Superfund Research Program
Health Effects of Metals in Native American Communities: A Longitudinal Multi-omics Study
Project Leader: Ana Navas-Acien
Grant Number: P42ES033719
Funding Period: 2022-2027
- Project Summary
Project Summary (2022-2027)
Native American populations have higher rates of cardiometabolic disease, including cardiovascular disease (CVD) and diabetes, than any other racial/ethnic group in the U.S. In the Strong Heart Study (SHS), the most important study of CVD and its risk factors in Native American communities, researchers 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, this project is establishing 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). The researchers are leveraging 30 years of data and a new visit planned for 2022–23 to address the following aims:
- 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 High Resolution Models of Groundwater Metal Exposures and Isotopic Tracing of Sources and Cycling of Hazardous Metal Mixtures projects.
- Determine the longitudinal epigenetic and metabolomic effects of childhood and adult As and U exposures overall and by sex, region, and nutritional status. Collaborators 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.
- Develop a predictive multi-omics fingerprint that quantifies latent and concurrent cardiometabolic risk due to As and U exposures. They 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. The team also conducts a cross-species multi-omics comparison with Causal Molecular Mechanisms Linking Drinking Water Metal Exposures to Cardiometabolic Disease project’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 U.S. and globally.