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）复合物编码多种对免疫功能至关重要的高度多态性分子。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。 HLA 和 KIR 基因组区域的特定等位基因以及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造血细胞移植和生殖成功的结果有关。对于许多这些关联，由于这些基因组区域的复杂性，很难确定致病等位基因。先前分离致病突变的研究需要多种方法和漫长的程序。相比之下，我们开发了一种高通量、经济高效的方法，使我们能够捕获 HLA (4.8 Mb) 和 KIR (100-250 kb) 区域的完整单倍型并对其进行测序。我们将在目标 1 中采用这种方法来研究皮肌炎 (DM)，一种自身免疫性特发性肌病。 DM 与 HLA 之间的关系尚不清楚，但人们却知之甚少。病变组织中 HLA I 类表达的变化以及先天免疫对疾病过程的贡献表明 KIR 参与其中。特定的临床表型与特定自身抗体的存在相关。我们将从每个主要临床组的患者获得完整的 HLA 和 KIR 单倍型序列，并将其与健康 HLA 匹配对照的序列进行比较。将在组内和组间进行比较，以确定导致或加剧疾病的个体标记或复合基因型。在目标 2 中，我们将研究 HLA 和 KIR 多态性与先兆子痫的关系，先兆子痫是一种全身性妊娠高血压疾病，也是孕产妇死亡的主要原因，特别是在非洲血统的妇女中；在美国，非洲裔美国女性患先兆子痫的可能性是其他女性的五倍。我们将对一组非洲妇女及其婴儿进行分析，以补充我们在本轮融资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，即先兆子痫的风险最高的是母亲有两个 KIR A 单倍型拷贝且胎儿从父亲那里遗传了 C2 配体的妊娠。与欧洲队列相比，KIR2DS1 具有保护作用，而非洲队列的保护作用与着丝粒 KIR2DS5（一种非洲人群特有的基因）相关。目前尚不清楚非洲人群中着丝粒 KIR2DS5 基因的多态性是否可以为 KIR2DS1 的缺失提供功能替代。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 区域中的 HLA-G 和 KIR 区域中的 KIR2DL4。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结果的贡献。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。