Identifying Epigenetic Biomarkers of Cardiovascular Disease Risk In Humans

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，似乎在未来的死亡率趋势中占主导地位。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。传统的心血管疾病危险因素，如胰岛素抵抗、高脂血症和吸烟，都与表观遗传标记的改变有关，表观遗传失调的特征可以在外周血样本中检测到。存在于透析患者外周血中的单核细胞（CD14+CD16+）预测心血管疾病的发病率，暗示这种细胞类型参与疾病病理。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+患者的血液中也观察到这些单核细胞的百分比增加。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， 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CVD风险较高的HIV+个体的单核细胞也表现出对炎症刺激的高反应性。有趣的是，我们观察到，在促炎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。单核细胞炎症与CVD风险之间的机制联系可能是基本的，但在炎症反应加剧的个体中更容易检测到，例如感染艾滋病毒的个体。因此，这一提议将验证一个假设，即单核细胞引起的炎症反应加剧，由于环境不稳定位点（包括促炎基因）的表观遗传失调，导致心血管疾病的风险增加。这可能与HIV感染状况无关。为了解决这一假设，我们的目标是评估基于CVD风险临床参数选择的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，并将这些数据与这些单核细胞的全基因组DNA甲基化和基因表达谱进行表征、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心血管疾病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。（摘要结束）

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)