Insights Into Immune-Related Diseases Born from Population Genomics

对群体基因组学产生的免疫相关疾病的见解

• 批准号: 10449317
• 负责人: Paul John Norman
• 金额: $ 72万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-06 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10449317
• 关键词: Address; Affect; African American; African ancestry; Algorithms; Alleles; Allergic; Allergic Disease; American; Amerindian; Antibody Formation; Asthma; Atopic Dermatitis; Autoimmune; Autoimmune Diseases; Bioinformatics; Cell physiology; Cell-Mediated Cytolysis; Cells; Cessation of life; Child; Chromosome 19; Chromosome 6; Chronic; Complex; Country; DNA; Data; Development; Disease; Education; European; Exhibits; Extrinsic asthma; Family; Frequencies; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genomic Segment; Genomics; Genotype; Goals; Graph; HLA Antigens; Haplotypes; Health; High Prevalence; Hispanic; Histocompatibility Antigens Class I; Histocompatibility Antigens Class II; Homozygote; Human; Human Genome; Hypersensitivity; IgE; Immune; Immune response; Immunity; Immunoglobulins; Immunologics; Incidence; Individual; Infection; Inflammatory; Intervention; Killer Cells; Knowledge; Lead; Link; Major Histocompatibility Complex; Major Histocompatibility Complex Gene; Measures; Mediating; Medical; Methodology; Methods; Natural Immunity; Natural Killer Cells; Nature; Outcome; Pathway interactions; Patients; Population; Population Group; Predisposition; Pregnancy; Prevalence; Production; Prognosis; Property; Proteins; Receptor Cell; Reproduction; Resistance; Resolution; Respiratory physiology; Role; Serum; Severities; Signal Transduction; Specificity; Structure; Study Subject; Syndrome; T-Lymphocyte; Testing; Transplantation; Variant; Work; adaptive immunity; allergic response; arm; bioinformatics pipeline; causal variant; chronic inflammatory lung disease; cohort; combinatorial; cost effective; cost estimate; design; flexibility; genetic association; genome-wide; hematopoietic cell transplantation; insight; novel; pathogen; pressure; receptor; reproductive success; response; targeted sequencing; tool; user-friendly

The major histocompatibility complex (MHC) of chromosome 6 and the killer cell immunoglobulin-like receptor (KIR) region of chromosome 19 are among the most variable and medically important regions of the human genome. The MHC encodes the highly polymorphic human leukocyte antigens (HLA) that are central to immunity and reproduction, and another 140 genes, many with supporting roles in immunity. A subset of HLA allotypes interact with KIR, which are expressed by Natural Killer (NK) cells, modulating their activities in initiating and controlling the immune response. Specific alleles as well as compound genotypes of MHC and KIR have been implicated in susceptibility or resistance to infectious, allergic, inflammatory, and autoimmune diseases, as well as to outcomes of hematopoietic cell transplantation and reproductive success. Asthma is one of the most common inflammatory diseases affecting over 30 million Americans, with 5,000 deaths per year. Atopic dermatitis (AD) occurs in 20% of children and predisposes to asthma. Together they pose significant burden on the health and economy of the country, costing an estimated $82 billion per year. Common to these diseases are a strong genetic component, an environmental or infection trigger, and complex interplay between innate and adaptive immunity. Accordingly, there are long standing associations with MHC diversity and asthma susceptibility, which have been confirmed by recent large scale genome studies, but they remain poorly refined due to the complexity and difficulty of sequencing the region. For the same reasons, the KIR region has never been studied to high resolution in AD or asthma. To overcome difficulties in analyzing these complex genomic regions, we developed a targeted sequencing and bioinformatics approach to analyze MHC and KIR regions at high throughput and resolution. In Aim 1 we will use the methods to analyze the complete MHC genomic regions from 5,000 patients and 5,000 controls, investigating each gene as well as their pathways of interaction. We will study well defined cohorts of individuals from diverse backgrounds, focusing on African ancestry, which associates with the highest prevalence and poorest outcome. We will sequence the entire MHC with high accuracy to determine the full context of any variants associated with asthma susceptibility. In Aim 2 we will perform the first high resolution analysis of NK cell diversity in asthma, supported by directed functional analyses of the activity and specificity of NK cells in disease. By combining high- resolution analysis of KIR and HLA genes with known functional properties of these interactions, we will be able to determine the role of NK cell diversity in asthma. To enhance our methodology and solve the most difficult genomic structural variation, in Aim 3 we will design and implement the first methods to target long-read sequencing specifically to the MHC and KIR regions, and a bioinformatics pipeline to annotate and analyze the data. In doing so we will expand the MHC reference set and tools for large-scale analysis. Through these three Aims we will accelerate understanding of the natural immunity of atopic asthma and begin to identify novel targets for intervention

染色体6和杀伤细胞免疫球蛋白样受体的主要组织相容性复合物（MHC） （KIR）19染色体的区域是人类最大和最重要的区域之一 基因组。 MHC编码具有免疫力核心的高度多态性人白细胞抗原（HLA） 和繁殖，还有140个基因，许多基因在免疫中具有支持作用。 HLA同型的子集 与KIR相互作用，KIR由天然杀手（NK）细胞表达，调节其启动和 控制免疫反应。 MHC和KIR的特定等位基因以及复合基因型已经 还与感染性，过敏性，炎症性和自身免疫性疾病有关 关于造血细胞移植和生殖成功的结果。 哮喘是影响超过3000万美国人的最常见炎症性疾病之一，5,000人死亡 每年。特应性皮炎（AD）发生在20％的儿童中，并且患有哮喘。他们一起摆姿势 该国的健康和经济负担很大，估计每年耗资820亿美元。常见的 这些疾病是强大的遗传成分，环境或感染触发因素和复杂的相互作用 在先天和适应性免疫之间。因此，与MHC多样性有长期的联系 以及最近大规模基因组研究证实的哮喘易感性，但它们仍然存在 由于对区域的复杂性和难度，精致的精致不佳。由于相同的原因，KIR地区 从未对AD或哮喘进行高分辨率研究。 为了克服分析这些复杂基因组区域的困难，我们开发了一个靶向测序和 生物信息学方法以高通量和分辨率分析MHC和KIR区域。在AIM 1中，我们将使用 分析来自5,000名患者和5,000例对照的完整MHC基因组区域的方法，研究 每个基因及其相互作用途径。我们将研究来自不同的人群的明确定义的人群 背景是关注非洲血统，该血统与最高的患病率和最差的结果相关联。 我们将以高精度对整个MHC进行对，以确定与 哮喘的敏感性。在AIM 2中，我们将对哮喘中NK细胞多样性进行第一个高分辨率分析， 由NK细胞在疾病中的活性和特异性的定向功能分析支持。通过高 - 具有这些相互作用的已知功能特性的KIR和HLA基因的分辨率分析，我们将能够 确定NK细胞多样性在哮喘中的作用。增强我们的方法论并解决最困难的方法 基因组结构变化，在AIM 3中，我们将设计和实施第一个针对长阅读的方法 专门针对MHC和KIR区域进行测序，以及一个生物信息学管道，以注释和分析 数据。为此，我们将扩展MHC参考集和用于大规模分析的工具。通过这三个 目的我们将加速对特应性哮喘的自然免疫的理解，并开始识别新的靶标 干预