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: 9307690
• 负责人: PETER R PARHAM
• 金额: $ 84.58万
• 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/9307690
• 关键词: Adopted; Affect; Africa; African; African American; Algorithms; Alleles; Allergic; Alpha Cell; 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; Histocompatibility Antigens Class I; Histocompatibility Antigens Class II; Human; Human Genome; Immune; Immune response; Immunogenetics; Immunoglobulin Variable Region; Immunoglobulins; Immunological Models; Individual; Infection; Inflammatory; Inherited; International; Killer Cells; Laboratories; Length; Life; Ligands; Link; Lymphocyte Function; Maps; Maternal Mortality; Mediating; Methods; 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 immune response; base; clinical phenotype; cohort; cost effective; disease phenotype; experimental study; genetic association; genomic data; healthy pregnancy; hematopoietic cell transplantation; high risk; human disease; immune function; improved; insight; mortality; novel; public health relevance; receptor; reproductive success; 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(人类白细胞抗原)复合体编码多种高度多态的分子，这些分子对免疫功能至关重要。其中某些分子作为同样多态的杀伤细胞免疫球蛋白样受体(KIR)的配体。人类白细胞抗原和KIR基因区域的特定等位基因和复合基因与感染性、过敏性、炎症性和自身免疫性疾病的易感性或抵抗力有关，也与造血细胞移植和生殖成功的结果有关。对于这些关联中的许多，由于这些基因组区域的复杂性，一直很难识别致病等位基因。以前分离致病突变的研究需要多种方法和漫长的程序。相反，我们开发了一种高通量、成本效益高的方法，使我们能够捕获和测序人类白细胞抗原(4.8Mb)和KIR(100-250kb)区域的完整单倍型。我们将在目标1中使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与人类白细胞抗原有明确的联系，但人们对此知之甚少。病变组织中HLAI类表达的变化和先天免疫在疾病过程中的作用表明KIR参与了KIR。特定的临床表型与特定自身抗体的存在有关。我们将从每个主要临床组的患者中获得完整的人类白细胞抗原和KIR单倍型序列，并将它们与健康的人类白细胞抗原匹配的对照组的序列进行比较。将在组内和组间进行比较，以确定导致或加剧疾病的单个标记或复合基因类型。在目标2中，我们将研究人类白细胞抗原和KIR基因多态性与先兆子痫的关系，先兆子痫是一种系统性的妊娠高血压疾病，也是导致孕产妇死亡的主要原因，特别是在非洲裔妇女中；在美国，非裔美国妇女患先兆子痫的可能性高达5倍。将对一批非洲妇女及其婴儿进行分析，以补充我们在本轮筹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在怀孕期间，母亲有两个KIR A单倍型副本，而胎儿从父亲那里遗传了C2配体。在欧洲人群中，KIR2DS1是保护性的，而在非洲人群中，保护与着丝粒基因KIR2DS5相关，着丝粒基因是非洲人口特有的基因。目前尚不清楚非洲人群中着丝粒基因KIR2DS5的多态是否可以提供功能替代KIR2DS1的缺失。其他可能与生殖成功有关的连锁和功能相互作用的基因座包括位于人类白细胞抗原(HL A)区域的人类白细胞抗原-G(HL A-G)和位于KIR区域的KIR2DL4。通过获得先兆子痫和对照队列中的人类白细胞抗原和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局的贡献。目标3和目标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)部分。