Genetics and Gene Expression Profiling in Asthma

哮喘的遗传学和基因表达谱

• 批准号: 7839331
• 负责人: Benjamin Alexander Raby
• 金额: $ 28.92万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-12-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7839331
• 关键词: 3' Flanking Region; Affect; African American; Asthma; Bioinformatics; Biological; CD4 Positive T Lymphocytes; Canada; Candidate Disease Gene; Cataloging; Catalogs; Caucasians; Caucasoid Race; Childhood Asthma; Clinical; Costa Rica; DNA; DNA Resequencing; Data; Development; Diagnostic; Disease; Epidemiology; Family; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genie; Genomics; Genotype; IgE; Lead; Linear Models; Linkage Disequilibrium; Metabolic Pathway; Methods; Modeling; Molecular; Molecular Profiling; Molecular Target; Morbidity - disease rate; Napping; Natural History; Parents; Patients; Phenotype; Population Genetics; Predisposition; Prevalence; Process; RNA; Regulation; Research Personnel; Respiratory physiology; Sampling; Serum; Severities; Single Nucleotide Polymorphism; Single Nucleotide Polymorphism Map; Staging; Techniques; Technology; Testing; Therapeutic; Transcript; United States; Variant; base; clinical phenotype; cohort; functional genomics; genetic association; genetic variant; genome-wide; high throughput technology; novel; peripheral blood; prognostic; programs; therapeutic target; tool; young adult

DESCRIPTION (provided by applicant): Asthma affects over 17 million people in the United States. Nearly one-half of patients do not respond to treatment with the most effective classes of currently available asthma therapeutics. In order to develop novel therapies, a comprehensive catalog of modifiable genetic targets and their metabolic pathways that contribute to the development and progression of asthma is needed. Genomic technologies including expression microarrays and high-throughput genotyping platforms offer an unprecedented opportunity to advance this process. The overarching premise of this project is that combining gene expression data with population genetics will lead to the identification of critical molecules that contribute to the development and progression of asthma. We will generate genome-wide gene expression profiles from total RNA derived from peripheral blood CD4+ lymphocytes from 370 young adults with asthma of varying severity participating in the Childhood Asthma Management Program Continuation Study (CAMP CS2) to identify differentially expressed gene transcripts that are associated with asthma severity phenotypes. Using DNA samples from these subjects and their parents, we will then genotype single nucleotide polymorphisms (SNPs) mapping to 200 of the most differentially expressed genes and perform family-based genotype-gene-expression association analysis to identify regulatory SNPs (rSNP) that strongly regulate gene expression. Those genes with the strongest evidence of rSNP regulation will be evaluated as asthma candidate genes evaluating whether SNPs in these genes are associated with asthma-related clinical phenotypes. Using this approach we anticipate that we will identify at least 20 genes with significant evidence of cis-acting regulatory genetic variation and that many of these genes will also harbor genetic variation that directly influence asthma susceptibility and severity. Genes with the strongest evidence of association will be evaluated in other family- based asthma cohorts for evidence of replicated association and will be resequenced as part of a SNP- discovery effort to identify functional polymorphisms. We anticipate that by combining gene expression data with population genetics, this project will identify novel genes that harbor genetic variation that influence the natural history of asthma, thereby identifying ideal asthma-candidate genes for possible therapeutic targeting. These findings could ultimately lead to the development of novel therapies and a clinical prognostic test for this common disease.

描述（由申请人提供）：哮喘在美国影响超过1700万人。将近一半的患者对当前最有效的哮喘治疗剂的治疗没有反应。为了开发新的疗法，需要综合的可修改遗传靶标及其代谢途径的综合目录，这些目录需要有助于哮喘的发展和发展。包括表达微阵列和高通量基因分型平台在内的基因组技术为推进这一过程提供了前所未有的机会。该项目的总体前提是，将基因表达数据与种群遗传学相结合，将导致鉴定有助于哮喘发展和进展的关键分子。我们将产生全基因组的基因表达谱，来自来自外周血CD4+淋巴细胞的总RNA，来自370名年轻人，患有不同严重程度的哮喘，参与儿童哮喘管理计划持续研究（CAMP CS2），以鉴定与差异表达的基因转录物，这些基因与AsthmA的严重程度相关。然后，我们将使用来自这些受试者及其父母的DNA样品，然后将基因型单核苷酸多态性（SNP）映射到200个最差异表达的基因，并执行基于家庭的基因型基因表达关联分析，以识别强烈调节基因表达的调节性SNP（RSNP）。那些具有最强RSNP调节证据的基因将被评估为评估这些基因中SNP是否与哮喘相关临床表型相关的哮喘候选基因。使用这种方法，我们预计我们将至少鉴定20个基因，并有大量证据表明调节性遗传变异，其中许多基因还将携带直接影响哮喘易感性和严重性的遗传变异。将在其他基于家庭的哮喘同类群中评估具有最大关联证据的基因，以证明具有复制的关联证据，并将作为SNP-Discovery努力的一部分进行重新公平，以识别功能性多态性。我们预计，通过将基因表达数据与种群遗传学相结合，该项目将确定具有影响哮喘自然史的遗传变异的新基因，从而确定了理想的哮喘cand依基因，以实现可能的治疗靶向。这些发现最终可能导致对这种常见疾病的新疗法发展和临床预后测试。