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

• 批准号: 8803666
• 负责人: Alika Keolaokalani Maunakea
• 金额: $ 14.98万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 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/8803666
• 关键词: Address; Adult; Age; Bioinformatics; Biological Assay; Biological Markers; Blood; 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; Gene Expression Profile; Genes; HIV; HIV Infections; HIV Seropositivity; Hawaii; High Prevalence; Human; Hyperlipidemia; IL6 gene; IL8 gene; Incidence; Individual; Inflammation; Inflammatory; Inflammatory Response; Insulin Resistance; Interleukin-1; Interleukin-6; Link; Lipopolysaccharides; Massive Parallel Sequencing; Measures; Mediating; Messenger RNA; Methods; Modification; Molecular Profiling; Myelogenous; Organism; Pathology; Patients; Pattern; Peripheral Blood Mononuclear Cell; Persons; Phenotype; Play; Promoter Regions; Protein Isoforms; Publishing; RNA; RNA Splicing; Research; Risk; Risk Factors; Role; Smoking; Stimulus; Stratification; Technology; Testing; Variant; abstracting; base; bead chip; bisulfite sequencing; cardiovascular disorder risk; cell type; differential expression; epigenetic marker; epigenomics; genome-wide; high risk; immune activation; improved; mRNA Precursor; macrophage; methylation pattern; methylome; monocyte; mortality; novel; oxidized low density lipoprotein; peripheral blood; response; transcriptome sequencing; transcriptomics; trend

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贡献者，似乎将主导未来的死亡趋势。新的证据表明，单核细胞/巨噬细胞引起的炎症有助于CVD的发展。传统的CVD风险因素，如胰岛素抵抗、高脂血症和吸烟，已与表观遗传标记的修饰相关，并且可以在外周血样品中检测表观遗传失调的特征。透析患者外周血中的单核细胞（CD 14 + CD 16+）可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CD 14 + CD 16+单核细胞的百分比增加。在HIV+患者的血液中也观察到这些单核细胞的百分比增加。来自我们合作者的数据表明，HIV感染者的单核细胞对氧化LDL或LPS反应过度，产生高水平的IL-1 β、IL 6和IL 8。因此，HIV介导的单核细胞免疫激活可能在CVD的发展中发挥作用。为了支持这一联系，我们的初步数据表明，来自HIV+个体的单核细胞，CVD风险升高，也表现出对炎症刺激的高反应性。有趣的是，我们观察到促炎基因启动子区域的特异性表观遗传标记DNA甲基化水平部分解释了临床确定的CVD“低”或“高”风险个体的单核细胞对炎症刺激的反应程度不同。单核细胞炎症和CVD风险之间的机制联系可能是根本性的，但在炎症反应增强的个体中更容易检测到，例如感染HIV的个体。因此，该提议将检验由单核细胞引起的升高的炎症反应由于环境不稳定基因座（包括促炎基因）的表观遗传失调而赋予CVD增加的风险的假设。这可能与HIV感染状况无关。为了解决这一假设，我们的目标是评估单核细胞炎症反应库血液标本从艾滋病毒感染和匹配的未感染的个人选择的基础上CVD风险的临床参数，并表征，比较，并整合这些数据与全基因组DNA甲基化和基因表达谱从这些单核细胞。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风险相关的新生物标志物，从而改善心血管疾病的风险分层策略。(End摘要）