Establishing the role of genetic variation in vitamin D-regulated gene expression in Sjogrens disease pathogenesis

确定遗传变异在维生素 D 调节的基因表达中在干燥病发病机制中的作用

• 批准号: 10537064
• 负责人: Defne Yilmaz
• 金额: $ 3.92万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-30 至 2025-08-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10537064
• 关键词: 25-hydroxyvitamin D; Affect; Affinity; Apoptosis; Autoimmune Diseases; Autoimmunity; Binding; Binding Sites; Biological; Biological Process; CD8-Positive T-Lymphocytes; Cardiovascular Diseases; Cardiovascular system; ChIP-seq; Chronic; Clinical; Clinical Data; Data; Data Set; Development; Dihydroxycholecalciferols; Disease; Ethnic Origin; Fellowship; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genetic Variation; Genome; Genomic Segment; Goals; Immune; Immunologics; Individual; Ingestion; International; Light; Lymphocyte; Malignant Neoplasms; Measures; Mediating; Mendelian randomization; Mental Depression; Methods; Morbidity - disease rate; Osteoporosis; Outcome; Pathogenesis; Phenotype; Predisposition; Publishing; Race; Registries; Regulation; Regulatory Pathway; Research; Risk; Risk Factors; Role; SS-A antibodies; Serum; Severities; Sialadenitis; Single Nucleotide Polymorphism; Sjogren' s Syndrome; Stains; Study Subject; Study of serum; Testing; United States; Variant; Vitamin D; Vitamin D Deficiency; Vitamin D3 Receptor; Woman; Work; calcium metabolism; case control; cell growth; cell type; chronic autoimmune disease; genetic risk factor; genome wide association study; immune function; immunoregulation; improved; lymphoblastoid cell line; receptor binding; whole genome

Project Summary Sjögren’s Disease (SjD, previously known as Sjögren’s syndrome) is a chronic, multisystem autoimmune disease that causes significant morbidity. Experts estimate that 1.3 million individuals have SjD in the United States alone. Previous research, particularly Mendelian randomization (MR) analyses, has provided strong evidence for low vitamin D as a risk factor contributing to several autoimmune conditions. Vitamin D is important for dozens of biological processes. The gene transcription that occurs with the binding of vitamin D to vitamin D receptors (VDRs) produces downstream effects implicated in immunomodulation, calcium metabolism, cellular growth, proliferation and apoptosis, and other important immunologic functions. Single nucleotide polymorphisms (SNPs) associated with genetic variation in VDR binding affinity (VDR-BVs) have been previously identified in lymphoblastoid cell lines (LCLs); these VDR-BVs are enriched in genomic regions associated with several autoimmune diseases, cardiovascular disease, osteoporosis, depression, and cancer. To date, available research on vitamin D in SjD has been limited to small studies of serum vitamin D levels in SjD cases and controls which observed lower vitamin D levels in cases. There have been no published studies investigating: 1) low vitamin D as a risk factor for SjD using MR analysis, or 2) genetic variation within individual VDR binding sites as a risk factor for SjD. VDR-BVs are therefore strong candidates to investigate for their genetic contribution to SjD. The overall objective of this F31 application is to identify VDR-BVs across the genome and characterize their association with SjD susceptibility, severity, and related clinical outcomes. We hypothesize that altered VDR binding disrupts downstream gene regulation by vitamin D and increases the risk of developing SjD or results in more severe disease. Our approach will use an assembled dataset with more than 1,500 SjD cases and 27,000 controls (for which the data are already available) matched on race/ethnicity, with whole genome SNP profiles and demographic and clinical data from the Sjögren’s International Collaborative Clinical Alliance (SICCA) registry. For this project, we will use VDR-BVs previously identified through ChIP-seq analysis in LCLs and conduct subsequent analyses in primary CD4+ and CD8+ T cells. The proposed study will: 1) Identify VDR binding sites through ChIP-exo analysis in primary CD4+ and CD8+ T cells using the SICCA cases and controls; 2) Estimate the association between VDR-BVs and vitamin D-related SNPs and SjD susceptibility among SICCA study subjects using MR methods; and 3) Estimate the association between VDR-BVs and vitamin D-related SNPs and clinical SjD phenotypes among SICCA study subjects using MR methods. Results from the proposed aims will identify genetic risk factors for SjD related to vitamin D and identify new genes and regulatory pathways involved in the development of SjD. Ultimately, the goal of this work is to understand the mechanisms by which vitamin D affects this immune-mediated disease.

项目摘要 Sjögren病（SJD，以前称为Sjögren综合征）是一种慢性多系统自身免疫性疾病 这会引起明显的发病率。专家估计，美国有130万人在美国拥有SJD 独自的。以前的研究，特别是门德利兰塞利亚（MR）分析，提供了有力的证据 对于低维生素D作为导致多种自身免疫性条件的危险因素。维生素D对于数十个很重要 生物过程。与维生素D与维生素D接收器结合发生的基因转录 （VDR）产生的下游效应与免疫调节，代谢，细胞生长， 增殖和凋亡以及其他重要的免疫功能。单核苷酸多态性（SNP） 与VDR结合亲和力（VDR-BV）的遗传变异有关的 淋巴母细胞系（LCLS）；这些VDR-BV富含与几个相关的基因组区域 自身免疫性疾病，心血管疾病，骨质疏松症，抑郁症和癌症。迄今为止，可用 SJD中维生素D的研究仅限于SJD病例中血清维生素D水平的小型研究和 在情况下观察到较低维生素D水平的对照。没有发表的研究调查： 1）低维生素D作为使用MR分析的SJD的危险因素，或2）单个VDR结合内的遗传变异 站点是SJD的危险因素。因此，VDR-BV是研究其遗传贡献的强大候选者 到SJD。该F31应用的总体目的是确定整个基因组和 表征他们与SJD敏感性，严重程度和相关临床结果的关联。我们 假设改变VDR结合会破坏维生素D的下游基因调节，并增加风险 开发SJD或导致更严重的疾病。我们的方法将使用包含更多的数据集 在种族/族裔中匹配的1,500个SJD案件和27,000个对照（已经可用的数据）， 从Sjögren的国际 协作临床联盟（SICCA）注册表。对于此项目，我们将使用先前确定的VDR-BV 通过LCLS中的CHIP-SEQ分析，并在初级CD4+和CD8+ T细胞中进行后续分析。这 拟议的研究将：1）通过主要CD4+和CD8+ T细胞中的CHIP-EXO分析识别VDR结合位点 使用SICCA案例和对照； 2）估计VDR-BV和维生素D相关SNP之间的关联 SICCA研究对象中使用MR方法的SJD敏感性； 3）估计 SICCA研究受试者中VDR-BV和维生素D相关的SNP和临床SJD表型使用MR 方法。提出的目标的结果将确定与维生素D相关的SJD的遗传危险因素 并确定与SJD发展有关的新基因和调节途径。最终，目标 这项工作是了解维生素D影响这种免疫介导的疾病的机制。