Genetics and Gene Expression Profiling in Asthma

哮喘的遗传学和基因表达谱

基本信息

批准号：
8586533
负责人：
Benjamin Alexander Raby
金额：
$ 82.56万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-03-10 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8586533
关键词：
17q Affect Alleles Allelic Imbalance Arachidonic Acids Asthma Biological Assay Biology Candidate Disease Gene Cell Line Cellular Assay Childhood Asthma Chromatin Chromosomes Chronic DNA DNA-Protein Interaction Data Data Set Development Diet Modification Eczema Eicosanoids Ensure Epidemiology Epithelial Cells Evaluation Factor XIII Fatty Acid Desaturases Fatty Acids Foundations Galactosaminidase Gene Expression Gene Expression Profile Gene Expression Profiling Gene Targeting Genes Genetic Genetic Polymorphism Genetic Variation Genomics Goals Human In Vitro Inflammation Mediators Intake Leukotrienes Linkage Disequilibrium Lipids Lung diseases Maps Meta-Analysis Modeling Modification Molecular Mus Natural History Pathogenesis Phenotype Population Population Heterogeneity Predisposition Progress Reports Protocols documentation Quantitative Trait Loci Regulation Reporter Reporting Resolution Role Serum Solid Susceptibility Gene Testing Translational Research Variant Weight Work atopy base cell type cohort drug development fatty acid metabolism functional genomics genetic association genetic variant genome wide association study genome-wide insight novel respiratory therapeutic development

项目摘要

DESCRIPTION (provided by applicant): Asthma is the most common chronic respiratory lung disease, affecting more than 17 million people in the US; identification of its molecular determinants remains an important priority in translational science. Four years ago, we proposed an integrative genomic approach that combined genome-wide genetic and expression studies (so-called expression quantitative trait locus (eQTL) mapping) to facilitate the identification of novel regulatory genetic variation contributing to the pathogenesis and natural history of asthma. Using this approach, we identified novel regulatory genetic variants that confer susceptibility to asthma at four distinct genomic regions: the chromosome 17q locus (that includes the genes ZPBP2, GSDMB and ORMDL3); the Fatty Acid Desaturase locus (FADS1 & FADS2); the N-acetyl galactosaminidase (NAGA) locus, and the factor XIII A subunit (F13A1) locus. We now propose to extend these studies with the goals of (1) mapping additional regulatory variants that contribute to the pathogenesis of asthma; (2) identifying the specific functional regulatory variants underlying the genetic associations with asthma; and (3) characterizing the functional role of these candidate genes in the development of asthma. In Specific Aim 1 we will extend our previous work in the integrative genomics by performing a first of its kind eQTL meta-analysis using data from four large existing datasets of more than 4,000 subjects of diverse ancestry. Results from this effort will be used to reinterpret a meta-analysis of asthma genome-wide association studies. Associations will be replicated in three additional asthma cohorts (n E12,000). In Specific Aim 2, we will perform functional fine-mapping of three of the novel asthma loci (FADS2, NAGA and F13A1) in human bronchial epithelial cells and related cell types by means of allelic imbalance screens, chromatin-based DNA-DNA and DNA-protein interaction studies, and allele specific reporter assays. Confirmed functional variants will be tested for genetic association with asthma in the EVE Consortium cohorts. In Specific Aim 3, we will conduct a functional evaluation of the FADS2 gene in an established murine model, with confirmation of the molecular mechanisms using in vitro cellular assays in both murine- and human-derived human bronchial epithelial cells. This project has high potential to precisely localize functional genetic variants contributing to the pathogenesis of asthma, and provide a better understanding of the role of these genes in the pathogenesis of asthma, thereby establishing a solid foundation for new drug development aimed at modifying their aberrant gene expression.

描述（由申请人提供）：哮喘是最常见的慢性呼吸道肺部疾病，影响了美国超过1700万人；识别其分子决定因素仍然是转化科学的重要优先级。四年前，我们提出了一种综合基因组方法，该方法将全基因组遗传研究和表达研究（所谓的表达定量性状基因座（EQTL）映射）结合在一起，以促进鉴定新的调节遗传变异，这有助于有助于哮喘的发病机理和自然史。使用这种方法，我们确定了在四个不同的基因组区域中赋予哮喘易感性的新型调节遗传变异：染色体17Q基因座（包括ZPBP2基因ZPBP2，GSDMB和ORMDL3）；脂肪酸去饱和酶基因座（FADS1＆FADS2）； N-乙酰基半乳酰胺酶（NAGA）基因座和XIII A亚基（F13A1）基因座。现在，我们建议将这些研究扩展到（1）绘制有助于哮喘发病机理的其他调节变体的目标；（2）识别遗传关联与哮喘的特定功能调节变体；（3）表征这些候选基因在哮喘发育中的功能作用。在特定目标1中，我们将使用来自四个大型现有数据集的数据集中的数据进行第一个eqtl荟萃分析，从而扩展了以前的基因组学中的先前工作。这项工作的结果将用于重新解释哮喘全基因组关联研究的荟萃分析。协会将在另外三个哮喘同龄人（N E12,000）中复制。在特定的目标2中，我们将通过等位基因失衡筛选，基于染色体的DNA-DNA和DNA-蛋白质相互作用研究以及等位基因的细胞蛋白研究，以及等位基因的报告研究，以及等位基因的细胞类型，对人支气管上皮细胞和相关细胞类型进行三个新型哮喘基因座（FADS2，NAGA和F13A1）的功能精细映射。确认的功能变异将在夏娃联盟队列中测试与哮喘的遗传关联。在特定的目标3中，我们将在既定的鼠模型中对FADS2基因进行功能评估，并在鼠类和人类衍生的人支气管上皮细胞中使用体外细胞测定法确认了分子机制。该项目具有很高的潜力，可以精确定位有助于哮喘发病机理的功能性遗传变异，并更好地理解这些基因在哮喘发病机理中的作用，从而为新药开发建立了旨在修饰其异常基因表达的新药物开发基础。