Linking Genetics, Genomics and Phenomics to Better Understand Asthma Severity

描述(由申请人提供)： 重症哮喘是一种由相关临床表型组成的异质性疾病，会产生高水平的发病率、死亡率和医疗费用。这种疾病的复杂性和异质性限制了临床的进步。然而，自2003年以来，NHLBI重症哮喘研究计划(SARP)已经成功招募了1000多名哮喘患者，其中包括近600名重症哮喘患者。这一重大机遇将使我们能够将以前和正在进行的全基因组关联研究(GWAS)与它们的分子图谱以及以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，支气管镜检查是对SARP参与者进行的常规检查。来自这些研究的上皮刷子和支气管肺泡灌洗(BAL)细胞将接受微阵列分析，以形成基因和表型之间的生物联系。这项建议的总体目标是建立世界上最广泛的关于各种表型/严重程度的成人哮喘患者的Gwas数据集，使用与疾病相关的细胞(肺细胞)来开发这些受试者的子集的分子图谱，然后将遗传和基因组数据联系起来，以极大地加快确定与治疗相关的靶向途径。潜在的假设是，肺细胞基因的表达受遗传背景(GWAS)和环境(表观遗传学特征)的调节，将跟踪有偏见和无偏见的临床表型，以加快哮喘治疗新方法的开发。为了验证这一假设，对与哮喘相关的细胞、肺细胞中的基因表达模式的分析将与相同患者及其临床表型的全基因组SNP图谱相结合。新的基因模块将被识别出来，它们表征、定义并可能机械地解释每一种表型的不同疾病模式。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3个具体目标：1.通过将现有的STAMPEED数据集与另外3000个来自特征良好的成人哮喘患者的GWA相结合，建立成人哮喘严重程度和表型的基因图谱；2.使用从200-250个特征良好的哮喘患者和50名正常对照的靶器官(肺)中新鲜分离的细胞，建立成人哮喘严重性和表型的基因表达谱；3.使用监督和非监督方法，生成整合了遗传、基因组、表观基因组和表观遗传学特征的组合模型，以加强对新的分子治疗靶点的识别。 公共卫生相关声明： 这一目的的目的是研究哮喘，特别是重症哮喘的潜在基因组学，以确定为什么有些人会发展成更严重和更难治疗的哮喘。我们的发现将促进专门针对严重哮喘患者的新疗法的开发。

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.