Genetic Linkage in Lupus

狼疮的遗传连锁

• 批准号: 10404993
• 负责人: Leah Claire Kottyan
• 金额: $ 48.87万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-07-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10404993
• 关键词: Alleles; Antibodies; Antibody Response; Antigens; Antinuclear Antibodies; Attention; B-Lymphocytes; Behavior; Binding; CD8-Positive T-Lymphocytes; Cells; ChIP-seq; Childhood; Complex; DNA Binding; Data; Data Analyses; Data Set; Disease; Epstein-Barr Virus Infections; Epstein-Barr Virus latency; Etiology; Foundations; Frequencies; GTP-Binding Protein alpha Subunits, Gs; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Risk; Genetic Transcription; Genome; Genomic Segment; Genomics; Human; Human Herpesvirus 4; Immune response; Infectious Mononucleosis; Knowledge; Location; Lupus; Major Depressive Disorder; Methods; Mutation; Neighborhoods; Nuclear Antigens; PC3 cell line; Patients; Process; Progress Reports; Publications; Publishing; Reagent; Regulation; Risk; Role; Screening procedure; Specificity; Systemic Lupus Erythematosus; Systems Biology; Technology; Testing; Variant; Viral Load result; Work; antigen processing; causal variant; cell transformation; cell type; disorder risk; exhaustion; experimental study; gene product; genetic linkage; genomic locus; infected B cell; programs; risk variant; transcription factor; transforming virus; virtual

Project Abstract There are 124 publications that establish 185 disease risk loci for the genetics of systemic lupus erythematosus (SLE) with robust supporting data. This is a completely different situation than when AI0274717 started 33 years ago as a search for genetic linkage. Now, in addition to the 185 risk loci we have strong circumstantial evidence for an etiologic role for Epstein-Barr virus (EBV) at the origin of SLE, especially considering the recently published powerful association between the location in the genome of transcription complexes containing the Latency III gene product, Epstein Barr Nuclear Antigen 2 (EBNA2) and the genetic risk loci of SLE. This association has been confirmed and extended to the at present known SLE risk loci. In addition, new data show that EBNA3C and EBNALP, both also EBV Latency III gene products, are also powerfully concentrated at the SLE risk loci, all three, EBNA2, -3C, & -LP, clustering together and in aggregate binding indirectly to more than half the known SLE risk loci. A set of human transcription factors and co-factors (TFs) tend to bind DNA at these same SLE risk loci. Our hypothesis is that many genetic mechanisms that cause SLE operate in the EBV transformed B cell, because of the EBV Latency III gene expression. Since ~90% of the plausibly causal variants in the 185 risk loci are in genomic regions, predicted to have regulatory function; therefore, the role of TFs promises to be important in the genetic mechanisms of SLE. What is missing, a serious gap in our knowledge, is the identify of the Target genes regulated by these risk variants. Given the unexpected, but dominating influence of the Latency III gene products in associations with the SLE risk loci, we conclude that the cell type in which to begin the systematic search for the disease relevant Target genes is the EBV-infected and transformed B cell. In Aim 1 we will focus on identifying Target genes in these cells for as many of the 185 SLE risk loci as possible with special attention focused on the involvement of EBNA2. In Aim 2 we will concentrate on the allelic differences in Target gene expression induced by the risk and non-risk alleles of SLE risk locus variants, again with special attention to the possible role of EBNA2. We have preliminary data that support our technical capacity to perform the experiments proposed and have constructed many of the reagents needed to perform the proposed experiments, which have been initiated. We will adapt high throughput systems biology methods to screen and explore the gene regulation of the 185 loci to build a foundation to evaluate the role EBNA2 has in SLE etiology relevant regulation. Extraordinary new commercially available methods will make the screening procedures proposed practical, feasible and affordable. If our hypothesis is correct and we demonstrate EBNA2-dependent mechanisms of gene regulation at the risk loci, then these would be nominated as potential causal mechanisms for the genesis of SLE. These results will lay the foundation for the important next step, to perturb the identified mechanism in ways that change the risk of developing SLE or that change the capacity of the illness to persist.

项目摘要 有124个出版物为全身性红斑狼疮的遗传学建立了185个疾病的位置 （SLE）具有强大的支持数据。这是与AI0274717开始33年时完全不同的情况 以前是寻找遗传联系。现在，除了185个风险基因座，我们还有大量的间接证据 为了在SLE起源的Epstein-Barr病毒（EBV）的病因学作用，特别是考虑到最近发表的 在包含潜伏期III的转录复合物基因组中的位置之间的强大关联 基因产物，爱泼斯坦Barr核抗原2（EBNA2）和SLE的遗传风险基因座。这个协会有 已确认并扩展到目前已知的SLE风险基因座。此外，新数据显示EBNA3C EBNNP也是EBV潜伏期III基因产品，也有力地集中在SLE风险基因座上 第三，ebna2，-3c和-lp，聚集在一起，并间接地结合到已知的一半以上 SLE风险基因座。一组人的转录因子和辅助因子（TFS）倾向于以这些相同的SLE风险结合DNA 基因座。我们的假设是，在EBV转化B细胞中导致SLE的许多遗传机制， 由于EBV潜伏期III基因表达。由于在185个风险基因座中约有90％的合理因果变体 位于基因组区域，预计具有调节功能；因此，TFS的作用有望很重要 在SLE的遗传机制中。缺少的是我们所知的严重差距，是目标的识别 受这些风险变异调节的基因。鉴于潜伏期III基因的意外但主导的影响 与SLE风险基因座关联的产品，我们得出结论，开始系统的细胞类型 搜索疾病相关的靶基因是EBV感染和转化的B细胞。在目标1中，我们将集中精力 关于在这些细胞中识别靶基因的185个SLE风险基因座中的尽可能多的靶基因，并特别注意 专注于EBNA2的参与。在AIM 2中，我们将集中于靶基因的等位基因差异 SLE风险基因座变体的风险和非风险等位基因引起的表达，再次特别注意 EBNA2的可能作用。 我们有初步数据支持我们执行提出的实验并具有的技术能力 构建了执行已启动的拟议实验所需的许多试剂。我们 将适应高通量系统生物学方法来筛选和探索185个基因座的基因调节 建立一个基础，以评估EBNA2在SLE病因学相关调节中的作用。非凡的新 市售方法将使筛选程序提出了实用，可行和负担得起的。 如果我们的假设是正确的，并且我们证明了基因调节的EBNA2依赖性机制 基因座，然后将这些被提名为SLE起源的潜在因果机制。这些结果将会 为下一步的重要下一步奠定基础，以改变风险的方式扰动已确定的机制 开发SLE或改变疾病持续存在的能力。