The aim of this project is to examine genetic and environmental factors that influence the risk of childhood respiratory illnesses and to evaluate gene-environment interactions. To this end, we have assembled a set of three international studies of school aged children from populations with three different asthma prevalences - Wuhan China (low), Mexico City (intermediate) and Southern California, US (high). The three sites provide a range of exposures to environmental factors that are likely to interact with genetic susceptibility. These include ozone, endotoxin and environmental tobacco smoke. Notable exposures in the Wuhan China population are indoor coal burning, high prevalence of environmental tobacco smoke, and ambient air pollution. The Mexico City site is notable for the highest levels of ozone in North America and endotoxin levels are also high. The Southern California study offers a range of well characterized exposures to air pollution. Procedures and techniques: The three studies in this project are conducted among school aged children with slightly different designs. The Wuhan study is a school-based study of 5,051 seventh graders at 22 schools enrolled in 1999. We collected environmental exposure and respiratory outcome data, pulmonary function and DNA from buccal cells. We are currently following the students for the third year. The Mexico City study uses the case-parent triad design. We are enrolling asthmatic children aged 7-17 at an inner city hospital along with their parents as controls. The case-parent triad design enables the examination of candidate gene associations from bias due to ethnic stratification, a potential problem in the two population mix of Mexico City. The case-parent triad design also allows the discernment of fetal versus maternal genetic effects. This Mexico City population experiences the highest ozone levels in North America. Ambient endotoxin is also elevated. We are examining candidate genes involved in respiratory responses to ozone, based on human and animal evidence. The Southern California study is a school-based air pollution cohort study that I helped establish before coming to NIEHS. Beginning in the spring of 1998, I initiated a collection of genetic material on the cohort to examine candidate genes for asthma and impaired growth of pulmonary function. This collection was so successful that it was incorporated into an NIEHS/EPA Children's Center grant and is now extramurally funded. However, I remain involved as a collaborator. I am also analyzing data from questionnaires that I designed for this study. Accomplishments: In the Wuhan study, we are completing an analysis of cross-sectional data from the first year. We have found that environmental tobacco smoke is most strongly related to cough and indoor coal burning is most strongly related to wheeze. Both of these relationships show a dose-response. We are preparing this manuscript for submission. Based on the questionnaire data, we have selected cases and a comparison group for genetic studies and have begun genotyping for a common set of candidate genes as in the Mexico City study. In the Mexico City study, we have extracted DNA on over 200 triads and are completing genotyping for polymorphisms in several genes that appear to be involved in pulmonary response to ozone in mouse models. We will continue enrollment until a goal of 500 triads is reached. In the Southern California study, the genetic samples are still being collected. However, we have demonstrated a gene-environment interaction based on family history of asthma and allergy. Maternal smoking in pregnancy was most strongly related to early onset persistent asthma among family history positive subjects. This result suggests that early life environmental exposures may be more detrimental in genetically predisposed children.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Intramural Research (Z01)
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U.S. National Inst of Environ Hlth Scis
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Magnus, Maria C; Wright, Rosalind J; Røysamb, Espen et al. (2018) Association of Maternal Psychosocial Stress With Increased Risk of Asthma Development in Offspring. Am J Epidemiol 187:1199-1209
Kothari, Parul H; Qiu, Weiliang; Croteau-Chonka, Damien C et al. (2018) Role of local CpG DNA methylation in mediating the 17q21 asthma susceptibility gasdermin B (GSDMB)/ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3) expression quantitative trait locus. J Allergy Clin Immunol 141:2282-2286.e6
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Joubert, Bonnie R; den Dekker, Herman T; Felix, Janine F et al. (2016) Maternal plasma folate impacts differential DNA methylation in an epigenome-wide meta-analysis of newborns. Nat Commun 7:10577
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