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 have taken two approaches in this study. As with most other investigators, we previously focused on candidate gene association. We have examined 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. In the field of asthma genetics, genes identified through positional cloning have not always replicated well in association studies. We examined the GPRA gene which was identified through positional cloning in two populations of European ancestry. We did not find association to asthma or atopy in our data. We therefore did a careful review of the previous association studiese. We found that although previous publications claimed replication, it is rarely the same SNPs or haplotype or the same subphenotypes that are associated in these publications. Thus on balance, the level of replication for GRPA is low. Given the known problem of publication bias, we expect the true level of replication to be even lower. ? ? 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 the only other study in a population of Mexican heritage. We plan to genotype our top hits in that population. We also appreciate that greater samples sizes are needed for main effects replication and certainly to examine interactions. Therefore we have entered into a consortium with other investigators who are doing whole genome association genotyping in studies of asthma in the US. Through this collaboration we will be able to rank our SNP associations by level of significance for comparision with several other studies. As has found in studies of other phenotypes, such as body mass index, SNPs that replicate well across multiple studies are not necessarily those with the lowest genome wide p values in any given study and well replicated associations would have been missed by limiting replication to SNPs with genome wide levels of signficance in any given study.? ? There is only one published study of whole genome SNP association in asthma. This study identified a novel gene associated with asthma - ORMDL3. Replication is crucial. We therefore looked at the SNP with the lowest P value from that study as well as another SNP associated with both disease and level of gene expression. We found comparable associations with the original report. We also performed a meta-analysis of published data where we find a high level of replication across studies. This manuscript is under review.
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