3.1．Characteristics of study population
The characteristics of the participants was shown in Table 1, where the median [P25, P75] age of the study participants was 44 [31, 57] years, with approximately similar distribution for both genders. But there are significantly statistical difference between genders in SUA, SCr, and majority of covariates, thus all the following analysis were by genders.
3.2．Distributions and correlations for multiple heavy metals
The lowest, 5th, 25th, 50th,75th, 95th percentiles and highest values of blood Cd, Pb, Hg and urinary Cd, Pb, Hg, As for men and women were summarized in Table 2. There were significantly statistical differences between genders in blood Cd, Pb, urinary Cd, Pb, As, but blood Pb, Hg and urinary Pb, Hg, As in men were higher than those of women, while blood Cd and urinary Cd in men were lower than those of women. Further, the level of heavy metals in blood were higher than the corresponding ones in urinary.
Figure 1A & 2A also illustrate the Spearman rank correlation coefficients (rs) between metal concentrations among men and women, respectively. Metals were weakly to highly correlated with each other, where rs ranged -0.03 to 0.79 in men, and -0.02 to 0.66 in women, with blood Pb and urinary Pb having the highest correlation (rs = 0.79 in men and 0.66 in women).
3.3．Multivariable linear regression analyses
Single metal linear regression analyses and multiple metals linear regression analyses were used to assess the associations between heavy metals and SUA/SCr (SUA). In general, blood Pb and urinary Cd were positively associated with SUA/SCr in both single and multivariate regression analysis, and urinary Pb was inversely associated with SUA/SCr only in multivariate analysis (Table 3). No associations between Hg (blood and urinary) and SUA/SCr were found in multivariate analysis. Similar results were also found in SUA (supplementary Table S1).
3.3.1．Associations between heavy metals and UA levels in single metal model
The single metal model showed that blood Pb (β = 0.454, P < 0.001), Hg (β = 0.140, P = 0.034), urinary Cd (β = 0.205, P = 0.001) and As (β = 0.159, P = 0.005) were positively associated with SUA/SCr level. While in sex-stratified analysis, urinary As (β = 0.278, P < 0.001) was positively associated with SUA/SCr levels only in men. Blood Pb and urinary Cd showed significantly positive associations with SUA/SCr levels both in men (blood Pb: β = 0.284, P = 0.034, urinary Cd: β = 0.159, P = 0.040) and in women (blood Pb: β = 0.470, P = 0.003, urinary Cd: β = 0.269, P = 0.004).
3.3.2．Associations between heavy metals and UA levels in multiple metals model
The multiple metals model showed that there were negative associations between SUA/SCr levels and blood Cd (βoverall = -0.237, P = 0.022) and urinary Pb (βoverall = -0.720, P <0.001; βmen = -0.462, P = 0.003; βwomen = -0.838, P <0.001), whereas positive associations were found between SUA/SCr levels and blood Pb (βoverall = 0.987; βmen = 0.651, P = 0.002; βwomen = 1.014, P <0.001), urinary Cd (βoverall = 0.461, P <0.001; βmen = 0.252, P = 0.027; βwomen = 0.613, P <0.001) and urinary As (βoverall = 0.206, P = 0.006; βmen = 0.351, P <0.001).
Firstly, we assessed the relative importance of metals, indicated by posterior inclusion probabilities (PIPs), an indicator for the importance of mixture components.
Urinary As was estimated to have the highest PIP (1.000), followed by blood Pb (0.926) and urinary Pb (0.868) in men, while blood Pb, urinary Cd and Pb were estimated to have the highest PIP (1.000) in women (Supplementary Table S2).
Secondly, we evaluated the association between all metals and UA levels, where the association was evaluated as the expected change in UA when values for all seven metals changed simultaneously from their median values to a particular quantile. As shown in Figure 1B and Supplementary Figure S3B, we found an increasing trend in the UA levels with the jointly increasing percentiles of all metals in men. Similar trend was found in women (Figure 2B & Supplementary Figure S4B).
Further, an exposure-response relationship of each metal with UA was also fitted respectively to assess the potential nonlinearity of the exposures, when the other metals were fixed at their 50th percentile. Urinary Pb was inversely associated with SUA/SCr, whereas blood Pb and urinary Cd were positively associated with SUA/SCr both in men and women. Blood Cd showed inverse and urinary As showed positive associations with SUA/SCr levels in men, but not in women (Figure 1C & 2C).
Finally, the component-specific exposure-outcome relationships and potential exposure-exposure interactions were examined, where the UA changes were studied with a single metal increasing from the 25th percentile to the 75th percentile, when all the other metals were fixed at the 25th, 50th, and 75th percentile. Blood Cd and urinary Pb showed signiﬁcantly negative effects on SUA/SCr, whereas blood Pb, urinary Cd and As performed signiﬁcantly negative effects in men (Figure 1D). Specifically, a change in blood Cd and Pb (blood Pb, urinary Cd and As) from their 25th percentile to 75th percentile was significantly associated with a decreased (increased) level of SUA/SCr, when the other six metals were set at the 25th, 50th, and 75th percentiles, respectively. Similar trend was found in urinary Cd and As. In women (Figure 2D), urinary Pb showed a signiﬁcantly negative effect on SUA/SCr, whereas blood Pb and urinary Cd displayed signiﬁcantly negative effects. A change in urinary Pb (blood Pb, urinary Cd) from their 25th percentile to 75th percentile were significantly associated with a decreased (increased) level of SUA/SCr, when the other six metals were set at the 25th, 50th, and 75th percentiles, respectively.
We further investigated the potential interactions between metals, and no interactions were identified, as indicated by the finding that all of the metals’ confidence intervals encompassed zero (supplementary Figure S2). Moreover, similar results were also found in the associations between metals and SUA (supplementary Figure S3 and S4).
We further excluded 510 participants, whose urinary creatinine concentrations <30 mg/dL or >300 mg/dL, and found that the results were consistent with the analysis aforesaid (Figure S5 – S8).