Asthma is one of the most common, chronic diseases. Its pathogenesis reflects complex interactions between genetic and environmental factors. We propose that the genes that influence asthma-associated quantitative traits have sex-specific effects and/or interact with environmental factors to determine risk for disease. In this application, we propose to study 9 QTs that are associated with asthma and bronchial hyperresponsiveness (BHR) in the Hutterites, a founder population of European origins that lives communally. Genome-screens have identified 12 genome-wide significant signals in 10 regions for 5 asthma- associated quantitative traits, nearly all of which have sex-specific effects. The overall objectives of our studies are to identify the genes that influence asthma-associated quantitative traits in the Hutterites, and to characterize their effects on the development and course of disease in well-characterized outbred populations and in functional studies. We propose three specific aims: 1) Conduct 10+ year follow-up studies in >1,000 Hutterites and collect additional phenotypes, including fractional exhaled nitric oxide (FeNO);2) Perform genome-wide association (GWA) studies to identify additional asthma associated quantitative trait loci (QTL) in the Hutterites using Affymetrix GeneChip?1/2 500k Array;and 3) Identify genes in regions linked to or associated with asthma-related quantitative traits, characterize their function and mechanism for sex- specific effects, and elucidate the relationship between genotype and disease risk and pathogenesis. The spectrum of asthma-associated QTs under investigation and the explicit recognition of the importance of sex- specific genetic effects will facilitate gene identification and ultimately provide novel insights into asthma pathogenesis.
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