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: 10470853
• 负责人: Christopher J Lessard
• 金额: $ 74.83万
• 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/10470853
• 关键词: Acinar Cell; Affect; American; Antigen Presentation; Autoantibodies; Autoimmune; Autoimmune Diseases; B-Lymphocytes; Bioinformatics; Biological Markers; Biological Products; 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; diagnostic tool; 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