Epigenetic Biomarkers of Common Chronic Diseases

描述(由申请人提供)：本申请名为“常见慢性病的表观遗传生物标记物”，涉及广泛的挑战领域(03)生物标记物的发现和验证以及特定的挑战主题，03-OD-101：使用血细胞中的表观遗传特征来预测疾病。糖尿病、肾脏疾病和高血压引起的微血管并发症(在大脑、外周动脉和冠状动脉)是公众健康的主要负担(1，2)，在一些人群亚群中聚集的频率似乎比仅凭偶然预期更频繁。例如，与非西班牙裔白人相比，非洲裔美国人患上这些疾病的流行比例更高，年龄也更早(3，4)。虽然传统的糖尿病或肾脏疾病诊断标准确定了具有削弱临床结果的高风险的个人，如截肢和透析，但迫切需要在出现临床诊断症状之前识别高危个人，以避免这些严重的健康后果。影响基因表达的可遗传和不可遗传现象被称为表观遗传机制(DNA甲基化、组蛋白修饰和microRNA)，在多种细胞过程中发挥关键作用，并被假设为环境因素、生活方式和慢性病易感性变化之间的联系(5，6)。DNA甲基化图谱的个体间差异有可能在症状前阶段确定疾病结局的风险个体，此时预防措施将是最有益的(7)。DNA甲基化图谱，也称为表观遗传学图谱，是很有希望的生物标记物，用于评估这些慢性疾病表型的预测效用，并且很容易通过外周血样获得。在过去的14年里，动脉病遗传流行病学网络一直致力于收集微血管和宏观血管疾病的临床和亚临床指标及其对高血压患者肾脏、心脏、大脑和外周动脉的影响-高血压患者是美国最常见和最高风险的亚组之一。糖尿病在这一高危人群中也非常普遍，部分原因是所谓的代谢综合征。热那亚研究创造了丰富的生物样本(DNA、血清、尿液)以及人口学、人体测量学、环境、临床、生化、生理和基因组数据，以了解慢性病及其风险因素的表观遗传预测因素。 公共卫生相关性(由申请人提供)：本申请针对特定的挑战主题03-OD-101：使用血细胞中的表观遗传特征来预测疾病，并提供了一个独特的机会来检验表观遗传特征作为生物标记物在非裔美国人中预测慢性疾病表型的实用性，非裔美国人是糖尿病、肾脏疾病和高血压微血管并发症风险增加的群体。这一拟议项目的目标是使用在易于获取的血细胞基因组中测量的表观遗传标记来识别常见疾病的新生物标记。我们的项目将在人群中的高危亚群中调查这些潜在的表观遗传生物标记物，这些亚群可以从先进的知识和加强的预防中受益良多。

DESCRIPTION (provided by applicant): This application, "Epigenetic Biomarkers of Common Chronic Diseases," addresses broad Challenge Area (03) Biomarker Discovery and Validation and specific Challenge Topic, 03-OD-101: Use of Epigenetic Signatures in Blood Cells to Predict Disease. Diabetes, kidney disease, and the microvascular complications from hypertension (in the brain, peripheral arteries, and coronary arteries) are a major burden on the public's health(1, 2) and appear to aggregate in some population subgroups more frequently than expected by chance alone. For example, African-Americans experience these diseases in epidemic proportion and at earlier ages than non-Hispanic Whites(3, 4). While traditional diagnostic criteria for diabetes or kidney disease identify individuals with high risk of debilitating clinical outcomes, such as extremity amputation and dialysis, there is a pressing need to identify at-risk individuals well before the presentation of clinical diagnostic symptoms to avert these severe health outcomes. Heritable and non-heritable phenomena that affect gene expression, known as epigenetic mechanisms (DNA methylation, histone modification, and microRNA), play a key role in multiple cellular processes and have been hypothesized as a link between environmental factors, lifestyle, and alterations in chronic disease susceptibility(5, 6). Inter-individual differences in DNA methylation profiles has the potential to identify individuals at risk for the development of disease outcomes at a presymptomatic stage when preventive efforts will be most beneficial(7). DNA methylation profiles, also known as epigenetic profiles, are promising biomarkers to assess for predictive utility for these chronic disease phenotypes and are easily accessible through peripheral blood samples. For the past 14 years, the Genetic Epidemiology Network of Arteriopathy has been working to collect clinical and subclinical measures of micro and macro vascular disease and its impact on the kidney, heart, brain, and peripheral arteries in hypertensives - one of the most prevalent and high risk subgroups in the US. Diabetes is also highly prevalent in this high risk subgroup due in part to what has been called the metabolic syndrome. The GENOA study has created a rich resource of biological samples (DNA, serum, urine) as well as demographic, anthropometric, environmental, clinical, biochemical, physiological, and genomic data for understanding the epigenetic predictors of chronic diseases and its risk factors. PUBLIC HEALTH RELEVANCE (provided by applicant): This application addresses the specific Challenge Topic, 03-OD-101: Use of Epigenetic Signatures in Blood Cells to Predict Disease and a provides a unique opportunity to examine the utility of epigenetic profiles as biomarkers for predicting chronic disease phenotypes in African-Americans, a group with increased risk of diabetes, kidney disease, and the microvascular complications from hypertension. The goal of this proposed project is to identify new biomarkers of common diseases using epigenetic markers that are measured in the genome of easily accessible blood cells. Our project will investigate these potential epigenetic biomarkers in a high risk subgroup of the population that could benefit greatly from advanced knowledge and increased prevention.