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

Abstract

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.