The association between serum copper concentrations and cardiovascular disease risk factors in children and adolescents in NHANES

Zang, Xiaodong; Huang, Hesuyuan; Zhuang, Zhulun; Chen, Runsen; Xie, Zongyun; Xu, Cheng; Mo, Xuming

doi:10.1007/s11356-018-1816-6

Cited by 42 publications

(21 citation statements)

References 31 publications

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“…The interplays among lipid, iron, and copper metabolism have been recognized, but they are complex and not fully elucidated. Epidemiological findings of the effect of copper on lipid metabolism are equivocal, with some studies showing negative associations of blood copper with both TC and LDL cholesterol [ 40 ], and others showing positive associations [ 41 ]. The relationship between iron status and blood lipids is similarly ambiguous.…”

Section: Discussionmentioning

confidence: 99%

The Causal Effects of Blood Iron and Copper on Lipid Metabolism Diseases: Evidence from Phenome-Wide Mendelian Randomization Study

et al. 2020

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Blood levels of iron and copper, even within their normal ranges, have been associated with a wide range of clinical outcomes. The available epidemiological evidence for these associations is often inconsistent and suffers from confounding and reverse causation. This study aims to examine the causal clinical effects of blood iron and copper with Mendelian randomization (MR) analyses. Genetic instruments for the blood levels of iron and copper were curated from existing genome-wide association studies. Candidate clinical outcomes were identified based on a phenome-wide association study (PheWAS) between these genetic instruments and a wide range of phenotypes in 310,999 unrelated individuals of European ancestry from the UK Biobank. All signals passing stringent correction for multiple testing were followed by MR analyses, with replication in independent data sources where possible. We found that genetically predicted higher blood levels of iron and copper are both associated with lower risks of iron deficiency anemia (odds ratio (OR) = 0.75, 95% confidence interval (CI): 0.67–0.85, p = 1.90 × 10−6 for iron; OR = 0.88, 95% CI: 0.78–0.98, p = 0.032 for copper), lipid metabolism disorders, and its two subcategories, hyperlipidemia (OR = 0.90, 95% CI: 0.85–0.96, p = 6.44 × 10−4; OR = 0.92, 95% CI: 0.87–0.98, p = 5.51 × 10−3) and hypercholesterolemia (OR = 0.90, 95% CI: 0.84–0.95, p = 5.34 × 10−4; OR = 0.93, 95% CI: 0.89–0.99, p = 0.022). Consistently, they are also associated with lower blood levels of total cholesterol and low-density lipoprotein cholesterol. Multiple sensitivity tests were applied to assess the presence of pleiotropy and the robustness of causal estimates. Regardless of the approaches, consistent evidence was obtained. Moreover, the unique clinical effects of each blood mineral were identified. Notably, genetically predicated higher blood iron is associated with an enhanced risk of varicose veins (OR = 1.28, 95% CI: 1.15–1.42, p = 4.34 × 10−6), while blood copper is positively associated with the risk of osteoarthrosis (OR = 1.07, 95% CI: 1.02–1.13, p = 0.010). Sex-stratified MR analysis further revealed some degree of sex differences in their clinical effects. Our comparative PheWAS-MR study of iron and copper comprehensively characterized their shared and unique clinical effects, highlighting their potential causal roles in hyperlipidemia and hypercholesterolemia. Given the modifiable nature of blood mineral status and the potential for clinical intervention, these findings warrant further investigation.

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Section: Discussionmentioning

confidence: 99%

The Causal Effects of Blood Iron and Copper on Lipid Metabolism Diseases: Evidence from Phenome-Wide Mendelian Randomization Study

et al. 2020

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“…Many epidemiological studies with mixed findings have investigated the associations between serum copper levels, cardiovascular disease and neurodegenerative diseases [9] , [10] , [11] , [12] . However, the association between copper status and the risk of osteoporosis and related diseases has been examined by only few observational studies and remains controversial because of inconsistent results [13] , [14] , [15] , [16] , [17] , [18] .…”

Section: Introductionmentioning

confidence: 99%

Serum copper levels are associated with bone mineral density and total fracture

Qiao

et al. 2018

Journal of Orthopaedic Translation

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BackgroundBoth copper deficiency and overexposure have been associated with adverse health effects. Evidence linking copper to bone mineral density (BMD) and total fracture, however, is limited.MethodsThis nationally representative cross-sectional study enrolled participants from the National Health and Nutrition Examination Survey (2011–2014) in the United States. Using unadjusted and multivariate adjusted logistic regression analyses and a two-piecewise linear regression model with a smoothing function, we evaluated the associations between serum copper levels, bone mineral density and total fracture in 722 participants.ResultsThe study sample (n = 722, mean age: 56.47 ± 11.55 y) represented a population of which 47.2% were men; 43.91% were non-Hispanic white, 18.84% non-Hispanic black and 13.71% Mexican American; 25.9% had total fracture. In the multivariate logistic regression analysis, individuals in the lowest category (<98.5 μg/dL) of serum copper concentration had 0.049 g/cm2 lower total femur BMD and 0.045 g/cm2 lower femoral neck BMD than those in the second concentration category (98.5–114 μg/dL). Individuals in the highest category (≥134 μg/dL) of serum copper concentration had an approximately 4-fold increase in the risk of total fracture than those in the second concentration category. There were no significant associations between per 10 μg/dL increases in serum copper levels and total fracture in multivariate logistic regression analysis after multivariate adjustment (all p > 0.05). However, a differential association between serum copper levels and total fractures between men and women was observed (odds ratio = 1.81, 95% confidence interval 1.08–3.03, p = 0.026 for men and odds ratio = 1.07, 95% confidence interval 0.86–1.32, p = 0.552 for women).ConclusionModerate serum copper levels are critically important for bone health. Lower serum copper levels are significantly associated with decreased BMD in the total femur and femoral neck. Higher serum copper levels are significantly associated with increased total fracture, especially in men.The Translational Potential of this ArticleThe impact of serum copper concentrations on bone mineral density and total fracture can provide insights into clinical application of copper-containing supplements and biomaterials.

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“…Copper deficiency have long been linked to increased risks of hyperlipidemia and cardiovascular diseases in both humans and animal models 32 , while copper supplementation in patients of hyperlipidemia was shown to improve the blood lipid profile 33 . Epidemiological findings, however, are conflicting, with some suggesting negative associations of serum copper with both TC and LDL 34 , and others showing positive associations 35 . The relationship between iron status and blood lipids is similarly convoluted.…”

Section: Discussionmentioning

confidence: 99%

The Causal Effects of Blood Iron and Copper on Lipid Metabolism Disease: Evidence from Phenome-wide Mendelian Randomization Study

Zhou

Liu

Francis

et al. 2020

Preprint

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Background: Blood levels of iron and copper, even within their normal ranges, have been associated with a wide range of clinical outcomes. Available epidemiological evidence on blood iron and copper association with potential clinical effects, such as lipid metabolism disorder, is inconsistent and scarce. This study aims to examine and disentangle the causal clinical effects of iron and copper. Methods: Genetic instruments for the blood level of iron and copper were curated from existing genome-wide association studies. Candidate clinical outcomes were identified based on a phenome-wide association study (PheWAS) between these genetic instruments and multiple phenotypes in 310,999 unrelated individuals of European ancestry from the UK Biobank. All signals passing stringent correction for multiple testing were followed by Mendelian randomization (MR) analyses, with replication in independent data sources where possible. Results: Genetically predicted higher blood levels of iron and copper are both associated with lower risks of iron deficiency anemia (OR = 0.75, 95% CI:0.67-0.85, p =1.90e-06 for iron; OR = 0.88, 95% CI: 0.78-0.98, p =0.03 for cooper), lipid metabolism disorders and its two subcategories, hyperlipidemia (OR = 0.90, 95% CI:0.85-0.96, p =6.44e-04 for iron; OR = 0.92, 95% CI:0.87-0.98, p = 5.51e-03 for cooper) and hypercholesterolemia (OR = 0.90, 95% CI:0.84-0.95, p = 5.34e-04 for iron; OR = 0.93, 95% CI:0.89-0.99, p =0.02 for cooper). Consistently, they are also associated with lower blood levels of total cholesterol and low-density lipoprotein cholesterol. Multiple sensitivity tests were applied to assess the pleiotropy and stability of the estimation, and consistent evidence across different approaches was obtained. Additionally, the unique clinical effects of each blood mineral were also pinpointed, and sex-stratified MR analysis further revealed the clinical implication of iron and copper exhibits some degree of sex differences. Conclusions: Our comparative PheWAS-MR study of iron and copper comprehensively characterized their shared and unique clinical effects, highlighting their novel causal roles in hyperlipidemia and hypercholesterolemia. Given the modifiable and variable nature of blood mineral status, these findings warrant further investigation.

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The association between serum copper concentrations and cardiovascular disease risk factors in children and adolescents in NHANES

Cited by 42 publications

References 31 publications

The Causal Effects of Blood Iron and Copper on Lipid Metabolism Diseases: Evidence from Phenome-Wide Mendelian Randomization Study

The Causal Effects of Blood Iron and Copper on Lipid Metabolism Diseases: Evidence from Phenome-Wide Mendelian Randomization Study

Serum copper levels are associated with bone mineral density and total fracture

The Causal Effects of Blood Iron and Copper on Lipid Metabolism Disease: Evidence from Phenome-wide Mendelian Randomization Study

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