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: 9100613
• 负责人: PETER R PARHAM
• 金额: $ 66.58万
• 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 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9100613
• 关键词: Adopted; Affect; Africa; African; African American; Algorithms; Alleles; Allergic; American; Antibodies; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Bioinformatics; Cell Line; Cells; Chromosomes; Chromosomes, Human, Pair 6; Clinical; Collaborations; Communicable Diseases; Complement; Complex; DNA; Data; Dermatomyositis; Developing Countries; Development; Disease; Disease Outcome; Ensure; Enzymes; Ethnic Origin; European; Family; Fathers; Fetus; Funding; Gene Family; Genes; Genetic Polymorphism; Genome Mappings; Genomic Segment; Genomics; Genotype; HLA Antigens; Haplotypes; Health; Human; Human Genome; Immune; Immune response; Immunogenetics; Immunoglobulin Variable Region; Immunoglobulins; Individual; Infection; Inflammatory; Inherited; International; Killer Cells; Laboratories; Length; Life; Ligands; Link; Lymphocyte Function; Maps; Maternal Mortality; Mediating; Methods; Modeling; Morbidity - disease rate; Mothers; Mutation; Myopathy; Natural Immunity; Natural Killer Cells; Outcome; Pathology; Patients; Phase; Placentation; Population; Population Genetics; Pre-Eclampsia; Predisposition; Pregnancy; Procedures; Process; Receptor Gene; Registries; Reproduction; Resistance; Resolution; Risk; Sampling; Techniques; Time; Tissues; Transplantation; Variant; Woman; adaptive immunity; base; clinical phenotype; cohort; cost effective; disease phenotype; genetic association; genomic data; hematopoietic cell transplantation; high risk; human disease; immune function; improved; insight; mortality; novel; receptor; reproductive success; research study; response; technology development; therapy outcome; tool

 DESCRIPTION (provided by applicant): The human leukocyte antigen (HLA) complex encodes multiple highly polymorphic molecules that are central to immune function. Certain of these molecules act as ligands for the equally polymorphic killer cell immunoglobulin-like receptors (KIR). Specific alleles as well as compound genotypes from the HLA and KIR genomic regions 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. For many of these associations it has been difficult to identify the causative alleles, due to the complexity of these genomic regions. Previous studies isolating causative mutations required multiple approaches and lengthy procedures. In contrast, we have developed a high-throughput, cost-effective method that allows us to capture and sequence the complete haplotypes of both the HLA (4.8 Mb) and KIR (100-250 kb) regions. We will employ this method in Aim 1 to study dermatomyositis (DM), an autoimmune idiopathic myopathy. DM has a well-defined, poorly-understood, association with HLA. Implicating KIR involvement are changes in HLA class I expression in diseased tissue and the contribution of innate immunity to the disease process. Specific clinical phenotypes track with the presence of specific autoantibodies. We will obtain complete HLA and KIR haplotype sequences from patients in each of the major clinical groups and compare them to those from healthy HLA-matched controls. Comparisons will be made within and between groups to identify individual markers or compound genotypes that cause or exacerbate disease. In Aim 2 we will examine the association of HLA and KIR polymorphism with preeclampsia, a systemic hypertensive condition of pregnancy and a leading cause of maternal mortality, particularly in women of African origin; in the US, African-American women are up to five times more likely to suffer from preeclampsia. A cohort of African women and their babies will be analyzed, complementing our study of European women undertaken in the current round of funding. Low- resolution analysis of the African cohort has replicated the finding observed in the European cohort, namely that highest risk for preeclampsia is in pregnancies where the mother has two copies of the KIR A haplotype and the fetus has inherited the C2 ligand from the father. In contrast to the European cohort, where KIR2DS1 is protective, in the African cohort protection is associated with centromeric KIR2DS5, a gene unique to African populations. Unknown is whether polymorphism at the centromeric KIR2DS5 gene in the African populations affords functional replacement for the lack of KIR2DS1. Other linked and functionally interacting loci that may contribute to reproductive success are HLA-G in the HLA region and KIR2DL4 in the KIR region. By obtaining complete sequence for the HLA and KIR haplotypes in the preeclampsia and control cohorts we will be able to assess the contribution of both individual and compound features to disease outcome. Aims 3 and 4 will continue to improve and extend the bioinformatic (Aim 3) and technical (Aim 4) components of our method.

 描述（由申请人提供）：人类白细胞抗原（HLA）复合物编码对免疫功能至关重要的多种高度多态性分子，其中某些分子充当同样多态性杀伤细胞免疫球蛋白样受体（KIR）的配体。以及 HLA 和 KIR 基因组区域的复合基因型与感染性、过敏性、炎症性和自身免疫性疾病的易感性或抵抗性以及结果有关由于这些基因组区域的复杂性，对于许多这些关联来说，很难确定致病等位基因。相反，我们开发了多种方法和漫长的程序。我们将采用这种高通量、经济有效的方法来捕获和测序 HLA (4.8 Mb) 和 KIR (100-250 kb) 区域的完整单倍型。目的 1 中的方法研究皮肌炎 (DM)，这是一种自身免疫性特发性肌病，其与 HLA 的关系尚不明确，但涉及 KIR 的是患病组织中 HLA I 类表达的变化以及先天免疫的贡献。我们将从每个主要临床组的患者中获得完整的 HLA 和 KIR 单倍型序列并进行比较。在目标 2 中，我们将检查 HLA 和 KIR 多态性与先兆子痫（一种全身性高血压）的关联。妊娠状况和孕产妇死亡的主要原因，特别是在美国的非洲裔妇女中，非洲裔美国妇女患先兆子痫的可能性是非洲妇女及其婴儿的五倍。将进行分析，补充我们在本轮资助中对欧洲妇女进行的研究，对非洲队列的低分辨率分析重复了在欧洲队列中观察到的发现，即先兆子痫的最高风险是母亲怀有两个孩子的情况。 KIR A 单倍型的拷贝，并且胎儿从父亲那里继承了 C2 配体。与欧洲群体中 KIR2DS1 具有保护作用相反，在非洲群体中，保护作用与着丝粒 KIR2DS5（一种独特的基因）相关。尚不清楚非洲人群中着丝粒 KIR2DS5 基因的多态性是否可以替代 KIR2DS1 的缺失。其他可能有助于生殖成功的连锁和功能相互作用位点是 HLA 区域的 HLA-G 和 HLA 区域的 KIR2DL4。 KIR 区域。通过获得先兆子痫和对照队列中 HLA 和 KIR 单倍型的完整序列，我们将能够评估个体和复合特征对疾病的贡献。目标 3 和 4 将继续改进和扩展我们方法的生物信息学（目标 3）和技术（目标 4）组成部分。