David Carr

Glutathione S transferase deficiency and passive smoking increase childhood asthma

Background: It has been suggested that the genetically determined deficiency of glutathione S transferase (GST) enzymes involved in the detoxification of environmental tobacco smoke (ETS) components may contribute to the development of asthma. Methods: A large population of German schoolchildren (n = 3054) was genotyped for deficiencies of the GST isoforms M1 and T1. The association between GSTM1 and GSTT1 genotypes and asthma as well as atopy was investigated with respect to current and in utero ETS exposure. Results: In children lacking the GSTM1 allele who were exposed to current ETS the risk for current asthma (OR 5.5, 95% CI 1.6 to 18.6) and asthma symptoms such as wheeze ever (OR 2.8, 95% CI 1.3 to 6.0), current wheezing (OR 4.7, 95% CI 1.8 to 12.6) and shortness of breath (OR 8.9, 95% CI 2.1 to 38.4) was higher than in GSTM1 positive individuals without ETS exposure. Hints of an interaction between ETS exposure and GSTM1 deficiency were identified. In utero smoke exposure in GSTT1 deficient children was associated with significant decrements in lung function compared with GSTT1 positive children not exposed to ETS. Conclusions: GSTM1 and GSTT1 deficiency may increase the adverse health effects of in utero and current smoke exposure.

Association between polymorphisms in serine protease inhibitor, kazal type 5 and asthma phenotypes in a large German population sample.

Background Atopic diseases are characterized by immunoglobulin E (IgE)‐mediated immune responses towards common allergens, many of which are proteases. Recently it has been suggested that a proteinase inhibitor gene, SPINK5, which is located on chromosome 5q31, may play a role in the pathogenesis of atopic diseases.

A promoter polymorphism in the CD14 gene is associated with elevated levels of soluble CD14 but not with IgE or atopic diseases

Background:  A polymorphism in the promoter region of the CD14 gene, C‐159T, has been shown to be associated with increased levels of soluble CD14 (sCD14) and decreased serum immunoglobulin E (IgE) and the expression of a more severe atopic phenotype in previous studies.

Lung function of school children with low levels of α1-antitrypsin and tobacco smoke exposure

Exposure to environmental tobacco smoke (ETS) and other air pollutants has been associated with small decrements in lung function. The susceptibility to pollution exposure may, however, vary substantially between individuals. Children with an impaired protease-antiprotease balance may be particularly vulnerable. Therefore this study aimed to investigate the effects of ETS exposure on children with reduced levels of α1-antitrypsin (α1-AT). Random samples of school children (aged 9–11 yrs) (n=3,526) were studied according to the International Study of Asthma and Allergies in Childhood (ISAAC) phase II protocol, including parental questionnaires, pulmonary function and allergy testing. Blood samples were obtained to measure plasma levels of α1-AT and to genotype for pleomorphic protein inhibitor (Pi)Z and PiS alleles. Children with low levels of α1-AT (≤116 mg·dL−1) showed significant, albeit small decrements in baseline lung function. When exposed to ETS, pronounced decrements of pulmonary function, particularly in measures of mid- to end-expiratory flow rates, were seen in these children as compared to exposed children with normal levels of α1-AT. The mean levels of % predicted±se in both groups were: maximum expiratory flow at 50% of vital capacity 79.4±7.2 versus 99.0±1.5, maximum expiratory flow at 25% of vital capacity 67.4±10.0 versus 100.3±2.1, maximal midexpiratory flow 73.7±8.6 versus 99.9±1.7. These findings suggest that school children with low levels of α1-antitrypsin are at risk of developing pronounced decrements in pulmonary function, particularly if they are exposed to environmental tobacco smoke. Parents of children with heterozygous α1-antitrypsin deficiency resulting in significantly reduced blood concentrations should be advised to prevent their children from being exposed to environmental tobacco smoke and dissuade them from taking up smoking.

A Comprehensive Analysis of Interleukin-4 Receptor Polymorphisms and Their Association with Atopy and IgE Regulation in Childhood

Background: The interleukin (IL) 4/IL13 pathway is involved in the regulation of IgE production associated with atopic diseases. Numerous polymorphisms have been identified in the coding region of the IL4 receptor α chain (IL4Ra) and previous association studies have shown conflicting results. Based on their putative functional role, polymorphisms A148G, T1432C and A1652G, located in the coding region of IL4Ra, were selected for association and haplotype studies in a large German population sample (n = 1,120). Methods: Genotyping was performed using allele-specific PCR and restriction-enzyme-based assays. Haplotypes were estimated, and population-derived IgE percentiles (50% IgE >60 IU/ml, 66% IgE >115 IU/ml and 90% IgE >457 IU/ml) were calculated as outcome variables in a haplotype trend regression analysis. Results: In our population, only polymorphism T1432C showed a trend for a protective effect against atopic rhinitis (odds ratio, OR: 0.52, 95% confidence interval, CI: 0.26–1.02, p = 0.05). When haplotypes were calculated, one haplotype was significantly associated with elevated serum IgE levels at the 50th percentile (OR 1.60, 95% CI 1.08–2.37, p = 0.02). Conclusions: These data indicate that IL4Ra polymorphisms, although suggested to be functionally relevant by in vitro studies, have only a minor influence on IgE regulation in our large population sample.

α1 Antitrypsin and the prevalence and severity of asthma

In a random sample of children (aged 9–11 years; n = 5629), who were studied according to the ISAAC phase II protocol, heterozygosity of the α1 antitrypsin (α1-AT) Pi genotypes MS or MZ, or low α1-AT plasma levels, were not associated with an increased risk of developing asthma. Asthmatics with low levels of α1-AT were particularly prone to develop airway hyperresponsiveness and reduced lung function.

Polymorphismen in der IL-4/IL-13-Signalkaskade beeinflussen die IgE-Regulation und Asthma bronchiale

Background: The IL-4/IL-13 pathway plays a critical role in the IgE regulation and the development of asthma. Previous studies have described an association between genetic alterations in single genes of the IL-4/IL-13 pathway and these two phenotypes. In this study, we analyzed the combined effect of different genetic alterations in the genes of the IL-4/IL-13 pathway (IL-4, IL-13, IL-4Ra and STAT6) on the regulation of IgE and the development of asthma. Methods: In a large cross-sectional study population (ISAAC II) of 1,120 children, aged 9-11 years, 18 polymorphisms in the respective genes of the IL-4/IL-13 pathway were genotyped. Based on linkage disequilibrium and functional relevance, one polymorphism of each gene (IL-4 C-589T, IL-13 C-1112T, IL-4Ra A148G und STAT6 C2892T) was selected to assess gene by gene interactions using a stepwise haplotype procedure following a Cordell model. Results: Certain combinations of polymorphisms in the IL-4/IL-13 pathway significantly influence IgE regulation. Furthermore, a significant protective effect towards the development of asthma was identified. Compared to single gene effects, the risk to develop elevated serum IgE (> 90th percentile) decreased by 80% while the risk to develop asthma dropped by 60%. Conclusion: These data indicate that only a combined analysis of various genetic alterations within the IL-4/IL-13 pathway reveals the development of atopy and asthma bronchiale.