Discovery and Characterization of Genetic Risk Loci in Sjogren's Syndrome

干燥综合征遗传风险位点的发现和表征

• 批准号: 10256035
• 负责人: Christopher J Lessard
• 金额: $ 73.52万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-07 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10256035
• 关键词: Acinar Cell; Affect; American; Antigen Presentation; Autoantibodies; Autoimmune; Autoimmune Diseases; B-Lymphocytes; Bioinformatics; Biological; Biological Markers; Biological Response Modifier Therapy; Biological Response Modifiers; Biopsy; Blood Banks; Cell physiology; Cells; Clinical; Clinical Data; Clinical Trials; Complex; Coupled; Data; Dendritic Cells; Development; Diagnosis; Disease; Disease model; Dryness; Duct (organ) structure; Ductal Epithelial Cell; Epithelial Cells; European; Exhibits; Exocrine Glands; Fatigue; Feedback; Fostering; Functional disorder; Gene Expression; Genes; Genetic; Genetic Determinism; Genetic Predisposition to Disease; Genetic Risk; Genetic Transcription; Genetic study; Genomic Segment; Gland; Goals; Hematologic Neoplasms; Histologic; IL12A gene; Immune; Immune response; Immune system; Interferon Type II; Interferons; Interleukin-12; International; Knowledge; Laboratories; Lacrimal gland structure; Lead; Lesion; Life; Light; Link; Lung; Lung diseases; Lymphoma; Malignant neoplasm of lung; Mediating; Mediator of activation protein; Methodology; Minor; Modeling; Molecular; Morphology; Natural Killer Cells; Neurologic; Neuropathy; Organ; Outcome; PRDM1 gene; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patient Care; Patient Rights; Patients; Pattern; Peripheral; Pharmaceutical Preparations; Plant Roots; Population; Production; Proteomics; Publishing; Quantitative Trait Loci; Research; Resolution; Rheumatism; Ribonucleoproteins; Risk; Risk Factors; Role; STAT4 gene; Salivary Gland Tissue; Salivary Glands; Sample Size; Sampling; Signal Transduction; Sjogren' s Syndrome; Specificity; Stratification; Study Subject; Suggestion; Surrogate Markers; T-Lymphocyte; TYK2; Technology; Testing; Time; Tissue Banks; Tissues; Variant; Work; accurate diagnostics; base; causal variant; cell type; clinical translation; cohort; cytokine; disease heterogeneity; falls; gene discovery; genetic architecture; genetic association; genetic risk factor; genome wide association study; high risk; innovation; insight; lymphocyte trafficking; molecular marker; monocyte; new therapeutic target; novel; overexpression; pathogenic autoantibodies; patient biomarkers; patient stratification; patient subsets; peripheral blood; phenotypic data; response; risk variant; targeted treatment; therapeutic target; tool; transcriptomics

ABSTRACT Sjögren’s syndrome (SS) is a complex rheumatic disorder distinguished by autoimmune targeting of exocrine glands. Severe clinical manifestations may include debilitating dryness, pulmonary dysfunction, neuropathies, profound fatigue, and lymphoma. Salivary gland lesions involve activated ductal and acinar epithelial cells as well as irreversible immune-mediated tissue damage. Diagnosis and treatment of SS are notoriously difficult. Our group leads the international Sjögren’s Genetics Network (SGENE) comprised of 26 SS research groups dedicated to understanding the genetic architecture of SS. SGENE studies have identified 15 of the 16 SS risk loci thus far established in European-derived populations. SS risk loci coalesce in Type I and Type II interferon (IFN), NFkB signaling, antigen presentation, autoantibody production and lymphocyte trafficking pathways. Our genetic studies have provided strong evidence supporting a pathogenic role in SS from various innate and adaptive immune cell subsets, however, how these cell types are functionally affected by SS risk alleles remain poorly understood. Importantly, these studies also suggest new therapeutic targets, such as IL12 signaling, for which biologic therapies have been developed for related autoimmune diseases, but not previously considered in SS. Preliminary data in 2,809 SS cases suggest >40 additional candidate loci that warrant further study. Using insights from our genetic studies, we have developed a novel model of disease pathogenesis that differentiates 3 major patient subsets based on distinct molecular mechanisms. Our overall goals are to develop a more complete model of SS genetic determinants and to identify biomarkers that reflect the distinct molecular mechanisms represented in our disease model that could be developed into clinical tools for stratifying patients. In Aim 1, we will greatly expand our current genome-wide association studies by leveraging our unique access to samples, laboratory and clinical data from well-characterized SGENE cohorts (>10,000 SS cases). In Aim 2, we will test known SS risk variants for cell specific cis-regulatory effects on transcription in salivary gland tissues. Banked tissues obtained from minor labial gland biopsies from subjects (n=200) classified into the 3 major patient subsets defined in our proposed disease model, plus a subset of patients with lymphoma and controls will be evaluated. Spatial transcriptomic technologies will be utilized to generate gene expression data in which morphological context is retained at nearly single cell resolution. In Aim 3, we will integrate genetic, transcriptomic and proteomic data to develop multidimensional panels of soluble immune mediators that can serve as peripheral biomarkers for these patient subgroups to facilitate patient stratification. These studies will expand our understanding of genetic contributors to SS, identify cell-specific functional effects on transcription, foster development of new clinical tools for more accurate diagnostics, and establish the feasibility of rapid clinical translation for therapeutic targeting in well-defined patient subsets using novel and existing biologics directed against pathways and cell types that drive this complex autoimmune disorder. !

摘要 舍格伦综合征（SS）是一种复杂的风湿性疾病，其特征在于外分泌的自身免疫靶向 腺体严重的临床表现可能包括使人虚弱的干燥、肺功能障碍、神经病变， 极度疲劳和淋巴瘤唾液腺病变涉及激活的导管和腺泡上皮细胞， 以及不可逆的免疫介导的组织损伤。众所周知，SS的诊断和治疗非常困难。 我们的团队领导着由26个SS研究小组组成的国际舍格伦遗传学网络（SGENE） 致力于了解SS的遗传结构。SGENE研究已经确定了16种SS风险中的15种 迄今为止在欧洲衍生的人群中建立的基因座。I型和II型干扰素中SS风险位点的合并 (IFN)、NFkB信号传导、抗原呈递、自身抗体产生和淋巴细胞运输途径。我们 遗传学研究提供了强有力的证据，支持SS的致病作用， 然而，适应性免疫细胞亚群，这些细胞类型如何在功能上受到SS风险等位基因的影响仍然存在 不太了解。重要的是，这些研究还提出了新的治疗靶点，如IL 12信号转导，用于治疗 哪些生物疗法已被开发用于相关的自身免疫性疾病，但以前没有考虑过 在SS。2，809例SS病例的初步数据表明，有超过40个额外的候选基因座值得进一步研究。使用 从我们的遗传学研究的见解，我们已经开发出一种新的疾病发病机制模型， 基于不同分子机制的3个主要患者亚群。我们的总体目标是开发一个更 SS遗传决定因素的完整模型，并确定反映不同分子的生物标志物， 我们的疾病模型中所代表的机制，可以发展成为对患者进行分层的临床工具。 在目标1中，我们将通过利用我们独特的访问， 来自充分表征的SGENE队列（> 10，000例SS病例）的样本、实验室和临床数据。在目标2中， 我们将测试已知的SS风险变体对唾液腺组织中转录的细胞特异性顺式调节作用。 从分类为3例主要患者的受试者（n=200）的小阴唇腺活检中获得的库存组织 在我们提出的疾病模型中定义的子集，加上淋巴瘤患者和对照的子集， 评估。空间转录组学技术将用于生成基因表达数据，其中 形态学背景以接近单个细胞的分辨率保留。在目标3中，我们将整合遗传、转录组学 和蛋白质组学数据，以开发可作为外周免疫调节剂的多维可溶性免疫介质组。 这些患者亚组的生物标志物，以便于患者分层。这些研究将扩大我们的 了解SS的遗传贡献者，确定细胞特异性转录功能效应，培养 开发新的临床工具，以进行更准确的诊断，并建立快速临床诊断的可行性。 使用新的和现有的生物制剂在明确定义的患者亚群中进行治疗靶向的翻译， 对抗驱动这种复杂自身免疫性疾病的途径和细胞类型。 !