Characterization of European American and African American Sarcoidosis via Immunogenetics

通过免疫遗传学表征欧洲裔美国人和非洲裔美国人结节病

• 批准号: 10376788
• 负责人: Courtney Montgomery
• 金额: $ 77.52万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10376788
• 关键词: Affect; African; African American; African American population; American; Blood; Candidate Disease Gene; Cells; Characteristics; Charge; Chronic Disease; Clinical; Consensus; DNA Sequence; Data; Disease; Environment; Environmental Risk Factor; Etiology; European; Foundations; Funding; Future; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genotype; Goals; Grant; Granuloma; Granulomatous; Haplotypes; Immune; Immune system; Immunogenetics; Inflammatory; Knowledge; Medical; Organ; Paper; Pathology; Pathway interactions; Patient Recruitments; Patients; Phenotype; Predisposition; Publications; Publishing; RNA analysis; Race; Rare Diseases; Research; Research Personnel; Resources; Risk; Role; Sampling; Sarcoidal Granuloma; Sarcoidosis; Severities; Susceptibility Gene; Tissues; Variant; Whole Blood; Woman; Work; adaptive immune response; base; causal variant; cell type; cohort; design; differential expression; experimental study; genetic risk factor; genetic variant; genome wide association study; genome-wide; interest; men; novel; patient population; profiles in patients; programs; risk variant; sex; transcriptome sequencing; transcriptomics

ABSTRACT Sarcoidosis is a granulomatous inflammatory disease often dubbed a “medical mystery” yet significantly understudied. While it is known that sarcoidosis likely involves host genetic susceptibility and an innate and adaptive immune response to infectious, organic or inorganic agents, the mechanisms by which granulomas form and the determinants of severity and manifestation of disease remain elusive. Over the past several years, our team has led the charge to define the role of genetics in sarcoidosis. Specifically, under our current funding, we have published 13 papers with 3 more soon to be submitted describing genes for susceptibility, severity, ancestry specific and organ-specific effects. However, the mechanism(s) by which associated genetic variants influence sarcoidosis are still largely unknown. Our proposal will close this knowledge gap by characterizing functional variants and the tissue(s) in which they operate by 1) identifying differentially expressed (DE) genes in granulomatous tissue and blood, 2) characterizing the expression of DE and previously associated genes by specific cell type, 3) identifying tissue or cell-specific eQTLs for DE and previously associated genes, 4) creating clinical profiles of patients carrying risk alleles and 5) replicating our findings in an independent cohort. Specifically, in Aim 1, we will identify novel candidate genes and their most likely causal variants to be investigated in our future mechanistic studies of sarcoidosis susceptibility and persistence via DE analysis of RNA sequencing data of whole blood from both EA and AA sarcoidosis patients and matched controls AND DE analysis of granulomatous tissue from a subset of these same patients compared to healthy tissue. Additionally, we will perform eQTL analysis using the transcriptomic data from blood and tissue described above and ancestry-informative genome-wide genotyping data. In Aim 2, we will define the cell subsets in which the most likely causal variants operate and identify novel cell-specific effects by DE analysis of RNA sequencing data from blood-derived single cells in our cohort of EA and AA cases and matched controls. In order to identify cell-type specific eQTLs, analysis of the genotype and single cell transcriptomic data will also be performed. Finally, in Aim 3 we will replicate our list of candidate genes, their most likely causal variants and the specific cell type in which they influence disease using blood, tissue and single cells from a cohort of patients recruited based on the demographic and clinical criteria that are associated with our causal variants. Our work will be greatly facilitated by the extensive genotype, clinical and environmental data on our existing cohort AND the recently established Sarcoidosis Research Unit from both of which we have strong preliminary data to support the studies proposed herein. In summary, when this grant is complete, we will know the likely causal variants, the tissue and cell-types in which they function and the clinical characteristics of the patients in which they are most likely to be enriched from which detailed mechanistic experiments can be designed.

抽象的 结节病是一种肉芽肿性炎症性疾病，通常被称为“医学谜团” 研究了。虽然众所周知，结节病可能涉及宿主遗传敏感性和先天性和 对感染性，有机或无机剂的适应性免疫反应，颗粒瘤的机制 形式和严重程度和疾病表现的决定者仍然难以捉摸。过去几个 多年来，我们的团队领导了定义遗传学在结节病中的作用的指控。具体来说，在我们当前 资金，我们发表了13篇论文，还有3篇论文即将提交，以描述易感性的基因， 严重程度，祖先特异性和器官特异性效应。但是，与遗传相关的机制 变体影响结节病仍在很大程度上未知。我们的建议将缩小这一知识差距 表征功能变体和在其中操作的组织（S）以不同的方式识别。 在颗粒组织和血液中表达（DE）基因，2）表征DE和DE的表达 以前通过特定细胞类型相关的基因，3）识别DE和DE的组织或细胞特异性EQTL 以前相关的基因，4）创建带有风险等位基因的患者的临床特征，5）复制我们 独立队列中的发现。具体而言，在AIM 1中，我们将确定新颖的候选基因及其 在我们未来的结节病易感性的机械研究中，最有可能研究因果变异 通过对来自EA和AA结节病全血的RNA测序数据的DE分析和持久性 患者和匹配的对照和对这些患者子集的颗粒组织的DE分析 与健康组织相比。此外，我们将使用来自来自的转录组数据执行EQTL分析 上面描述的血液和组织以及祖先的全基因组基因分型数据。在AIM 2中，我们将 定义最有可能的因果变体运行并识别新细胞特异性的细胞子集 通过DE分析我们的EA和AA同类中血液来源单细胞的RNA测序数据 案例和匹配的控件。为了鉴定细胞类型特异性EQTL，分析基因型和单个 还将执行细胞转录数据。最后，在AIM 3中，我们将复制我们的候选人名单 基因，它们最可能的因果变异以及它们影响疾病的特定细胞类型 根据人口统计学和临床​​标准，来自一系列患者的血液，组织和单细胞 与我们的因果变体相关的。广泛的基因型将为我们的工作做准备 有关我们现有队列和最近建立的结节病研究部门的临床和环境数据 从这两种情况下，我们都有强大的初步数据来支持此处提出的研究。总而言之，什么时候 这笔赠款是完整的，我们将知道可能性的因果变体，组织和细胞类型的作用 以及最有可能富含详细的患者的临床特征 可以设计机械实验。