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

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

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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（由应用提供）：Sjogrens综合征（SS）是一种慢性，进行性自身免疫性疾病，其特征是外分泌网格的淋巴细胞浸润。临床表现可能涉及几乎任何器官系统，具有严重的口服和眼干性作为统一特征。 SS的病因尚不清楚，但显然涉及复杂的遗传结构，该遗传结构受环境因素影响，导致了异常的细胞和人类免疫复杂。正确诊断SS的困难与有效治疗选择的稀缺性相结合，通常会导致对外分泌腺的明显发病率和不可逆转的损害。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）方法完成了第一个无偏见的人类基因组屏幕，并已成功建立（PMETA <5x10-8）IRF5，STAT4，IL12A，IL12A，BLK，BLK，CXCR5，CXCR5，TNIP1，TNIP1，TNIP1和SS SS SS SS SS SS SS SS SS SS SS SESEASS SEASE SEASINE。有趣的是，IL12信号传导是由这些结果实现的中心途径。在确定的SS风险基因座中，IL12A编码IL12的p35亚基， IRF5用作IL12B的转录因子，IL12信号通过STAT4介导，而IL12是参与CXCR5转录的细胞因子。编码发表的最新研究表明，约80％的人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基因座。绝大多数的非蛋白质编码序列都会产生调节性RNA，其中许多序列有望授予转录因子和其他蛋白质的特定序列地址，并有可能负责大多数遗传与疾病的关联。现在，我们寻求利用广泛的基础设施，样本和临床数据资源，自身免疫性疾病遗传学的经验以及定义功能基因组元素的大量新公开数据，以识别SS风险统计关联的精确因果变异及其疾病机制。该项目的具体目的是在600个西班牙裔SS病例和2000个健康对照中使用跨种族和精细映射，以及1000个欧洲SS案例和1000个健康对照，通过利用区分LD结构来完善关联信号。然后，我们试图使用分子技术以及最先进的测序技术来定义两个SS风险基因IL12A和CXCR5中因果变异和单倍型的功能机制。这些研究很可能有助于发展SS遗传结构的连贯观点，并且重要的是提供基本的新知识，这些知识将转化为新型诊断方法和当前针对针对IL12的其他疾病的生物疗法的应用。