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.

项目概要 干燥病（SjD，以前称为干燥综合征）是一种慢性、多系统自身免疫性疾病 这会导致严重的发病率。专家估计美国有 130 万人拥有 SjD 独自的。先前的研究，特别是孟德尔随机化 (MR) 分析，提供了强有力的证据 低维生素 D 是导致多种自身免疫性疾病的危险因素。维生素 D 对数十人都很重要 的生物过程。维生素 D 与维生素 D 受体结合时发生的基因转录 （VDR）产生与免疫调节、钙代谢、细胞生长有关的下游效应， 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) 的遗传变异相关的先前已在 类淋巴母细胞系（LCL）；这些 VDR-BV 富含与多种相关的基因组区域 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 关于 SjD 中维生素 D 的研究仅限于 SjD 病例血清维生素 D 水平的小型研究， 对照组观察到病例中维生素 D 水平较低。尚未发表研究调查： 1) 使用 MR 分析将低维生素 D 作为 SjD 的危险因素，或 2) 个体 VDR 结合内的遗传变异 地点作为 SjD 的危险因素。因此，VDR-BV 是研究其遗传贡献的有力候选者 到 SjD。该 F31 应用的总体目标是识别整个基因组中的 VDR-BV，并 描述它们与 SjD 易感性、严重程度和相关临床结果的关系。我们 假设改变 VDR 结合会破坏维生素 D 的下游基因调控并增加风险 发展 SjD 或导致更严重的疾病。我们的方法将使用包含更多内容的组装数据集 超过 1,500 个 SjD 病例和 27,000 个对照（其数据已经可用）在种族/民族上进行匹配， 包含来自 Sjögren’s International 的全基因组 SNP 图谱以及人口统计和临床数据 合作临床联盟 (SICCA) 注册中心。对于这个项目，我们将使用之前确定的 VDR-BV 通过 LCL 中的 ChIP-seq 分析，并在原代 CD4+ 和 CD8+ T 细胞中进行后续分析。这 拟议的研究将： 1) 通过原代 CD4+ 和 CD8+ T 细胞中的 ChIP-exo 分析识别 VDR 结合位点 使用 SICCA 案例和控制； 2) 估计VDR-BV和维生素D相关SNP之间的关联 使用 MR 方法评估 SICCA 研究对象的 SjD 易感性； 3）估计之间的关联 使用 MR 分析 SICCA 研究对象中的 VDR-BV 和维生素 D 相关 SNP 以及临床 SjD 表型 方法。拟议目标的结果将确定与维生素 D 相关的 SjD 遗传风险因素 并确定参与 SjD 发展的新基因和调控途径。最终，目标 这项工作的目的是了解维生素 D 影响这种免疫介导疾病的机制。