AGE-Related Epigenetic Changes - Environmental Causes and Disease Consequences

描述（由申请人提供）： 表观遗传机制，如甲基化可能是非常重要的人类疾病，特别是老年人的疾病。然而，由于缺乏技术和生物样本资源，记录人类寿命中表观遗传变化、表观遗传标记对环境暴露的脆弱性以及对人类疾病的后续影响的研究受到限制。 一个团队已经组装了技术和资源，以测量同一个体中甲基化随时间的变化，以检查暴露与此类变化之间的关系，并通过将约翰霍普金斯的表观遗传学和流行病学专业知识与冰岛心脏协会（IHA）同事的资源相结合，评估甲基化与疾病之间的关系。自1967年以来，IHA已经跟踪了超过18000名雷克雅未克心脏研究的参与者，并且最近收集了5758名存活队列的广泛心血管和功能指标，作为AGES-Reykjavik研究的一部分。其中，638名参与者有DNA样本可用于表观遗传测量，来自跨越15年的两次访问，允许测量同一个体随时间的表观遗传变化，如果环境可以影响表观遗传标记，则必须发生，但从未在人群中直接观察到。此外，自1967年以来的饮食和吸烟数据和血清样本以及所有5758名AGES参与者（2004-2005年）的最新表型测量和疾病结果。具体目标包括评估：（1）环境因素，包括膳食鱼类摄入量，血清叶酸水平和吸烟对15年内全基因组和候选基因特异性甲基化个体间变化的影响;（2）甲基化15年变化与随后疾病相关定量测量（如血压，BMI，中心性肥胖和冠状动脉钙化）之间的关系;（3）尿镉（Cd）与候选基因甲基化之间的横截面关系;（4）候选基因甲基化与包括CVD和癌症在内的疾病结局之间的横截面关系。这种独特的资源和团队允许在同一人群中进行15年以上的纵向表观遗传测量，并将这些表观遗传测量与饮食和吸烟暴露以及癌症和心血管疾病后果联系起来。

DESCRIPTION (provided by applicant): Epigenetic mechanisms such as methylation may be very important in human disease, especially for diseases of older ages. Yet studies documenting epigenetic changes over the human lifespan, the vulnerability of epigenetic marks to environmental exposures, and the subsequent effects on human disease have been limited due to the absence of technical and biosample resources. A team has been assembled with the technology and resources to measure changes in methylation over time in the same individual for the purpose of examining a relationship between exposure and such changes, and assess the relationship between methylation and disease, by combining the epigenetic and epidemiologic expertise at Johns Hopkins with the resources of colleagues at the Icelandic Heart Association (IHA). The IHA has followed over 18K participants of the Reykjavik Heart Study since 1967 and has recently collected extensive cardiovascular and functional measures on 5758 of the surviving cohort as part of the AGES-Reykjavik study. Of these, 638 participants have DNA samples available for epigenetic measurement from two visits spanning 15 years, allowing for measurement of epigenetic changes over time in the same individual, which must occur if environment can influence epigenetic marks, but has never been directly observed in a human population. In addition, diet and smoking data and serum samples are available since 1967 as well as recent phenotype measures and disease outcomes for all 5758 AGES participants (2004-2005). The specific aims include assessing the: (1) Impact of environmental factors including dietary fish intake, serum folate levels, and smoking on inter-individual changes in whole-genome and candidate-gene specific methylation spanning 15 years; (2) Relationship between 15-year changes in methylation and subsequent disease-related quantitative measurements such as blood pressure, BMI, central adiposity, and coronary calcification; (3) Cross-sectional relationship between urinary cadmium (Cd) and candidate gene methylation; and (4) Cross-sectional relationship between candidate gene methylation and disease outcomes including CVD and cancer. This unique resource and team allows the first opportunity for longitudinal epigenetic measurement over 15 years in the same people, and connection of these epigenetic measurements to dietary and smoking exposures, as well as to cancer and cardiovascular disease consequences.