Association study of mast cell chymase polymorphisms with atopy

BACKGROUND: Atopic disorders are the result of complex interactions between genetic and environmental factors. Associations analyses between the promoter polymorphism rs1800875 in the mast cell chymase gene (CMA1) and atopy-related phenotypes have yielded inconsistent results. METHODS: We sequenced the CMA1 locus in 24 unrelated healthy individuals with serum IgE levels <50% percentile and 24 individuals with atopic eczema and serum IgE levels >90% percentile. Seven CMA1 single nucleotide polymorphisms (SNPs) were evaluated for evidence of associations with atopic phenotypes within a large population of German adults (n = 1875). Subjects were phenotyped by standardized questionnaires and interviews, skin prick testing and serum IgE measurements. Genotyping was performed using MALDI-TOF MS (Matrix-Assisted Laser Desorption Ionization-Time of Flight mass spectrometry). RESULTS: Promoter polymorphism rs1800875 was significantly associated with atopic eczema. No associations between any other single SNP and atopic phenotypes could be detected. Haplotype reconstruction revealed four of 128 possible haplotypes reaching estimated frequencies of 3% or more. Two of these haplotypes showed a borderline-significant association with atopic eczema, which did not remain significant after correction for multiple testing. CONCLUSIONS: Results confirm previous observations of a significant association between the CMA1 promoter polymorphism rs1800875 and atopic eczema, but not with serum IgE levels, and support the hypothesis that CMA1 serves as candidate gene for atopic eczema.     

Interleukin-4 gene promoter polymorphism [C590T] and asthma in Kuwaiti Arabs

BACKGROUND: Recent studies have demonstrated an association of the T allele of a promoter polymorphism [C590T] of interleukin-4 (IL-4) gene with asthma/atopy in the US and Japanese populations, but data from the UK and Australian families failed to find an association. We have investigated the association of this [C590T] promoter polymorphism in Kuwaiti Arabs with asthma. METHODS: This study included 184 subjects (84 asthmatics and 100 non-asthmatics, 47 of whom were totally unrelated normal healthy controls with no history of asthma/atopy in three generations of near relatives). The [C590T] promoter polymorphism of the IL-4 gene was analyzed by a polymerase chain reaction-restriction fragment length polymorphism method using the restriction enzyme AvaII. RESULTS: The frequency of the T allele was found to be 0.79 in asthmatics, 0.75 in non-asthmatic first-degree relatives and 0.76 in unrealted controls in Kuwaiti Arabs. No significant difference was detected in the distribution of the three genotypes (TT, CT and CC) between the asthmatic, non-asthmatic relatives and the unrelated controls. The incidence of co-existing phenotypes e.g. hay fever, eczema and a positive skin prick test was significantly higher in asthmatics than in the non-asthmatics irrespective of the [C590T] genotype. However, within the asthmatic group, a higher incidence of eczema was detected in asthmatics with a heterozygous CT genotype compared to the asthmatics with a TT genotype. CONCLUSIONS: Our results do not show an association between [C590T] promoter polymorphism of the IL-4 gene and asthma in Kuwaiti Arabs. Our results are in keeping with the reports from the UK and Australian families (no association) but in contrast to the findings from US and Japanese populations (an association reported).     

The cysteinyl-leukotriene type 1 receptor polymorphism 927T/C is associated with atopy severity but not with asthma

BACKGROUND: The cysteinyl-leukotriene receptor type 1 (CysLT1) mediates the bronchoconstrictor and pro-inflammatory actions of cysteinyl-leukotrienes (LTC4, LTD4, LTE4) in asthma and is the molecular target of the lukast class of oral anti-leukotriene drugs. We screened the CYSLTR1 gene on chromosome Xq13-21 for coding region polymorphisms, and investigated their associations with allergy and asthma. METHODS: Solid-phase chemical cleavage was used to screen polymorphisms in the coding region of CYSLTR1. A TaqMan allelic discrimination assay was used to genotype a 927T/C SNP and oligonucleotide ligation assays were used to genotype the previously reported 617T/C and 898G/A SNPs of CYSLTR1 in 341 asthmatic families from the UK. Associations with asthma diagnosis, atopic status, serum-specific IgE and severity of allergy and asthma were examined. RESULTS: Family-based association tests showed that the 927 T allele was associated with atopy severity, especially in female subjects, but not with asthma diagnosis or severity, atopic status, bronchial hyper-responsiveness to methacholine or forced expiratory volume in 1 s. CONCLUSION: Mutation screening identified only one polymorphism, 927T/C, in the coding region of the CysLT1 receptor. This polymorphsim is predictive of atopy severity, but not associated with asthma.     

Toll-like receptor 4 polymorphism and severity of atopy in asthmatics

Endotoxin exposure may have a protective effect against asthma and atopy. An Asp299Gly polymorphism in the Toll-like receptor 4 (TLR4) gene reduces responsiveness to endotoxin. This study determined the effect of TLR4 polymorphism on the risk and severity of asthma and atopy. In all, 336 UK Caucasian families with > or = 2 affected sibs (physician's diagnosis of asthma and current medication use) and 179 Caucasians without asthma or a family history of asthma were genotyped using ARMS-PCR. No association of the TLR4 polymorphism was found with the risk of developing asthma, either in parent-affected sibling trios, or in case-control analyses (P>0.05). In the first affected asthmatic siblings, the atopy severity score (based on size and number of positive skin-prick tests and specific IgE) was higher in those with the Asp/Gly or Gly/Gly genotypes (mean 1.8, s.d. 1.1, n=39) compared to those with the Asp/Asp genotype (mean 1.2, s.d. 1.0, n=279) (P=0.003, t-test). No associations were found with total IgE, FEV(1) % predicted, slope of FEV(1) response to methacholine or asthma severity score (P>0.05). This study confirms the previously observed lack of association of TLR4 polymorphisms with asthma. In contrast, the findings suggest that genetically determined hyporesponsiveness to endotoxin may increase atopy severity.     

A polymorphism in the promoter region of the human interleukin-16 gene is not associated with asthma or atopy in an Australian population

BACKGROUND: IL-16 is an immunomodulatory cytokine whose expression is increased in the bronchial mucosa, bronchoalveolar lavage fluid and induced sputum of asthmatic patients. It has been suggested that IL-16 has a regulatory role in the pathophysiology of asthma. A single-nucleotide polymorphism (T(-295)C) has been described in the promoter region of the gene and it has been hypothesized that this polymorphism may be associated with altered levels of IL-16 expression, and account for the increased levels of IL-16 seen in the asthmatic airway. OBJECTIVE: To determine the association between the T(-295)C promoter polymorphism and asthma, disease severity and atopy in a large Australian Caucasian population. METHODS: We used PCR and restriction fragment length polymorphism analysis to establish the allele frequency of the T(-295)C promoter polymorphism in a random Australian Caucasian population (n=176) and to characterize the polymorphism in a large Australian Caucasian population of mild (n=273), moderate (n=230) and severe (n=77) asthmatic patients, and non-asthmatic controls (n=455). Genotype association analyses were performed using chi(2) tests. RESULTS: The polymorphic C allele was present in 19% of the asthmatic population and 21% of the non-asthmatic population. There was no association between the polymorphism and asthma (P=0.153) nor with asthma severity (P=0.417) or atopy (P=0.157) in this population. CONCLUSION: Although it has been hypothesized that the T(-295)C promoter polymorphism may be associated with increased IL-16 gene expression, it is not associated with asthma, disease severity or atopy in this Australian population.     

(CCTTT)n repeat polymorphism in the NOS2 gene promoter is associated with atopy.

BACKGROUND: Several studies have shown that nitric oxide (NO) plays a role in the regulation of the T(H)1/T(H)2 balance, indicating the potential for NO to contribute to the development of atopy and several other allergic diseases, including bronchial asthma. NO synthase 2 (NOS2) is critically involved in the synthesis of NO during several inflammatory states, and the gene encoding NOS2 is located at chromosome 17q11.2-q12, where 2 genome scans have identified a candidate locus for atopy and asthma. OBJECTIVE: The 14-repeat allele of the (CCTTT)(n) repeat polymorphism in the NOS2 promoter region is a powerful enhancer of promoter activity in reporter constructs in vitro. We tested whether this potentially functional allele in the NOS2 gene influences the development of atopy and asthma. METHODS: We studied a total of 497 unrelated Japanese subjects (141 nonatopic healthy controls, 102 atopic healthy controls, 56 nonatopic asthmatic subjects, and 198 atopic asthmatic subjects). The odds ratio (OR) was calculated for atopy and asthma in carriers of the 14-repeat allele through use of logistic regression models. Atopy was defined as a positive specific IgE level to at least 1 of 10 common inhaled allergens. RESULTS: The 14-repeat allele was inversely associated with atopy (OR = 0.42, P < .01). The association remained significant when the model was controlled for asthmatic status (OR = 0.36, P < .01). This allele, however, was associated neither with the development of asthma nor with total serum IgE levels. CONCLUSION: Our findings suggest that the (CCTTT)(n) repeat polymorphism in the promoter of the NOS2 gene that affects promoter activity is a risk factor for the development of atopy, and this genetic effect seems independent of asthma.     

The association between atopy and asthma in a semirural area of Tanzania (East Africa)

BACKGROUND: Atopy is consistently associated with asthma, except in a study in Africa. We assessed the association between atopy and asthma in women from a semirural area of Tanzania (East Africa). METHODS: All pregnant women delivering at the district hospital during a 1-year period were recruited (n = 658, 60.6% of those selected). Asthma was investigated by a standard questionnaire and atopy by specific IgE (immunoglobulin E) antibodies to Dermatophagoides pteronyssinus (Der p 1) and cockroach. RESULTS: The prevalence of wheezing chest was 10.7%; of asthma, 3.5%. Levels of specific IgE of >0.35 kU/l (73%) and high levels of total IgE (62% higher than 1000 kU/l) were highly prevalent. Specific IgE antibody levels in sera were not associated with asthma (3.8% of women with negative specific IgE to any antigen had asthma in comparison to 4.0% of women with positive specific IgE; odds ratio [OR] = 1.06, 0.35-3.22). Total IgE was not different between women with asthma and women without asthma (P=0.36). CONCLUSIONS: In tropical regions, the association between allergy and asthma is complex, and specific IgE reactivity to environmental allergens may not be related to asthma.     

Relationship between IgE and specific aeroallergen sensitivity in Alaskan native children.

BACKGROUND: The relationship between atopic disease and serum IgE levels varies among populations and geographic regions. The close association of atopy with IgE may not occur in subarctic populations as it does in developed countries in temperate climates. OBJECTIVE: To evaluate the relationship between total and specific IgE concentrations and clinical atopy in 5- to 8-year-old Alaskan native children. METHODS: Medical record reviews, interviews, physical examinations, serum IgE measurements, and radioallergosorbent testing (RAST) were performed. RESULTS: The IgE geometric mean was 122.1 IU/mL. Fifty-eight percent of patients had IgE levels greater than 70 IU/mL, and 17% had levels greater than 1,000 IU/mL; 14% had RAST values greater than 0.35 kU/L. Both IgE levels greater than 70 IU/mL and greater than 1,000 IU/mL were associated with RAST values greater than 0.35 IU/L (P = .004) and early wheezing (P = .005) but not with current wheezing, asthma, eczema, or a history of allergies. A RAST value greater than 3.51 kU/L was associated with eczema (P = .04) but not with allergies or wheezing. Children with current wheezing were more likely to have allergies (P = .03) but not eczema, an IgE level greater than 70 IU/mL, or a positive RAST value. Children hospitalized with respiratory syncytial virus (RSV) were not more likely than controls to have current wheezing. CONCLUSIONS: Elevated serum IgE concentrations, including levels greater than 1,000 IU/mL, are common among Alaskan native children; positive RAST reactions to aeroallergens are not. The IgE levels do not relate to wheezing, eczema, a history of allergies, or past hospitalization for RSV infection but likely reflect infections other than RSV and environmental factors in subarctic indigenous populations.     

A novel (TG) n (GA) m repeat polymorphism 254 bp downstream of the mast cell chymase (CMA1) gene is associated with atopic asthma and total serum IgE levels

The gene for mast cell chymase (CMA1) is an ideal candidate for investigating genetic predisposition to atopic asthma, as it is an important mediator of inflammation and remodeling in the asthmatic lung. Various studies have examined the association between –1903 G/A polymorphism and allergic phenotypes, but inconsistent results have been obtained. We investigated the association of this SNP and a novel (TG)_n(GA)_m repeat polymorphism (accession no. BV210164) 254 bp downstream of the gene with asthma and its associated traits in a case-control study in two independent cohorts recruited from the Indian population. A significant association was observed for the (TG)_n(GA)_m repeat with asthma (p<0.05) in both the cohorts. Although no association was observed for the –1903 G/A SNP with asthma, a significant association was observed between the genotypes and serum IgE levels (p=0.003 and 0.0004 for cohort A and B). When haplotypes were compared between patients and controls, the haplotype G_43 was found at higher frequency in controls (p=0.05). Also, on comparing major haplotypes (>5%) with respect to log total serum IgE levels, a significant difference was obtained (p=0.018 and p=0.046 for cohorts A and B). These results suggest that the CMA1 gene contributes to asthma susceptibility and may be involved in regulating IgE levels in atopic asthma.     

Extraordinarily high serum IgE levels and consequences for atopic phenotypes.

BACKGROUND: IgE plays a central role in allergic diseases. Recent studies have postulated an association between serum IgE levels and bronchial asthma. OBJECTIVE: To examine the differences of atopic phenotypes in a group of individuals with extraordinarily high serum IgE levels (>10,000 kU/L) compared with children with moderately elevated IgE levels (400-1,000 kU/L). METHODS: We investigated 20 children with serum IgE levels greater than 10,000 kU/L and compared them with 56 age-matched children with serum IgE levels of 400 to 1,000 kU/L regarding prevalences of atopic dermatitis, bronchial asthma, allergic rhinoconjunctivitis, allergic sensitization, and history of anaphylaxis. RESULTS: The mean eczema severity score as determined by the Severity Scoring of Atopic Dermatitis Index was 56 vs 18 (P < 0.003), and anaphylactic reactions were reported in 20% of the group with very high serum IgE levels vs 7% in the group with moderate levels (P < 0.02). Sensitization to both aeroallergens and food allergens was detected in 80% of the group with very high serum IgE levels vs 32% of the group with moderate levels (P < 0.001). CONCLUSIONS: Our results indicate that children with very high serum IgE levels are at risk for anaphylactic reactions and more severe atopic dermatitis.     

Associations of the IL12B promoter polymorphism in longitudinal data from asthmatic patients 7 to 42 years of age

BACKGROUND: The IL12B gene encodes the p40 chain of IL-12, a proinflammatory cytokine that antagonizes TH2 expression and hence may play a critical role in the pathogenesis of airway inflammation observed in asthma. A promoter polymorphism of the gene was recently shown to be associated with asthma severity in children but only in heterozygotes. OBJECTIVE: The aim of the present study was to test the hypothesis that the IL12B promoter polymorphism is associated with asthma susceptibility, severity, and related phenotypes in a cohort with longitudinal phenotypic data, from childhood to adulthood. METHODS: Four hundred one 7-year-old children (106 control children, 295 asthmatic children) and 83 10-year-old children with severe asthma were recruited from a 1957 birth cohort. Atopic status and respiratory functions were determined at ages 7, 10, 14, 21, 28, 35, and 42 years. At age 42 years, blood samples were taken from 244 individuals for genotyping and the determination of plasma IgE levels and PHA- and house dust mite-induced IFN-gamma responses. Genotyping was done by the PCR restriction fragment length polymorphism method, using Alu I, and confirmed in 10% of the samples by direct sequencing. RESULTS: The IL12B genotypes were not associated with asthma susceptibility, severity, or atopy at ages 7 and 42 years. Total serum IgE levels at age 42 of men with at least one CTCTAA allele were higher than those homozygous for the GC allele (P = .042), whereas no difference was observed for women. At all ages, female subjects with at least 1 copy of the CTCTAA allele had lower mean percent predicted levels of FEV1 and FVC compared with those without this allele; these differences were significant at ages 10 and 14 years (P < .05) and in the asthmatic subgroup at age 7 years (P = .001). CONCLUSIONS: In this long-term study of asthmatic subjects with comprehensive data on asthma severity, we found no evidence to support the presence of a heterozygote effect of the IL12B promoter polymorphism on the level of asthma in early childhood or adulthood. The polymorphism was also not associated with asthma susceptibility, but the CTCTAA allele may have been associated with elevated serum IgE levels in male subjects and reduced pulmonary function in female subjects in early childhood.     

Immunogenetics of atopic asthma: association of DRB1*1101 DQA1*0501 DQB1*0301 haplotype with Dermatophagoides spp.-sensitive asthma in a sample of the Venezuelan population

BACKGROUND: Genes linked to the major histocompatibility complex (MHC), have been implicated in atopic asthma. Asthma is highly prevalent in the Venezuelan population (estimated at 20%) and genetic markers are needed to identify populations at risk and plan intervention strategies. OBJECTIVE: To study the influence of the MHC class I and class II genes in the susceptibility to atopic asthma. METHODS: MHC-class I HLA-A, -C, -B and MHC-class II HLA-DR, -DQ, -DP gene haplotype frequencies were determined in 135 Venezuelan mestizos, 71 belong to 20 atopic asthmatic families and 64 unrelated controls. The index cases were 20 atopic asthmatics with positive skin-prick tests and specific serum immunoglobulin E (IgE) for Dermatophagoides pteronyssinus (Der p) and Dermatophagoides farinae (Der f). To ascertain the genes associated with susceptibility to atopy and/or asthma, two control groups were studied, 41 non-atopic subjects with skin-prick negative test, and undetectable levels of specific IgE and 23 non-asthmatic atopic subjects with detectable specific IgE to Der p and Der f. A linkage analysis was performed in those families with two or more atopic siblings (with or without asthma). RESULTS: MHC-class I genes analysis showed that HLA-Cw7 was absent in the asthmatic patients studied, whereas the frequency of this allele was 14.3% in non-atopic controls (P = 0.0 17, PC = 0.19) and 20.8% in the atopic controls (P = 0.0066, PC = 0.07). MHC-class II gene analysis showed a significant increase of the HLA-DRB1*11 in the asthmatic patients compared with non-atopic controls (allele frequencies of 25.6 vs 4.4% P = 0.0017, PC = 0.02). There were no significant differences among asthmatic and atopic controls in the frequency of HLA-DRB1*11 (25.6 vs 17.4%). In contrast, the HLA-DRB1*1101+ haplotypes were significantly higher in asthmatics compared with atopic and non-atopic controls (19.6% vs 2.2% vs 2.3%, PC<0.05). The HLA-DRB1*1101, DQA1*0501, DQB1*0301 haplotype was found significantly increased in the patients vs non-atopic controls (15.4 vs 1.1%, PC< 0.01). The serum levels of specific IgE were detectable in both atopic asthmatics and atopic controls; however, it was higher in atopic asthmatics vs atopic controls Der p (median, 58.7 vs 2.7 kU/L, P<0.001) and Der f (median, 46.9 vs 2.7 kU/L, P<0.001). No linkage between MHC genes and mite-atopy could be documented on informative families with two or more atopic siblings. CONCLUSIONS: We have identified an association between the haplotype HLA-DRB1*1101, DQA1*0501, DQB1*0301 and atopic asthma that confers susceptibility to develop mite-sensitive asthma to atopics (relative risk, RR 8.2), and to non-atopic controls (RR = 15.8) that carry this haplotype. Conversely, the allele HLA-Cw7 was absent in the asthmatics studied and had higher frequencies in the atopic (RR = 0.05) and non-atopic (RR = 0.08) controls. Thus, it may have a protective role for developing atopic asthma in the population studied.     

The -590C/T and -34C/T interleukin-4 promoter polymorphisms are not associated with atopic eczema in childhood

Susceptibility to the development of asthma and other atopic diseases is known to have a genetic component. To date, several studies have linked chromosome 5q31 to asthma and atopy in human beings. This region harbors a cluster of cytokine and growth factor genes, IL-4 presenting as a prime atopy candidate gene, inasmuch as it plays a pivotal role in the atopy pathway. Our approach was to identify polymorphisms within the promoter regions of IL-4 and test their association with atopic eczema. Polymorphisms were typed in a cohort of 76 small nuclear families and 25 triads with childhood atopic eczema. The genotypes were used to test for linkage in the presence of association with atopic eczema. A new polymorphism, -34C/T, was identified and studied with a known polymorphism, -590C/T. On its own, each polymorphism showed no association with atopic eczema. The 2 polymorphisms were used to generate haplotypes, and a significant result was found for the -590C/-34C haplotype. However, after Bonferroni correction for multiple testing, the association became nonsignificant. Neither polymorphism predisposes to early-onset atopic eczema by itself, but suggestive linkage was found for the -590C/-34C haplotype in this study.     

Increased total serum IgE levels in patients with asthma and promoter polymorphisms at CTLA4 and FCER1B.

BACKGROUND: Increasing evidence indicates that total serum IgE levels are largely determined by genetic factors, and we recently established that the -109C/T promoter polymorphism at FCER1B is a genetic factor that affects total serum IgE levels. The gene encoding cytotoxic T lymphocyte antigen 4 (CTLA4) is another candidate factor in high IgE responsiveness, because B7-CD28/CTLA4 interaction can promote the differentiation and development of the T(H)2 lymphocyte subset. OBJECTIVE: We intended to determine whether CTLA4 is associated with increased levels of total serum IgE or with the development of asthma or atopy. METHODS: We performed a case-control study involving 339 patients with asthma and 305 healthy control subjects, of whom 226 of the patients with asthma and 219 of the healthy control subjects had previously been genotyped for the -109C/T promoter polymorphism at FCER1B. In the current study, we genotyped 2 polymorphisms in the CTLA4 gene, one involving the promoter (-318C/T) and the other involving exon 1 (+49A/G), in addition to the FCER1B promoter polymorphism. RESULTS: Patients with asthma who were homozygous for the -318C allele at the CTLA4 promoter region had higher levels of total serum IgE than patients with asthma carrying the -318T allele (P =.00470). The analysis of -318C/T (at CTLA4) and -109C/T (at FCER1B) promoter polymorphisms showed a significant correlation between the combined genotypes and increased levels of total IgE in patients with asthma (P =.000014). In contrast, no correlation between total serum IgE levels and -318C/T or +49A/G genotypes was detected in 305 healthy control subjects. There was no evidence indicating an association between a putative allele for asthma or atopy and alleles at any of the CTLA4 polymorphic loci. CONCLUSION: Our findings suggest that promoter polymorphisms of both CTLA4 and FCER1B are genetic factors that influence total serum IgE levels in patients with asthma. This supports the theory that variance in total serum IgE levels in patients with asthma is determined by mutations in multiple genes, each of which has a relatively small effect on the phenotype.     

IL-10基因启动子多态性与皖南地区汉族人群支气管哮喘的相关性研究

目的:探讨IL-10基因启动子-1082G/A(rs1800896)、-819C/T(rs1800871)、-592C/A(rs1800872)位点多态性与安徽皖南地区汉族人群支气管哮喘的相关性。方法:采用病例-对照方法,用聚合酶链反应及直接基因测序法比较183例支气管哮喘组与151例正常人对照组之间基因型、等位基因频率的差异。结果:哮喘组IL-10基因启动子-1082G/A、-592C/A位点基因型与对照组相比有差异(P<0.05),其等位基因型频率在哮喘组和对照组间亦有差异(P<0.05)。而-819C/T位点基因型及等位基因型频率在哮喘组和对照组间均无差异(P>0.05)。结论:IL-10基因启动子rs1800896(-1082G/A)位点和rs1800872(-592C/A)位点的多态性可能与安徽皖南地区汉族哮喘相关;而rs1800871(-819C/T)位点的多态性可能与安徽皖南地区汉族哮喘无相关。     

IgE Concentrations Measured by PRIST® in Serum of Healthy Adults and in Patients with Respiratory Allergy

In order to establish reference values for total serum IgE in an adult non-atopic population, 175 individuals. 17–85 years of age. were investigated. The usefulness of a sensitive method (PRIST®) for serum JgK determinations in discriminating atopy from mm-atopic conditions in a Her go logical routine diagnosis was elucidated by investigating 445 patients with symptoms of asthma, rhinitis, urticaria and eczema. Comparisons were made with case histories. in viva tests and circulating IgE antibodies.
The geometric mean for serum IgE in the reference material was 13.2 kU/1 with a 2 SD range of 1.53 to 114 kU/1. No significant difference between age groups or sexes was observed. In patients classified as non-atopic and pronounced atopic, the geometric mean values for IgE were 40, 123 and 458 kU/1 respectively. The IgE level correlated with number of allergens positive in RAST and with skin test results.
It is concluded that IgE determinations are of great help in discriminating atopic conditions from other diseases with similar symptoms. A serum IgE value above 100 kU/1 in a patient is strong evidence for the presence of an atopic disease while a value below 20 kU/l indicates that the symptoms are due to intrinsic or infectious disease.     

Does maternal immunoglobulin E decrease with increasing order of live offspring? Investigation into maternal immune tolerance

BACKGROUND: Identifying the protective effect of a higher number of siblings is a significant finding in understanding the aetiology of allergic sensitization, asthma, eczema, and hayfever. Knowledge about causes behind the sibling effect may allow us to prevent atopic manifestations. OBJECTIVE: We tested the hypothesis that rising order of live offspring increases maternal immune tolerance (immune non-reactivity) against allergens. To this end, we investigated whether maternal IgE levels are associated with the number of live offspring. METHODS: In a cohort of 1456 newborns recruited between January 1989 and February 1990 on the Isle of Wight, UK, we determined maternal and cord serum IgE, and the order of live offspring. The data were analysed by means of linear and path analysis. RESULTS: Maternal and cord serum IgE were available in 820 mother-infant pairs with birth order information. We found that the number of live offspring significantly reduces maternal IgE. The decline was more prominent in mothers with atopy (n=268). The geometric means of IgE after the first, second, and third or higher delivery were 74.4, 66.6, and 43.0 kU/L, respectively. Findings of path analysis suggest a significant direct effect of birth order on maternal IgE, but no direct effect of birth order on cord serum IgE. CONCLUSION: The findings support that maternal immune tolerance against allergens may increase with increasing order of live offspring and thus pass on a lower risk of developing atopy in children of higher birth order.     

The association of family size with atopy and atopic disease

Background Studies in children have shown that family size is negatively associated with atopy and atopic disease. Objective To describe the association of family size with atopy and atopic disease in young adults. Methods A randomly selected sample of 1159 men and women aged 20–44 years provided information on respiratory symptoms, hay fever and eczema. Blood samples were taken for assessment of total IgE and specific IgE to house dust mite, grass, cat, Cladosporium and birch. The association of family size and birth order with respiratory symptoms, atopy and total IgE was assessed by multiple logistic and linear regression. Results There was a negative association between family size and the reporting of ‘wheeze with breathlessness’ (adjusted odds ratio for an increase of one sibling 0.85; 95% confidence interval 0.75–0.98), ‘wheeze without a cold’ (adjusted odds ratio for an increase of one sibling 0.85; 95% confidence interva l0.75–0.98) and ‘asthma attacks’ in the last 12 months (adjusted odds ratio for an increase of one sibling 0.77; 95% confidence interval 0.61–0.97), current ‘hayfever and nasal allergies’ (adjusted odds ratio for an increase of one sibling 0.84; 95% confidence interval 0.75–0.94) and sensitization to grass (adjusted odds ratio for an increase of one sibling 0.87; 95% confidence interval 0.76–0.99). Birth order was negatively associated with ‘hayfever and nasal allergies’ only. A decreased risk of sensitization to grass in those from large families did not fully explain the negative association between family size and hayfever. No statistically significant (P > 0.05) association of family size or birth order with the reporting of other respiratory symptoms, eczema, sensitization to the other allergens or total IgE was observed. Conclusion There is a negative association between family size and some symptoms suggestive of asthma, ‘hayfever and nasal allergies’ and sensitization to grass in young adults. There is no consistent, significant association between family size and eczema, total IgE or sensitization to other allergens.     

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.