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：
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
项目类别：
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

项目摘要

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（由适用提供）：人白细胞抗原（HLA）复合物编码多个高度多态分子，这些分子是免疫功能核心的。这些分子的某些人充当了同样多态杀伤细胞免疫球蛋白样受体（KIR）的配体。来自HLA和KIR基因组区域的特定等位基因以及对感染性，过敏性，炎症性和自身免疫性疾病的敏感性或抗性，以及对造血细胞移植和再生成功的结果的耐受性。对于许多关联，由于这些基因组区域的复杂性，很难识别严重的等位基因。先前的研究隔离严重突变需要多种方法和冗长的程序。相比之下，我们开发了一种高通量，具有成本效益的方法，使我们能够捕获和对HLA（4.8 MB）和KIR（100-250 KB）区域的完整单倍型进行序列。我们将在AIM 1中采用这种方法来研究一种自身免疫性肌病（DM）（DM）。 DM与HLA有一个明确的，理解不佳的联系。与KIR的参与有关的是HLA I类表达的变化以及先天免疫学对疾病过程的贡献。特定的临床表型跟踪具有特定自身抗体的存在。我们将从每个主要临床组中的患者中获得完全的HLA和KIR单倍型序列，并将其与健康HLA匹配的对照组中的患者进行比较。将进行比较，以识别引起或加剧疾病的单个标记或复合基因型。在AIM 2中，我们将研究HLA和KIR多态性与先兆子痫的关联，一种系统的妊娠高血压状况以及孕产妇死亡率的主要原因，尤其是在非洲起源的妇女中；在美国，非洲裔美国妇女患有preeclamsia的可能性高出五倍。将分析一群非洲妇女及其婴儿，完成我们对当前一轮资金进行的欧洲妇女的研究。对非洲队列的低分辨率分析已复制了在欧洲队列中观察到的发现，即，preeclamsia的最高风险是在妊娠中，母亲有两份Kir A单倍型，并且胎儿从父亲那里继承了C2配体。与Kir2DS1受到保护的欧洲队列相反，在非洲队列保护中，保护与非洲人群独有的基因Cencrromeric Kir2DS5相关。未知的是非洲人群中心透体KIR2DDS5基因的多态性是否能够替代Kir2DS1的功能替代。在HLA区域中，HLA-G和KIR2DL4在KIR区域中，其他可能有助于生殖成功的链接和功能相互作用的基因座。通过获得先兆子痫和对照组中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结果的贡献。目标3和4将继续改善和扩展我们方法的生物信息学（AIM 3）和技术（AIM 4）组件。