A GENOME-WIDE METHYLATION STUDY ON ESSENTIAL HYPERTENSION

原发性高血压的全基因组甲基化研究

• 批准号: 8107275
• 负责人: XIAOLING WANG
• 金额: $ 60.41万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-05 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8107275
• 关键词: Adolescent; Adult; African American; Age; Animals; Biological Assay; Blood Pressure; Caucasians; Caucasoid Race; Cell Line; Cell physiology; Cells; Clinical; Code; Cohort Studies; Collection; DNA; DNA Methylation; DNA Methyltransferase Inhibitor; DNA Sequence; Development; Disease; Environmental Risk Factor; Epidemiology; Epigenetic Process; Essential Hypertension; Experimental Models; Family Study; Functional disorder; Gender; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genetic Transcription; Genomics; Health; Heart; Human Development; In Vitro; Inflammation; Inherited; Intervention; Knowledge; Left; Leukocytes; Longitudinal Studies; Measures; Methylation; Modification; Molecular Biology; Molecular Epidemiology; Monozygotic Twinning; Monozygotic twins; Nature; Pathogenesis; Play; Population; Predisposition; Prevention; Process; Public Health; RNA; Resolution; Risk; Role; Sampling; Screening procedure; Signal Transduction; Site; Staging; Stratification; Stress; Techniques; Testing; Time; Translating; Twin Multiple Birth; Twin Studies; Validation; Variant; Visit; base; blastocyst; case control; cohort; demethylation; design; follow-up; genome wide association study; genome-wide; health record; improved; insight; new therapeutic target; novel; novel strategies; outcome forecast; research study

DESCRIPTION (provided by applicant): From the recent 'genome-wide association studies' we have to conclude that the involvement of the primary DNA sequence does not explain the full genetic predisposition of essential hypertension (EH). A more thorough understanding of additional mechanisms potentially involved in EH is a prerequisite to prevention and development of novel therapies. Changes in DNA methylation (i.e., epigenetic modification of genetic information) can play an important regulatory role (by influencing transcription) in both normal and pathological cellular processes. Based on many recent studies that highlight the involvement of inflammation in the development of EH, we hypothesize that changes in DNA methylation of leukocytes are involved in the pathogenesis of EH. We aim to identify these differentially methylation sites using a multi-step genome wide approach. First, we will identify the CpG sites where DNA methylation differs between EH cases and controls (aim 1). We will employ a step-wise selection process involving 3 stages. After interrogation of 27,000 methylation sites in more than 14,000 genes in 100 monozygotic twin pairs discordant for EH (the the ideal experimental model for identifying disease related epigenetic signals) and 100 age and gender matched external controls selected from the Finnish Twin Cohort Study, we will choose the most promising for validation and replication in 500 EH cases and 500 healthy controls. Then, we will determine whether changes in methylation of these CpG sites are associated with changes in gene expression in the cells. Functional in vitro experiments will also be conducted to investigate whether demethylation of these CpG sites can activate gene expression, which will eventually leading to the (approximately) 20 most important sites. Next, we will determine the temporal relationship between DNA methylation status and EH in a nested case-control setting (380 newly developed EH cases and 380 controls) involving assessment of methylation status at baseline and EH status after 4 years follow-up (aim 2). Furthermore, we will determine the effect of DNA methylation status on blood pressure development in the BP stress cohort which has measured BP 8 times in 299 Caucasian adolescents during 11 years follow up (aim 3). Secondary specific aim will test whether the methylation sites identified in Caucasians are also involved in the pathogenesis of EH in African Americans in the Jackson Heart Study and the BP stress cohort. We expect to pinpoint specific methylation sites likely to be involved in the pathophysiology of EH. These results might play a key role in the development of new therapeutic targets for early risk stratification and intervention. PUBLIC HEALTH RELEVANCE: Relevance to public health Essential hypertension is a major health problem with global proportions. In USA, approximately one in three adults suffers from this disease. Our understanding of the interplay between heritable and environmental factors is only limited. Genome wide association studies only determined variants that can explain a very small variance of the blood pressure in the population, leaving the strong familial predisposition largely unexplained. A more thorough understanding of the mechanisms involved with EH is a prerequisite for new advantages. We put the new hypothesis forward that DNA methylation (of yet to be determined genes) is associated with essential hypertension. We will be operating at the interface of basic molecular biology and epidemiology and we will provide novel insights into the effects of DNA methylation and its downstream effects in essential hypertension. In this study we utilize the opportunity to thoroughly interrogate methylation sites genome wide, determine the most relevant ones and relate the identified methylation changes to the clinical development of EH. Identification of new factors associated with EH, will push the boundary of our understanding of this inherited and acquired disease.

描述（由申请人提供）： 从最近的“全基因组关联研究”中，我们不得不得出结论，主要DNA序列的参与并不能解释原发性高血压（EH）的全部遗传易感性。更深入地了解可能参与EH的其他机制是预防和开发新疗法的先决条件。DNA甲基化的变化（即，遗传信息的表观遗传修饰）可以在正常和病理细胞过程中起重要的调节作用（通过影响转录）。基于最近许多研究强调炎症参与EH的发展，我们假设白细胞DNA甲基化的变化参与EH的发病机制。我们的目标是确定这些差异甲基化位点使用多步全基因组的方法。首先，我们将确定DNA甲基化在EH病例和对照之间的差异的CpG位点（目的1）。我们将采用包括3个阶段的逐步选择过程。在询问了100对与EH不一致的单卵双生子的14，000多个基因中的27，000个甲基化位点后，（用于鉴定疾病相关表观遗传信号的理想实验模型）和100名年龄和性别匹配的外部对照，我们将选择最有希望的方法在500例EH病例和500例健康对照中进行验证和复制。然后，我们将确定这些CpG位点甲基化的变化是否与细胞中基因表达的变化相关。还将进行功能性体外实验，以研究这些CpG位点的去甲基化是否可以激活基因表达，这最终将导致（大约）20个最重要的位点。接下来，我们将在巢式病例对照组（380例新发EH病例和380例对照）中确定DNA甲基化状态与EH之间的时间关系，包括评估基线时的甲基化状态和4年随访后的EH状态（目标2）。此外，我们将确定DNA甲基化状态对BP应激队列中血压发展的影响，该队列在11年随访期间对299名白人青少年测量了8次血压（目的3）。第二个具体目标将测试在高加索人中鉴定的甲基化位点是否也参与杰克逊心脏研究和BP应激队列中非洲裔美国人的EH发病机制。我们希望能够精确定位可能参与EH病理生理学的特定甲基化位点。这些结果可能在开发早期风险分层和干预的新治疗靶点方面发挥关键作用。 公共卫生关系： 原发性高血压是一个全球性的重大健康问题。在美国，大约三分之一的成年人患有这种疾病。我们对遗传因素和环境因素之间相互作用的了解有限。全基因组关联研究仅确定了可以解释人群中血压非常小的变异的变异，使得强烈的家族易感性在很大程度上无法解释。对EH相关机制的更透彻理解是获得新优势的先决条件。我们提出了新的假设，即DNA甲基化（尚未确定的基因）与原发性高血压有关。我们将在基础分子生物学和流行病学的界面上进行操作，我们将提供对DNA甲基化及其下游效应在原发性高血压中的影响的新见解。在这项研究中，我们利用这个机会彻底询问全基因组的甲基化位点，确定最相关的甲基化位点，并将鉴定的甲基化变化与EH的临床发展联系起来。识别与EH相关的新因素，将推动我们对这种遗传性和获得性疾病的理解。