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

项目3总结 美洲原住民的心脏代谢疾病（包括心血管疾病）发病率较高 （心血管疾病）和糖尿病的发病率高于美国任何其他种族/族裔群体。在强心研究 (SHS) 中，最 在美洲原住民社区对 CVD 及其危险因素进行的重要研究中，我们发现长期砷 (As) 暴露可以部分解释心脏代谢疾病的超额负担。铀 (U) 暴露量为 与职业群体中的 CVD 相关，但一般人群的数据有限。重要的是，作为和 U 是超级基金所在地和部落土地中的常见污染物，因此接触这些污染物可能会 美洲原住民心脏代谢疾病发病率增加的部分原因。前进 对与金属相关的心脏代谢疾病的有效干预需要关于金属的持久影响的可靠数据 过去的暴露、As 和 U 的联合效应以及相关机制，包括下游分子 影响。为了满足这些需求，我们将建立强心 As/U 终身 (SHAUL) 研究（n=1,300）： 将 SHS 访问 1 (1989-91) 参与者的数据与其在 SHS 家庭期间招募的后代联系起来 2001-03 年的扩展（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 以下目标。 (1) 确定儿童和成人的心脏代谢影响（糖尿病和CVD） As 和 U 的总体暴露量以及按性别、地区和营养状况划分的暴露量。尿液金属生物标志物可用 在访问 1（反映儿童暴露）和 4（反映成人暴露）时进行测量，并将在访问 5 时进行测量 (2006-09) 和 7 (2022-23) 重建终身暴露。水金属数据，包括空间模式， 时间趋势和追踪潜在来源的稳定同位素数据将从项目 1 和 2 中获得。(2) 确定儿童和成人 As 和 U 的纵向表观遗传和代谢组学影响 总体暴露量以及按性别、地区和营养状况划分的暴露量。我们将测量全基因组 DNA 甲基化 (DNAm) 在访视 4 和 5 时，利用来自同一访视的现有靶向和非靶向代谢组学，并使用 DNAm/代谢组学联合多组学策略。 (3) 开发预测性多组学指纹 量化 As 和 U 暴露导致的潜在和并发心脏代谢风险。我们将使用机器 表征 DNAm 和代谢组图谱的学习方法，以识别有糖尿病风险的个体 或由于过去或当前的金属暴露而引起的 CVD。我们还将进行跨物种多组学比较 使用 Project 4 的鼠标数据。心血管疾病、糖尿病和金属暴露是我们最关心的问题 北部平原的合作社区。通过研究 As 和 U 的潜在和并发影响 SHAUL 研究可以揭示金属诱发健康的表观遗传和代谢组学机制 影响、识别易感人群并为风险评估提供信息。研究结果将产生直接影响 预防和控制受影响社区的水污染物和心脏代谢疾病， 包括北部平原、超级基金地点附近以及美国和全球其他污染地区附近。

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.