Serum 25-hydroxyvitamin D mediates the association between heavy metal exposure and cardiovascular disease

Abstract

Background: Mediation analysis aims to determine how intermediate variables affect exposure to disease. In this study, 25-hydroxyvitamin D (25(OH)D) was evaluated to assess its role in mediating heavy metal exposure and cardiovascular disease (CVD).

Methods: A total of 9,377 participants from the National Health and Nutrition Examination Survey (NHANES) for the years 2011-2018 were included. Firstly, restricted cubic spline (RCS), and multivariable logistic regression model were performed to estimate the association between heavy metal exposure (Cadmium, Lead, Mercury, Manganese, and Selenium), as well as serum 25(OH)D and CVD. Secondly, using generalized linear regression model and generalized additive models with smooth functions, we investigated the correlation between heavy metal exposure and serum 25(OH)D. Finally, the mediation effect of serum 25(OH)D in the associations between heavy metal exposure and CVD was explored.

Results: The RCS plots revealed that Cadmium, and Lead were positively and linearly associated with CVD, while Mercury, and Manganese were inversely and linearly associated with CVD. Additionally, a roughly L- and U-shaped relationship existed between Selenium, as well as 25(OH)D and CVD. When potential confounding factors were adjusted for, serum 25(OH)D had negative associations with Cadmium, Lead, and Manganese, while serum 25(OH)D had positive relationship with Selenium. There was a mediation effect between Manganese exposure and CVD, which was mediated by 25(OH)D.

Conclusion: According to the mediation analysis, the negative association between Manganese exposure and incident CVD was increased by 25(OH)D. The increasing dietary intake of Vitamin D could increase the protective effect of manganese intake on CVD.

Keywords: Cardiovascular disease; Heavy metals exposure; Mediation analysis; Serum 25-hydroxyvitamin D; United States.

Fig. 1

Study flow chart. Abbreviations: NHANES, National Health and Nutrition Examination Surveys; CVD, cardiovascular disease; serum 25(OH)D, serum 25-hydroxyvitamin D

Fig. 2

A Correlation heat map of the five heavy metal relationships; B Weight of exposure effect of five heavy metals on cardiovascular events

Fig. 3

The restricted cubic spline plots of associations of heavy metals (Cadmium, Lead, Mercury, Manganese, and Selenium) and serum 25(OH)D with prevalence of CVD. Note: Heavy metals, and 25(OH)D are log10 transformed. Analyses were adjusted for age, sex, race /ethnicity, education level, family poverty-income ratio, the history of hypertension, diabetes mellitus, smoking, alcohol use, body mass index, mean energy intake, hemoglobin, high-density cholesterol, triglycerides, cholesterol, blood urea nitrogen, serum creatinine, uric acid. The solid and dashed lines represent the log-transformed odds ratios and the corresponding 95% confidence intervals. Abbreviations: 25(OH)D, 25-hydroxyvitamin D

Fig. 4

The association of serum 25(OH)D with heavy metals. A The association between 25(OH)D and Cadmium; B The association between 25(OH)D and Lead; C The association between 25(OH)D and Mercury; D The association between 25(OH)D and Manganese; E The association between 25(OH)D and Selenium. Abbreviations: 25(OH)D, 25-hydroxyvitamin D

Fig. 5

Mediation analysis of serum 25(OH)D on the interaction between heavy metals and CVD. A Mediation models of 25(OH)D, Cadmium, and CVD: direct effect (TE = 0.018056; P = 0.008) of 25(OH)D (exposure) toward CVD (outcome), and 25(OH)D medication proportion is 1.45%; indirect effect (IE = 0.000294; P < 0.001) of 25(OH)D (exposure) toward 25(OH)D (mediator) and effect CVD (DE = 0.017762; P < 0.001), from 25(OH)D (mediator) toward CVD (outcome). B Mediation models of 25(OH)D, Lead, and CVD: direct effect (TE = 0.00348; P = 0.140) of 25(OH)D (exposure) toward CVD (outcome), and 25(OH)D medication proportion is 2.56%; indirect effect (IE = 0.000114; P < 0.240) of 25(OH)D (exposure) toward 25(OH)D (mediator) and effect CVD (DE = 0.00337; P < 0.150), from 25(OH)D (mediator) toward CVD (outcome). C Mediation models of 25(OH)D, Mercury, and CVD: direct effect (TE = -0.000893; P = 0.510) of 25(OH)D (exposure) toward CVD (outcome), and 25(OH)D medication proportion is 2.21%; indirect effect (IE = −0.000057; P < 0.220) of 25(OH)D (exposure) toward 25(OH)D (mediator) and effect CVD (DE = −0.000836; P < 540), from 25(OH)D (mediator) toward CVD (outcome). D Mediation models of 25(OH)D, Manganese, and CVD: direct effect (TE = −0.0046; P < 0.001) of 25(OH)D (exposure) toward CVD (outcome), and 25(OH)D medication proportion is 6.7%; indirect effect (IE = −0.0003; P < 0.001) of 25(OH)D (exposure) toward 25(OH)D (mediator) and effect CVD (DE = −0.0043; P < 0.001), from 25(OH)D (mediator) toward CVD (outcome). E Mediation models of 25(OH)D, Manganese, and CVD: direct effect (TE = −0.0000649; P < 0.620) of 25(OH)D (exposure) toward CVD (outcome), and 25(OH)D medication proportion is 6.7%; indirect effect (IE = −0.0000075; P = 0.023) of 25(OH)D (exposure) toward 25(OH)D (mediator) and effect CVD (DE = −0.0000574; P = 0.650), from 25(OH)D (mediator) toward CVD (outcome). Abbreviations: 25(OH)D, 25-hydroxyvitamin D; CVD, Cardiovascular disease