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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。

基本信息

批准号：
9769721
负责人：
Raymond David Hawkins
金额：
$ 39.94万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9769721
关键词：
Address Asthma Autoimmune Diseases Automobile Driving Binding Biological Assay Catalogs Categories Cells ChIP-seq Chromatin Code Crohn&apos s disease Data Disease Distal Enhancers Equilibrium Etiology Evaluation Gene Expression Gene Targeting Genes Genetic Genetic Enhancer Element Genetic study Genome Goals Helper-Inducer T-Lymphocyte Human Immune system Insulin Insulin-Dependent Diabetes Mellitus Intercistronic Region Introns Light Linkage Disequilibrium Location Maps Mediating Methods Multiple Sclerosis 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 causal variant cell type genome wide association study genome-wide high throughput screening innovation next generation sequencing public health relevance risk variant trait transcription factor

项目摘要

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.