? ? Asthma is the most common chronic disease affecting children and is a major clinical and public health problem. Another key indicator of children's respiratory health is lung function, and most importantly, lung function development. Deficits in lung function development as a child can lead to a lifetime of respiratory health problems and ultimately, to increased risk of mortality later in adult life. The Children's Health Study (CHS) is an ongoing cohort study of over 11,000 children, investigating the impact of air pollution and candidate genes involved in oxidative stress and inflammation on both childhood asthma and lung function development. In this proposal, we will use the extensive existing data from the CHS to accomplish the following specific aims: ? ? Aim 1: To conduct a genome-wide association study using a panel of over 300,000 single nucleotide polymorphisms (SNPs, optimized to tag the vast majority of common genetic variation in the entire genome) to identify new genetic variants that increase risk of childhood asthma or affect lung function development. ? ? Aim 2: To identify potentially important pathways related to asthma or lung function, by testing for gene-environment interaction (with ozone, particulate matter, traffic exposure, or passive tobacco smoke), and gene-gene interaction (with GSTM1) in the search for new genetic variants. ? ? Aim 3: To replicate associations identified in our genome screen using two additional samples derived from the CHS, including a sample of parent-offspring trios and a large independent set of asthmatic cases and non-asthmatic controls. ? ? We propose to use a cost-efficient multi-stage study design that unifies the detection of genetic main effects and interactions. Both asthma and lung function are complex traits that depend on both genetic and environmental factors. Our novel use of air-pollution and existing candidate-gene data in the scan has the potential to identify new genes that act synergistically with important, established determinants of children's respiratory health. (End of Abstract) ? ? ?
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