Epigenome-Wide Association Study of DNA Methylation and Atherosclerosis

DNA 甲基化与动脉粥样硬化的全表观基因组关联研究

• 批准号: 7727328
• 负责人: YONGMEI LIU
• 金额: $ 73.46万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7727328
• 关键词: Atherosclerosis; Biological Assay; Biological Markers; Blood specimen; Calcified; Carotid Arteries; Clinical; Complex; Coronary; DNA; DNA Methylation; Disease; Epigenetic Process; Etiology; Follow-Up Studies; Future; Gene Expression; Genes; Genome; Genomics; Hispanics; Intervention; Knowledge; Maps; Measures; Medial; Messenger RNA; Methylation; Modification; Molecular Profiling; Morbidity - disease rate; Participant; Pathogenesis; Pattern; Phenotype; Population; Promoter Regions; RNA; Role; Sampling; Schedule; Severities; Site; Thick; Transcript; Work; X-Ray Computed Tomography; cohort; disease diagnosis; epigenomics; genome-wide; human very old age (85+); mRNA Expression; monocyte; mortality; public health relevance; quantitative ultrasound; therapeutic target

DESCRIPTION (provided by applicant): Epigenetic modifications, especially alterations in DNA methylation in promoter regions of genes, are increasingly being recognized as key factors in the pathogenesis of a wide variety of complex disorders. We propose to investigate the association of global DNA methylation patterns in circulating monocytes in relation to atherosclerosis and monocyte gene expression profiles in the Multi-Ethnic Study of Atherosclerosis (MESA). DNA and RNA will be purified from monocytes isolated from blood samples of a large sample (n=1600) of MESA subjects (44-85 year old, 40% Whites, 27% Blacks, and 21% Hispanics) who are free of clinical atherosclerotic cardiovascular disease (ASCVD) and scheduled to undergo quantitative ultrasound assessment of carotid artery intimal-medial thickness (IMT) and computed tomography-determined calcified coronary plaque at MESA exam 5 (in 2010-2011). The DNA samples will be used to determine genome-wide DNA methylation profiles in a random 1/2 (800) of the participants. Commercial platforms will be used to assay methylation of approximately 27,000 CpG sites covering more than 14,000 well-annotated genes and most CGIs in the genome. RNA from the same monocytes will be used to perform expression profiling of ~25,000 genes, of which more than 12,700 are also present on the methylation assay. Associations between DNA methylation patterns and the extent of atherosclerosis measured by carotid IMT will be determined. Integrative analyses will be performed to elucidate the connections between DNA methylation markers and cellular mRNA expression of cognate genes. Follow-up studies will be performed on subsets of these genes in the remaining cohort to verify DNA methylation/mRNA transcript relationships and their associations with subclinical atherosclerosis. Genomic regions representing confirmed associations will be subsequently investigated using 540 MESA subjects (selected from the 1600 MESA participants) with extremes of IMT phenotypes to reveal functional implications. The proposed studies utilizing this unique and well characterized population will transform the understanding of the role of epigenomics and DNA methylation in relation to atherosclerosis and ASCVD. The knowledge obtained should yield new biomarkers for ASCVD diagnosis and uncover unique therapeutic targets for future targeted interventions. Public Health Relevance: Atherosclerotic cardiovascular disease (ASCVD) remains one of the leading causes of morbidity and mortality world-wide. We propose to investigate the epigenomics of ASCVD through mapping of monocytic DNA methylation profiles. This interdisciplinary, cooperative work will transform our understanding of the etiology and severity of ASCVD.

描述（由申请人提供）：表观遗传修饰，尤其是基因启动子区域中DNA甲基化的改变，越来越多地被认为是多种复杂疾病发病机理中的关键因素。我们建议在动脉粥样硬化研究（MESA）中研究与动脉粥样硬化和单核细胞基因表达谱相关的循环单核细胞中全局DNA甲基化模式的关联。 DNA和RNA将从从大量样本（n = 1600）受试者（44-85岁）（44-85岁，40％的白人，27％黑人和21％西班牙裔）的单核细胞中纯化，这些受试者（44-85岁，40％的白人和21％西班牙裔）都没有临床动脉粥样硬化心血管疾病（ASTIRESS疾病），并计划不及格的超级群体群的群体和不足的群体。 （IMT）和计算机断层扫描确定的钙化冠状斑块（2010-2011）。 DNA样品将用于确定全基因组DNA甲基化谱在随机的1/2（800）参与者中。商业平台将用于测定大约27,000个CPG位点，其中涵盖了14,000多个良好的基因和大多数基因组中的CGI。来自同一单核细胞的RNA将用于执行约25,000个基因的表达分析，其中甲基化测定法也存在12,700多个基因。将确定DNA甲基化模式与通过颈动脉IMT测得的动脉粥样硬化程度之间的关联。将进行综合分析，以阐明DNA甲基化标记与同源基因的细胞mRNA表达之间的联系。将在其余人群中对这些基因的子集进行随访研究，以验证DNA甲基化/mRNA转录关系及其与亚临床动脉粥样硬化的关联。随后将使用540名MESA受试者（从1600个MESA参与者中选择）和IMT表型极端的基因组区域进行确认关联的基因组区域，以揭示功能含义。提出的利用这种独特且特征良好的人群的研究将改变对表观基因组学和DNA甲基化在动脉粥样硬化和ASCVD方面的作用的理解。获得的知识应为ASCVD诊断提供新的生物标志物，并发现未来靶向干预措施的独特治疗靶标。公共卫生相关性：动脉粥样硬化心血管疾病（ASCVD）仍然是全球发病率和死亡率的主要原因之一。我们建议通过映射单核DNA甲基化谱图研究ASCVD的表观基因组学。这项跨学科的合作工作将改变我们对ASCVD的病因和严重性的理解。