of this study was to evaluate the possible role of the IL-4 receptor alpha gene in modulating allergic response and asthma in the Japanese population. METHODS: We conducted linkage analysis using microsatellite markers flanking the IL-4 alpha receptor gene in 82 families ascertained through asthmatic children. The IL-4 receptor Q576R polymorphism was also genotyped by PCR-restriction fragment length polymorphism analysis. RESULTS: We did not find evidence for linkage of the asthma and atopy phenotypes with the markers D16S298 and D16S403 (P = 0.10 and P = 0.56, respectively, for the atopy phenotype and P = 0.17 and P = 0.60, respectively, for the asthma phenotype). The IL-4 receptor R576 allele was not preferentially transmitted to atopy- or asthma-affected children (chi2 = 1.67, P = 0.24 for atopy and chi2 = 0.91, P = 0.40 for asthma). In addition, the prevalence of the R576 allele among parents with and without atopy was similar, 20 of 81 (24.7%) parents with atopy and 22 of 77 (28.6%) parents without atopy. CONCLUSION: Our findings indicate that the IL-4 receptor alpha gene does not exert a substantial influence on the inheritance of atopy or asthma in this Japanese population.     

Analysis of the Ser786Pro Interleukin-4 Receptor α Allelic Variant in Allergic and Nonallergic Asthma and Its Functional Consequences

Asthma and other atopic disorders affect a large percentage of the population. While many factors contribute to the phenotype of asthma, there is a strong genetic predisposition. IL-4 is a central mediator of allergic inflammation. Along with IL-13, it is the major cytokine responsible for the induction of IgE synthesis. Furthermore, IL-4 acts on Th0 cells and promotes their differentiation into Th2 cells resulting in the production of more IL-4 and IL-13, thereby propagating the allergic cascade. Both IL-4 and IL-13 utilize IL-4Rα as a component of their cognate receptor complexes. Eight polymorphisms of the IL-4Rα gene resulting in amino acid changes in the coding sequence have been described, and several have been associated with asthma. The central objective of this study was to elucidate the role of the Ser786Pro polymorphism in asthma and its impact on IL-4R function. One-hundred ninety-six individuals with asthma and 53 controls were genotyped for Pro786. Pro786 occurred infrequently in the general population with an allele frequency of 1.8% and, thus, is unlikely to play a major role in atopy or asthma. The Pro786 allele frequency was 1.5% in the asthma group and 2.8% in the control group. The asthma group was subdivided into allergic and nonallergic asthma, and the Pro786 allele frequencies were 1.7 and 1.0%, respectively. The data suggested linkage disequilibrium between Ser786Pro and the Gln576Arg allele, which is associated with atopy. In order to study the impact of the polymorphism on receptor signaling function, we transfected a mouse B lymphoma cell line with the wild-type and Pro786 variants of human IL-4Rα. The Ser786Pro polymorphism in isolation did not affect IL-4R function.     

Association of interferon-γ and interferon regulatory factor 1 polymorphisms with asthma in a family-based association study in Taiwan

BACKGROUND: Asthma is a multi-factorial disorder caused by complex interactions between genetic and environmental factors. IFN-gamma and IFN regulatory factor 1 (IRF-1) affect Th1/Th2 cytokine balance, and influence the differentiation of Th2 cells, which influence the development of asthma. OBJECTIVE: This study investigated CA repeats polymorphism of the IFN-gamma gene and GT repeats polymorphism of the IRF-1 gene, which may predispose individuals to asthma pathogenesis. METHODS: In the present study, we used the transmission/disequilibrium test (TDT) to investigate the relationship between asthma and the IFN-gamma and IRF-1 polymorphisms by studying 348 subjects composed of 232 parents and 116 asthmatic children. RESULTS: For global TDT test, IFN-gamma CA repeats and IRF-1 GT repeat polymorphisms showed a significant association with asthma in children (P=0.009 and 0.017, respectively). We demonstrated that 13 CA repeats (138 bp) of IFN-gamma gene and 11 GT repeats (306 bp) of IRF-1 gene are significantly preferentially transmitted to asthmatic children (T/NT=89/61, chi2=8.43, P<0.005 and T/NT=75/49, chi2=8.18, P<0.005, respectively). The offspring will have an increased risk of asthma when their parents transmit IFN-gamma 13 CA repeats (OR=1.83, P=0.009) and IRF1 11 GT repeats (OR=1.88, P=0.007) to them. But we observed that the IFN-gamma and IRF-1 polymorphisms are not associated with IgE concentrations. CONCLUSION: These findings provide strong evidence of which IFN-gamma CA repeat and IRF-1 GT repeat polymorphisms influence the risk of asthma for children in Taiwan.     

Analysis of the Ser786Pro interleukin-4 receptor alpha allelic variant in allergic and nonallergic asthma and its functional consequences

Asthma and other atopic disorders affect a large percentage of the population. While many factors contribute to the phenotype of asthma, there is a strong genetic predisposition. IL-4 is a central mediator of allergic inflammation. Along with IL-13, it is the major cytokine responsible for the induction of IgE synthesis. Furthermore, IL-4 acts on Th0 cells and promotes their differentiation into Th2 cells resulting in the production of more IL-4 and IL-13, thereby propagating the allergic cascade. Both IL-4 and IL-13 utilize IL-4Ralpha as a component of their cognate receptor complexes. Eight polymorphisms of the IL-4Ralpha gene resulting in amino acid changes in the coding sequence have been described, and several have been associated with asthma. The central objective of this study was to elucidate the role of the Ser786Pro polymorphism in asthma and its impact on IL-4R function. One-hundred ninety-six individuals with asthma and 53 controls were genotyped for Pro786. Pro786 occurred infrequently in the general population with an allele frequency of 1.8% and, thus, is unlikely to play a major role in atopy or asthma. The Pro786 allele frequency was 1.5% in the asthma group and 2.8% in the control group. The asthma group was subdivided into allergic and nonallergic asthma, and the Pro786 allele frequencies were 1.7 and 1.0%, respectively. The data suggested linkage disequilibrium between Ser786Pro and the Gln576Arg allele, which is associated with atopy. In order to study the impact of the polymorphism on receptor signaling function, we transfected a mouse B lymphoma cell line with the wild-type and Pro786 variants of human IL-4Ralpha. The Ser786Pro polymorphism in isolation did not affect IL-4R function.     

Promoter polymorphism of the IL-18 gene is associated with atopic asthma in Tunisian children

Several lines of evidence point to a relevant role of IL-18 in the process of asthma. Some studies suggest that the polymorphism in the gene of IL-18 can be involved in many inflammatory and atopic diseases such as asthma. The aim of our study is to estimate the frequency of the IL-18-607 C/A (rs 1946518) promoter polymorphism in Tunisian children with asthma. We investigated whether the presence of this polymorphism -607 C/A was associated with asthma or atopy and whether this polymorphism influenced the severity of asthma in affected children. We examined also the relationship between the IL-18 gene polymorphism and the serum total IgE level. The IL-18/-607 C/A polymorphism was analysed by polymerase chain reaction and restriction fragment-length polymorphism (PCR-RFLP) analysis. A total of 105 asthma patients and 112 controls as part of the whole children population were studied in a case-control study. Among the 105 children with asthma, 40 were also studied for linkage analyses with their respective parents. We noted that the A allele was associated with statistically significant increases in the risk of asthma in the case-control study (odd ratio (OR) = 1.55, 95% confidence interval (CI) 1.03-2.33. Moreover, the A allele was also associated with atopic asthma (P = 0.008), but not with asthma severity. The transmission disequilibrium test (TDT) analysis in this family study did not suggest a preferential transmission of the IL-18/ -607 C/A polymorphism to affected children. There is no correlation between the IgE level and the IL-18 -607 C/A promoter polymorphism. Our data indicate that IL-18 -607 C/A promoter polymorphism is associated with susceptibility to developing asthma in Tunisian population.     

The common G-allele of interleukin-18 single-nucleotide polymorphism is a genetic risk factor for atopic asthma. The SAPALDIA Cohort Study

BACKGROUND: IL-18 is a pleiotrophic cytokine involved in both, T-helper type 1 (Th1) and Th2 differentiation. Recently genetic variants in the IL-18 gene have been associated with increased risk of atopy and asthma. OBJECTIVE: To examine the relationship of a genetic, haplotype-tagging promotor variant -137G/C in the IL-18 gene with atopic asthma in a large, well-characterized and population-based study of adults. METHODS: Prospective cohort study design was used to collect interview and biological measurement data at two examination time-points 11 years apart. Multivariate logistic regression analysis was used to assess the association of genotype with asthma and atopy. RESULTS: The G-allele of the IL-18 promotor variant (-137G/C) was associated with a markedly increased risk for the prevalence of physician-diagnosed asthma with concomitant skin reactivity to common allergens. Stratification of the asthma cases by skin reactivity to common allergens revealed an exclusive association of IL-18 -137 G-allele with an increased prevalence of atopic asthma (adjusted odds ratio (OR): 3.63; 95% confidence interval: (1.64-8.02) for GC or GG carriers vs. CC carriers), and no according association with asthma and concomitant negative skin reactivity (adjusted OR: 1.13; 0.66-1.94). The interaction between IL-18 -137G/C genotype and positive skin prick test was statistically significant (P=0.029). None of 74 incident asthma cases with atopy at baseline exhibited the CC genotype. CONCLUSION: Our results strongly suggest that this variant of the IL-18 gene is an important genetic determinant involved in the development of atopic asthma.     

MCP-1 gene regulatory region polymorphism in Chinese children with mild, moderate and near-fatal asthma

BACKGROUND: A polymorphism in the monocyte chemoattractant protein 1 (MCP-1) gene regulatory region has been associated with asthma in Caucasians. This polymorphism is possibly endemic to the Asian region, but its impact on Asian populations is unclear. In addition, the relationship of this marker with life-threatening asthma has not been clarified. The aim of this study was to test the genetic association between the MCP-1 -2518A/G polymorphism and asthma/atopy in a cohort of Chinese children, with particular emphasis on those patients who had experienced life-threatening asthma attacks. METHODS: Forty-eight children with near-fatal asthma, 134 mild-to-moderate asthmatics, 69 allergic-disorder cases without asthma, and 107 nonasthmatic, nonatopic control children were genotyped by a polymerase chain reaction-based assay. RESULTS: Comparison of the four groups of children (n = 358) revealed no detectable differences in genotype or allele frequencies of the MCP-1 -2518A/G polymorphism. There was no evidence of association between the polymorphism and any of the outcomes of interest including clinical severity, blood eosinophil count, atopy, total serum IgE levels, and degree of bronchial hyper-responsiveness. CONCLUSION: These results suggest that the MCP-1 -2518A/G polymorphism is not a risk factor for near-fatal asthma. Furthermore, this polymorphism seems to play no role in the development of asthma or atopy in Chinese subjects, possibly as a result of the genetic heterogeneity between Asian and Caucasian populations with respect to regulation of MCP-1 expression. Our results underscore the necessity of accounting for ethnic background in the investigation of asthma-predisposition genes.     

The detection of IRF-1 promoter polymorphisms and their possible contribution to T helper 1 response in chronic hepatitis C.

We described the interferon (IFN) regulatory factor-1 (IRF-1) promoter single nucleotide polymorphisms (SNPs), and the clinical and immunologic implications of these SNPs have been investigated. We successfully determined the mutation at -300 of the IRF-1 promoter by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and this mutation linked with other mutations in the promoter region. In our Japanese population, the frequency of the type -300*A/A was 11.9%, type A/G was 54.2%, and type G/G was 33.9%. We found no significant difference without IFN stimulation in the production levels of IFN-gamma and interleukin-10 (IL-10) from peripheral blood mononuclear cells (PBMC) between subjects with -300*A/A and those with other types. IFN-alpha stimulation, however, increased the levels of IFN-gamma significantly and decreased the IL-10 production level significantly only in the subject with -300*A/A type. Flow cytometric analysis showed that the Th1-type CD4(+) cell population was significantly increased by IFN-beta administration only in the patient with chronic hepatitis C with -300*A/A type. These results suggest that the IRF-1 promoter SNP types are positively involved in Th1-type response and, consequently, the -300*A/A type may be beneficial for viral elimination in chronic hepatitis C and IFN therapy.     

The RANTES promoter polymorphism: a genetic risk factor for near-fatal asthma in Chinese children

BACKGROUND: RANTES promoter polymorphisms were found associated with asthma/atopy in some studies but not others, possibly reflecting the genetic heterogeneity among different ethnicities and different asthma severity. OBJECTIVE: The purpose of this investigation was to test the genetic association between the RANTES -28C/G and -403G/A polymorphisms and asthma/atopy in a cohort of Chinese children, with particular emphasis on those patients who had experienced life-threatening asthma attacks. METHODS: Forty-eight children with near-fatal asthma, 134 children with mild-to-moderate asthma, 69 children with allergic disorders but no asthma, and 107 nonasthmatic nonatopic control children were genotyped through use of a PCR-based assay. RESULTS: No significant difference was demonstrated for frequency of the RANTES -28C/G polymorphism when the mild-to-moderate asthma, atopic/nonasthmatic, and normal control groups were compared. The RANTES -28G allele was present in a significantly higher proportion of the children with near-fatal asthma compared with the nonasthmatic nonatopic controls (odds ratio, 2.93 [1.41-6.06]; P =.006) and the children with mild-to-moderate asthma (odds ratio, 3.52 [1.73-7.16]; P =.001). The frequency of -28G allele carriage correlated with asthma severity. The RANTES -28G allele was also associated with an increased blood eosinophil count and a higher degree of bronchial hyperresponsiveness. The RANTES -403G/A polymorphism did not influence asthma/atopy susceptibility, blood eosinophil count, or bronchial hyperresponsiveness. Interestingly, a higher frequency of -403A allele carriage was observed in the moderate asthma subgroup compared with the mild asthma analog. CONCLUSIONS: We conclude that the RANTES -28C/G polymorphism exacerbates asthma severity, representing a genetic risk factor for life-threatening asthma attacks in Chinese children. In addition, the linkage disequilibrium between these 2 polymorphisms is a potential confounder that must be considered in the design and interpretation of RANTES gene association studies.     

Sequence variants of the secreted phosphoprotein 1 gene are associated with total serum immunoglobulin E levels in a Japanese population

BACKGROUND: Secreted phosphoprotein 1 (SPP1) is a cytokine with pleiotrophic immunological activities, including activation of macrophage chemotaxis and T-helper type 1 (Th1) immune responses. SPP1 gene polymorphisms have been shown to be associated with several immune inflammatory diseases including multiple sclerosis (MS), which is characterized by fewer allergic symptoms and lower numbers of allergen sensitizations. OBJECTIVE: The present study examined whether SPP1 gene polymorphisms are associated with total serum IgE levels, atopy and asthma in a Japanese population. METHODS: This case-control association analysis examined 611 subjects, including 268 subjects with asthma. We genotyped three promoter and two exon polymorphisms at SPP1: -1687A/G; -381T/C; -94 deletion/G; 5891C/T; and 7052T/C. Results Association analyses of SPP1 polymorphisms showed that homozygosities for the 5891T allele (P=0.009) and 7052C allele (P=0.001) were significantly associated with increased levels of total IgE in non-asthmatic subjects. However, these variants were not associated with asthma and atopy. Interestingly, individuals carrying the 5891C allele, which is more prevalent in patients with MS in Japanese populations, displayed significantly lower levels of total serum IgE. Individuals homozygous for the 7052C allele, which is associated with development of systemic lupus erythematosus, displayed significantly higher total serum IgE levels. CONCLUSION: These findings suggest that genetic polymorphisms in SPP1 may play a role in controlling basal levels of total serum IgE, independent of atopy.     

Analysis of TGF-beta(1) gene polymorphisms in Hong Kong Chinese patients with asthma

BACKGROUND: The C-509T polymorphism of TGF-beta(1) gene has been associated with asthma and atopy in white populations. OBJECTIVE: We investigated the association between asthma and previously identified polymorphisms at C-509T and T869C of the TGF-beta(1) gene among 250 Chinese patients with asthma and 308 healthy controls in Hong Kong. METHODS: Genotyping was performed on peripheral blood genomic DNA by using PCR-RFLP. RESULTS: There were no differences in the frequencies of genotypes and alleles between patients and controls. The C-509T and T869C polymorphisms were in tight linkage disequilibrium (P < .01). Among atopic subjects, significant differences were found in genotype and allele frequencies for T869C polymorphism between patients and controls (P = .014 and P = .019, respectively), and individuals bearing the CC genotype were associated with increased risk for the development of asthma (odds ratio, 2.58; 95% CI, 1.17-5.66; P = .018) after adjusting for age, sex, and smoking status. Individuals with asthma bearing the CT genotype of the C-509T polymorphism had significantly increased risk for severe airflow obstruction compared with individuals who had mild obstruction (odds ratio, 4.00; 95% CI, 1.06-15.08; P = .035). CONCLUSION: Our results indicate that the polymorphisms at C-509T and T869C of the TGF-beta(1) gene are associated with asthma susceptibility in atopic subjects of the Hong Kong Chinese population, and the C-509T polymorphism may play a role in the pathogenesis of airflow obstruction.     

Childhood atopic asthma: positive association with a polymorphism of IL-4 receptor alpha gene but not with that of IL-4 promoter or Fc epsilon receptor I beta gene

We examined the relative contributions of three representative candidate genes for atopy (Fc epsilon receptor I beta, IL-4, and IL-4 receptor alpha) to the development of atopic asthma. Four polymorphisms of the three candidate genes including Ile50Val and Gln551Arg of IL-4 receptor alpha, -590C/T of IL-4 promoter and Glu237Gly of Fc epsilon receptor I beta were studied in 100 patients with atopic asthma and 100 nonatopic controls in the northern Kyushu area in Japan. Among the four polymorphisms of the three candidate genes, the Ile50 allele of the IL-4 receptor alpha chain gene demonstrated an association with atopic asthma subjects (p = 0.044), especially in patients with onset at 2 years of age or earlier (p = 0.034) and in patients with moderate to severe atopic asthma (p = 0. 031). Gln551Arg of IL-4 receptor alpha, -590C/T of IL-4 promoter and Glu237Gly of Fc epsilon receptor I beta showed no association with atopic asthma. A slight linkage disequilibrium between Ile50Val and Gln551Arg polymorphisms of the IL-4 receptor alpha chain gene was observed in both patients and nonatopic controls. The identification of additional atopy genes in areas with a certain genetic background is essential for genetic diagnosis and to establish new therapeutic modalities for atopic asthma.     

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   

A functional CD86 polymorphism associated with asthma and related allergic disorders

Background

Several studies have documented a substantial genetic component in the aetiology of allergic diseases and a number of atopy susceptibility loci have been suggested. One of these loci is 3q21, at which linkage to multiple atopy phenotypes has been reported. This region harbours the CD86 gene encoding the costimulatory B7.2 protein. The costimulatory system, consisting of receptor proteins, cytokines and associated factors, activates T cells and regulates the immune response upon allergen challenge.

Methods

We sequenced the CD86 gene in patients with atopy from 10 families that showed evidence of linkage to 3q21. Identified polymorphisms were analysed in a subsequent family‐based association study of two independent Danish samples, respectively comprising 135 and 100 trios of children with atopy and their parents. Functional analysis of the costimulatory effect on cytokine production was performed in an autologous cell‐based system based on cells expressing CD86 variants.

Results

Two polymorphisms were identified, encoding the amino acid changes Ile179Val and Ala304Thr, respectively. Significant associations were observed between the Ile179Val polymorphism and allergy phenotypes in both samples (eg, asthma, p = 4×10⁻³ in the two samples combined). The undertransmitted (protective) Val179 allele was found to induce higher production of both Th1 and Th2 cytokines than the overtransmitted (risk) Ile179 allele, suggesting a functional impact of the polymorphism.

Conclusion

The CD86 gene, and specifically the Ile179Val polymorphism, may be a novel aetiological factor in the development of asthma and related allergic disorders.     

Polymorphism of the mast cell chymase gene (CMA1) promoter region: lack of association with asthma but association with serum total immunoglobulin E levels in adult atopic dermatitis

BACKGROUND: Mast cell chymase has the potential to be an important mediator of inflammation and remodelling in the asthmatic lung. Previous studies have examined association between promoter polymorphism of the chymase gene (CMA1) and allergic phenotypes but the significance of this polymorphism is unclear. We have examined association of a CMA1 variant in relation to asthma in a large UK Caucasian family cohort. METHODS: A polymorphism of the CMA1 gene promoter (-1903G/A) was genotyped in 341 asthmatic families and in 184 non-asthmatic adults recruited from the UK PCR-RFLP based genotyping. Association with asthma diagnosis, atopy, specific and total IgE, and atopy and asthma severity was examined. RESULTS: Case-control studies did not reveal a significant difference in allele frequency between asthmatics and controls. A significant association was found between CMA1 genotypes and total IgE levels in subjects with self-reported eczema that remained significant after correction for multiple testing (median total serum IgE GG 297 kU/L, GA 144 kU/L, AA 48.4 kU/L, Pc=0.0032). CONCLUSION: These data suggest that CMA1 promoter polymorphism does not contribute to asthma susceptibility or severity but may be involved in regulating IgE levels in patients with eczema.     

Candidate gene and mutational analysis in asthma and atopy

BACKGROUND: Using quantitative phenotype scores, we have genotyped four markers close to the FcepsilonRI-beta gene on chromosome 11q and 17 markers on chromosome 12. We have also determined the frequency of the I181L/V183L and E237G polymorphisms in our population. METHODS: 131 randomly ascertained families and 109 families with an asthmatic proband were recruited. Written and video questionnaires, bronchial challenge, and skinprick tests were administered and IgE levels measured. Phenotype scores were derived using principal-component analysis. The asthma score incorporated the questionnaire data reduced to two variables (wheeze and video), the ratio of predicted to observed FEV1, and bronchial hyperresponsiveness calculated as the slope of the dose-response curve. Total IgE, with the highest heritability of the atopy variables, was used as the atopy score. I181L/V183L polymorphism was determined by sequencing and E237G polymorphism by the amplification refractory mutation system. The data were analyzed using the BETA programme. RESULTS: No examples of the I181L/V183L polymorphism were identified. The E237G polymorphism was identified with a frequency of 3.5% with weak evidence for linkage (lod 1.522) to asthma. Linkage was found to markers on chromosome 12 and asthma. The largest single locus lod was achieved for D12S366 and wheeze (lod 3. 307). Using multipoint analysis, a maximum lod score of 2.29 centres around D12S97 at location 173.5 cM for the asthma score. CONCLUSION: The linkage results for chromosome 12 justify further interest in this region. Future endeavours will be directed towards fine mapping in the hope of identifying novel candidate genes.     

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.