Genetic Analyses For Epidemiologic Studies Of Respiratory Disease

这个项目描述了斯蒂芬妮·伦敦的实验室在呼吸生物学实验室中的作用，以支持她的流行病学研究。该实验室使用生物信息学方法，对伦敦博士的呼吸道疾病流行病学研究样本进行基因分型分析，以选择多态进行分析。在过去的一年里，我们专注于墨西哥城儿童哮喘的研究(在题为儿童呼吸健康中的遗传和环境因素的项目中描述)。 在这项研究中，我们采取了两种方法。与大多数其他研究人员一样，我们之前关注的是候选基因关联。我们已经检查了有希望的哮喘候选基因，然后我们可以检查这些基因与二手烟和臭氧的相互作用。我们还检查了极有可能参与对这些病原体的呼吸或免疫反应的基因。在哮喘遗传学领域，通过位置克隆确定的基因在关联研究中并不总是复制得很好。我们检测了GPRA基因，该基因是通过定位克隆在两个欧洲血统的群体中鉴定出来的。在我们的数据中，我们没有发现与哮喘或过敏症有关。因此，我们仔细回顾了以前的协会研究。我们发现，尽管以前的文献声称存在复制，但很少有相同的SNPs或单倍型或与这些文献相关的相同的亚型。因此，总的来说，GRPA的复制水平较低。考虑到已知的发表偏见问题，我们预计真实的复制水平会更低。 我们正在采取的另一种方法是全基因组关联。我们一直忙于为全基因组关联研究(Illumina 550K)准备墨西哥城哮喘研究样本。由于复制在全基因组关联中的重要性，对于这个项目，我们将与墨西哥血统人群中唯一的另一项研究合作复制发现。我们计划在这一人群中对我们最热门的歌曲进行基因分型。我们还认识到，需要更大的样本大小来进行主效应复制，当然也需要检查相互作用。因此，我们与其他正在美国哮喘研究中进行全基因组关联基因分型的研究人员组成了一个联盟。通过这次合作，我们将能够根据重要性程度对我们的SNP关联进行排名，以便与其他几项研究进行比较。正如在体重指数等其他表型的研究中发现的那样，在多个研究中复制良好的SNP不一定是任何给定研究中全基因组p值最低的SNP，如果将复制限制在任何给定研究中具有全基因组显著水平的SNP，则可能会错过良好复制的关联。 目前只有一项已发表的关于哮喘与全基因组SNP关联的研究。这项研究发现了一个与哮喘相关的新基因-ORMDL3。复制至关重要。因此，我们研究了该研究中P值最低的SNP，以及与疾病和基因表达水平相关的另一个SNP。我们发现了与原始报告类似的联系。我们还对已发表的数据进行了荟萃分析，在这些数据中，我们发现研究中的重复程度很高。这份手稿正在审阅中。

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.