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

项目3摘要 美洲原住民人群心脏代谢疾病的发病率较高，包括心血管疾病 (CVD)和糖尿病，比美国任何其他种族/族裔群体。在强心研究（SHS）中， 在美国原住民社区进行的一项关于CVD及其危险因素的重要研究中，我们发现长期砷 (As)暴露可以部分解释心脏代谢疾病的过度负担。铀（U）暴露是 在职业人群中，与CVD相关，但来自一般人群的数据有限。重要的是， 铀是超级基金场地和部落土地上常见的污染物，因此接触这些污染物可能是 部分原因是美洲原住民人群中心脏代谢疾病的发病率增加。推进 金属相关心脏代谢疾病的有效干预需要关于以下因素的持久影响的可靠数据： 过去的暴露，砷和铀的联合作用，以及相关的机制，包括下游分子 方面的影响.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访视1（1989-91）参与者的数据与SHS家庭期间招募的后代联系起来 2001-03年扩展（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， 以下目标。(1)确定儿童和成人的心脏代谢效应（糖尿病和CVD） 砷和铀暴露的总体和性别，地区和营养状况。尿金属生物标志物可用 在访视1（反映儿童暴露）和4（反映成人暴露）时，并将在访视5时测量 （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2将提供时间趋势和追踪潜在来源的稳定同位素数据。（二） 确定儿童和成人As和U的纵向表观遗传和代谢组学效应 总体和按性别、地区和营养状况分列的暴露情况。我们将测量全基因组DNA甲基化 在访视4和5时，利用来自相同访视的现存靶向和非靶向代谢组学，并使用 联合DNAm/代谢组学多组学策略。(3)开发预测性多组学指纹， 量化了砷和铀暴露引起的潜在和并发心脏代谢风险。我们将使用机器 学习方法来表征DNA和代谢组学概况，以识别糖尿病风险个体 或CVD由于过去或当前的金属暴露。我们还将进行跨物种多组学比较 Project 4的鼠标数据。心血管疾病、糖尿病和金属暴露是我们的主要关注点。 北方平原的合作社区。通过研究砷和铀的潜在效应和并发效应， 暴露，SHAUL研究可以揭示金属诱导健康的表观遗传和代谢组学机制 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， 包括在北方平原、超级基金场地附近以及美国和全球其他污染区域附近。

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.