Insights into immune-related disease 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: 8292223
• 负责人: PETER R PARHAM
• 金额: $ 50.36万
• 依托单位: STANFORD UNIVERSITY
• 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 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8292223
• 关键词: Affect; African; Age; Alleles; Allergic Disease; Animal Model; Antigens; Asia; Autoimmune Diseases; Biological; Blindness; Caucasians; Caucasoid Race; Cells; Cessation of life; Characteristics; Child; Chromosomes; Clinical; Communicable Diseases; Complex; DNA; Data; Databases; Developing Countries; Development; Diagnostic; Disease; Ensure; Equilibrium; Evolution; Family; Gene Duplication; Gene Family; Genes; Genetic; Genetic Polymorphism; Genetic Recombination; Genetic Variation; Genomics; Graft Rejection; HLA Antigens; Haplotypes; Health; Hematopoietic Stem Cell Transplantation; Human; Human Genome; Immune; Immune response; Immune system; Immunogenetics; Immunoglobulin Variable Region; Immunoglobulins; Immunology; Individual; Infection; Killer Cells; Knowledge; Lead; Ligands; Linkage Disequilibrium; Lymphocyte; Lymphocyte Function; Malignant Neoplasms; Mediating; Methods; Morbidity - disease rate; Mothers; Mus; NK cell receptor NKB1; Natural Immunity; Natural Killer Cells; Nature; Outcome; Patients; Point Mutation; Population; Population Group; Predisposition; Pregnancy; Primates; Principal Investigator; Receptor Gene; Reproduction; Research; Resistance; Resolution; Running; Serological; Staging; Surveys; Syndrome; System; T-Cell Receptor; T-Lymphocyte; Techniques; Therapeutic; Time; Translating; Transplantation; Transplanted tissue; Variant; Vasculitis; Woman; cohort; cost effective; design; flexibility; genetic association; human disease; immune function; improved; insight; mortality; patient population; pregnancy disorder; public health relevance; receptor; reproductive success; tool

DESCRIPTION (provided by applicant): The 4.7Mbp HLA region contains numerous immune-system genes, notably those involved in detecting the presence of infection, malignancy and transplanted tissue and providing ligands that interact with lymphocyte receptors to trigger human innate and adaptive immune responses. Some of these genes are extraordinarily polymorphic, subject to balancing selection and associated with resistance/susceptibility to a wide range of infectious, autoimmune and allergic diseases, as well as being major arbiters of transplant rejection, graft-versus- disease following hematopoietic stem cell transplantation, and pregnancy syndromes. Despite the wide-ranging importance of the HLA region, and its dominance in the genetic associations with many human diseases, no concerted effort to systematically study the variation in HLA haplotype sequences has been undertaken. We propose to do this by developing a method that will allow characterization of hundreds of haplotypes in an accurate and cost-effective manner. Recent advances in immunology, have shown that killer-cell immunoglobulin-like receptors, which are primate-specific and reach their utmost complexity in the human species, are natural killer (NK) cell receptors for HLA class I, interactions that are formative in human innate immune defense and reproduction. That both HLA class I and KIR are highly polymorphic, but segregate on different chromosomes, is an extraordinary situation, because almost all individuals express receptors for ligands that they lack and vice versa. KIR polymorphism is increasingly being associated with disease, and in combination with HLA class I can yield stronger associations than either ligand or receptor alone. Because of these functional and genetic interactions, we will also sequence KIR haplotypes (130-250Kbp) from the same individuals whose HLA haplotypes are sequenced. The proposed research will cover the ethnic diversity of the human population, and will examine two types of disease that are associated with HLA/KIR factors. Central to this project is development of new methods that will advance biological understanding of HLA and KIR diversity to much higher level, and will also be applicable to clinical HLA and KIR typing as diagnostics for disease and improving the choice of donors for therapeutic transplantation. PUBLIC HEALTH RELEVANCE (provided by applicant): The human leukocyte antigen (HLA) complex and the killer cell immunoglobulin-like receptor (KIR) gene family are functionally interacting genomic regions associated with a wide range of human infectious and autoimmune diseases, as well as reproductive success and the outcome of therapeutic transplantation. In this project we will precisely define HLA and KIR genetic variation within the human population. This information will enable the identification of disease-causing genes and their mechanism of action.

描述(申请人提供)：4.7MBP的人类白细胞抗原区域包含许多免疫系统基因，特别是那些参与检测感染、恶性肿瘤和移植组织的存在，并提供与淋巴细胞受体相互作用的配体以触发人类先天和获得性免疫反应的基因。这些基因中的一些具有极高的多态，受到平衡选择的影响，与对一系列传染病、自身免疫性疾病和过敏性疾病的抵抗力/易感性有关，也是移植排斥、移植物抗宿主病的主要仲裁者。 造血干细胞移植后的疾病和妊娠综合征。尽管人类白细胞抗原区域具有广泛的重要性，而且它在与许多人类的遗传联系中占据主导地位 对于疾病，还没有共同努力来系统地研究人类白细胞抗原单倍型序列的变异。我们建议通过开发一种方法来实现这一点，该方法将允许以准确和具有成本效益的方式表征数百种单倍型。免疫学的最新进展表明，杀伤细胞免疫球蛋白样受体是人类先天免疫防御和生殖中形成的自然杀伤(NK)细胞受体，它是灵长类动物特有的，在人类物种中达到最高的复杂性。HLAI类和KIR都是高度多态的，但分离在不同的染色体上，这是一种特殊的情况，因为几乎所有的个体都表达他们缺乏的配体的受体，反之亦然。KIR基因多态性与疾病的关联性越来越强，与人类白细胞抗原I类结合时，可以产生比单独使用配体或受体更强的关联性。由于这些功能和遗传上的相互作用，我们还将对测序的同一个体的KIR单倍型(130-250Kbp)进行测序。这项拟议的研究将涵盖人类人口的种族多样性，并将检查与人类白细胞抗原/KIR因素相关的两种疾病。这个项目的核心是开发新的方法，以促进对 人类白细胞抗原(HL A)和人类免疫缺陷病毒(KIR)的基因分型将提高到更高的水平，也将适用于临床的人类白细胞抗原(HL A)和人类免疫缺陷病毒(KIR)分型，作为疾病的诊断和改善治疗性移植供体的选择。 公共卫生相关性(申请人提供)：人类白细胞抗原(HLA)复合体和杀伤细胞免疫球蛋白样受体(KIR)基因家族是与广泛的人类传染病和自身免疫性疾病相关的功能相互作用的基因组区域，以及生殖成功和治疗性移植的结果。在这个项目中，我们将精确定义人类群体中的人类白细胞抗原和KIR基因变异。这些信息将使识别致病基因及其作用机制成为可能。