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，似乎主导着未来的死亡率趋势。新的证据表明，单核/巨噬细胞引起的炎症有助于心血管疾病的发展。传统的心血管危险因素，如胰岛素抵抗、高脂血症和吸烟，已被认为与表观遗传标志物的修饰有关，并且在外周血样本中可以检测到表观遗传失调的迹象。透析患者外周血中的单核细胞(CD14+CD16+)可以预测心血管疾病的发病率，提示这种细胞类型与疾病病理有关。事实上，在冠心病患者的血液中观察到CD14+CD16+单核细胞的百分比增加。在HIV+患者的血液中，这些单核细胞的比例也增加了。来自我们合作者的数据表明，艾滋病毒感染者的单核细胞对氧化型低密度脂蛋白或脂多糖高度反应，产生高水平的IL-1�、IL 6和IL 8。因此，HIV介导的单核细胞免疫激活可能在CVD的发生发展中起一定作用。为了支持这种联系，我们的初步数据表明，来自HIV+患者的单核细胞，他们患心血管疾病的风险增加，也表现出对炎症刺激的高反应性。有趣的是，我们观察到致炎基因启动子区域的特定表观遗传标记DNA甲基化的水平部分解释了来自临床确定的心血管疾病低风险或高风险个体的单核细胞对炎症刺激的不同程度的反应。单核细胞炎症和心血管疾病风险之间的机制联系可能是基本的，但在炎症反应增强的人中更容易检测到，例如感染艾滋病毒的人。因此，这一提议将检验这样一种假设，即单核细胞引发的高度炎症反应会增加心血管疾病的风险，这是由于环境不稳定基因的表观遗传失调，包括促炎基因。这可能与艾滋病毒感染状况无关。为了解决这一假设，我们的目标是评估基于心血管疾病风险的临床参数选择的HIV感染和匹配的未感染个体的库血样本中的单核细胞炎症反应，并将这些数据与全基因组DNA甲基化和这些单核细胞的基因表达谱进行特征、比较和整合。总而言之，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心血管疾病风险相关的新生物标记物，从而改进心血管疾病的风险分层策略。(摘要结束)