Functional Evaluation of Established Sjogren's Syndrome Immune Response Loci

已建立的干燥综合征免疫反应位点的功能评估

基本信息

批准号：
8810502
负责人：
Christopher J Lessard
金额：
$ 51.9万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8810502
关键词：
Address Affect Alleles Architecture Autoimmune Diseases B-Lymphocytes BLR1 gene Basic Science Biological Response Modifier Therapy Blood CD4 Positive T Lymphocytes CXCL13 gene Cell Differentiation process ChIP-seq Chromatin Chronic Clinical Clinical Data Clinical Research Code Collaborations Complex Coupled Data Dendritic Cells Development Diagnosis Disease Disease susceptibility Dryness Elements Enhancers Environmental Risk Factor Etiology European Evaluation Exocrine Glands Fatigue Functional disorder Genes Genetic Genetic Polymorphism Genetic Risk Genetic Transcription Genetic Variation Genomics Genotype Goals Grant Haplotypes Helper-Inducer T-Lymphocyte Hispanics Histones Human Genome IL12A gene IL12B gene Immune response Individual Infiltration Inflammation Interferons Interleukin-12 International Knowledge Lead Lung Lymphoma Lymphocyte Maps Mediating Membrane Molecular Morbidity - disease rate Natural Killer Cells Neuropathy Oral PRDM1 gene Pathogenesis Pathway interactions Patients Phenotype Play Predisposition Process Production Protein Binding Protein Binding Domain Proteins Publishing Receptors, Antigen, B-Cell Regulation Research Infrastructure Research Personnel Resources Rheumatoid Arthritis Risk Role STAT4 gene Sampling Signal Transduction Site Sjogren&apos s Syndrome Structure Structure of germinal center of lymph node Syndrome Systemic Lupus Erythematosus T cell differentiation T-Lymphocyte Techniques Technology Testing Therapeutic Translating Untranslated RNA Variant Vasculitis Xerostomia autoimmune exocrinopathy body system clinical care cohort cytokine experience eye dryness follow-up functional genomics genetic association genetic resource genome wide association study mRNA Expression monocyte multidisciplinary novel novel diagnostics novel therapeutics palliative promoter protein expression public health relevance receptor binding research study risk variant transcription factor

项目摘要

DESCRIPTION (provided by applicant): Sjogrens syndrome (SS) is a chronic, progressive autoimmune disorder characterized by lymphocytic infiltration of the exocrine glands. Clinical manifestations may involve virtually any organ system, with severe oral and ocular dryness as a unifying feature. The etiology of SS is poorly understood, but clearly involves a complex genetic architecture influenced by environmental factors that lead to abnormal cellular and humoral immune responses. Difficulty in correctly diagnosing SS combined with the scarcity of effective therapeutic options often results in significant morbidity and irreversible damage to the exocrine glands. To determine genetic risk variants for SS, we have recently completed the first unbiased screen of the human genome using the genome-wide association (GWA) approach and have successfully established (Pmeta<5x10-8) IRF5, STAT4, IL12A, BLK, CXCR5, TNIP1 and variants in the HLA region as SS disease loci. Interestingly, IL12 signaling was central pathway implicated by these results. Of the SS risk loci identified, IL12A encodes the p35 subunit of IL12, IRF5 functions as a transcription factor for IL12B, IL12 signaling is mediated through STAT4, and IL12 is a cytokine involved in transcription of CXCR5. Recent studies published by ENCODE have revealed that ~80% of the human genome is biologically active but only 2-5% of the human genome encodes protein coding loci. The vast majority of non-protein coding sequences generate regulatory RNAs, many of which are expected to grant sequence specific addresses to transcription factors and other proteins and have potential to be responsible for most genetic associations with disease. We now seek to leverage our extensive infrastructure, sample and clinical data resources, experience in autoimmune disease genetics, and the wealth of new publicly available data defining functional genomic elements to identify precise causal variants and their disease mechanisms that underlie the statistical associations of risk loci in SS. The specific aims of this project are to use transracial and fine mapping in 600 Hispanic SS cases and 2000 healthy controls as well as 1000 European SS cases and 1000 healthy controls to refine association signals by leveraging the differing LD structure. We then seek to define the functional mechanisms of causal variants and haplotypes in two SS risk genes, IL12A and CXCR5 using molecular techniques coupled with cutting-edge sequencing technology. These studies are likely to facilitate development of a coherent view of the SS genetic architecture and importantly, provide fundamental new knowledge that will translate into novel diagnostic approaches and application of biological therapies currently being developed for other diseases that target IL12.

描述（由申请人提供）：干燥综合征（SS）是一种慢性、进行性自身免疫性疾病，其特征是外分泌腺的淋巴细胞浸润，临床表现几乎可累及任何器官系统，以严重的口腔和眼睛干燥为统一特征。对 SS 的了解甚少，但显然涉及受环境因素影响的复杂遗传结构，导致细胞和体液免疫反应异常，难以正确诊断 SS 组合。由于缺乏有效的治疗方案，通常会导致显着的发病率和外分泌腺的不可逆损伤。为了确定 SS 的遗传风险变异，我们最近使用全基因组关联 (GWA) 方法完成了首次对人类基因组的无偏见筛查。并已成功建立 (Pmeta<5x10-8) IRF5、STAT4、IL12A、BLK、CXCR5、TNIP1 和 HLA 区域的变异体作为 SS 疾病位点。 IL12 信号传导是这些结果所涉及的中心途径，IL12A 编码 IL12 的 p35 亚基。 IRF5 充当 IL12B 的转录因子，IL12 信号传导通过 STAT4 介导，IL12 是参与 CXCR5 转录的细胞因子，ENCODE 发表的最新研究表明，约 80% 的人类基因组具有生物活性，但只有 2-5% 具有生物活性。 %的人类基因组编码蛋白质编码位点，大量的非蛋白质编码序列产生大多数调节RNA，其中许多有望为转录因子和其他蛋白质提供序列特异性地址，并有潜力我们现在寻求利用我们广泛的基础设施、样本和临床数据资源、自身免疫性疾病遗传学方面的经验以及定义功能基因组元素的大量新的公开数据来识别精确的因果变异及其疾病。该项目的具体目标是在 600 名西班牙裔 SS 病例和 2000 名健康对照以及 1000 名欧洲 SS 病例和 1000 名健康对照中使用跨种族和精细图谱来分析 SS 风险位点统计关联的机制。然后，我们利用分子技术与尖端测序技术相结合，寻求定义两个 SS 风险基因 IL12A 和 CXCR5 的因果变异和单倍型的功能机制。 SS 遗传结构的连贯观点，重要的是，提供基本的新知识，这些知识将转化为目前正在开发的针对其他靶向 IL12 疾病的新诊断方法和生物疗法的应用。