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Epidemiologic evidence on metal mixtures and non-alcoholic fatty liver disease (NAFLD) is limited. We aimed to assess the relationship between multiple metal co-exposure and NAFLD among male adults in Northern China. We conducted a cohort-based case-control study with 648 NAFLD and 648 non-NAFLD males. Seven metal concentrations (calcium, copper, iron, magnesium, manganese, selenium, and zinc) were determined in the blood. We used logistic regression and restricted cubic splines (RCS) to estimate the associations between the single metal and NAFLD. The impact of metal mixtures was quantified by the environmental risk score (ERS) in the adaptive elastic-net regression, and the association with NAFLD was estimated by logistic regression. Age-adjusted RCS showed linear relationships between blood calcium, selenium, and NAFLD. Blood copper, iron, magnesium, and manganese were non-linearly associated with NAFLD. Single metal analysis observed significant relationships between calcium, copper, manganese, and NAFLD, with the adjusted odds ratio (95% confidence interval) for quartile 1 vs. quartile 4 of 1.99 (1.30, 3.05), 2.36 (1.52, 3.64), and 1.77 (1.22, 2.55), respectively. However, metal mixtures analysis revealed one squared term (copper [β = −0.146]) and five metal-metal interactions (calcium × copper [β = 0.200], copper × magnesium [β = 0.188], copper × selenium [β = 0.188], iron × magnesium [β = 0.143], magnesium × selenium [β = −0.297]) except the three main effects. Higher ERS indicated a higher risk for NAFLD when exposed to metal mixtures, with an adjusted odds ratio = 6.50 (95% confidence interval: 4.36–9.69) for quartile 4 vs. quartile 1. Mediation analysis suggested that 11.66% of the effect of ERS on NAFLD was suppressed by fasting blood glucose. Our results show that exposure to metal mixtures is associated with a higher risk for NAFLD than the single metal. Interactions between metals suggest the importance of balancing the various metals for health benefits. Prospective cohorts and mechanism studies need to confirm the findings. [Display omitted] •Lower blood Ca, Cu, and Mn may be potential risk factors for NAFLD in non-occupational exposed males. •Exposure to metal mixtures is associated with a significantly higher risk for NAFLD than a single metal. •Interactions between metals suggest the importance of balancing the various metals for NAFLD prevention. [ABSTRACT FROM AUTHOR]

As both a toxic and essential trace element in humans, limited research focuses on the association between blood manganese (Mn) and nonalcoholic fatty liver disease (NAFLD). We aimed to assess blood Mn concentration and its relationship with NAFLD among adults in Northern China. We conducted a cohort-based case-control study among 1816 patients with NAFLD (970 males and 846 females) and 1111 healthy controls (598 males and 513 females). We used the restricted cubic splines method to investigate the potential non-linear relationship and logistic regression models to analyze the association between blood Mn and NAFLD. The median (p 25 , p 75) of blood Mn concentration in males was 10.08 (8.42,11.98) μg/L, higher than that in females [9.79 (8.01,12.04)] μg/L, P = 0.011. Compared with the tertile 1 group of Mn in males, the odds ratio (95 % confidence interval) of NAFLD for tertile 2 and tertile 3 group was 0.82 (0.61,1.10) and 0.64 (0.47,0.87), respectively. The reverse correlation was consistent in patients with different fibrosis severity determined by fibrosis-4 score. The protective association was more evident in those with triglycerides ≥1.7 mmol/L [odds ratio (95 % confidence interval) of tertile 3 vs. tertile 1: 0.40 (0.22,0.75)]. We found a non-significant U-shaped relationship between Mn and NAFLD in women. There may exist sex differences for the association between blood Mn and NAFLD. Higher blood Mn may be a potential protective factor for NAFLD in males. The subjects with TG ≥ 1.7 mmol/L would benefit more from higher blood Mn levels. [Display omitted] •Blood manganese levels were sex-specific associated with NAFLD in Chinese adults. •Higher blood manganese correlated with lower NAFLD risk in males. •Triglycerides may modify the association between blood manganese and NAFLD in males. [ABSTRACT FROM AUTHOR]