Large-Scale Methylation Profiling in Metabolic Syndrome Phenotypes

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，使个体易患糖尿病和心血管疾病。虽然在确定这种综合征的遗传贡献方面取得了相当大的进展，但我们仍然对调节疾病发展和进展的机制知之甚少，特别是在表观遗传水平上。代谢综合征等复杂疾病的遗传学研究因一系列可能与疾病严重程度或进展相关的表型而进一步复杂化。通过使用一种不仅关注疾病状态，而且关注表征复杂疾病的表型的方法，我们可以获得更大的力量来探索疾病的分子发病机制。该项目将使用这种方法在一项大规模研究中调查约14，000个基因中超过27，000个CpG位点的甲基化状态，旨在确定与代谢综合征和相关表型相关的表观遗传变化。启动子和基因5'区域内CpG岛的基因组甲基化通常导致该基因沉默，这是一种可逆效应。这种类型的表观遗传畸变在许多复杂疾病中被识别，包括癌症、自身免疫性疾病、精神疾病和最近的代谢疾病。很少有研究调查代谢综合征和相关疾病的基因组甲基化，但有证据表明，它可能在这些疾病的发展中发挥重要作用。该项目致力于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27，578个CpG位点的基因组甲基化谱; 2）评估甲基化作为数量性状并确定与代谢综合征表型的相关性; 3）表征选择性代谢综合征候选基因的整个CpG岛; 4）在两个另外的群体中验证选择性代谢综合征候选基因的CpG岛特征; 5）进行功能分析以确定所选代谢综合征候选基因中基因组甲基化的下游后果。我们预计，该项目将产生丰富的信息，表观遗传变异的作用与代谢综合征及其相关的表型，这将有重要的意义，涉及心血管疾病和糖尿病。通过研究代谢综合征、糖尿病和心血管疾病等复杂疾病的基础生物学，我们可以确定可能有助于诊断和预后的生物标志物，并更好地确定潜在治疗干预的靶点。 公共卫生相关性：代谢综合征是糖尿病和心血管疾病的危险因素，其发病率和死亡率极高，已成为人们关注的焦点。在这个项目中，我们将进行大规模的基因组甲基化分析在一个大的墨西哥裔美国人的人口从扩展的谱系，以调查代谢综合征和相关表型的潜在影响。对这种表观遗传机制的进一步全面表征将极大地有助于理解与代谢综合征相关的分子病理学。

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.