BACKGROUND:

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. The study initially 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 longitudinal study of children's respiratory health in 12 Southern California communities. The investigators 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. Their findings add to the growing body of evidence that pathways involving glutathione (GSH) play important roles in respiratory health.

DESIGN NARRATIVE:

In the initial grant period, the investigators studied the effects of ambient air pollution and tobacco smoke on children's respiratory health and the role of diet, physical activity and genetic variation on susceptibility to ambient air pollutants and completed each of the specific aims. They noted associations between genotypes studied and reduced lung function growth, increased sensitivity to in utero exposure to maternal smoking, increased the risk of asthma, and risk of respiratory-related school absences, varied by GSTM1 and GSTP1 genotype. They noted that diets low in antioxidant vitamins were associated with deficits in lung function and that low magnesium intake was associated with lung function deficits. Finally, the investigators identified haplotype structure and tag single nucleotide polymorphisms (SNPs) for selected candidate loci and employed a limited version of haplotype analysis for investigation of association of three ICAM-1 variants on childhood asthma.

The investigators will extend their candidate gene association study using existing data from the Children's Health Study (CHS), to examine the role of sequence variation in 38 genes in five glutathione (GSH) pathways including GSH production, transport, and redox cycling, electrophil and oxidation products detoxification, and nitric oxide cell signaling. The exposures of interest are ozone (O3), nitric oxide (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. They 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.