Association between asthma and an intragenic variant of CC16 on chromosome 11q13

The β subunit of high affinity immunoglobulin E (IgE) receptor (FcɛRIβ) and the Clara cell derived inflammatory molecule, CC16 have been cited as candidate genes for atopic asthma on chromosome 11q13. A genetic association study was performed with an intragenic microsatellite repeat of CC16 gene on chromosome 11q12–13 in relation to atopic and non-atopic asthma. Whereas variants of FcɛRIβ at chromosome 11q13 show association with atopy and asthma, no significant association was found between asthma and CC16 genotypes irrespective of atopic status. These data support the candidacy of FcɛRIβ rather than CC16 for the atopic asthma locus on chromosome 11q.     

Association between high serum total IgE levels and D11S97 on chromosome 11q13 in Japanese subjects.

The genetic linkage of atopy to chromosome 11q13 through maternally derived alleles has been previously reported. Linkage analysis in Japanese families did not confirm the existence of a major gene for atopy at this locus under the model of autosomal dominant inheritance. However, we observed a significant association between serum total IgE levels and genetic markers at this locus both in 14 Japanese atopic families and in 120 unrelated Japanese subjects. We detected eight alleles at the D11S97 locus and eight alleles in the CA/GT repeat region in the fifth intron of the Fc epsilon RI beta gene. A significantly increased frequency of the D11S97/PstI 0.96 kb allele was observed in the chromosomes of the subjects with high serum total IgE levels both in the family study (p < 0.001) and in the population study (p < 0.05). However, multipoint linkage analysis again did not show any evidence for the existence of a major gene regulating atopy on chromosome 11q13 with location scores to -35 under the model of maternal inheritance. Evidence against linkage was confirmed by the non-parametric linkage analysis, using the affected pedigree member method. Also, there was no substitution of isoleucine for leucine in the fourth transmembrane domain of Fc epsilon RI beta (Leu181), which was reported to be responsible for a subset of atopy in the British population. Therefore, the association of serum total IgE levels with chromosome 11q13 indicates that a gene or genes at this locus may contribute to the expression of high IgE levels in the Japanese population as well as in the British population, but the heterogeneity of the genetic regulation of serum total IgE levels is evident between the two populations.     

Lack of linkage between atopy and locus 11q13

Atopy as defined in terms of IgE responsiveness was reported to be controlled by a single gene in British families, and this concept was further supported by a significant linkage between atopy and restriction fragment length polymorphism (RFLP) detected by a DNA probe specific to chromosome 11q13. To confirm this observation in a Japanese population, segregation and linkage analyses were done in four large families. Although segregation patterns of atopy were in agreement with the pattern of autosomal dominant inheritance, there was no significant linkage between atopy and locus 11q13. Alterations in the definitions of atopy did not affect the results. These findings suggested the presence of heterogeneity in genetic elements of atopy, even though atopy may be determined mainly by a single dominant gene.     

Familial atopy in Australian pedigrees: adventitious linkage to chromosome 8 is not confirmed nor is there evidence of linkage to the high affinity IgE receptor

Atopy frequently displays autosomal dominant inheritance and recent studies have favoured genetic linkage between atopy and the human chromosome 11q13. We have studied 12 extended families with aggregation of atopy consistent with autosomal dominant inheritance. The families have been studied for linkage of asthma and atopy to loci on chromosome 8p following the observation that one family suggested preliminary evidence of linkage to an anonymous hypervariable locus cloned from a DNA fingerprint and mapped to 8pter-p22. Subsequent analysis shows this putative linkage to be adventitious as the remaining 11 families do not support linkage between atopy and 8p, We have analysed the same families for evidence of linkage of atopy to loci on 11q13. In these families there is no evidence of association between atopy and the 11q loci stronger than that expected by chance alone; furthermore there is no suggestion subpopulation of these families display linkage between atopy and the loci. In addition neither the 8p loci nor the 11q loci exhibit evidence of linkage to atopy by affected sib-pair analysis. This also conflicts with previously published data for 11q.     

Factors confounding genetic linkage between atopy and chromosome 11q

The results of testing for linkage between atopy and the chromosome 11 marker D11S97 is shown for all the 723 subjects genotyped by us up to January 1992. Lod score estimations were confounded by the high population prevalence of atopy, maternal inheritance of atopy at the 11q locus, genetic heterogeneity, and excess of atopy in families not ascertained through a single proband. Affected sib-pair analysis shows evidence for linkage which is not dependent on the definition of atopy or model specification. We suggest that presentation of sib-pair data will be suitable for meta-analysis of the different studies of genetic linkage and atopy.     

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.     

High frequency of IgE receptor FcεRIß variant (Leu181/Leu183) in Kuwaiti Arabs and its association with asthma

The presence of IgE receptor FcεRIβ polymorphism (181/183) was investigated in Kuwaiti asthmatic patients and controls using an allele refractory mutation screening (ARMS) test. The variant sequence (Leu181/Leu183) was detected in 72% (320/442) chromosomes analysed. Homozygous LL genotype was detected in 48% (46/96) asthmatic subjects compared to 31% (39/125) in non-asthmatics. In 11/52 families mothers of the asthmatic children were themselves asthmatic and 3/11 asthmatic mothers had homozygous LL genotype. 80% of the homozygous LL asthmatics showed a positive skin prick test (SPT) compared with 28% of non-asthmatics with the same genotype. In heterozygous NL asthmatics a positive SPT was found in 60% cases compared to 17% in non asthmatics with the same genotype. The incidence of hay fever (HF) and eczema (E) was also found to be higher in homozygous LL asthmatics compared with the non-asthmatics with the same genotype. This study reports a high prevalence of IgE receptor FcεRIβ variants in Kuwaiti Arabs compared with British, Australian and Austrian populations studied before. The association of Leu181/Leu183 variant with asthma in Kuwaitis underlines its significance as a risk factor in manifesting the clinical phenotype in this population.     

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.     

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.     

Genome-wide search for atopy susceptibility genes in Dutch families with asthma

BACKGROUND: Atopy is a phenotype associated with asthma that has a heritable component. However, the role of atopysusceptibility genes in the development and expression of asthma and allergic disorders is not understood. OBJECTIVE: We sought to study the familial aggregation and co-occurrence of atopic phenotypes within family members of patients with asthma and to identify chromosomal regions that may contain genes that regulate different atopic phenotypes. METHODS: In 200 families (n = 1174) ascertained through a proband with asthma, genome-wide screen and linkage analysis was performed for the following atopic phenotypes: (1) specific IgE to common aeroallergens (Phadiatop assay); (2) specific IgE to Der p 1; (3) positive skin test responses to house dust mite; (4) positive skin test responses to 1 or more of 16 allergens; and (5) peripheral blood eosinophils. Results were compared with the linkage results for total serum IgE levels. RESULTS: There was clear familial aggregation of atopy. A high total serum IgE level in combination with a positive Phadiatop result or a normal total IgE level in combination with a negative Phadiatop result was found in 56.1% of the probands and 66.9% of the offspring. Several chromosomal regions that showed evidence for linkage to an atopic phenotype (ie, 2q, 6p, 7q, and 13q) also showed evidence of linkage with total serum IgE (Xu et al. Am J Hum Genet 2000;67:1163-73). Specific regions of interest for atopic traits were also detected on chromosomes 11q, 17q, and 22q. CONCLUSIONS: Atopic phenotypes show familial aggregation, although family members may differ in expression of atopy. Specific chromosomal regions appear to be important in susceptibility to different phenotypes of atopic responsiveness.     

Genetic analysis of atopy in three large kindreds: no evidence of linkage to D11S97

Both genetic and environmental influences have been implicated in the pathogenesis of atopic disease. A recent report suggested that a major gene providing susceptibility to atopy was transmitted in a pattern consistent with autosomal dominant inheritance and evidence was presented that places the disease locus near the D11S97 marker on human chromosome 11q. In this report, we present three large, highly characterized pedigrees in which atopy is transmitted in a pattern consistent with autosomal dominant inheritance. Genotypes at the D11S97 and HLA loci were evaluated using both lod score and sib pair methods of analysis. In these pedigrees, we reject close moderate linkage (up to 10 cM) of atopy with both D11S97 and HLA.     

Asthma and atopy - a total genome scan for susceptibility genes

BACKGROUND: Allergic asthma is an increasingly common disease of complex inheritance. Several studies have suggested candidate regions, but genetic heterogeneity, ethnic differences and varying study designs may in part explain the lack of identified and confirmed susceptibility genes. Investigation of different populations will further clarify the topic. We therefore evaluated allergic asthma and increased total and specific IgE in 39, 45 and 57 sib-pairs from 100 Danish allergy families. METHODS: Affected sib-pairs meeting a narrow phenotype definition were selected for the three phenotypes atopy, allergic asthma and increased total IgE. We performed a total genome scan using 446 microsatellite markers and obtained nonparametric linkage results from the MAPMAKER/SIBS computer program. RESULTS: Our study revealed four candidate regions (MLS > 2) on chromosome 1p36, 3q21-q22, 5q31 and 6p24-p22, and 15 candidate regions (1 < MLS < 2) that may contain susceptibility genes for asthma and atopy. We did not find linkage to the candidate genes TNF-beta, FcER1beta and Il4R-alpha, except for weak support for linkage of the asthma phenotype to TNF-beta (MLS = 1.18). CONCLUSIONS: We found evidence for two new asthma and atopy loci, 1p36 and 3q21-q22, and supported linkage in the Danish population to seven previously reported candidate regions.     

Coding single nucleotide polymorphism in the high-affinity immunoglobulin E receptor b chain (Fc"RI-b) gene is associated with immunoglobulin E receptor-mediated histamine release from basophils

BACKGROUND: Our previous work on linkage analysis showed that histamine release from basophils to anti-IgE stimuli was linked to the gene marker of chromosome 11q13, where the beta chain of the high-affinity receptor for IgE (FcepsilonRI-beta) is located. OBJECTIVE: To evaluate the association between FcepsilonRI-mediated histamine release from basophils and four bi-allelic single nucleotide polymorphisms of the FcepsilonRI-beta gene. METHODS: Phenotypes of asthma, such as maximal histamine release from basophils and atopy, were measured from 80 randomly recruited asthmatic children. Polymorphisms of the FcepsilonRI-beta gene were determined by PCR-based methods. RESULTS: The polymorphism in exon 7, resulting in Glu to Gly substitution, was significantly associated with histamine release from basophils to anti-IgE stimuli, but not with total IgE levels and skin test responses to aeroallergens. CONCLUSION: This study supports a role for the FcepsilonRI-beta gene in the expression of high affinity IgE receptor-mediated histamine release from basophils.     

Confirmation of genetic linkage between atopic IgE responses and chromosome 11q13.

Genetic linkage between atopic IgE responses and chromosome 11q13 (D11S97) has been previously reported in a limited number of extended families. Difficulties of phenotyping in the older family members, poor family structure in some families, and genetic heterogeneity were proposed as possible explanations for the variability in lod scores. To test this finding a second linkage study of 64 young nuclear families was undertaken and gave a two point lod score of 3.8 at theta = 0.07 (assuming theta m = theta f). A test of genetic heterogeneity in the nuclear families shows that atopic IgE responses are linked to this locus in 60 to 100% of families (approximate 95% confidence limits).     

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.     

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)     

Linkage between bronchial responsiveness to methacholine and gene markers of IL-4 cytokine gene cluster and T-cell receptor α/δ gene complex in Korean nuclear families

BACKGROUND: Several candidate genes have been reported to be linked to intermediate phenotypes of asthma in Caucasian populations. OBJECTIVE: To evaluate linkage between phenotypes of asthma and gene markers of high affinity IgE receptor-beta gene (D11S97), IL-4 cytokine gene cluster (IL-4R1), and T-cell receptor alpha/delta gene complex (D14S50) in Korean nuclear families. METHODS: Nuclear families (127 probands and their 130 siblings) for the linkage analysis were ascertained through asthmatic children. Linkages between total serum IgE response, skin responses to common aeroallergens, and bronchial responsiveness to methacholine were performed using a sib-pair approach. RESULTS: The square difference of the slope of the dose-response curve (DRS) between sib-pairs with two IL-4R1 identical alleles was smaller than with one or with neither IL-4R1 identical allele (P = 0.004). As for D14S50, the differences of DRS between sib-pairs with two identical alleles and with one identical allele were smaller than with neither identical alleles (P = 0.01). As for D11S97, no significant differences were observed among the groups with identical alleles of two, one or zero. With regard to total serum IgE levels, no significant linkage was found between this phenotype and the above three gene markers. As for skin responses to common aeroallergens, significant evidence was obtained to establish a linkage between this phenotype and the marker IL-4R1 (P = 0.01). However, no significant linkage was found between this phenotype and the markers D11S97 and D14S50. CONCLUSION: The expression of bronchial responsiveness to methacholine may be influenced by genetic factors in the IL-4 cytokine gene cluster and/or T-cell receptor alpha/delta gene complex, but the genetic influence of the FcepsilonRI-beta gene may be minimal in the expression of bronchial responsiveness in Korean nuclear families.     

Associations of FceεR1-bβ polymorphisms with immunoglobin E antibody responses to common inhalant allergens in a rural population

BACKGROUND: Polymorphisms within the beta subunit of the high-affinity receptor for IgE (Fc epsilon R1-beta ) on chromosome 11q13 have been related to atopy and asthma and the lymphotoxin alpha (LT alpha) gene on chromosome 6 is implicated in asthma. OBJECTIVE: To elucidate the association of polymorphisms in the Fc epsilon R1-beta and LT alpha genes to IgE responses and asthma in a family-orientated rural population. METHODS: A total of 461 adult farmers, who participated in an epidemiological follow-up study on respiratory symptoms among farmers on the Swedish island of Gotland, were examined. The traits assessed included serum total IgE, IgE antibody responses to 21 common inhalant allergens and asthma. RESULTS: The 237G mutation was only detected in seven persons. Atopy was found to be associated with the RsaI-ex7 AB-genotype (OR = 1.9; P = 0.04). The RsaI-ex7 B allele had a significant influence on IgE responses to pollens and dust mites (OR = 5.5; P = 0.03 and OR = 5.2; P = 0.049, respectively). The influence of this allele was stronger when the association towards single dust mite species (Lepidoglyphus destructor) was estimated (OR = 7.1, P = 0.03) and the association increased even more when the major allergen of L. destructor (rLep d 2) was analysed (OR = 11.2, P = 0.02). These associations were independent of sex, age and smoking, and the estimates of RsaI-in2 independent of RsaI-ex7. RsaI-in2, RsaI-ex7 and LT alpha genotypes were unassociated with total serum IgE. No significant difference in the distribution of RsaI-in2, RsaI-ex7 and LT alpha genotypes was found among subjects with atopy or asthma compared to healthy controls. CONCLUSION: This study supports the notion that polymorphisms in the Fc epsilon R1-beta gene have significant effects on IgE responsiveness. Secondly, dust mites in rural populations influence the expression of genes on chromosome 11q13.     

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.