Structural Genetic Variation in Asthma

描述（由研究者提供）：拷贝数变异（CNVs）是由大的DNA片段组成的结构性遗传变异，其数量在个体之间有所不同。这些大规模得失的重要性直到最近才被认识到：CNVs非常普遍，占总遗传变异的很大一部分，并对表型变异和疾病易感性有很大贡献。在美国，哮喘影响着超过1700万人，是发病率的重要原因。尽管20多个哮喘易感位点的全基因组遗传调查的累积结果已经成功地确定了几个新的哮喘基因，但这些先前的研究都没有评估CNVs在哮喘发病机制中的作用。在对400个哮喘家庭的50万个单核苷酸多态性基因型进行全基因组筛选的初步研究中，我们的研究小组已经确定了几个基因组区域，其中包含与哮喘易感性密切相关的已知结构变异，包括一些先前发现的哮喘基因。根据这些初步数据，我们假设常见的结构基因组变异对多个人群的哮喘患病率具有重要的易感性。我们提出了4个具体目标来检验这一假设。在Specific Aim 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，对患有儿童哮喘的非西班牙裔白人家庭进行基于家族的全基因组关联研究。然后，我们将在技术上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CNV区域。在Specific Aim 2中，我们将在三个独立的哮喘队列（总样本量约为6000名受试者）中重复这些关联，包括西班牙裔白人和非西班牙裔黑人人群。在Specific Aim 3中，我们将对候选基因进行测序，并在哮喘队列中进行后续SNP基因分型和关联检测，以确定2个复制哮喘相关CNV区域中哮喘相关核苷酸的变异。在Specific Aim 4中，我们将评估180例哮喘患者哮喘相关cnv内或附近的候选基因对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，可以识别出对哮喘病理生物学至关重要的新分子靶点。结构遗传变异由大的DNA片段组成，其数量因人而异。该项目旨在确定导致哮喘发展的结构性遗传变异。我们建议在一组儿童哮喘患者中对这种变异进行全基因组调查，对这些区域进行随访，并在代表美国三个主要种族群体的人群中进行复制研究。确定哮喘的遗传决定因素将最终导致新疗法和诊断测试的发展。

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.