Health Effects of Metals in Native American Communities: A Longitudinal Multi-omics Study

项目3的摘要 美洲原住民患心脏代谢性疾病的比率较高，包括心血管疾病 患心血管疾病和糖尿病的人比美国其他任何种族/民族都要多。在强心研究(SHS)中，最 对美洲原住民社区心血管疾病及其危险因素的重要研究表明，长期的砷 (As)暴露可以部分解释心脏代谢性疾病的过度负担。铀(U)暴露是 在职业队列中与心血管疾病有关，但来自普通人群的数据有限。重要的是，AS和 U是超级基金地点和部落土地上的常见污染物，因此接触到这些污染物可能是 这是美洲原住民心脏代谢性疾病发病率增加的部分原因。前进 对金属相关心脏代谢性疾病的有效干预需要关于以下物质持久影响的可靠数据 过去暴露、砷和铀的联合作用及其相关机制，包括下游分子 效果。为了满足这些需求，我们将通过以下方式建立STRONG心脏AS/U终身(SAUL)研究(n=1300) 将SHS访问1(1989-91年)参与者的数据与他们在SHS家庭中招募的后代联系起来 2001-03年度的扩展(访问4)。我们将利用30年的数据和计划于2022-23年进行的新访问来解决 目标有以下几点。(1)确定儿童和成人的心脏代谢影响(糖尿病和心血管疾病) 总体而言，按性别、地区和营养状况划分的砷和铀暴露水平。尿液金属生物标志物是可用的 在访问1(反映儿童接触)和访问4(反映成人接触)时，将在访问5测量 (2006-09)和7(2022-23)，以重建终身暴露。水金属数据，包括空间模式， 项目1和项目2将提供时间趋势和追踪潜在来源的稳定同位素数据。 确定儿童和成人AS和U的纵向表观遗传和代谢效应 按性别、地区和营养状况进行总体暴露。我们将测量全基因组DNA甲基化 (DNaM)在访问4和5时，利用同一访问中现有的靶向和非靶向代谢组学，并使用 DNaM/代谢组多组学联合策略。(3)开发一种预测性多组学指纹 量化由砷和铀暴露引起的潜在和并发的心脏代谢风险。我们将使用机器 识别糖尿病风险个体的dNaM和代谢组特征的学习方法 或由于过去或目前的金属暴露而导致的脑血管病。我们还将进行跨物种多组学比较 用项目4‘S鼠标数据。心血管疾病、糖尿病和金属暴露是我们的主要担忧 在北部平原的合作社区。通过调查As和U的潜在和协同效应 暴露，Shaul的研究可以揭示金属诱导健康的表观遗传和代谢机制 影响，确定易感人群，并为风险评估提供信息。这些发现将产生直接的影响 在受影响社区预防和控制水污染物和心脏代谢性疾病， 包括在北部平原、超级基金地点附近，以及美国和全球其他受污染地区附近。

Summary of Project 3 Native American populations have higher rates of cardiometabolic disease, including cardiovascular disease (CVD) and diabetes, than any other racial/ethnic group in the US. In the Strong Heart Study (SHS), the most important study of CVD and its risk factors in Native American communities, we showed that long-term arsenic (As) exposure can explain part of the excess burden of cardiometabolic disease. Uranium (U) exposure is associated with CVD in occupational cohorts, but data from general populations are limited. Importantly, As and U are common contaminants in Superfund sites and tribal lands, so exposure to these contaminants could be partially responsible for increased rates of cardiometabolic disease in Native American populations. Advancing effective interventions for metal-related cardiometabolic diseases requires robust data on the lasting effects of past exposures, the joint effects of As and U, and the relevant mechanisms, including downstream molecular effects. To address these needs, we will establish the Strong Heart As/U Lifelong (SHAUL) study (n=1,300) by linking data from participants at SHS visit 1 (1989–91) with their offspring recruited during the SHS family expansion in 2001–03 (visit 4). We will leverage 30 years of data and a new visit planned for 2022–23 to address the following aims. (1) Determine the cardiometabolic effects (diabetes and CVD) of childhood and adult As and U exposures overall and by sex, region, and nutritional status. Urinary metal biomarkers are available at visits 1 (reflecting childhood exposure) and 4 (reflecting adult exposure), and will be measured at visits 5 (2006–09) and 7 (2022–23) to reconstruct lifelong exposures. Water metal data, including spatial patterns, temporal trends, and stable isotope data tracing potential sources, will be available from Projects 1 and 2. (2) Determine the longitudinal epigenetic and metabolomic effects of childhood and adult As and U exposures overall and by sex, region, and nutritional status. We will measure genome-wide DNA methylation (DNAm) at visits 4 and 5, leverage extant targeted and untargeted metabolomics from the same visits, and use a joint DNAm/metabolomic multi-omics strategy. (3) Develop a predictive multi-omics fingerprint that quantifies latent and concurrent cardiometabolic risk due to As and U exposures. We will use machine learning approaches to characterize DNAm and metabolomic profiles that identify individuals at risk of diabetes or CVD due to past or current metal exposures. We will also conduct a cross-species multi-omics comparison with Project 4’s mouse data. Cardiovascular disease, diabetes, and metal exposures are major concerns for our partnering communities in the Northern Plains. By investigating the latent and concurrent effects of As and U exposures, the SHAUL study can reveal epigenetic and metabolomic mechanisms for metal-induced health effects, identify susceptible populations, and inform risk assessment. The findings will have direct implications for the prevention and control of water contaminants and cardiometabolic diseases in affected communities, including in the Northern Plains, near Superfund sites, and near other contaminated areas in the US and globally.