Genetic Analyses For Epidemiologic Studies Of Respiratory Disease

呼吸道疾病流行病学研究的基因分析

• 批准号: 7734420
• 负责人: STEPHANIE JOAN LONDON
• 金额: $ 11.58万
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7734420
• 关键词: Area; Asthma; Bioinformatics; Biology; Body mass index; Candidate Disease Gene; Childhood; Childhood Asthma; Chronic Obstructive Airway Disease; Chronic Obstructive Asthma; Cities; Collaborations; Data; Data Analyses; Data Set; Disease; Environmental Risk Factor; Environmental Tobacco Smoke; Epidemiologic Studies; Equilibrium; European; Extrinsic asthma; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genome; Genotype; Haplotypes; Health; Immune response; Laboratories; London; Lung diseases; Manuscripts; Meta-Analysis; Methods; Mexican; Mexico; North America; Nucleotides; Ozone; Parents; Phenotype; Polymorphism Analysis; Population; Preparation; Publication Bias; Publications; Publishing; Reporting; Research Personnel; Role; Sample Size; Sampling; Sampling Studies; Significance Level; Smoke; Triad Acrylic Resin; atopy; base; gene environment interaction; genetic analysis; genome wide association study; novel; positional cloning; respiratory

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.

该项目描述了斯蒂芬妮·伦敦实验室在呼吸生物学实验室中的作用，以支持其流行病学研究。该实验室使用生物信息学方法和伦敦博士在呼吸道疾病流行病学研究中的样本进行基因分析分析进行了多态性的选择。在过去的一年中，我们专注于墨西哥城儿童哮喘的研究（在儿童呼吸健康中标题为遗传和环境因素的项目中描述）。 我们在这项研究中采取了两种方法。与大多数其他研究者一样，我们以前专注于候选基因关联。我们已经检查了有希望的哮喘候选基因，然后可以检查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药物的呼吸或免疫反应的基因。在哮喘遗传学领域，通过位置克隆鉴定的基因在关联研究中并不总是很好地复制。我们检查了GPRA基因，该基因是通过两个欧洲血统种群中的位置克隆确定的。在数据中，我们没有发现与哮喘或特应性的关联。因此，我们对先前的关联研究进行了仔细的审查。我们发现，尽管以前的出版物声称复制，但很少与这些出版物相关的SNP或单倍型或相同的亚表型。因此，总的来说，GRPA的复制水平较低。鉴于已知的出版偏见问题，我们希望真正的复制水平会更低。 我们采用的另一种方法是整个基因组关联。我们一直在忙于为整个基因组协会研究（Illumina 550k）准备墨西哥城哮喘研究样本。由于在整个基因组协会中复制的重要性，对于这个项目，我们将与墨西哥遗产人群中唯一的其他研究合作，以复制发现。我们计划在该人群中进行最佳打击。我们还感谢主要效果复制需要更大的样品尺寸，并且可以肯定地检查相互作用。因此，我们已经与其他研究人员一起进入了一个联盟，他们在美国哮喘研究中进行了整个基因组关联基因分型。通过这项合作，我们将能够按照与其他几项研究的比较水平对我们的SNP关联进行排名。正如其他表型的研究中发现的那样，在任何给定的研究中，在多个研究中复制良好研究的SNP不一定是那些在任何给定研究中都将复制到具有基因组广泛签名水平的SNP的SNP。 在哮喘中，只有一项关于整个基因组SNP关联的已发表研究。这项研究确定了与哮喘-ORMDL3相关的新基因。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。我们发现与原始报告相当的关联。我们还对已发表的数据进行了荟萃分析，在该数据中发现了整个研究的高度复制水平。此手稿正在审查中。