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，可能在人类疾病中非常重要，特别是对年龄较大的疾病。然而，由于缺乏技术和生物样本资源，记录人类寿命的表观遗传变化、表观遗传标记对环境暴露的脆弱性以及随后对人类疾病的影响的研究一直受到限制。一个拥有技术和资源的团队已经组建起来，通过将约翰·霍普金斯大学的表观遗传学和流行病学专业知识与冰岛心脏协会(IHA)的同事资源相结合，测量同一个人随着时间的推移甲基化的变化，目的是检查暴露和这种变化之间的关系，并评估甲基化和疾病之间的关系。自1967年以来，IHA跟踪了超过18K名雷克雅未克心脏研究的参与者，最近收集了5758名幸存队列的广泛心血管和功能测量，作为AGES-雷克雅未克研究的一部分。其中，638名参与者拥有跨越15年的两次访问的可用于表观遗传学测量的DNA样本，从而能够测量同一个体随着时间的推移而发生的表观遗传学变化，如果环境可以影响表观遗传学标记，则必须发生这种变化，但从未在人类群体中直接观察到。此外，自1967年以来可以获得饮食和吸烟数据和血清样本，以及所有5758名年龄段参与者(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，包括饮食鱼类摄入量、血清叶酸水平和吸烟对跨越15年的全基因组和候选基因特异性甲基化的个体间变化的影响；(2)15年甲基化变化与随后的疾病相关量化指标，如血压、体重指数、中心性肥胖和冠状动脉钙化之间的关系；(3)尿镉(Cd)和候选基因甲基化之间的横截面关系；以及(4)候选基因甲基化与包括心血管疾病和癌症在内的疾病结果之间的横断面关系。这一独特的资源和团队使得首次有机会在同一人身上进行超过15年的纵向表观遗传学测量，并将这些表观遗传学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.