Eotaxin polymorphisms and serum total IgE levels in children with asthma

BACKGROUND: Eotaxin (chemokine, CC motif, ligand; CCL11) is a potent eosinophil chemoattractant strongly implicated in the pathobiology of asthma. Genetic variation at the CCL11 locus has been correlated with serum total IgE, blood eosinophil counts, and circulating eotaxin protein levels in several case-control asthma studies. Family-based association studies of CCL11 genetic variants have not been reported to date. OBJECTIVE: To evaluate 9 common CCL11 single nucleotide polymorphisms (SNPs) in nuclear families ascertained through patients with asthma participating in the Childhood Asthma Management Program study. METHODS: Single nucleotide polymorphism genotyping was performed by using minisequencing and probe hybridization platforms. Family-based association analysis for asthma and 4 asthma-related intermediate quantitative phenotypes was performed by using FBAT. RESULTS: One SNP, -384A>G, was associated with asthma among African American families (P = .01). CCL11 SNPs and haplotypes were not associated with asthma among white or Hispanic families. Two low-frequency alleles in strong pairwise linkage disequilibrium, -426C and IVS2+199A, were associated with lower serum total IgE levels (P = .0006 and P = .009, respectively) in white families, whereas 2 more common variants, -576C and g.4438C, were associated with higher IgE levels in African American families (P = .01-.04). Haplotype analysis in the white cohort provided additional evidence of association with serum total IgE, implicating 2 haplotypes. No single SNP or haplotype associations were observed with blood eosinophil levels, FEV(1), or airway responsiveness. CONCLUSION: These findings provide further evidence that genetic variation at the CCL11 locus is an important determinant of serum total IgE levels among patients with asthma.     

The alpha-chain of high-affinity receptor for IgE (FcepsilonRIalpha) gene polymorphisms and serum IgE levels

BACKGROUND: The high-affinity receptor for immunoglobulin-E (IgE) (FcepsilonRI) plays a major role in the pathogenesis of allergy, but there are only two published studies on its alpha subunit (FcepsilonRIalpha) genetic variability in allergic diseases. AIMS OF THE STUDY: Mutational screening in the region of the FcepsilonRIalpha gene promoter and the first exon with subsequent genetic variability assessment in allergic patients and a random population sample. METHODS: Allergic subjects were individuals with asthma or urticaria. Age- and sex-matched controls were randomly selected from a large population sample. Mutational screening was performed using a single-stranded conformational polymorphism and subsequent sequencing. Detected polymorphisms were genotyped by restriction fragment length polymorphism. Total serum IgE was measured in allergic subjects and controls. Skin prick tests, blood eosinophil count and aspirin challenge test were performed only in the subjects. A subgroup of the subjects was further characterized by autologous serum skin test, histamine release test, Phadiatop and IgE antibodies against staphylococcal enterotoxins. RESULTS: Two linked polymorphisms -344 C>T and -95 T>C were found within the FcepsilonRIalpha gene. The allele -344 T frequency was 0.45 vs 0.37 (P = 0.33), and the allele -95 C frequency was 0.26 in subjects vs 0.30 in controls (P = 0.62). Serum IgE was significantly higher in subjects homozygous for the -344T allele (TT genotype) than in those carrying the -344 C allele (CT or CC genotype; P = 0.003), but this association was not detectable in controls. CONCLUSIONS: Our findings of genotype-related differences in IgE levels in allergic patients suggest an impact of -344 C>T but not -95 T>C gene polymorphism of FcepsilonRIalpha on total levels of IgE. The genetic variability in FcepsilonRIalpha at the -344 nucleotide of its regulatory sequence, though not related to atopy, predicts higher levels of the immunoglobulin.     

Relation between total serum IgE levels and IgE antibody production in rats.

Five different rat strains were immunized with 100 microgram ovalbumin and 1 mg Al (OH)3. A good correlation was found between the total serum IgE level of a rat strain before immunization and the IgE antibody production. Good IgE antibody-producing strains had high total serum IgE levels and vice versa. A discordance between the evolution of the total serum IgE level after immunization and the changes in IgE antibody level was found in all strains.     

Relationship between antigen-specific IgE antibody (RAST) and total serum IgE levels.

Although the total serum IgE level is generally higher in atopic than in non-atopic individuals, high total serum IgE levels and atopic diseases are not invariably associated. In 42 atopic patients with the total serum IgE levels less than 100 U/ml, 27% of RAST against 14 allergens were positive whereas in 45 atopic patients with the total serum IgE levels greater than 500 U/ml, 57% of RAST against 14 allergens were positive. The mean RAST values against four grass antigens expressed as a percentage of antigen-disc bound radioactivities were significantly lower in the group with the lower total serum IgE levels. Low or normal total serum IgE levels are likely to be found in atopic patients who are allergic to a relatively few grass antigens.     

Relationship between extremely low total serum IgE levels and rhinosinusitis.

BACKGROUND: The few studies examining clinical manifestations in adults with serum IgE levels less than 2.0 IU/mL provide conflicting information. OBJECTIVE: To examine self-reported respiratory disease in women with total serum IgE levels less than 2.0 IU/mL to further elucidate previous reports of an association between IgE deficiency and chronic rhinosinusitis. METHODS: In a geographically based cohort of 626 pregnant women, total serum IgE levels were measured using a standard assay with a lower limit of detection of 2.0 IU/mL. Sera with IgE levels less than 2.0 IU/mL were assayed again using a low IgE protocol with a detection limit of 0.02 IU/mL. RESULTS: Twenty-one individuals (3.4%) were found to have IgE levels less than 2.0 IU/mL. On repeated assay, 20 of these individuals with available clinical data were found to have detectable IgE levels ranging from 0.5 to 2.1 IU/mL (geometric mean, 1.2 IU/mL). None of these individuals with low IgE levels had physician-diagnosed sinusitis compared with 19.3% (113/585) of those with IgE levels of 2.0 IU/mL or greater (P = .03). Physician-diagnosed asthma was also less prevalent (1/19, 5.3%) in the low IgE group compared with 20.6% in those with higher IgE levels, but this was not significant (P = .14). The low IgE group reported a higher prevalence of hay fever symptoms than the remaining cohort (31.6% vs 24.4%; P = .43) but had less physician-diagnosed hay fever (5.3% vs 15.8%; P = .34). CONCLUSIONS: Low serum IgE levels were relatively common in these pregnant women. In contrast to previous studies, a low IgE level was not associated with chronic rhinosinusitis.     

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.     

Association of tumor necrosis factor polymorphisms with asthma and serum total IgE

Tumor necrosis factors (TNF; TNFA and TNFB) are major pro-inflammatory cytokines that are thought to be important in the pathogenesis of asthma. However, the functions of genetic polymorphisms in these cytokines have not been thoroughly examined in the context of asthma pathology. In an effort to discover polymorphism(s) in genes whose variant(s) have been implicated in asthma phenotypes, we examined the genetic effects of TNF (TNFA and TNFB) polymorphisms on asthma and total serum IgE level. Seven common single-nucleotide polymorphisms (SNP) in TNF genes were genotyped in a Korean asthma cohort (asthmatics n=550, normal controls n=171). Six common haplotypes could be constructed in the TNF gene cluster due to very strong LD between TNFA and TNFB, located 13 kb apart on chromosome 6p21. One SNP (TNFA-308G>A) showed a significant association with the risk of asthma (P=0.0004). The frequency of TNFA-308A allele-containing genotype in asthmatics (9.8%) was much lower than that in normal controls (22.9%). The protective effects of this polymorphism on asthma were also evident in separated subgroups by atopic status (P=0.05 in non-atopic subjects and P=0.003 in atopic subjects). The most common haplotype of the TNF gene (TNF-ht1[GGTCCGG]) was associated with total serum IgE (immunoglobulin E) levels in asthma patients, especially in non-atopic patients (P=0.004). Genetic variants of TNF might be involved in development of asthma and total serum IgE level in bronchial asthma patients. The results of this study could be helpful to understand the function of important TNF genes in asthma and IgE production.     

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

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

哮喘家系成员血清总IgE的遗传学分析

目的 探讨哮喘家系成员血清总IgE的遗传方式。方法 收集哮喘遗传家系，用酶联免疫吸附测定方法检测哮喘家系成员病人和正常人的血清总IgE，并取无哮喘家族史和无过敏家族史的正常人作为对照组，进行总IgE的遗传分析。结果 哮喘家系成员的血清总IgE分布是双形态分布，父母一方及其子女IgE超常的占56％，父母双方及其子女IgE超常的占50％。结论 总IgE可能是以单基因遗传控制为主，且总IgE的超常(H)可能是因常染色体显性遗传伴不完全外显。     

Association between a C+33T polymorphism in the IL-4 promoter region and total serum IgE levels

Susceptibility to asthma and other atopic diseases is known to be associated with elevated total IgE levels. Several investigators have linked the interleukin-4 (IL-4) gene and nearby markers located on chromosome 5q to elevated total IgE levels. A single nucleotide polymorphism in the IL-4 gene promoter region (C+33T) has recently been identified. As part of an effort to identify genetic variants contributing to the susceptibility to elevated total serum IgE levels, an association analysis of a newly identified promoter polymorphism (C+33T) with total serum IgE levels was conducted. The study was conducted using 240 Japanese subjects (120 asthmatics and 120 healthy controls). The IL-4 C+33T polymorphism was genotyped by PCR-restriction fragment length polymorphism analysis. The frequency of the T allele was 0.675 in asthmatic subjects and 0.671 in healthy controls. An ANOVA model adjusted for age, sex and disease status suggested a genetic association of C+33T polymorphism with elevated total serum IgE levels (P < 0.05). The data suggest that IL-4 promoter C+33T polymorphism may be one of the genetic polymorphisms that explain genetic linkage or association between elevated total serum IgE levels and markers on chromosome 5q.     

Relation between frequency of asthma and IgE antibody levels against Dermatophagoides farinae and total serum IgE levels in schoolchildren

The relation between the frequency of wheezing illness and IgE antibody levels against Dermatophagoides farinae (Df) and total IgE levels was examined in 457 randomly selected schoolchildren. From the response to the ATS-DLD-78-C respiratory symptoms questionnaire, 14 subjects (3.1%) were found to have asthma syndrome (recurrent episodes of attacks of shortness of breath with wheezing) and 17 subjects (3.7%), wheezing syndrome (only wheezing). The percentage of the asthma syndrome increased with increasing levels of Df-specific IgE, and there was an intimate correlation between the percentage of asthma syndrome and Df-specific IgE levels (r = 0.97; p less than 0.001), whereas such association was not found between the two (r = -0.19; p greater than 0.5). Similar relations were found between the frequencies of the specific syndromes and total IgE levels. There was a significant correlation between total IgE levels and Df-specific IgE levels in the total population (r = 0.7; p less than 0.001). These results suggest that allergic reaction greatly contributes to the development of asthma in children.     

Association of Eotaxin gene family with asthma and serum total IgE

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Association of Eotaxin gene family with asthma and serum total IgE

The Eotaxin gene family (Eotaxin1, Eotaxin2 and Eotaxin3) recruits and activates CCR3-bearing cells such as eosinophils, mast cells and Th2 lymphocytes that play a major role in allergic disorders. To date, the effect of polymorphisms of Eotaxin genes on asthma phenotypes has not been thoroughly examined. In our research, we sequenced whole regions of the Eotaxin gene family to identify polymorphisms, which may be involved in the development of asthma and total serum IgE. We have identified 37 SNPs in the Exotaxin gene family (Exotaxin1, 2 and 3), and 17 common polymorphic sites were selected for genotyping in our asthma cohort (n=721). Statistical analysis revealed that the EOT2+1265A>G G* allele showed significantly lower frequency in asthmatics than in normal healthy controls (0.14 versus 0.23, P=0.002), and that distribution of the EOT2+1265A>G G* allele-containing genotypes was also much lower in asthmatics (26.3 versus 40.8%, P=0.003). In addition, a non-synonymous SNP in Eotaxin1, EOT1+123Ala>Thr showed significant association with total serum IgE levels (P=0.002-0.02). The effect of EOT1+123Ala>Thr on total serum IgE appeared in a gene-dose-dependent manner. Our findings suggest that the development of asthma may be associated with EOT2+1265A>G polymorphisms, and the susceptibility to high IgE production may be attributed to the EOT1+123Ala>Thr polymorphism. Eotaxin variation/haplotype information identified in this study might provide valuable insights into strategies for the control of asthma.     

Influence of total serum IgE levels on the in vitro detection of β-lactams-specific IgE antibodies

Background Allergic reactions to β-lactams are a frequent cause of adverse drug reactions; the diagnosis is based on history, clinical examination, skin testing (prick and intradermal) and demonstration of serum-specific IgE antibodies (Abs).
Objective We compared the diagnostic performance of the Phadia CAP system for the detection of IgE to β-lactams carried out using the new test with cut-off limits of 0.10 kUA/L and the old test with cut-off limits of 0.35 kUA/L for positive results; subsequently, we analysed the effect of total serum IgE values and of atopic phenotype on the diagnostic performance of the tests.
Methods The study comprised a total of 34 patients with a history of immediate adverse reactions to β-lactams, which were confirmed by positive skin testing, and 115 control subjects with tolerance to β-lactams over the last year. The Phadia CAP System was used for the determination of serum total and specific IgE Abs towards penicilloyl G (c1), penicilloyl V (c2), ampicilloyl (c5) and amoxicilloyl (c6). The overall diagnostic performance was assessed as a diagnostic odds ratio (DOR).
Results The new test showed a higher sensitivity (85% vs. 44%) than the old test and a lower specificity (54% vs. 80%) but the overall diagnostic performance was poor (DOR 6.78 vs. 3.16, P =0.333) in both tests. The total IgE value influences the DOR of both tests; DOR was better for values under 200 kU/L [DOR=66; 95% confidence interval (CI): 11.3–384.1] or 500 kU/L (DOR=45.7; 95% CI: 5.3–394.4) for the new and old tests, respectively.
Conclusions The reduction in the positive cut off value has not significantly improved the overall diagnostic performance of the β-lactams-specific IgE assay. Because of the influence of serum total IgE on the detection of β-lactam-specific IgE Abs, the combination of both tests is mandatory in the in vitro diagnostic approach of β-lactam allergy.