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

金属对美洲原住民社区健康的影响：一项纵向多组学研究

• 批准号: 10354271
• 负责人: Ana Navas-Acien
• 金额: $ 49.41万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10354271
• 关键词: Address; Adult; Affect; Area; Arsenic; Biological Markers; Blood; Cardiometabolic Disease; Cardiovascular Diseases; Childhood; Clinical Data; Communities; Congresses; DNA Methylation; Data; Diabetes Mellitus; Dietary Intervention; Disease; Epigenetic Process; Ethnic group; Etiology; Excision; Exposure to; Family; Family Study; Fingerprint; Funding; General Population; Genotype; Health; Heart; Individual; Intervention; Isotopes; Joints; Link; Machine Learning; Measures; Mediation; Metal exposure; Metals; Modification; Molecular; Monitor; Mothers; Multiomic Data; Mus; National Heart, Lung, and Blood Institute; Native Americans; Nutritional status; Occupational; Outcome; Participant; Pathway interactions; Pattern; Phenotype; Plasma; Population; Populations at Risk; Prevention; Research; Risk Assessment; Risk Factors; Risk Reduction; Schedule; Site; Source; Subgroup; Superfund; Time; Time trend; Tissues; Universities; Uranium; Urine; Visit; Water; Water Pollutants; base; cardiometabolic risk; cardiometabolism; cohort; contaminated water; design; diabetes risk; disorder risk; drinking water; effective intervention; epidemiologic data; epigenomics; experience; genome-wide; ground water; innovation; metabolomics; multiple omics; northern plains; offspring; programs; racial and ethnic; recruit; sex; spatiotemporal; stable isotope; superfund site; trend; tribal community; tribal lands; urinary; wasting

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.

项目3摘要 美洲原住民的心脏代谢疾病率较高，包括心血管疾病 （CVD）和糖尿病，比美国其他任何种族/族裔群体。在强大的心脏研究（SHS）中，最多 CVD的重要研究及其在美洲原住民社区中的风险因素，我们表明长期砷 （AS）暴露可以解释心脏代谢疾病过量燃烧的一部分。铀（U）暴露是 与占领队列中的CVD相关，但来自一般人群的数据有限。重要的是，和 u是超级基金地点和部落土地上的常见污染物，因此暴露于这些污染物可能是 部分原因是美洲原住民人口中心脏代谢疾病率提高。前进 与金属相关心脏代谢性疾病的有效干预措施需要关于持久影响的强大数据 过去的暴露，A和U的关节效应以及相关机制，包括下游分子 效果。为了满足这些需求，我们将建立强大的心脏作为/U终生研究（Shaul）研究（n = 1,300） 链接来自SHS参与者的数据访问1（1989-91）与他们的后代在SHS家族中招募 2001 - 03年的扩展（访问4）。我们将利用30年的数据和计划在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效应（糖尿病和CVD） AS和U可以通过性别，地区和营养状况暴露。有尿金属生物标志物可用 在访问1（反映儿童期暴露）和4（反映成人暴露），将在访问中进行测量5 （2006-09）和7（2022–23）重建终身暴露。水金属数据，包括空间模式， 临时趋势和稳定的同位素数据追踪潜在来源将从项目1和2中获得。（2） 确定儿童和成人的纵向表观遗传和代谢组作用 总体和性别，地区和营养状况的暴露。我们将测量全基因组DNA甲基化 （DNA）在访问4和5时，从相同的访问中利用广泛的针对性和无靶向代谢组学，并使用 联合DNAM/代谢组学策略。 （3）开发一种预测性多摩斯指纹 量化由于AS和U暴露引起的潜在和并发心脏代谢风险。我们将使用机器 识别有糖尿病风险的个体的DNAN和代谢组谱的学习方法 或CVD由于过去或当前的金属暴露而引起的。我们还将进行跨物种多摩斯比较 使用项目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问题 与北部平原的社区合作。通过研究AS和U的潜在和同时影响 曝光，Shaul研究可以揭示用于金属诱导健康的表观遗传和代谢组机制 效果，确定易感人群并为风险评估提供信息。这些发现将有直接影响 为了预防和控制受影响社区的水污染物和心脏代谢疾病， 包括在北部平原，超级基金地点附近以及美国和全球其他受污染区域附近。