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以触发人类先天和适应性免疫反应的配体的基因。其中一些基因是非常多态的，受平衡选择的影响，与对广泛的感染性、自身免疫性和过敏性疾病的抗性/易感性相关，同时也是移植排斥反应、移植物抗-反应的主要仲裁者