Combined Effects and Potential Mechanisms of Multiple Metals Exposure on Coronary Artery Disease in the US Population: An Integrated Epidemiological and Network Toxicology Study.

Abstract

Coronary artery disease (CAD) emerged as a major global health burden, but the relationship between multiple metals exposure and CAD and its toxicological mechanism were not fully understood. We analyzed the data from the National Health and Nutrition Examination Survey (NHANES) from 2001 to 2016, and evaluated the association between multiple metals exposure and CAD, including barium, cadmium, cobalt, cesium, molybdenum, lead, antimony, thallium, and uranium. Weighted Quantile Sum (WQS) regression and Quantile g-computation were constructed to explore the joint association of multiple metals exposure on CAD. Metal-related and CAD targets were obtained from Comparative Toxicogenomics Database (CTD) and Gene Expression Omnibus (GEO). Network toxicology was used to explore potential biological pathways of key metal exposure and CAD. A total of 8,962 participants was included in our study. In single metal analysis, cadmium [odds ratio (OR) and 95% confidence interval (CI) = 1.77, 95%CI:1.51-2.08], barium (OR = 0.87, 95%CI:0.78-0.97), cobalt (OR = 1.31, 95%CI:1.14-1.50) and uranium (OR = 1.20, 95%CI:1.05-1.37) were associated with CAD in total population. WQS regression and Quantile g-computation revealed that cadmium, was assigned the largest positive contribution on CAD. Network toxicology identified 44 overlapping targets potentially related to cadmium exposure and CAD. Subsequent STRING and Cytoscape analyses were used to construct a protein-protein interaction (PPI) network and highlight 13 key targets. Machine learning algorithms further identified the gene MMP9 as a key target. Our study found that multiple metals mixture exposure was associated with higher CAD prevalence and network toxicology identified MMP9 as core target. These findings should be interpreted as hypothesis-generating and further longitudinal and experimental studies are warranted to validate the role of cadmium exposure and MMP9-related pathways in CAD.