Genetics of Asthma and Bronchial Hyperresponsiveness

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DESCRIPTION (provided by applicant): Asthma is an inflammatory airways disease caused by an interaction between susceptibility genes for asthma and atopy and a diverse group of environmental exposures. It appears that there is no single susceptibility gene that confers major risk, but more likely a series of genes with interactive effects that increase the risk for asthma and/or other atopic conditions after exposure to specific environmental factors. We have collected a well-characterized Dutch asthma population of 200 families, which has been recently expanded to include an additional 437 trios with bronchial hyperresponsiveness (BHR), 366 of whom have clinical asthma. These two samples of Dutch families form the basis for this competitive renewal. We have been collaborating with Professor Dirkje S Postma MD, PhD and her colleagues at the University of Groningen, the Netherlands for over 10 ten years. Our studies on this homogeneous Dutch population from northern Holland ascertained through a parent with asthma who was originally characterized approximately 25 years previously have been very productive. We hypothesize that important susceptibility genes for asthma and atopy map to chromosomes 2q and 5q where we have strong evidence for linkage. To investigate this, we will continue positional cloning approaches for these two chromosomes in conjunction with positional candidate gene association studies using both our Dutch families and trios, with the evaluation of gene-environment interactions (exposure to passive smoking). The specific aims of this proposal are: 1) Complete the phenotypic data set on the new 437 trios and perform analyses of their clinical characteristics for comparison with the family population 2) Identify genes on chromosome 2q related to asthma for two phenotypes: FEV1/VC and total serum IgE levels using a combination of positional cloning and positional candidate gene approaches in the Dutch trios and families, 3) Identify susceptibility genes for asthma and BNR on chromosome 5q31-33 using a combination of positional cloning and positional candidate gene approaches in the Dutch trios and families, 4) Evaluate asthma susceptibility genes to determine significance in our Dutch populations and their potential role in asthma severity (progression of asthma) using the longitudinal data on the 200 probands. These scientific approaches will allow us to prioritize candidate genes based on available knowledge of map position and biological relevance, obtain genomic structure and study sequence variants in our populations to facilitate the identification of genes that are important in the development of asthma and associated phenotypes.