Functional assessment of distal regulatory SNPs associated with type 1 diabetes.

与 1 型糖尿病相关的远端调节 SNP 的功能评估。

• 批准号: 9118987
• 负责人: Raymond David Hawkins
• 金额: $ 48.45万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9118987
• 关键词: Address; Asthma; Autoimmune Diseases; Automobile Driving; Binding; Biological Assay; CD4 Positive T Lymphocytes; Cataloging; Catalogs; Categories; Cells; ChIP-seq; Chromatin; Code; Crohn' s disease; Data; Disease; Distal; Enhancers; Equilibrium; Etiology; Evaluation; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Enhancer Element; Genetic study; Genome; Goals; Health; Helper-Inducer T-Lymphocyte; Human; Immune system; Insulin; Insulin-Dependent Diabetes Mellitus; Intercistronic Region; Introns; Light; Linkage Disequilibrium; Location; Maps; Mediating; Methods; Multiple Sclerosis; Mutation; National Human Genome Research Institute; Nucleic Acid Regulatory Sequences; Pathogenesis; Play; Process; Psoriasis; Regulatory Element; Reporter; Research; Rheumatoid Arthritis; Series; Single Nucleotide Polymorphism; T cell differentiation; T cell regulation; T-Lymphocyte; Technology; Testing; Time; Twin Multiple Birth; Ulcerative Colitis; Validation; Variant; base; cell type; genome wide association study; genome-wide; high throughput screening; innovation; next generation sequencing; risk variant; trait; transcription factor

 DESCRIPTION (provided by applicant): Type 1 diabetes (T1D) is an autoimmune disease resulting in the loss of insulin- producing cells. Genetic studies, including those in twins, sugget a strong genetic basis for this disease. Genome-wide association studies (GWASs) have produced large numbers of T1D-associated single-nucleotide polymorphisms (SNPs), but often fail to determine a causative mutation. This may be due to the complexity of the disease; or in part, due to many associated SNPs lying outside of gene coding regions. A recent assessment of GWASs illustrated that 45% of disease or trait associated SNPs fell in introns, while 43% lie in intergenic regions. Global methods for determining chromatin states have shown that associated SNPs can overlap distal regulatory regions such as enhancers. We have constructed enhancer maps based H3K4me1 localization in isolated, human T cells. We analyzed the T1D-associated SNPs from the NHGRI GWAS catalog for overlap with our global T helper cell enhancer predictions. Using 1000 Genomes data we identified additional SNPs in linkage disequilibrium to expand the number of T1D-associated SNPs at enhancer elements. Goal: Our goal is to functionally validate T1D-associated rSNPs. We will use a series of high- throughput assays and systematic evaluation to determine the most functionally relevant rSNPs. We will also determine the target genes of enhancers overlapping T1D SNPs in order to identify new genes important in the etiology of T1D pathogenesis. We will do so through the following specific aims. Specific Aim 1. Determine the effect of T1D rSNPs on enhancer activity. Specific Aim 2. Determine if TF binding is disrupted at T1D-associated enhancer SNPs. Specific Aim 3. Identification of target genes for enhancers harboring associated SNPs.

 描述（由申请人提供）：1型糖尿病（T1 D）是一种导致胰岛素产生细胞丧失的自身免疫性疾病。遗传学研究，包括对双胞胎的研究，表明这种疾病有很强的遗传基础。全基因组关联研究（GWAS）已经产生了大量的T1 D相关的单核苷酸多态性（SNP），但往往无法确定致病突变。这可能是由于疾病的复杂性;或者部分是由于许多相关的SNP位于基因编码区之外。最近对GWAS的评估表明，45%的疾病或性状相关SNP位于内含子中，而43%位于基因间区域。用于确定染色质状态的全局方法已经表明，相关的SNP可以与远端调控区如增强子重叠。我们已经构建了增强子地图的基础上H3 K4 me 1在分离的人T细胞定位。我们分析了来自NHGRI GWAS目录的T1 D相关SNP与我们的全球T辅助细胞增强子预测的重叠。使用1000个基因组数据，我们确定了连锁不平衡中的额外SNP，以扩大增强子元件处T1 D相关SNP的数量。目标：我们的目标是功能验证T1 D相关的rSNP。我们将使用一系列高通量检测和系统评价来确定功能上最相关的rSNP。我们还将确定与T1 D SNP重叠的增强子的靶基因，以鉴定在T1 D发病机制的病因学中重要的新基因。我们将通过以下具体目标这样做。具体目标1。确定T1 D rSNP对增强子活性的影响。具体目标2。确定TF结合是否在T1 D相关增强子SNP处被破坏。具体目标3。携带相关SNP的增强子的靶基因的鉴定。