Large-Scale Methylation Profiling in Metabolic Syndrome Phenotypes

代谢综合征表型的大规模甲基化分析

基本信息

批准号：
7865069
负责人：
Melanie Carless
金额：
$ 61.34万
依托单位：
TEXAS BIOMEDICAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-20 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7865069
关键词：
Autoimmune Diseases Biological Biological Assay Biological Markers Biology Blood Pressure Body mass index Candidate Disease Gene Cardiovascular Diseases Cause of Death Characteristics Complex CpG Islands Data Development Diabetes Mellitus Diagnosis Disease Disease Progression Dyslipidemias Enrollment Epigenetic Process European Family Fasting Fatty acid glycerol esters Gallbladder Gene Proteins Gene Silencing Genes Genetic Genetic Research Genome Genomics Genotype Health Heritability High Density Lipoprotein Cholesterol High Prevalence Hour Hypertension Incidence Individual Insulin Investigation LDL Cholesterol Lipoproteins Leptin Life Style Luciferases Malignant Neoplasms Mental disorders Metabolic Metabolic Diseases Metabolic syndrome Methylation Mexican Americans Molecular Morbidity - disease rate Non-Insulin-Dependent Diabetes Mellitus Obesity Overnutrition Pathogenesis Phenotype Play Population Predisposition Prevalence Promoter Regions Proteins Regulation Relative (related person)Research Design Resources Risk Risk Factors Role Sampling Severities Site Specificity Syndrome Therapeutic Intervention Time Triglycerides Variant Wisconsin adiponectin base bisulfite density diabetes risk epigenetic variation fasting glucose genetic pedigree genome-wide meetings member molecular pathology mortality outcome forecast pandemic disease promoter protein expression public health relevance sedentary trait waist circumference

项目摘要

DESCRIPTION (provided by applicant): Metabolic syndrome is becoming one of the most significant health issues of modern times, predisposing individuals to diabetes and cardiovascular disease. Although considerable advances have been made in identifying genetic contributions to this syndrome, we still understand very little about the mechanisms that regulate development and progression of the disease, particularly at the epigenetic level. Genetic studies of complex diseases like metabolic syndrome, are further complicated by an array of phenotypes that likely associate with the severity or progression of the disease. By using an approach that focuses not only on disease status but also on the phenotypes that characterize a complex disorder, we can achieve a much greater power to explore the molecular pathogenesis underlying the disease. This project will use such an approach to investigate the methylation status in more than 27,000 CpG sites within approximately 14,000 genes in a large-scale study designed to identify epigenetic changes associated with metabolic syndrome and related phenotypes. Genomic methylation of CpG islands within the promoter and 5' region of a gene typically causes silencing of that gene, which is a reversible effect. This type of epigenetic aberration is recognized in a number of complex diseases, including cancer, autoimmune disorders, psychiatric disorders and most recently metabolic disorders. Few studies have investigated genomic methylation in metabolic syndrome and associated disorders, but there is evidence to suggest that it may play a strong role in the development of such disorders. This project endeavors to uncover the role of genomic methylation in metabolic syndrome and related phenotypes by: 1) determining the genomic methylation profile of 27,578 CpG sites in 1,200 Mexican Americans; 2) assessing methylation as a quantitative trait and determining correlations with metabolic syndrome phenotypes; 3) characterizing entire CpG islands of selective metabolic syndrome candidate genes; 4) verifying CpG island characteristics of selective metabolic syndrome candidate genes in two additional populations; 5) performing functional analyses to determine downstream consequences of genomic methylation in selected metabolic syndrome candidate genes. We anticipate that this project will yield a wealth of information on the role of epigenetic variation associated with metabolic syndrome and its' related phenotypes, which will have important implications relating to cardiovascular disease and diabetes. By investigating the underlying biology of complex disorders, such as metabolic syndrome, diabetes and cardiovascular disease, we can identify biomarkers that may aid in diagnosis and prognosis and better identify targets for potential therapeutic intervention. PUBLIC HEALTH RELEVANCE: The escalating prevalence of metabolic syndrome, which predicts risk for diabetes and cardiovascular disease, is of major concern due to the extremely high mortality and morbidity associated with its' consequential diseases. In this project we will undertake large-scale genomic methylation profiling in a large population of Mexican Americans from extended pedigrees to investigate potential implications for metabolic syndrome and related phenotypes. Additional comprehensive characterization of this epigenetic mechanism will contribute immensely to understanding the molecular pathology associated with metabolic syndrome.

描述（由申请人提供）：代谢综合征正在成为现代最重要的健康问题之一，使人容易患糖尿病和心血管疾病。尽管在确定对该综合征的遗传贡献方面取得了很大进步，但我们仍然对调节疾病发育和进展的机制了解很少，尤其是在表观遗传水平上。一系列可能与疾病的严重程度或进展相关的表型，对复杂疾病（如代谢综合征）等复杂疾病的遗传研究更加复杂。通过使用一种不仅关注疾病状况的方法，而且还针对表征复杂疾病的表型，我们可以实现更大的能力来探索疾病的分子发病机理。在一项大规模研究中，该项目将使用这种方法来研究大约14,000个基因中27,000多个CpG位点的甲基化状况，旨在鉴定与代谢综合征和相关表型相关的表观遗传变化。基因启动子和5'区域内CpG岛的基因组甲基化通常会导致该基因的沉默，这是可逆的作用。这种表观遗传畸变在许多复杂的疾病中都得到了认可，包括癌症，自身免疫性疾病，精神疾病和最近的代谢疾病。很少有研究研究代谢综合征和相关疾病中的基因组甲基化，但是有证据表明，它可能在此类疾病的发展中起着重要作用。该项目努力揭示基因组甲基化在代谢综合征和相关表型中的作用：1）确定1,200名墨西哥裔美国人中27,578 CpG位点的基因组甲基化谱； 2）评估甲基化作为定量性状，并确定与代谢综合征表型的相关性； 3）表征整个选择性代谢综合征候选基因的CpG岛； 4）验证另外两个人群中选择性代谢综合征基因的CpG岛特征； 5）进行功能分析以确定选定代谢综合征候选基因基因组甲基化的下游后果。我们预计该项目将获得有关与代谢综合征及其相关表型相关的表观遗传变异作用的大量信息，这些表型将具有与心血管疾病和糖尿病有关的重要意义。通过研究复杂疾病的潜在生物学，例如代谢综合征，糖尿病和心血管疾病，我们可以鉴定出可能有助于诊断和预后的生物标志物，并更好地识别潜在治疗干预的靶标。公共卫生相关性：代谢综合征的不断升高，该综合症预测糖尿病和心血管疾病的风险，由于其与其后果疾病相关的死亡率和发病率极高，因此引起了重大关注。在这个项目中，我们将在大量的墨西哥裔美国人中进行大规模的基因组甲基化分析，以研究对代谢综合征和相关表型的潜在影响。这种表观遗传机制的其他全面表征将极大地理解与代谢综合征相关的分子病理。