Identifying Epigenetic Biomarkers of Cardiovascular Disease Risk In Humans

识别人类心血管疾病风险的表观遗传生物标志物

基本信息

批准号：
9198044
负责人：
Alika Keolaokalani Maunakea
金额：
$ 16.84万
依托单位：
UNIVERSITY OF HAWAII AT MANOA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-11-15 至 2018-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9198044
关键词：
Address Adult Age Bioinformatics Biological Assay Blood Blood Banks Blood specimen CD14 gene Cardiovascular Diseases Clinical Cohort Studies Collaborations Coronary heart disease DNA DNA Methylation Data Databases Development Dialysis patients Disease Epigenetic Process Exhibits FCGR3B gene Future Gene Expression Genes HIV HIV Infections HIV Seropositivity Hawaii High Prevalence Human Hyperlipidemia IL6 gene IL8 gene Immunologics Incidence Individual Inflammation Inflammatory Inflammatory Response Insulin Resistance Interleukin-1 Interleukin-6 Life Link Lipopolysaccharides Low-Density Lipoproteins Massive Parallel Sequencing Measures Mediating Messenger RNA Methods Modification Molecular Profiling Myelogenous Pathology Patients Pattern Peripheral Blood Mononuclear Cell Persons Phenotype Play Promoter Regions Protein Isoforms Publishing Quantitative Reverse Transcriptase PCR RNA RNA Splicing Research Risk Risk Factors Risk stratification Role Smoking Stimulus System Technology Testing Variant Viral base bead chip bisulfite sequencing cardiovascular disorder risk cell type differential expression epigenetic marker epigenomics genetic signature genome-wide high risk immune activation improved mRNA Precursor macrophage methylation pattern methylome monocyte mortality novel novel marker oxidized low density lipoprotein peripheral blood response transcriptome transcriptome sequencing transcriptomics trend

项目摘要

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is the largest single contributor to global mortality and appears to dominate mortality trends in the future. New evidence is emerging that inflammation attributable to monocytes/macrophages contributes to the development of CVD. Traditional CVD risk factors, such as insulin resistance, hyperlipidemia, and smoking, have been associated with modification of epigenetic markers and signatures of epigenetic dysregulation can be detected in peripheral blood samples. Monocytes (CD14+CD16+) residing in peripheral blood from dialysis patients predicted cardiovascular disease incidence, implicating this cell type in disease pathology. Indeed, an increased percentage of CD14+CD16+ monocytes were observed in the blood of patients with coronary heart disease. An increased percentage of these monocytes were also observed in the blood of HIV+ patients. Data from our collaborators indicate that monocytes from persons with HIV infection are hyper-responsive to oxidized LDL or LPS, producing high levels of IL-1�, IL6 and IL8. Thus, HIV-mediated immune activation in monocytes may play a role in the development of CVD. In support of this link, our preliminary data demonstrate that monocytes from HIV+ individuals, who have an elevated risk for CVD, also exhibit hyper-responsiveness to inflammatory stimuli. Interestingly, we observed that the level of a specific epigenetic mark, DNA methylation, at the promoter region of a pro- inflammatory gene in part explained the varying degree to which monocytes from individuals with clinically determined "low" or "high" risk for CVD responded to inflammatory stimuli. The mechanistic link between monocyte inflammation and CVD risk may be fundamental, but more easily detectable in individuals with heightened inflammatory response, such as those infected with HIV. This proposal will therefore test the hypothesis that a heightened inflammatory response elicited by monocytes confers an increased risk to CVD due to epigenetic dysregulation of environmentally labile loci, including at pro-inflammatory genes. This may be independent of HIV infection status. To address this hypothesis, we aim to evaluate monocyte inflammatory response in banked blood specimens from HIV-infected and matched uninfected individuals selected based on clinical parameters of CVD risk, and characterize, compare, and integrate this data with genome-wide DNA methylation and gene expression profiles from these monocytes. Collectively, this unique clinical, immunological, and epigenomic database will allow us to identify novel biomarkers associated with CVD risk that may enable improved risk stratification strategies for cardiovascular disease. (End of Abstract)

描述（由申请人提供）：心血管疾病 (CVD) 是全球死亡率的最大单一因素，并且似乎主导未来的死亡率趋势，新的证据表明单核细胞/巨噬细胞引起的炎症会导致传统 CVD 的发生。胰岛素抵抗、高脂血症和吸烟等危险因素与表观遗传标记的修饰有关，并且可以在外周血单核细胞样本中检测到表观遗传失调的特征。存在于透析患者外周血中的 CD14+CD16+ 可以预测心血管疾病的发病率，表明这种细胞类型与疾病病理学有关。事实上，在冠心病患者的血液中观察到 CD14+CD16+ 单核细胞的百分比有所增加。我们的合作者的数据表明，艾滋病毒感染者的单核细胞对氧化低密度脂蛋白或氧化低密度脂蛋白反应过度。 LPS 产生高水平的 IL-1、IL6 和 IL8，因此，单核细胞中 HIV 介导的免疫激活可能在 CVD 的发展中发挥作用，我们的初步数据表明，来自 HIV+ 个体的单核细胞，对于心血管疾病风险较高的人，也对炎症刺激表现出过度反应，我们观察到促炎症基因启动子区域的特定表观遗传标记（DNA 甲基化）水平部分解释了这种变化。临床上确定的“低”或“高”CVD风险个体的单核细胞对炎症刺激的反应程度单核细胞炎症和CVD风险之间的机制联系可能是根本性的，但在患有哮喘炎症反应的个体中更容易检测到。因此，该提案将检验这样的假设：由于环境不稳定基因座（包括促炎症基因）的表观遗传失调，单核细胞引发的重要炎症反应会增加 CVD 风险。为了解决这一假设，我们的目标是根据 CVD 风险的临床参数选择来自 HIV 感染者和匹配的未感染者的血液样本中的单核细胞炎症反应，并将这些数据与基因组进行表征、比较和整合。总的来说，这个独特的临床、免疫学和表观基因组数据库将使我们能够识别与 CVD 风险相关的新型生物标志物，从而改进心血管疾病的风险分层策略。（摘要完）