Role of DNA methylation in lupus

DNA 甲基化在狼疮中的作用

基本信息

批准号：
8626354
负责人：
Amr H Sawalha
金额：
$ 39.4万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-25 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8626354
关键词：
Accounting Address Adverse effects Affect Alleles Animal Model Autoimmune Diseases Biological Process CD4 Positive T Lymphocytes Chromatin Chronic CpG Islands DNA Methylation DNA Methyltransferase DNA Modification Methylases DNA Resequencing DNA biosynthesis Defect Disease Disease susceptibility Environment Enzymes Epigenetic Process Etiology Flare Frequencies Gene Expression Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease Genome Haplotypes Heritability Human Biology Human Genome IRAK1 gene Individual Interferon Type I Knowledge Literature Lupus Maintenance Maps Mediating Methyl-CpG-Binding Protein 2 Methylation Morbidity - disease rate Pathogenesis Patients Predisposition Promoter Regions Recruitment Activity Relapse Reporting Resolution Risk Role Site Specificity Susceptibility Gene Systemic Lupus Erythematosus T-Lymphocyte T-Lymphocyte Subsets Time Transcriptional Regulation Variant Work base body system falls genetic association genetic variant genome wide association study genome-wide insight mortality next generation sequencing novel novel diagnostics promoter public health relevance research study risk variant systemic autoimmune disease transcription factor

项目摘要

DESCRIPTION (provided by applicant): Systemic lupus erythematosus is a chronic relapsing autoimmune disease that involves multiple organ systems. The etiology and pathogenesis of lupus are incompletely understood. There is a strong evidence for genetic contribution to the pathogenesis of lupus, however, despite the enormous progress in mapping lupus susceptibility genes, only a small fraction of lupus heritability is accounted for by the genetic associations discovered. A large body of literature supports the contention that epigenetic dysregulation, particularly T cell DNA methylation defect, contributes to the pathogenesis of lupus. Indeed, demethylated T cells are sufficient to cause lupus in animal models. We believe that epigenetic differences between lupus patients and controls contribute towards the "missing" heritability of the disease. We propose to determine and functionally characterize differentially methylated genetic loci in specific T cell subsets in lupus patients compared to normal controls, using a genome-wide approach, the feasibility of which has been confirmed in our own preliminary experiments. We will further Identify and validate DNA methylation changes over time in relation to disease activity in lupus patients. We hypothesize that genetic variants associated with lupus will alter DNA methylation in known lupus susceptibility loci in an allele-specific manner. Therefore, we will determine allele specific DNA methylation changes in validated genetic susceptibility loci for lupus. We previously reported the genetic association between SNPs within MECP2 and lupus. MECP2 (methyl-CpG-binding protein 2) is a key transcriptional regulator for methylation sensitive genes, and is also known to recruit the DNA methylation enzyme DNMT1 during DNA synthesis. We will resequence the MECP2/IRAK1 LD block using next generation sequencing to identify the causal variants in this locus.

描述（由申请人提供）：全身性红斑狼疮是一种慢性复发自身免疫性疾病，涉及多个器官系统。狼疮的病因学和发病机理尚不完全理解。有强有力的证据表明，尽管在映射狼疮易感基因的映射方面取得了巨大进展，但发现狼疮的遗传力的一小部分是由发现的遗传关联所解释的，但仅有一小部分狼疮。大量文献支持表观遗传失调，尤其是T细胞DNA甲基化缺陷的争论，有助于狼疮的发病机理。实际上，脱甲基化的T细胞足以在动物模型中引起狼疮。我们认为，狼疮患者和对照组之间的表观遗传差异有助于疾病的“缺失”遗传力。我们建议使用全基因组方法与正常对照组相比，在特异性T细胞子集中确定并在功能上表征差异的甲基化遗传基因座，其可行性已在我们自己的初步实验中得到了证实。我们将进一步识别和验证与狼疮患者疾病活性有关的DNA甲基化变化。我们假设与狼疮相关的遗传变异将以等位基因特异性方式改变已知狼疮易感基因座的DNA甲基化。因此，我们将确定狼疮验证的遗传敏感性基因座的特异性DNA甲基化变化。我们先前报道了MECP2和狼疮中SNP之间的遗传关联。 MECP2（甲基-CPG结合蛋白2）是用于甲基化敏感基因的关键转录调节剂，也已知可以在DNA合成过程中募集DNA甲基化酶DNMT1。我们将使用下一代测序来重新设置MECP2/IRAK1 LD块，以识别该基因座中的因果变体。