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: 7992673
• 负责人: PETER R PARHAM
• 金额: $ 55.9万
• 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/7992673
• 关键词: Affect; African; Age; Alleles; Allergic Disease; Animal Model; Antigens; Asia; Autoimmune Diseases; Autoimmune Process; Biological; Blindness; Caucasians; Caucasoid Race; Cells; Cessation of life; Characteristics; Child; Chromosomes; Clinical; 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; design; flexibility; genetic analysis; 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（由申请人提供）：4.7Mbp HLA 区域包含许多免疫系统基因，特别是那些涉及检测感染、恶性肿瘤和移植组织的存在以及提供与淋巴细胞受体相互作用以触发人类先天性和适应性免疫反应的配体的基因。其中一些基因具有非凡的多态性，受到平衡选择的影响，与对多种感染性、自身免疫性和过敏性疾病的抵抗/易感性相关，并且是移植排斥、移植物抗-移植物抗性的主要仲裁者。 造血干细胞移植后的疾病和妊娠综合征。尽管 HLA 区域具有广泛的重要性，并且在与许多人类的遗传关联中占据主导地位， 疾病，尚未采取一致的努力来系统地研究 HLA 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目标，该方法能够以准确且经济高效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灵长类动物特异性的，在人类中达到最复杂的程度，是 HLA I 类的自然杀伤 (NK) 细胞受体，这种相互作用在人类中形成先天免疫防御和繁殖。 HLA I 类和 KIR 都具有高度多态性，但在不同染色体上分离，这是一种特殊的情况，因为几乎所有个体都表达他们缺乏的配体受体，反之亦然。 KIR 多态性越来越多地与疾病相关，并且与 I 类 HLA 结合可以产生比单独配体或受体更强的关联。由于这些功能和遗传相互作用，我们还将对 HLA 单倍型已测序的同一个体的 KIR 单倍型 (130-250Kbp) 进行测序。拟议的研究将涵盖人类的种族多样性，并将检查与 HLA/KIR 因子相关的两种类型的疾病。该项目的核心是开发新方法，以促进生物学对 HLA和KIR多样性达到更高水平，也将适用于临床HLA和KIR分型作为疾病诊断并改善治疗性移植供体的选择。 公共卫生相关性（由申请人提供）：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) 基因家族是功能上相互作用的基因组区域，与多种人类传染病和自身免疫性疾病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 HLA 和 KIR 遗传变异。这些信息将有助于识别致病基因及其作用机制。