Content area
Abstract
Asthma is a complex polygenic disorder, and its prevalence is on the rise. Fortunately, in parallel with this tendency, the more and more expanding knowledge of genomics and the rapidly developing technologies offer powerful tools to be able to gain deeper insight into the genetic background of the disease. In our studies, we used gene expression microarray and single nucleotid polymorphism (SNP)-based methods to investigate the pathogenesis of allergic asthma. We carried out gene and microRNA expression profile analysis in the lung of mice undergoing allergen-induced experimental asthma at different time points during the experimental protocol. The study showed extensive changes in gene expression in the lungs in response to allergen at all time points. We applied GO and Gene Set Enrichment Analyses in order to gain a comprehensive insight into the biological processes and functions of the asthmatic response. Using these methods, we were able to relate gene expression changes to cellular processes and integrate our results into multiple levels of information available in public databases. We identified the high upregulation of miR-155, a microRNA that plays an important role in the development of immune response, in the lungs of allergic mice. Among the top downregulated transcripts, an antioxidant enzyme, paraoxonase-1 (PON1) was identified. In human asthmatic patients we found that serum PON1 activity was reduced at asthma exacerbations, but increased in parallel with improving asthma symptoms. PON1 gene polymorphisms, which affect the expression and the activity of the coded enzyme, did not influence the susceptibility to the disease. Our observations suggest that an altered PON1 activity might be involved in the pathogenesis of asthma, and PON1 might be a potential new therapeutic target as well as a diagnostic tool for following up the effect of therapy.
In our gene-environment interaction studies, we showed that C pneumoniae-specific IgG positivity is associated with asthma, when children carrying the TNFα-308A allele are considered. Furthermore, children infected with C pneumoniae in the past (IgG positivity) carrying the TNFα-308A allele have considerably higher risk of developing asthma than children with similar infection status carrying normal genotypes.
