Structural Genetic Variation in Asthma

哮喘的结构遗传变异

• 批准号: 8070006
• 负责人: Benjamin Alexander Raby
• 金额: $ 82.2万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8070006
• 关键词: Affect; African American; Asthma; Bioinformatics; Biological; Biological Assay; Candidate Disease Gene; Child; Childhood; Childhood Asthma; Clinical; Complex; Costa Rica; Custom; Cytogenetics; DNA; DNA Resequencing; DNA Sequence Rearrangement; DNA copy number; Data; Development; Diagnostic; Diagnostic tests; Disease; Disease susceptibility; Enzyme-Linked Immunosorbent Assay; Epidemiology; Ethnic Origin; Ethnic group; Family; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Determinism; Genetic Variation; Genomics; Genotype; Health; Hispanics; Human; Individual; Lead; Messenger RNA; Methods; Molecular Target; Morbidity - disease rate; Not Hispanic or Latino; Nucleotides; Oligonucleotide Microarrays; Parents; Pathogenesis; Phenotype; Population; Predisposition; Prevalence; Proteins; RNA; Research Personnel; Resolution; Risk; Role; Sample Size; Sampling; Single Nucleotide Polymorphism; Statistical Methods; Surveys; Testing; Time; Transcript; United States; Validation; Variant; base; cohort; cost; density; design; follow-up; genetic variant; genome wide association study; genome-wide; high throughput technology; human disease; lymphoblastoid cell line; novel; prognostic; programs; protein expression; structural genomics; therapeutic target; tool

DESCRIPTION (provided by investigator): Copy number variants (CNVs) are structural genetic variants consisting of large DNA segments whose number varies between individuals. The importance of these large-scale gains and losses has only recently been recognized: CNVs are extremely common, represent a large proportion of the total genetic variation, and contribute substantially to phenotypic variation and disease susceptibility. Asthma affects over 17 million people in the U.S. and represents a significant cause of morbidity. Though the cumulative results of more than 20 genome-wide genetic surveys for asthma susceptibility loci have successfully identified several novel asthma genes, none of these prior studies have assessed the role of CNVs in the pathogenesis of asthma. In preliminary studies using a genome-wide, family-based screen of ~500,000 single nucleotide polymorphism genotypes in 400 families with asthma, our group has identified several genomic regions harboring known structural variation that are strongly associated with asthma susceptibility, including several containing previously identified asthma genes. From these preliminary data, we hypothesize that common structural genomic variants confer important susceptibility to asthma prevalence in multiple populations. We propose 4 Specific Aims to test this hypothesis. In Specific Aim 1 we will perform a family-based genome-wide association study in non-Hispanic white families with childhood asthma using high-resolution CNV genotype data generated with Affymetrix SNP6.0 microarrays. We will then technically validate the top 20 asthma- associated CNV regions identified using high-density oligonucleotide arrays and quantitative PCR methods. In Specific Aim 2, we will replicate these associations in three independent asthma cohorts (total sample size ~6000 subjects), including Hispanic white and non-Hispanic black populations. In Specific Aim 3 we will sequence candidate genes and perform follow-up SNP genotyping and association testing in the asthma cohorts to identify asthma-related nucleotide variation in 2 replicated asthma-associated CNV regions. In Specific Aim 4 we will evaluate the impact of asthma-associated CNVs on mRNA gene expression and target protein expression levels for candidate genes residing within or near the asthma-associated CNVs in 180 asthmatics. This project has high potential to identify novel molecular targets critical to the pathobiology of asthma for therapeutic targeting. PUBLIC HEALTH RELEVANCE Structural genetic variants consist of large DNA segments whose number varies between individuals. This project aims to identify structural genetic variation that contributes to the development of asthma. We propose to conduct a genome-wide survey for such variation in a cohort of childhood asthmatics, with follow-up characterization of these regions and replication studies in populations representing the three major ethnic groups in the United States. Defining the genetic determinants of asthma will ultimately lead to the development of novel therapies and diagnostic tests.

描述（由研究者提供）：拷贝数变体（CNV）是结构性遗传变异，由大型DNA片段组成，其数量在个体之间有所不同。这些大规模收益和损失的重要性直到最近才被认识到：CNV极为普遍，代表了总遗传变异的很大比例，并且对表型变异和疾病敏感性产生了重大贡献。哮喘影响美国超过1700万人，代表了发病率的重要原因。尽管针对哮喘易感性基因座的20多个全基因组遗传调查的累积结果成功地鉴定出了几个新的哮喘基因，但这些先前的研究都没有评估CNV在哮喘发病机理中的作用。在使用全基因组的初步研究中，在400个患有哮喘的家族中，基于全基因组的基于〜500,000个单核苷酸多态性基因型，我们的小组已经鉴定出几个具有与哮喘易感性密切相关的已知结构变异的基因组区域，其中几种含有先前鉴定的哮喘基因。从这些初步数据中，我们假设常见的结构基因组变体赋予多个人群中哮喘患病率的重要敏感性。我们提出了4个特定的目的来检验这一假设。在特定目标1中，我们将使用Affymetrix SNP6.0微阵列生成的高分辨率CNV基因型数据对非西班牙裔白人家庭进行基于家庭的全基因组关联研究。然后，我们将技术验证使用高密度寡核苷酸阵列和定量PCR方法鉴定的前20个哮喘相关的CNV区域。在特定的目标2中，我们将在三个独立的哮喘同龄人（总样本尺寸约6000名受试者）中复制这些关联，包括西班牙裔白人和非西班牙裔黑人种群。在特定的目标3中，我们将在哮喘同龄人中对候选基因进行测序，并执行随访的SNP基因分型和关联测试，以鉴定与哮喘相关的2个复制哮喘相关的CNV区域中与哮喘相关的核苷酸变异。在特定目标4中，我们将评估与180种哮喘患者中与哮喘相关基因内或附近的候选基因的哮喘相关CNV对MRNA基因表达和靶蛋白表达水平的影响。该项目具有很高的潜力，可以识别对治疗靶向哮喘病理学至关重要的新分子靶标。公共卫生相关性结构性遗传变异包括大型DNA片段，其数量在个体之间有所不同。该项目旨在确定有助于哮喘发展的结构性遗传变异。我们建议对童年哮喘患者的这种差异进行整个基因组的调查，并在这些地区进行了随访，并在代表美国三个主要种族的人群中进行了复制研究。定义哮喘的遗传决定因素最终将导致新的疗法和诊断测试的发展。