Genetic studies, both association studies and more recently genome wide association studies (GWAS), have identified a large number of DNA variants that potentially confer risk for the development of atopy, asthma and COPD. However, in the majority of these studies the functional variant has not been identified. This largely reflets the fact that, in most cases, the polymorphism(s) identified do not alter the structure of the proteins encoded by genes located in these regions;rather the variants are generally found in non-coding DNA. While these regions often include sequences that could play an important role in regulation of gene expression, including promoters, enhancers or insulator regions, limited tools are currently available to assess the importance of these DNA variations in determining the expression of a given gene during normal development and, perhaps more importantly, in determining the impact of these variations on risk for disease, disease progression and/or the response of the patient to specific therapeutic intervention(s). Furthermore, in most cases it is clear that DNA variants at multiple loci, together with environmental factors, determine risk for disease: these interactions remain particularly difficult to define. In this application we propose to test the hypothesis that mouse models can be developed for testing the impact of disease associated non-coding DNA variants. These mouse models will allow testing of risk associated haplotypes as well as provide a means of resolving the contribution of an individual DNA variation on gene expression. The impact of the change in gene regulation conferred by the risk associated haplotype or individual variant can be evaluated in combination with environmental factors and also in combination with disease associated DNA variants at other unlinked loci.
One in 15 Americans suffer from asthma and in 50% of the cases disease is associated with allergies. The health care costs associated with both asthma and other lung diseases such as COPD are enormous. COPD costs exceed $23 billion dollars a year and the annual cost of asthma is estimated to be nearly $18 billion www.aafa.org. Genetic studies over the past ten years have identified numerous candidate genes that carry DNA variants associated with increased risk for asthma and COPD. The purpose of the studies described here are to develop a method for identifying which of these many polymorphisms uncovered in human genetic studies play an important role in either risk for developing asthma or in the progression of the disease. These studies will not only help to identify individuals at risk, thus allowing early environmental and therapeutic intervention, but they will also help in th identification of new targets for disease intervention.