The role of the ORMDL3 susceptibility gene in the pathogenesis of asthma

Asthma is a very common disease with up to 8% of children and 3% of adults in Belgium affected. Several studies have been performed to find out if the genetic makeup of an individual confers risk to develop the disease. A particular genetic locus on chromosome 17 (17q21) has been found in almost all genome wide association studies of asthma. This locus contains two genes (ORMDL3 and Gasdermin B) of which the expression is increased in asthmatics. This locus confers risk of developing asthma in childhood, particularly when children are exposed to passive smoking, and also confers risk of frequent episodes of rhinovirus induced wheezing in young children. We have created unique mouse models in which the ORMDL3 gene is deleted or overexpressed in cells of the lungs or the immune system and will test if ORMDL3 is causally related to asthma. We will also study how cigarette smoke exposure and viral infection affects the interaction of ORMDL3 with asthma. ORMDL3 has been sown to control two cell-biologial processes, sphingolipid metabolism
and the unfolded protein response. We will test how lack or overexpression of ORMDL3 affects
these processes in steady state and in mice exposed to allergens, cigarette smoke and viral
infection. At the end of this project, we will have obtained evidence if and how ORMDL3 is causally
related in the gene-environment interaction leading to asthma. Interfering with this molecule could
lead to new therapeutics for asthma.