Researching Epigenetics, Weathering, Aging & Residential Disadvantage (REWARD)

项目总结 无论是生活在隔离的社会经济贫困城市社区的非裔美国人，还是 农村地区资源贫乏的居民过早死亡率高，不成比例 心血管疾病、癌症和其他不利健康状况的负担。解释变化很大 物质和社会劣势的经历体现并随后表现为种族和 地理健康差异是研究、政策和实践面临的关键挑战。在坚持社交的同时 众所周知，劣势会塑造健康差距，这一过程背后的生物机制-- 所谓的风化--仍有待阐明。生物衰老速率差异的最新发现 (使用DNA甲基化测量)在面临早期生活劣势的亚群中表明 表观基因组可能在风化过程中起关键作用。表观遗传标记也与已知的 多种慢性病的差异。表观遗传学、风化、老化与居住研究 劣势(回报)研究将促进我们对DNA甲基化作为一种表观遗传学的理解 将社会、经济和地理劣势与加速老龄化和 炎症和心脏代谢性疾病。我们的目标是确定不同维度的 劣势--包括个人特征(例如种族认同、社会经济地位和 相关的歧视经历)和邻里层面的背景特征(例如 集中贫困、种族隔离和农村孤立)-通过表观遗传塑造健康差距 机械装置。我们假设，早年和累积的个人和背景劣势可以预测DNA 甲基化模式，创造风化的生物特征，有助于加速生物 脆弱人群中的衰老、炎症和心脏代谢性疾病。很少有研究具有时间性 需要测试的跟踪范围、地理多样性以及种族隔离和农村隔离的极端情况 假设在整个生命过程中，个人和邻里层面的劣势会导致 逆境的生物信号。奖励使用来自持续人口的丰富数据来填补这些空白 威斯康星州以明显的差异而闻名，包括城市种族隔离和农村孤立。 使用850K Infinium EPIC芯片阵列，我们将分析1400名参与者的全血DNA和血清 在威斯康星州健康调查(SHOW)中，一个持续的、特征良好的、以人口为基础的队列 威斯康星州的成年人。这个多元化的团队包括来自威斯康星大学麦迪逊分校的科学家 医学与公共卫生和社会学系，以及来自 西北大学和加州大学洛杉矶分校的遗传学家和生物统计学家开发了Horvath 表观遗传时钟。这项奖励研究的独特组合包括遗传、社会人口、行为和 邻里层面的数据将使我们的多学科研究团队能够在(AIM 1)之前提供新的见解 检查多个劣势领域的DNA甲基化签名的差异；(目标2) 研究生物衰老加速与功能基因表达相关的表观遗传学机制， 炎症和心脏代谢性疾病；以及(目标3)描述不利因素对 关于衰老和疾病的表观遗传标志物的纵向变化的生命过程。这项研究的发现将 强调人类对逆境的生物反应的可变性，并提供预防和治疗的干预措施 减少和缩小健康差距，改善老龄人口的健康状况。

PROJECT SUMMARY Both African Americans living in segregated socioeconomically disadvantaged urban neighborhoods and resource-poor residents of rural areas experience high rates of premature mortality and a disproportionate burden of cardiovascular disease, cancer, and other adverse health conditions. Explaining how varied experiences of material and social disadvantage become embodied and subsequently manifest in racial and geographic health disparities is the key challenge for research, policy, and practice. While persistent social disadvantage is known to shape health disparities, the biological mechanisms that underlie this process – known as weathering – remain to be elucidated. The recent discovery of differential rates of biological aging (measured using DNA methylation) across subpopulations facing early life disadvantage suggest that the epigenome may play a key role in weathering. Epigenetic markers have also been linked with known disparities in multiple chronic conditions. The Researching Epigenetics, Weathering, Aging & Residential Disadvantage (REWARD) study will advance our understanding of DNA methylation as one epigenetic mechanism linking social, economic, and geographic disadvantage with accelerated aging and phenotypes of inflammation and cardio-metabolic diseases. Our goal is to determine how different dimensions of disadvantage – including individual characteristics (e.g. racial identification, socioeconomic status, and associated experiences of discrimination), and neighborhood-level contextual characteristics (e.g. concentrated poverty, racial segregation, and rural isolation) – shape health disparities through epigenetic mechanisms. We hypothesize that early-life and cumulative personal and contextual disadvantage predict DNA methylation patterns, creating biological signatures of weathering that contribute to accelerated biological aging, inflammation, and cardiometabolic disease in vulnerable populations. Few studies possess the temporal range of follow-up, geographic diversity, and extremes in racial segregation and rural isolation needed to test the hypothesis that individual and neighborhood-level disadvantage across the life course contribute to biological signatures of adversity. REWARD fills these gaps using rich data from an ongoing population based cohort in Wisconsin -- a state known for stark disparities including urban racial segregation and rural isolation. Using the 850K Infinium EPIC Chip array, we will analyze whole blood DNA and serum from 1400 participants in the Survey of the Health of Wisconsin (SHOW), an ongoing, well-characterized, population-based cohort of Wisconsin adults. The diverse team includes scientists from the University of Wisconsin-Madison’s School of Medicine and Public Health and Department of Sociology, as well as a leading biological anthropologist from Northwestern University and the UCLA-based geneticist and biostatistician who developed the Horvath epigenetic clock. The REWARD Study’s unique combination of genetic, socio-demographic, behavioral, and neighborhood-level data will allow our multidisciplinary research team to provide new insights by (Aim 1) examining differences in DNA methylation signatures across multiple domains of disadvantage; (Aim 2) investigating the epigenetic mechanisms linking accelerated biological aging with functional gene expression, inflammation, and cardio-metabolic disease; and (Aim 3) characterizing the impact of disadvantage across the life course on longitudinal changes in epigenetic markers of aging and disease. Findings from this research will highlight the variability in human biological response to adversity and inform interventions to prevent and treat age-related disease, reduce and mitigate health disparities, and improve the health of aging populations.