Genes, Air Pollution, Oxidant Stress, and Children's Respiratory Health

University Of Southern California, Los Angeles CA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Ambient air pollutants and tobacco smoke produce adverse respiratory health effects in children. Pro-oxidants and oxidants that produce oxidative stress mediate adverse effects of air pollution. Multiple genes determine intensity and biologic effects of oxidative stress following exposure to air pollution. The investigators hypothesize that genetic variants that increase oxidative stress or decrease antioxidant defenses increase adverse outcomes. Gene-environment and gene-gene interactions within and between oxidative stress pathways, as well as gene interactions with dietary intake, may be important determinants of adverse respiratory outcomes. To evaluate these hypotheses, the investigators will conduct a candidate gene association study in a cohort of 6,000 children in the CHS, a 10-year longitudinal study in 12 Southern California communities. To further evaluate interactions between genes, air pollution, diet and gene-gene interactions, they propose to conduct a population-based prospective family cohort study including 3,000 trios of children in the CHS and their parents. They will establish the family cohort by collecting questionnaire data and buccal cell specimens for genomic DNA from parents of CHS participants. Genomic DNA will be analyzed for genes involved in xenobiotic metabolism (CYP1A1, AhR, NQO1, GSTM1, GSTM3, GSTT1, GSTP1, EPHX1), reactive oxygen species metabolism (MN-SOD, EC-SOD, GPX1, GPX3, catalase), oxidative damage detoxification (GPX1, GPX3, GSTM1, GSTM3, GSTT1, GSTP1), inflammatory oxidant production (MPO, TNFa), and antioxidant defenses (HMOX-1). The exposures of interest are ambient air pollution and environmental tobacco smoke (ETS). The respiratory health outcomes of interest are lung function growth and level, respiratory symptoms, asthma, and respiratory infections. Associations of respiratory health outcomes with air pollution and polymorphisms in these genes will be assessed separately, jointly and in conjunction with other factors related to oxidant stress. The family study will provide an expanded opportunity to control for confounding by admixture and investigate gene-gene interactions within and between pathways. The family study will provide a well characterized population-based resource to confirm the effects of newly identified candidate genes. Understanding the role of genetic variation in the context of diet and exposure to air pollutants may provide information to identify and protect susceptible groups of children. The CHS and the new family cohort study will have future utility to test hypotheses growing out of the Human Genome Project.