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

项目摘要 Sjögren病是一种慢性、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130万人患有SJD 独自一人。以前的研究，特别是孟德尔随机化(MR)分析，已经提供了强有力的证据 低维生素D是导致几种自身免疫性疾病的危险因素。维生素D对几十个人来说很重要 关于生物过程的。维生素D与维生素D受体结合时发生的基因转录 (VDR)产生下游效应，涉及免疫调节、钙代谢、细胞生长、 增殖和凋亡等重要免疫功能。单核苷酸多态(SNPs) 与VDR结合亲和力(VDR-BV)的遗传变异相关的基因已在 淋巴母细胞样细胞系(LCLS)；这些VDR-BV在与几个 自身免疫性疾病、心血管疾病、骨质疏松症、抑郁症和癌症。到目前为止，可用 对SJD中维生素D的研究仅限于对SJD患者和 观察到病例中维生素D水平较低的对照组。目前还没有公开发表的研究对此进行调查： 1)通过MR分析，低维生素D是SJD的危险因素，或2)个体VDR结合中的遗传变异 网站是SJD的风险因素。因此，VDR-BV是研究其遗传贡献的有力候选者 去了SJD。此F31应用程序的总体目标是识别整个基因组中的VDR-BV 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VDR结合改变扰乱了维生素D对下游基因的调控，并增加了风险 或导致更严重的疾病。我们的方法将使用集合的数据集，其中包含 1,500多名SJD病例和27,000名对照(已经有数据可用)在种族/民族上匹配， 来自Sjögren‘s International的全基因组SNP图谱以及人口统计学和临床数据 协作临床联盟(SICCA)注册。对于此项目，我们将使用之前确定的VDR-BV 通过对LCLS中的CHIP-SEQ分析，并在原代CD4+和CD8+T细胞中进行后续分析。这个 拟议的研究将：1)通过芯片-exo分析确定原代CD4+和CD8+T细胞中的VDR结合部位 使用SICCA病例和对照；2)估计VDR-BV与维生素D相关SNPs之间的关联 和SICCA研究对象的SJD易感性之间的关系；3)估计 SICCA研究对象VDR-BVS、维生素D相关SNPs和临床SJD表型的MR研究 方法：研究方法。拟议目标的结果将确定与维生素D有关的SJD的遗传风险因素 并确定与SJD发展有关的新基因和调控途径。最终，我们的目标是 这项工作的重点是了解维生素D影响这种免疫介导性疾病的机制。

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.