Linking Genetics, Genomics and Phenomics to Better Understand Asthma Severity

描述（由申请人提供）： 严重哮喘是一种由相关临床表型组成的异质性疾病，其发病率、死亡率和医疗保健费用都很高。这种疾病的复杂性和异质性限制了临床进展。然而，自2003年以来，NHLBI重度哮喘研究计划（SARP）已成功招募了1000多名哮喘患者，其中包括近600名重度哮喘患者。这个绝佳的机会将使我们能够将之前和正在进行的全基因组关联研究（GWAS）与其分子特征以及之前和新发现的临床表型密切联系起来。与任何其他NHLBI网络不同，SARP参与者定期进行支气管镜检查。来自这些研究的上皮刷拭和支气管肺泡灌洗（BAL）细胞将进行微阵列分析，以形成基因型和表型之间的生物学联系。该提案的总体目标是建立世界上最广泛的成人哮喘表型/严重程度的GWAS数据集，使用与疾病相关的细胞（肺细胞）开发这些受试者子集的分子谱，然后将遗传和基因组数据联系起来，以大大加快识别与治疗相关的靶向途径。潜在的假设是，肺细胞基因表达，由遗传背景（GWAS）和环境（表观遗传分析）调节，将跟踪偏倚和无偏倚的临床表型，以加速哮喘治疗新方法的开发。 为了研究这一假设，分析与哮喘相关的细胞肺细胞中的基因表达模式，将与相同患者及其临床表型的全基因组SNP图谱相结合。将鉴定表征、定义和潜在地从机制上解释每种表型中疾病的不同模式的新基因模块。此外，我们将有机会确定表观遗传/环境因素是否解释了遗传和基因组变异之间的差异。有三个具体目标：1。通过将现有的STAMPEED数据集与来自充分表征的成人哮喘患者的另外3000个GWAS相结合，建立成人哮喘严重程度和表型的遗传谱; 2.使用来自200 - 250名良好表征的哮喘患者和50名正常对照的靶器官（肺）的新鲜分离的细胞建立成人哮喘严重程度和表型的基因表达谱; 3.使用监督和非监督方法，生成整合遗传、基因组、表观基因组和表型特征的组合模型，以增强新型分子治疗靶点的识别。 公共卫生相关性声明： 该目的的目的是研究哮喘，特别是严重哮喘的潜在基因组学，以确定为什么一些个体发展为更严重和更难治疗的哮喘。我们的发现将促进新疗法的发展，特别是针对严重哮喘患者。

DESCRIPTION (provided by applicant): Severe asthma, a heterogeneous disease consisting of related clinical phenotypes, generates high levels of morbidity, mortality and health care costs. The complexity and heterogeneity of the disorder have limited clinical advances. However, the NHLBI Severe Asthma Research Program (SARP) has successfully recruited over 1000 asthmatics, including nearly 600 severe asthmatics since 2003. This GRAND OPPORTUNITY will allow us to closely link previous and on-going genome-wide association studies (GWAS) with their molecular profiles and previous and newly identified clinical phenotypes. Unlike any other NHLBI network, bronchoscopies are routinely performed on SARP participants. Epithelial brushings and bronchoalveolar lavage (BAL) cells from these studies will undergo microarray analysis to form the biologic link between the genotype and phenotype. The overall objective of this proposal is to establish the world's most extensive GWAS dataset on adult asthmatics over a range of phenotypes/severity, to develop molecular profiles on a subset of these subjects using cells of relevance to the disease (lung cells) and to then link the genetic and genomic data to greatly speed the identification of targeted pathways of relevance for therapy. The underlying hypothesis is that lung cell gene expression, modulated by the genetic background (GWAS) and the environment (epigenetic profiling), will track with biased and unbiased clinical phenotypes to speed development of novel approaches to asthma therapy. To investigate this hypothesis, analysis of gene expression patterns in cells lung cells of relevance to asthma, will be integrated with whole genome SNP maps of the same patients and their clinical phenotypes. New modules of genes that characterize, define and potentially mechanistically explain the distinct pattern of disease in each phenotype will be identified. In addition, we will have an opportunity to determine whether epigenetic/environmental factors explain the differences between genetic and genomic variation. There are 3 Specific Aims: 1. Establish genetic profiles for adult asthma severity and phenotypes by combining the existing STAMPEED dataset with an additional 3000 GWAS from well characterized adult asthmatics; 2. Establish gene expression profiles for adult asthma severity and phenotypes using freshly isolated cells from the target organ (lung) of 200-250 well characterized asthmatics and 50 normal controls; 3. Using supervised and unsupervised approaches, generate combined models integrating genetic, genomic, epigenomic and phenomic characteristics to enhance identification of novel molecular therapeutic targets. Public Health Relevance Statement: The aim of this purpose is to study the underlying genomics of asthma, especially severe asthma to determine why some individuals develop more severe and difficult to treat asthma. Our findings will facilitate the development of new therapies especially targeted for severe asthmatics.