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

• 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
• 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' 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

 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。临床表现可能涉及几乎任何器官系统，严重的口腔和眼睛干燥是一个统一的特征。SS的病因尚不清楚，但显然涉及受环境因素影响的复杂遗传结构，导致异常的细胞和体液免疫反应。SS的诊断困难加上缺乏有效的治疗方法，往往会导致严重的发病率和不可逆的损害外分泌腺。为了确定SS的遗传风险变体，我们最近使用全基因组关联（GWA）方法完成了人类基因组的首次无偏筛选，并成功建立了（Pmeta<5x 10 -8）IRF 5，STAT 4，IL 12 A，BLK，CXCR 5，TNIP 1和HLA区域中的变体作为SS疾病基因座。有趣的是，IL 12信号传导是这些结果所涉及的中心途径。在鉴定的SS风险基因座中，IL 12 A编码IL 12的p35亚基， IRF 5作为IL 12 B的转录因子发挥作用，IL 12信号传导通过STAT 4介导，并且IL 12是参与CXCR 5转录的细胞因子。ENCODE最近发表的研究表明，约80%的人类基因组具有生物活性，但只有2-5%的人类基因组编码蛋白质编码位点。绝大多数非蛋白质编码序列产生调控RNA，其中许多预期将序列特异性地址授予转录因子和其他蛋白质，并且具有负责与疾病的大多数遗传关联的潜力。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新的公开数据的财富，以确定精确的因果变异及其疾病机制，这些变异及其疾病机制是SS风险位点统计学关联的基础。该项目的具体目标是在600例西班牙SS病例和2000例健康对照以及1000例欧洲SS病例和1000例健康对照中使用跨种族和精细映射，通过利用不同的LD结构来细化关联信号。然后，我们试图定义的致病变异和单倍型的功能机制，在两个SS风险基因，IL 12 A和CXCR 5使用分子技术结合尖端测序技术。这些研究很可能促进SS遗传结构的连贯观点的发展，重要的是，提供了基础性的新知识，这些知识将转化为新的诊断方法和目前正在开发的针对IL 12的其他疾病的生物疗法的应用。