Childhood respiratory diseases and their pathophysiologic antecedents are important clinical and public health problems that have both environmental and genetic determinants. Although progress has been made in identifying the genes and exposures related to asthma occurrence, respiratory symptoms and lung function, more research is needed to understand the role of genetics in susceptibility and identify critical pathways and vulnerable populations for interventions. This project proposes to investigate the contribution of genetic variation in inflammatory responses during childhood to 1) the occurrence of common respiratory diseases. 2) inter-individual differences in lung function growth, and 3) susceptibility for adverse respiratory effects of ambient air pollutants. The proposed program of research builds on the rich health, exposure and genetic data resources of the Children's Health Study (CHS), an ongoing cohort study investigating both genetic and environmental factors related to children's respiratory disease in over 11,000 southern California children. We will assess the broad hypotheses that inter-related pathways involved in inflammatory responses (innate, adaptive systems) and oxidative/nitrosative stress 1) are determinants of childhood asthma and lung function development, and 2) modulate susceptibility to ambient respirable particles (PM[0.25], PM[0.25-2.50, and PM[2.5-10] characteristics, constituents), ozone and nitrogen dioxide. We propose to conduct a pathways-driven candidate gene-environment association study to examine the relationships between outcomes (asthma incidence, respiratory symptoms), lung function growth and 273 key genes in key inflammatory pathways. To characterize the genetic contribution of each locus, tagging SNPs will be selected including conserved SNPs or SNPS with coding or regulatory functions. Children in the CHS (n=7700) would be genotyped for 6,000 SNPs across the 273 genes and each genetic locus tested for associations with each phenotype. Tests of a subset of gene-environment and gene-gene interactions would be conducted based on genetic main effects and a priori hypotheses-based pathway topologies. Our approach that employs genotype-based coefficient of ancestry, emerging analytic methods for global and specific tests of association, and novel methods to include prior biological knowledge of disease pathophysiology is complementary to discovery approaches such as whole genome association studies. The CHS offers a unique resource to assess the effects of genetic variation in critical pathways on children's respiratory health. The size, substantial genotype data, high levels of exposure and longitudinal health data make the project proposed in this application feasible, cost-effective and timely. The results will guide future mechanistic studies and intervention strategies for primary and secondary prevention of asthma and chronic obstructive respiratory diseases.
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