Environment-wide association study of cardiovascular-kidney-metabolic syndrome based on NHANES 2013–2016

Environmental chemical exposure has emerged as an important risk factor for cardiometabolic and other chronic diseases. Cardiovascular-kidney-metabolic (CKM) syndrome conceptualizes the overlap of cardiovascular, kidney, and metabolic diseases as a systemic condition, providing a comprehensive framework for systematically identifying their risk factors. This study aimed to assess the associations between multiple environmental chemicals and CKM syndrome and to examine the potential mediating role of inflammation. The analysis was based on NHANES data from the 2013-2016 period. An exposome-wide approach was applied to identify environmental chemicals associated with CKM syndrome. Restricted cubic splines (RCS) were used to examine potential nonlinear associations. To evaluate the joint associations of multiple exposures, both weighted quantile sum (WQS) regression and quantile-based g-computation (Qgcomp) were employed. Mediation analyses were performed to explore inflammation as a possible pathway. Six environmental chemicals were found to be associated with CKM syndrome, including metals (tin), volatile organic compound metabolites (VOCMs: n-A-S-(3-hydrxprpl-1-metl)-L-cys, n-ace-S-(3,4-dihidxybutl)-L-cys), polycyclic aromatic hydrocarbons (PAHs: 1-hydroxyphenanthrene, 2&3-hydroxyphenanthrene), and iodine. A U-shaped relationship was observed between barium, cobalt, strontium, thallium, nitrate, and 2&3-hydroxyphenanthrene and the risk of advanced CKM syndrome. Mixed exposure analyses suggested that combined exposure to multiple metals was associated with a higher risk of advanced CKM syndrome. Moreover, inflammation may mediate the association between environmental chemicals and CKM syndrome. This study underscored the importance of controlling exposure to harmful environmental chemicals in the prevention and control of chronic multisystem diseases, and provided new research perspectives for elucidating the potential biological mechanisms underlying CKM syndrome.