Screening of the FcεRI-β-Gene in a Swiss Population of Asthmatic Children: No Association with E237G and Identification of New Sequence Variations

Background: The gene of the beta subunit of the high affinity receptor for IgE (FcεRI-β) encoded on chromosome 11q13 has recently been identified as a candidate gene for asthma and atopy. Two coding variations, E237G and I181L have been described as being associated with asthma and atopy. Our aim was to investigate a Swiss population of atopic and asthmatic children for variations in this gene.Methods: We screened all 7 exons of the FcεRI-β- gene in 224 atopic/asthmatic, 68 relatives and 159 control subjects using exon amplification by PCR and single strand conformation polymorphism (SSCP) analysis followed by fluorescence based DNA sequencing.Results: The sequence variant E237G was found in 3.7% in atopics and in 2.6% in the control population. None of the samples carried the I181L mutation. In addition, we characterised nine novel mutations (1 nonsense mutation, 2 missense mutations, mutation, 2 silent mutations, 4 intronic mutations).Conclusions: Our results suggest that the E237G does not have a primary effect on the development of atopy and asthma, and thus excludes the FcεRI-β locus from being a candidate gene directly involved in these diseases.     

Atopy and bronchial hyperresponsiveness: exclusion of linkage to markers on chromosomes 11q and 6p

Previous studies have reported a familial predisposition for the development of atopy, bronchial hyperresponsiveness and clinical asthma, and therefore have suggested the presence of a heritable component to these disorders. The specific contributions of genetic and environmental factors in the pathogenesis of allergic disease and asthma have not been determined although Cookson et al. [1] have postulated linkage between atopy and chromosome 11q. We have studied 20 families (two and three generations) ascertained through a proband identified as having asthma (90% were also allergic) during the period of time between 1962 and 1970. Of those who were originally skin test positive, 82% remained positive. All probands whose pulmonary function allowed retesting (FEV1 > 1.2 l) remained hyperresponsive to histamine. The children of these probands are now in the same age range as their parents when they were originally evaluated; 66% are atopic using criteria described by Cookson et al. (one or more positive skin tests > or = 2 mm, an elevated total serum IgE or a positive specific IgE) and 22% demonstrate bronchial hyperresponsiveness (PC20 FEV1) to histamine. Using the highly polymorphic marker INT2 (which maps 2 cM from p lambda MS.5 l on chromosome 11q) and atopy, we obtained a lod score of -2.00 at a recombination fraction of 0.12. In addition, because many studies have suggested an association between atopy and certain HLA antigens, we investigated the possibility of linkage between atopy and bronchial hyperresponsiveness and D6S105, a polymorphic marker on chromosome 6p, located 7 cM from HLA-DR. For this marker and atopy, we observed a lod score of -2.00 with a recombination fraction of 0.07.(ABSTRACT TRUNCATED AT 250 WORDS)     

Investigation of an interleukin-4 promoter polymorphism for associations with asthma and atopy.

The cytokine cluster located on chromosome 5 has been shown by linkage studies to play a role in the genetic determination of circulating immunoglobulin E (IgE) levels in atopic subjects. In the study presented here, the reported chromosome 5 linkage has been investigated in two sets of subjects. The first consisted of a general population sample of 230 nuclear families (n = 1004) from Busselton, a small West Australian country town. The second group consisted of 124 unrelated atopic asthmatics and 59 unrelated non-atopic, non-asthmatic controls, all resident in the Oxfordshire Regional Health Authority area in the United Kingdom. A previously reported interleukin-4 (II-4) promoter polymorphism (-590 C-->T) was analysed in these populations by a newly designed method of specific PCR amplification and BsmFI restriction endonuclease digestion. In the Busselton population the polymorphism was shown to be weakly associated with specific IgE to house dust mite (Mann-Whitney-U test, p = 0.013) and to wheeze (MWU test, p = 0.029), but not with specific IgE to grass pollen, total serum IgE, bronchial hyperresponsiveness, eosinophil count, or asthma. In the Oxfordshire subjects there were no statistically significant associations with any measure of asthma or atopy. These data show that the -590 C-->T II-4 promoter polymorphism is only weakly associated with certain measures of asthma and atopy in some subjects. It was specifically not associated with serum IgE concentration or asthma in either of the two groups in this study.     

Linkage and association of atopic asthma to markers on chromosome 13 in the Japanese population.

Chromosome 13 contains several candidate genes for asthma and atopy, and markers on this chromosome have been shown to be linked to phenotypes of atopy or asthma in two genome-wide searches. We conducted a linkage study for atopic asthma using markers spanning the whole of chromosome 13 in Japanese families ascertained through asthmatic children and examined associations of atopic asthma with markers where linkage was suggested. Data were analysed using MAPMAKER/SIBS for the multipoint lod score (MLS) analysis and SIB-PAIR for the transmission dis-equilibrium test (TDT). Three peaks which exceeded a lod score of 1.0 were observed (MLS 2.4 between D13S175 and D13S217, MLS 2.0 between D13S153 and D13S156, and MLS 1.4 between D13S285 and D13S293). The global TDT for atopic asthma was significant for the marker D13S153 ( P = 0.0065) and the 96 bp allele of D13S153 was preferentially transmitted to atopic asthma-affected children ( P = 0.0009, Bonferroni correction 5% = 0. 0037, 1% = 0.00072). These findings indicate that genes on chromosome 13 may play an important role in the development of atopy or asthma across various populations.     

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

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

Genetic analysis of the linkage between chromosome 11q and atopy

Previous work has suggested that there is a genetic predisposition for the development of both asthma and atopy. A recent study has also shown that there is a striking link between chromosome 11q and the IgE response underlying asthma and rhinitis. To further assess the linkage between chromosome 11q and atopy, we have studied nine families of two and, in many instances, three generations with the index case having asthma and/or atopy. Using two restriction fragment length polymorphism probes associated with the regions 11q12-q13.2, namely PYGM and INT2, we have been unable to confirm a significant link between this region of chromosome 11q and atopy as defined by a positive skin-prick test and/or a raised specific IgE and/or a raised total IgE.     

Genetic analysis using DNA polymorphism of the linkage between chromosome 11q13 and atopy and bronchial hyperresponsiveness to methacholine.

Previous studies have suggested that there is a genetic predisposition for the development of asthma and atopy. A recent study has also demonstrated that there is a striking link between chromosome 11q and the IgE response underlying asthma and rhinitis. To assess the linkage between chromosome 11q (region D11S97) and atopy or bronchial hyperresponsiveness (BH), we have studied nine families of two and, in many instances, three generations with the index case having asthma and/or atopy. With variable number of tandem repeat analysis with the probe, p lambda-MS.51, we have been unable to confirm a significant link between region D11S97 of chromosome 11q and either atopy or BH to methacholine. We have demonstrated that atopy and BH produce similar log of odds scores with linkage analysis at each recombination fraction from 0.001 to 0.5 with both Hinf1 and Taq1 restriction digests and that the use of either a positive skin prick test or positive RAST as a definition of atopy does not significantly alter the log of odds score.     

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

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

Chromosome 11q13 and atopic asthma

Asthma is a complex syndrome in which bronchial inflammation and smooth muscle hyperactivity lead to labile airflow obstruction. The commonest form of asthma is that due to atopy, which is an immune disorder where production of IgE to inhaled antigens leads to bronchial mucosal inflammation. The ultimate origins of asthma are interactive environmental and genetic factors. The genetics is acknowledged to be heterogeneous, and one chromosomal region of interest and controversy has been 11q13. To clarify the nature of the chromosome 11q13 effect in atopy and asthma, we conducted a genetic association study in subjects with marked atopic asthma and matched controls, which incorporated the study of 13 genetic variants over a distance of 10-12 cM and which took account of detailed immune and clinical phenotyping. Association with high IgE levels was limited to the interval flanked by D11S1335 and CD20 in a 0.8-Mb interval and was greatest for variants of Fc epsilonRIbeta and HTm4; these variants also associated with asthma (recurrent wheeze with labile airflow obstruction and need for regular inhaler treatment). At the more telomeric marker, D11S480, variants associated with asthma, but not with high IgE levels. The data might support the possibility of multiple loci relevant to atopic asthma on chromosome 11q13.     

Linkage between severe atopy and chromosome 11q13 in Japanese families

Atopy, characterised by allergic asthma and rhinitis, is due to increased IgE responses to common aeroallergens. An Oxford group has described maternal inheritance of atopy, where there is significant linkage between IgE responsiveness and a VNTR marker D11S97 and a CA microsatellite within a candidate gene, the high affinity IgE receptor β subunit(FcεRIβ), on chromosome 11q. Attempts at independent replication have produced conflicting results. We therefore recruited 270 atopic asthmatic probands in a Japanese community population for genetic linkage analysis. Four families, each with more than 15 meioses and a clear phenotype for atopy, were selected for genetic analysis. Atopy was defined as presence of all of raised total IgE, positive RAST and skin tests to three or more aeroallergens; non-atopy, as absence of all these criteria. Linkage analysis showed a maximum two-point lod score of 9.35 for D11S97 and FcεRIβ under the assumption of unequal rates of maternal and paternal recombination. Two families showed close genetic linkage with FcεRIβ with a pattern of maternal inheritance. These results from a Japanese population provide further evidence for genetic linkage between severe atopy and chromosome 11q13 and the likelihood of genomic imprinting at the locus.     

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

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

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.     

Linkage to atopy on chromosome 19 in north-eastern Italian families with allergic asthma

BACKGROUND: Allergic asthma is a multifactorial disease for which there is a widely assessed, although poorly understood, genetic involvement. Genome-wide screens reported evidence for linkage of allergic asthma-related phenotypes to several chromosomal locations. Markers on chromosome 19 have been linked to allergic asthma phenotypes in different populations in independent studies. OBJECTIVE: The aim of this study was to perform a genetic linkage analysis on chromosome 19 to search for DNA markers linked to phenotypes related to allergic asthma. METHODS: Using non-parametric multipoint linkage analysis on a total of 22 random DNA markers in 2 stages, a sample of 111 families (542 subjects) from north-eastern Italy, recruited through an asthmatic allergic proband, was investigated. Phenotypes examined were: clinical asthma, total serum elevated IgE, skin prick test positivity, bronchial hyper-responsiveness, and atopy defined as skin prick test positivity and/or elevated IgE. Simulation studies were performed to confirm the significance of the results. RESULTS: A novel linkage of atopy and skin prick test positivity to marker D19S601 (19q13.3) was found. Modest evidence for linkage of atopy, skin prick test positivity, and IgE was also found to marker D19S591 (19p13.3). Simulation analysis for atopy gave an NPL-Z > 3.326 in 2 replicates out of 1000 (P = 0.002) for D19S601, and an NPL-Z > 2.56 in 16 replicates out of 1000 (P = 0.016) for D19S591. CONCLUSIONS: On chromosome 19, suggestive linkage of atopy and skin prick test positivity with marker D19S601 (19q13.3) and modest evidence of linkage of marker D19S591 (19p13.3) to the atopic phenotypes investigated were found. These results suggest that these regions may contain susceptibility loci associated to atopic phenotypes.     

Chromosome 7p linkage and GPR154 gene association in Italian families with allergic asthma

BACKGROUND: Several genome scans have reported linkage of markers on chromosome 7p with asthma and related phenotypes in different populations. A fine mapping in Finnish and French-Canadian populations has associated the GPR154 gene (also known as G-protein-coupled receptor for asthma susceptibility, GPRA) with elevated IgE or asthma. OBJECTIVE: To confirm chromosome 7p linkage and candidate gene association in Italian families with atopic asthma. METHODS: In a two-phase approach, we first performed a linkage analysis of chromosome 7, and then a family-based association study on the GPR154 gene for allergic asthma phenotypes in the Italian population. RESULTS: The screening of 117 families with 19 microsatellite markers showed potential linkage for elevated IgE (P<0.002 at 22 cM from p-ter), asthma (P<0.005 at 44 cM), or atopy (P<0.005 at 54 cM). In the second phase of the present study, candidate gene GPR154, which is located in the phase one-linked region, was investigated in 211 families with seven single nucleotide polymorphisms (SNPs) that tag most haplotype variability, by the pedigree disequilibrium test. Elevated IgE levels were associated with two GPR154 gene SNPs (SNP 546333, P=0.0046; rs740 347, P=0.006), and with haplotypes in the global test (P=0.013). Haplotype analysis performed in nuclear families having at least 1 asthmatic parent showed a significant association with asthma (P=0.0173), atopy (P=0.0058), SPT (P=0.0025), and bronchial hyper reactivity (P=0.0163). CONCLUSION: These results support a susceptibility locus for asthma and related phenotypes on chromosome 7, and are in agreement with recent reports suggesting that a common susceptibility factor for atopic manifestations in asthma is likely conferred by the locus containing the GPR154 gene.     

Linkage analysis of the 5q31-33 candidate region for asthma in 240 UK families

Atopy and asthma are complex genetic diseases resulting from the interactions of a number of genetic and environmental factors. We had previously reported allelic association between the IL9 marker on chromosome 5q31-33 and atopy. In order to further investigate the role of susceptibility genes on 5q31-33 in the development of atopy and asthma we have studied 240 UK families comprising 131 families selected at random, 60 multiplex families with affected sib pairs, and 49 single proband nuclear families. Polymorphic markers on 5q31-33 were genotyped and both single and multipoint linkage analysis was undertaken using the BETA program. We have used both affection status and quantitative scores for atopy and asthma for phenotypic variables, combining data into scores for asthma and atopy. The strongest suggestion of linkage using multipoint analysis was centred around D5S410 with a maximum Lod of 1.946 at location 171.3 cM and a standard error of 3.3 for the asthma quantitative score. There was no evidence of linkage with atopy, the atopy quantitative score or total serum IgE.     

Association and functional relevance of E237G, a polymorphism of the high-affinity immunoglobulin E-receptor β chain gene, to airway hyper-responsiveness

BACKGROUND: The hyper-sensitivity reaction of IgE, with its high-affinity receptors (FcepsilonRI), is central to the phenomenon of atopic diseases. OBJECTIVE: To evaluate the genetic effects of non-synonymous single-nucleotide polymorphisms (SNPs) of FcepsilonRI on intermediate phenotypes of asthma, i.e. atopy and airway hyper-responsiveness (AHR), in the Korean general population. SUBJECTS AND METHODS: Atopy and AHR were evaluated in a cohort of 2055 subjects, aged 10-18 years, using skin prick tests (SPTs) for common aeroallergens and total serum IgE and methacholine bronchial provocation tests. All FcepsilonRI-alpha, FcepsilonRI-beta, and FcepsilonRI-gamma gene exons of 24 healthy subjects were sequenced to locate informative non-synonymous SNPs (minor allele frequency>2%). Informative SNPs were then scored, using the high-throughput single base extension method. Relative risk (RR) was determined by multiple logistic regression analysis, after adjusting for confounding factors. The functional relevance of non-synonymous SNPs was analysed using the sorting intolerant from tolerant (SIFT) program. RESULTS: The SNP search found only one informative non-synonymous SNP in FcepsilonRI-beta: E237G (minor allele frequency=0.21). The positive rate of AHR was lower among subjects with the 237*E allele than among those with 237*G [RR (95% confidence interval)=0.41 (0.19-0.89); P=0.01]. However, the E237G substitution was not associated with either a positive SPT response or total serum IgE levels. Sequence evolution analysis predicted that the E237G variation is an intolerant amino acid substitution, with functional importance. CONCLUSION: In the Korean general population, AHR is significantly associated with the E237G polymorphism of FcepsilonRI-beta, which results in an intolerant amino acid substitution.     

Association of the FcepsilonRIbeta gene with bronchial hyper-responsiveness in an Italian population.

A study of two DNA polymorphisms (i2 RsaI, E237G) in the gene for the beta subunit of the IgE high affinity receptor (FcepsilonRIbeta) was performed in 168 Italian families with atopic asthmatic children. The prevalence of the E237G allele in the Italian population was 4%, so this polymorphism was unsuitable for this study. The i2 RsaI polymorphism minor allele frequency was 44%, and it had a PIC value of 0.37. Linkage analysis indicated a significant allele sharing in affected sib pairs for bronchial hyper-responsiveness (BHR, p=0.048), but not for allergic asthma. These data indicate an association of bronchial hyper-responsiveness with the FcepsilonRIbeta gene.     

Association study using combination analysis of SNP and STRP markers: CD14 promoter polymorphism and IgE level in Taiwanese asthma children

Chromosome 5, especially the 5q31-33 region, may contain one or more loci to control total serum IgE as well as asthma and bronchial hyperresponsiveness. To investigate the regions related with IgE level in chromosome 5, we performed a case-control association study on 105 high-IgE-level and 85 normal-IgE-level asthmatic children using 43 microsatellite markers that span the whole chromosome 5 with 5 cM intervals. One of microsatellite marker, D5S2011, had significantly different allele frequency between the two asthmatic groups. E allele (143 bp) of the D5S2011 marker was more frequent in high-IgE asthmatics. CD14 is the candidate gene of atopy and asthma and is distant from D5S2011 by about 1 Mb. We analyzed the SNP genotypes in the CD14 gene region alone and in combination with microsatellite marker D5S2011. The CD14/–2984 polymorphism but not the CD14/–159 is associated with IgE level in Taiwanese asthmatic children. The CD14/–159 allele was observed only to be associated with IgE level when –159T was part of a haplotype containing a D5S2011 E allele. The combination analysis using SNP and STRP markers provided a novel method for increasing detection power in candidate gene association studies.     

Absence of linkage between 5q markers and serum IgE levels in four large atopic families

Background Both genetic and environmental influences have been suggested to control the immunoglobulin (Ig)E response to allergens and, as a result, provide susceptibility to atopic disease. Two recent reports suggested that a major gene controlling basal IgE levels in humans was transmitted in a pattern consistent with autosomal recessive inheritance and was located on the long arm of chromosome 5 in the interleukin (IL)-4 gene complex. Objective The purpose of this report is to evaluate evidence for linkage of IgE with polymorphic genetic markers in the candidate region of 5q in four large pedigrees originally selected for studies of atopy. Method Four large, highly characterized pedigrees in which IgE levels had been determined and genotypes at markers in the 5q candidate region were evaluated using both lod score and sib pair methods of analysis. Results In these pedigrees, we reject close to moderate hnkage (up to 5 cM) of an IgE locus with markers on 5q. Conclusion The genetic aspects of IgE regulation and its role in atopy remain controversial. The data suggest that should major genes be involved in the inheritance of atopy susceptibility, they are likely to be multiple in number and likely to involve interaction with other (exogenous) environmental exposures.     

Mutation screening of interferon regulatory factor 1 gene (IRF-1) as a candidate gene for atopy/asthma.

BACKGROUND: IL-4 gene cluster on chromosome 5 contains several candidate genes for atopy and asthma. Several independent studies have shown evidence for linkage between the markers flanking IL-4 gene cluster and asthma and/or asthma-related traits. Interferon regulatory factor 1 (IRF-1) is located approximately 300 kb telomeric to IL-4 and recent study reveals that IRF-1 deficiency results in an elevated production of Th2-related cytokines and a compensatory decrease in the expression of native cell- and Th1-related cytokines. OBJECTIVE: To determine if there are any mutations associated with the development of atopy and asthma present in the coding exons and 5' flanking region of the IRF-1 gene. METHODS AND RESULTS: We have screened the promoter and coding regions of the IRF-1 gene in atopic asthmatics and controls by SSCP method. We found three novel nuclear variants (the -300G/T and 4396 A/G polymorphisms and the 6355G > A rare variant) in the IRF-1 gene. No variants causing amino acid alterations of IRF-1 were detected. The -300G/T polymorphism was in nearly complete linkage disequilibrium with the 4396 A/G polymorphism. An association between the 4396 A > G polymorphism and atopy/asthma was examined by transmission disequilibrium test in 81 asthmatic families. Either of 4396 A or 4396G alleles was not significantly preferentially transmitted to atopy- or asthma-affected children. CONCLUSION: The IRF-1 gene is less likely to play a substantial role in the development of atopy and asthma in the Japanese population.