Ambient air pollutants and tobacco smoke produce adverse respiratory health effects in children. Differences in susceptibility for these outcomes are likely to involve genetic variation in multiple pathophysiological pathways that modulate responses and subsequent biologic effects following exposure. In the initial grant, we investigated the hypothesis that genetic variants in oxidant stress pathways modulate the occurrence of adverse outcomes using a candidate gene approach in the Children's Health Study (CHS), a 10-year longitudinal study of children's respiratory health in 12 Southern California communities. We found that variants in GSTM1 (null), GSTP1 (A105G), TNF (- 308), and ICAM-1 (241) were associated with reduced lung function growth, increased asthma occurrence, and increased respiratory illnesses. These variants also showed gene-environment and gene-gene interactions with tobacco smoke and ambient air pollutants. Our findings add to the growing body of evidence that pathways involving glutathione (GSH) play important roles in respiratory health. In this application, we propose to extend our candidate gene association study using existing data from the CHS, to examine the role of sequence variation in 38 genes in five GSH pathways including GSH production, transport, and redox cycling, electrophil and oxidation products detoxification, and nitric oxide cell signaling. The exposures of interest are O3, NO2, ambient PM2.5, and tobacco smoke. The respiratory health outcomes are lung function growth, asthma, and respiratory absences. Associations of respiratory health outcomes with sequence variants in candidate genes and air pollution will be assessed using haplotypes and functional SNPs. We will test for overall association of a locus with outcomes using functional SNPs and a haplotype-based approach, and gene-gene and gene-environment interaction within and between pathways will also be examined using approaches to minimize multiple comparisons issues. Confounding by admixture will be addressed using SNP-based genome-wide control methods. Finally, hierarchical Bayesian models of these complex pathways incorporate a priori knowledge about biological relationships to efficiently examine interactions within and between pathways. The comprehensive approach proposed to assess the role of genetic variation in a large established cohort of children provides a unique opportunity to advance our understanding of children's respiratory health. ? ? ?
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