Epigenetic Biomarkers of Common Chronic Diseases

描述（由申请人提供）：本申请，“常见慢性疾病的表观遗传生物标志物”，涉及广泛的挑战领域（03）生物标志物发现和验证和特定的挑战主题，03-OD-101：使用血细胞中的表观遗传特征预测疾病。糖尿病、肾脏疾病和高血压的微血管并发症（脑、外周动脉和冠状动脉）是公众健康的主要负担（1，2），在某些人群亚组中聚集的频率似乎比预期的更高。例如，非裔美国人经历这些疾病的流行比例和年龄比非西班牙裔白人（3，4）。虽然糖尿病或肾脏疾病的传统诊断标准识别具有使人衰弱的临床结果（例如肢体截肢和透析）的高风险的个体，但迫切需要在临床诊断症状呈现之前识别处于风险中的个体，以避免这些严重的健康结果。影响基因表达的遗传和非遗传现象，称为表观遗传机制（DNA甲基化，组蛋白修饰和microRNA），在多个细胞过程中发挥关键作用，并被假设为环境因素，生活方式和慢性疾病易感性改变之间的联系（5，6）。DNA甲基化谱的个体间差异有可能在症状前阶段识别出有疾病发展风险的个体，此时预防措施将是最有益的（7）。DNA甲基化谱，也称为表观遗传谱，是评估这些慢性疾病表型的预测效用的有希望的生物标志物，并且可以通过外周血样本轻松获得。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大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-美国最流行和高风险的亚组之一。糖尿病在这个高风险亚组中也非常普遍，部分原因是所谓的代谢综合征。GENOA研究创造了丰富的生物样本资源（DNA，血清，尿液）以及人口统计，人体测量，环境，临床，生化，生理和基因组数据，用于了解慢性疾病及其风险因素的表观遗传预测因子。 公共卫生相关性（由申请人提供）：本申请涉及特定挑战主题03-OD-101：使用血细胞中的表观遗传特征预测疾病，提供了一个独特的机会来检查表观遗传特征作为生物标志物的效用，用于预测非裔美国人的慢性疾病表型，非裔美国人是糖尿病，肾病，以及高血压引起的微血管并发症该项目的目标是使用在容易获得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志物。我们的项目将调查这些潜在的表观遗传生物标志物在高风险亚组的人口，可以大大受益于先进的知识和增加预防。

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.