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

基本信息

批准号：
8676643
负责人：
PETER R PARHAM
金额：
$ 46.88万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
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/8676643
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 Data Databases Developing Countries Development Diagnostic Disease Ensure Equilibrium Evolution Family Gene Duplication Gene Family Genes Genetic Genetic Polymorphism Genetic Recombination Genetic Variation Genomic DNA 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

项目摘要

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.

描述（由申请人提供）：4.7Mbp HLA区域包含许多免疫系统基因，特别是参与检测感染，恶性肿瘤和移植组织的存在的人，并提供与淋巴细胞受体相互作用的配体以触发人生和适应性免疫反应。这些基因中的某些基因具有非常多的多态性，可以依赖于均衡选择，并且与广泛的感染性，自身免疫性和过敏性疾病相关，并且是移植抑制的主要仲裁者，移植物反相 - 造血干细胞移植和妊娠综合征后的疾病。尽管HLA地区的重要性广泛，并且其在与许多人的遗传关联中的主导地位疾病，没有进行系统地研究HLA单倍型序列变化的努力。我们建议通过开发一种可以准确且具有成本效益的方式来表征数百种单倍型的方法来做到这一点。免疫学方面的最新进展表明，具有灵长类动物特异性并在人类中达到其最大复杂性的杀手型免疫球蛋白样受体是HLA I类的自然杀伤（NK）细胞受体，是人类先天免疫防御和繁殖的相互作用。 HLA I级和KIR都是高度多态性的，但是在不同的染色体上隔离是一种非凡的情况，因为几乎所有个体都表达了缺乏的配体受体，反之亦然。 KIR多态性越来越多地与疾病有关，与HLA I类结合使用，比单独的配体或受体可以产生更强的关联。由于这些功能性和遗传相互作用，我们还将从对HLA单倍型进行测序的同一个个体的KIR单倍型（130-250kbp）序列。拟议的研究将涵盖人口的种族多样性，并将检查与HLA/KIR因素有关的两种类型的疾病。该项目的核心是开发新方法，这些方法将提高对生物学理解 HLA和KIR的多样性达到更高的水平，也将适用于临床HLA和KIR分型作为疾病的诊断，并改善了治疗移植的供体选择。