Integrative genomics approaches in JIA and response to therapy

幼年特发性关节炎的综合基因组学方法和治疗反应

• 批准号: 8213329
• 负责人: SUSAN D THOMPSON
• 金额: $ 48.2万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-22 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8213329
• 关键词: Address; Adolescent; Aftercare; Apoptotic; Arthritis; Autoimmune Diseases; Autoimmune Process; Biological; Biological Assay; Biological Process; Biological Response Modifiers; Blood; Blood Cells; CD8B1 gene; Cataloging; Catalogs; Cells; Childhood; Chronic Childhood Arthritis; Clinical; Clinical Management; Collection; Complex; Custom; DNA; DNA Markers; DNA Resequencing; DNA Sequence; Data; Data Set; Databases; Development; Disease; Disease Outcome; Disease susceptibility; Etiology; Evaluation; Exposure to; Family; Family history of; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genetic Variation; Genome; Genomics; Genotype; Haplotypes; Heterogeneity; Histones; IGF1R gene; IL2 gene; IL2RA gene; Immune; Instruction; Interleukin-12; Maps; Methotrexate; Methylation; Molecular; Odds Ratio; Outcome; PTPN22 gene; Pathway interactions; Patients; Pattern; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phenotype; Phosphorylation; Positioning Attribute; Predisposition; Principal Investigator; Publishing; RNA Splicing; Regulation; Relative (related person); Relative Risks; Research Design; Resources; Rheumatism; Risk; Risk Factors; STAT1 gene; STAT4 gene; Sampling; Scanning; Siblings; Signal Transduction; Single Nucleotide Polymorphism; Single Nucleotide Polymorphism Map; Subgroup; T-Lymphocyte; TNF gene; Testing; Transcript; Treatment outcome; Variant; arthropathies; base; cohort; disabling disease; disease phenotype; disorder risk; disorder subtype; follow-up; genetic association; genetic variant; genome wide association study; innovation; novel; programs; response; trait; treatment response

Juvenile idiopathic arthrifis (JIA) is the most common rheumatic disease of childhood and constitutes a heterogeneous group of pediatric arthropathies that range from mild and self-limited to severe and disabling. The etiology of JIA is complex and includes genetic factors. Our recent genome-wide association study (GWAS) in JIA identified single nucleotide polymorphisms (SNPs) as risk factors for development of disease. These included SNPs in genes that are associated with other autoimmune diseases, as well as SNPs in genes uniquely associated with JIA. Two genes strongly implicated as risk factors have plausible functions in disease that are supported by our gene expression data. Specifically, JMJD1C is a histone demethylase that may be involved in transcripfional programming and determining cell fate, and PTPN2 is a key regulator of immune cell signaling including regulation of JAK-STAT pathways. In the first cycle of the Program Project, analysis of peripheral blood mononuclear cell (PBMC) samples in patients prior to the start of methotrexate (MTX), demonstrated that transcripts for both PTPN2 and JMJD1C were expressed in greater amounts in patients who subsequentiy did not respond to MTX compared to those who did respond Furthermore, increased expression of both genes was associated with a PBMC T Cell Signature that was associated with persistently active disease and will be studied in Project 1. In fact, JMJD1C was one of the 50 genes that defined this T Cell Signature. Based on these findings, we hypothesize that genetic variability in PTPN2 and/or JMJD1C is important to both JIA susceptibility and clinical variability in treatment response Following from this, an overiap is predicted between the biological pathways influenced by effective drugs and pathways that influence disease risk. The gene expression datasets available in this Program Project place us in a particularly powerful position to evaluate relationships between genetic variants and gene expression signatures. We will focus on PTPN2 and JMJD1C as two key players, potentially risk factors for disease (or sub-phenotype) and predictors of outcomes. We propose to first catalogue genefic variation in both the JMJD1C and PTPN2 regions using re-sequencing and fine mapping approaches. Next, we will utilize the gene expression datasets being developed within the Program Project to complete an integrative analysis of genotype and gene expression data. Finally, we will evaluate risk-altering variants relative to differential splicing, histone methylation (JMJD1C), and STAT1 phosphorylation {PTPN2). Our long-term objective is to understand the molecular basis for JIA in a way that reduces heterogeneity and informs the development of DNA tests that guide treatment choices in JIA. RELEVANCE (See instructions): We have identified two genes that we believe are key players as risk factors for juvenile arthritis and predictors of response to treatment or disease outcome. In this project, we will evaluate DNA sequence variation within these genes and relate it to patterns of gene expression in blood cells. We look for differences between patients and controls and difference between patients who respond to treatment and those who do not respond. Understanding how the variation in these two genes relates to disease and response to treatment may sen/e to identify DNA markers to guide treatment.

青少年特发性关节炎（JIA）是最常见的儿童风湿性疾病，构成了 从轻度和自限制到严重和残疾的各种儿科关节疾病的异质群。 JIA的病因很复杂，包括遗传因素。我们最近全基因组协会的研究 （GWAS）在JIA中，将单核苷酸多态性（SNP）确定为疾病发展的风险因素。 其中包括与其他自身免疫性疾病相关的基因中的SNP，以及SNP 与JIA独特相关的基因。两个基因强烈牵涉到风险因素中具有合理的功能 我们的基因表达数据支持的疾病。具体而言，JMJD1C是组蛋白脱甲基酶 这可能涉及转铺编程和确定细胞命运，而PTPN2是关键调节器 免疫细胞信号传导包括调节JAK-STAT途径。在程序的第一个周期中 项目，在开始之前的患者外周血单核细胞（PBMC）样品的分析 甲氨蝶呤（MTX）证明了PTPN2和JMJD1C的转录本在更大的范围内表达 与确实回应的患者相比 此外，两个基因的表达增加与PBMC T细胞特征有关 与持续活跃的疾病有关，并将在项目1中进行研究。实际上，JMJD1C是其中之一 定义该T细胞特征的50个基因。基于这些发现，我们假设遗传变异性 在PTPN2和/或JMJD1C中，对JIA的敏感性和治疗反应的临床变异性很重要 随之而来的是，在受有效药物影响的生物途径之间预测了过度 以及影响疾病风险的途径。该程序项目中可用的基因表达数据集 将我们置于评估遗传变异与基因之间关系的特别强大的位置 表达签名。我们将专注于PTPN2和JMJD1C作为两个关键参与者，可能是可能的风险因素 疾病（或亚表型）和结果的预测指标。我们提议首先分类基因FAIFIC变化 JMJD1C和PTPN2区域均使用重新测序和精细的映射方法。接下来，我们会的 利用程序项目中正在开发的基因表达数据集来完成集成 基因型和基因表达数据的分析。最后，我们将评估相对于改变风险的变体 差异剪接，组蛋白甲基化（JMJD1C）和STAT1磷酸化{PTPN2）。我们的长期 目的是了解JIA的分子基础，以降低异质性并告知其 开发DNA测试，指导JIA的治疗选择。 相关性（请参阅说明）： 我们已经确定了两个我们认为是关键参与者的基因是少年关节炎和 预测对治疗或疾病结果的反应指标。在这个项目中，我们将评估DNA序列 这些基因内的变异并将其与血细胞中基因表达的模式相关联。我们寻找 患者与对照之间的差异以及对治疗反应的患者之间的差异和差异 那些不回应的人。了解这两个基因的变异与疾病和 对治疗的反应可能会识别DNA标记以指导治疗。