This project describes the role of the lab of Stephanie London in the Laboratory of Respiratory Biology in support of her epidemiologic studies. The laboratory is engaged in selection of polymorphisms for analysis, using bioinformatic methods and genotyping analysis of samples from Dr. London's epidemiologic studies of respiratory disease. In the past year, we have focused on the study of childhood asthma in Mexico City (described under project entitled Genetic And Environmental Factors In Childhood Respiratory Health). ? ? We are taking two approaches in this study. The first is candidate gene association. We focus on promising asthma candidate genes that we can then examine for interaction with secondhand smoke and ozone. We also examine genes that are highly likely to be involved in respiratory or immune response to these agents. Along these lines in the past year, we have published on several different mechanistic candidate genes. One is the tumor necrosis factor alpha gene (TNF). This is an asthma candidate gene that has been shown to be important in the pulmonary response to both ozone and environmental tobacco smoke. We found associations with two functional SNP in the promoter region of this gene and found evidence of interaction with environmental tobacco smoke. Associations were primarily seen among subjects whose parent did not smoke. We believe that in an area with high ozone exposure, the genetic component of TNF regulation may be detected more readily in subjects lacking this important co-exposure. We also found that functional SNPs in the transforming growth factor beta gene (TGFB1) were related to asthma and atopy risk and published this finding in the past year. Most recently, we were the first to examine genetic variants in the GSNOR gene. A recent paper (Que, Science 2005) had identified a novel nitric oxide pathway in mouse models of asthma and identified GSNOR as the key gene. We found that SNPs in GSNOR were associated with asthma, but not degree of atopy, which is consistent with the mouse models. ? ? The other approach that we are taking is whole genome association. We have been busy preparing the Mexico City Asthma Study samples for a whole genome association study (Illumina 550K). Because of the importance of replication in whole genome association, for this project, we will collaborate for replication of findings with two other asthma studies -- another study in Latino subjects and a family study in Europeans.
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