Dyslipidaemia state modifies the association of urinary heavy metals with all-cause mortality: Findings from the NHANES and GEHAS cohorts

BACKGROUND: Heavy metals persist in global populations, yet their independent and combined effects on all-cause mortality remain inconclusive. The potential moderating role of dyslipidaemia on these associations has not been systematically evaluated. METHODS: We analysed data from two cohorts-GEHAS (2018-2019) and NHANES (2003-2016)-and measured urinary metal and lipid profiles at baseline. Dyslipidaemia was defined per international standards. Mortality was confirmed via the National Death Index. Cox regression was used to assess the associations between heavy metals and mortality, and restricted cubic spline (RCS) regression was used to evaluate nonlinearities. Interactions between metals and dyslipidaemia were analysed multiplicatively and additively. The quantile-based G-computation (QGComp) method was used to evaluate the combined effects of metal mixtures. RESULTS: The baseline metal distributions differed between the cohorts; thallium was inversely related to mortality in both cohorts (GEHAS: HR = 0.56, 95%CI: 0.36 - 0.88); NHANES: HR = 0.08, 95%CI: 0.02 - 0.34). Arsenic was correlated positively with mortality only in the GEHAS (HR = 1.72, 95%CI: 1.08 - 2.75). In the NHANES, elevated cadmium (HR = 3.35, 95%CI: 2.44 - 4.61), molybdenum (HR = 1.22, 95%CI: 1.00 - 1.48), antimony (HR = 2.64, 95%CI: 1.03 - 6.77), and cobalt (HR = 1.56, 95%CI: 1.21 - 2.01) concentrations increased mortality risk. Dyslipidaemia significantly influenced the association between heavy metals and all-cause mortality across both cohorts, In the GEHAS study, the association between Pb and all-cause mortality was influenced by dyslipidemia status, shifting from a positive linear relationship (HR = 4.22, 95%CI: 1.38 - 12.86) to a non-linear association (P-nonlinear = 0.042). In the dyslipidaemia cohort of the NHANES study, Co exhibited a linear relationship with mortality (P-overall = 0.034), whereas Tl, U, and W demonstrated non-linear associations with mortality (P-nonlinear < 0.05); these relationships were not observed in the Individuals without dyslipidaemia. CONCLUSION: Metal exposure significantly increased the all-cause mortality risk in both study cohorts. Furthermore, dyslipidaemia exerts a modulatory effect on heavy metal toxicity, specifically influencing the mode of action of lead (Pb) in the GEHAS cohort and amplifying the risk intensity of cobalt (Co), thallium (Tl), uranium (U), and tungsten (W) in the NHANES cohort. Subsequent research should focus on elucidating the underlying pathophysiological pathways.