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.

项目总结