Asthma Clinical Trial
To investigate gene-environment interactions that may influence susceptibility to respiratory illness in children living in highly polluted areas in California.
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.
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