Genetic and epigenetic contributions to Sjogren's syndrome

遗传和表观遗传对干燥综合征的影响

基本信息

批准号：
8991063
负责人：
Lindsey Ann Criswell
金额：
$ 23.71万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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：
2015-01-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8991063
关键词：
Affect Algorithms Autoantibodies Autoimmune Diseases Autoimmunity B-Lymphocytes Biological Assay Biological Markers Biopsy Blood Blood specimen Budgets CD14 gene CD19 gene CD4 Positive T Lymphocytes Carbon Cell Separation Cells Clinical Clinical Data Collection Complex Country CpG dinucleotide Cytosine DNA DNA Methylation Data Data Analyses Data Set Development Diagnosis Enrollment Epigenetic Process Etiology European Exhibits Gene Expression Genes Genetic Genome Genomic Segment Genotype Health Histocompatibility Testing Human Individual International Labial Salivary Gland Lead Machine Learning Meta-Analysis Methodology Methods Methylation Modeling Modification Molecular Genetics National Institute of Dental and Craniofacial Research Not Hispanic or Latino Oral Participant Patients Peripheral Blood Mononuclear Cell Phenotype Play Population Prevention approach Principal Component Analysis Production Research Project Grants Resources Risk Risk Factors Role SNP genotyping Sample Size Sampling San Francisco Site Sjogren&apos s Syndrome Statistical Data Interpretation Study Subject Subgroup Syndrome T-Lymphocyte Subsets Technology Tissues Transcriptional Regulation Whole Blood Work base case control cell type clinical phenotype disorder risk genome wide association study genome-wide high throughput technology human DNA interest member monocyte repository systemic autoimmune disease whole genome

项目摘要

DESCRIPTION (provided by applicant): High throughput whole genome platforms to quantitatively and efficiently assay human DNA methylation provide an extraordinary opportunity to accelerate progress in the identification of epigenetic mechanisms for complex human autoimmune diseases such as Sjogren's Syndrome (SS). Epigenetic modifications, such as methylation of the 5' carbon of cytosine which occurs in the context of CpG dinucleotides, do not affect the genetic sequence; however, they do play a critical role in transcriptional regulation of a gene and subsequent gene expression. We have applied this technology, in conjunction with whole genome SNP genotyping to a clinically well-characterized collection of SS cases and controls developed specifically for genetic and epigenetic studies. Samples from the Sjogren's International Collaborative Clinical Alliance (SICCA) repository (total n=3,500 individuals) will b utilized, given the careful phenotype characterization and standardized collection of biospecimens that has been performed for each participant. For this proposal, we have initially obtained DNA from peripheral blood mononuclear cells (PBMCs) and sorted cell populations with high purity, including CD14+ monocytes, CD19+ B cells, CD4+ T cells, as well as labial salivary gland biopsy tissue from 120 SICCA participants (100 SS cases and 20 controls). Data collected for ~450,000 highly informative CpG sites spanning 22,000 genes across the genome will provide a comprehensive assessment of DNA methylation for each individual for our proposed study Aims. As part of Aim 1, DNA methylation profiles will be examined using three main approaches: 1) Global DNA methylation profiles will be analyzed for association with SS risk in all sample types; 2) Multidimensional scaling analysis (MDS) and principal components analysis (PCA) will be performed to determine whether SS case samples can be distinguished from control samples; and 3) Local analyses will also be performed and will focus specifically on DNA methylation changes within candidate SS genes and genes demonstrating at least 1.5 fold methylation differences between cases and controls. Our proposal will take advantage of available whole genome data for each study participant and results from the largest genome wide association study (GWAS) in SS. In Aim 2, we will utilize DNA methylation profiles and methods from Aim 1 to determine whether important SS case phenotypes can be distinguished from one another. We will identify top ranked CpG sites that are either hypo or hyper methylated in specific SS case groups or that distinguish cases from controls using supervised machine learning algorithms. We will attempt replication for all top findings in an independent dataset, followed by random effects meta-analysis to incorporate other SS risk factors. Finally, we will determine whether DNA methylation profiles of interest from Aims 1 and 2 can be detected in DNA from whole blood for potential use as a biomarker. The identification of unique epigenetic profiles in SS, and an understanding of these profiles in the context of different cell and tissue types and genetic background have the potential to significantly transform our understanding of SS etiology.

描述（由申请人提供）：高吞吐量的整个基因组平台，以定量有效地测定人DNA甲基化，这为复杂人类自身免疫性疾病（例如Sjogren's综合征（SS）的复杂人类自身免疫性疾病的表观遗传机制鉴定，都可以加速进步。表观遗传修饰，例如在CpG二核苷酸背景下发生的5'胞嘧啶的甲基化不会影响遗传序列；但是，它们确实在转录调节中起着至关重要的作用基因和随后的基因表达。我们已经将这项技术与整个基因组SNP基因分型一起应用于临床良好的SS病例集合，并专门针对遗传和表观遗传学研究开发。鉴于仔细的表型表征和为每个参与者执行的生物测量收集，Sjogren国际合作临床联盟（SICCA）存储库中的样本将B使用B使用。对于这一建议，我们最初从外周血单核细胞（PBMC）和具有较高纯度的细胞群中获得了DNA，包括CD14+单核细胞，CD19+ B细胞，CD4+ T细胞，CD4+ T细胞以及唇唾液酸唾液腺唾液腺体生物疾病的组织（来自120 Sicca参与者（100 SS CASE和20对照组））。在整个基因组中跨越22,000个基因的约450,000个信息丰富的CPG站点收集的数据将为我们提出的研究目的提供全面评估DNA甲基化。作为目标1的一部分，将使用三种主要方法检查DNA甲基化谱：1）将分析全球DNA甲基化谱，以与所有样本类型中的SS风险关联； 2）将执行多维缩放分析（MDS）和主成分分析（PCA），以确定是否可以将SS案例样本与对照样品区分开； 3）也将进行局部分析，并将专门集中于候选SS基因和基因中的DNA甲基化变化，并证明病例和对照之间至少1.5倍甲基化差异。我们的建议将利用每个研究参与者的可用全基因组数据，并从SS中最大的基因组广泛关联研究（GWAS）的结果。在AIM 2中，我们将利用AIM 1的DNA甲基化谱和方法来确定是否可以彼此区分重要的SS病例表型。我们将确定在特定SS病例组中脱甲基化或过度甲基化的最高排名的CPG位点，或使用监督的机器学习算法将病例与对照区分开。我们将尝试在独立数据集中的所有最佳发现中复制，然后进行随机效应荟萃分析以纳入其他SS风险因素。最后，我们将确定是否可以从全血中的DNA中检测到来自AIM 1和2的DNA甲基化谱，以作为生物标志物的潜在使用。在不同的细胞和组织类型和遗传背景的背景下对SS中独特的表观遗传谱的鉴定以及对这些谱的理解有可能显着改变我们对SS病因的理解。