Association between serum copper and blood glucose: a mediation analysis of inflammation indicators in the NHANES (2011-2016).

Background: The rising prevalence of diabetes underscores the need for identifying effective prevention strategies. Recent research suggests environmental factors, particularly heavy metals like copper, significantly influence health outcomes, including diabetes, through mechanisms involving inflammation and oxidative stress. This study aims to explore how serum copper levels affect blood glucose, employing NHANES data from 2011 to 2016, to provide insights into environmental health's role in diabetes prevention and management. Methods: The study analyzed data from 2,318 NHANES participants across three cycles (2011-2016), focusing on those with available data on serum copper, inflammatory markers, and blood glucose levels. We utilized principal component analysis for selecting inflammatory markers, mediation analysis to examine direct and indirect effects, multiple linear regression for assessing relationships between markers and glucose levels, and weighted quantile sum regression for evaluating individual and collective marker effects, adjusting for demographic variables and serum copper. Results: Participants averaged 42.70 years of age, with a near-even split between genders. Average serum copper was 119.50 µg/dL, white blood cell count 6.82 × 109/L, and fasting blood glucose 107.10 mg/dL. Analyses identified significant mediation by inflammatory markers (especially white blood cells: 39.78%) in the copper-blood glucose relationship. Regression analyses highlighted a positive correlation between white blood cells (estimate: 1.077, 95% CI: 0.432 to 2.490, p = 0.013) and copper levels and a negative correlation for monocyte percentage (estimate: -1.573, 95% CI: 0.520 to -3.025, p = 0.003). Neutrophil percentage was notably influential in glucose levels. Sensitive analyses confirmed the study's findings. Conclusion: Serum copper levels significantly impact blood glucose through inflammatory marker mediation, highlighting the importance of considering environmental factors in diabetes management and prevention. These findings advocate for public health interventions and policies targeting environmental monitoring and heavy metal exposure reduction, emphasizing the potential of environmental health measures in combating diabetes incidence.

High serum copper as a risk factor of all-cause and cause-specific mortality among US adults, NHANES 2011-2014.

Background: Several studies have shown that serum copper levels are related to coronary heart disease, diabetes, and cancer. However, the association of serum copper levels with all-cause, cause-specific [including cardiovascular disease (CVD) and cancer] mortality remains unclear. Objectives: This study aimed to prospectively examine the association of copper exposure with all-cause, CVD, and cancer mortality among US adults. Methods: The data for this analysis was obtained from the National Health and Nutrition Examination Survey (NHANES) between 2011 and 2014. Mortality from all-causes, CVD, and cancer mortality was linked to US National Death Index mortality data. Cox regression models were used to estimate the association between serum copper levels and all-cause, CVD, and cancer mortality. Results: A total of 2,863 adults were included in the main study. During the mean follow-up time of 81.2 months, 236 deaths were documented, including 68 deaths from cardiovascular disease and 57 deaths from cancer. The weighted mean overall serum copper levels was 117.2 ug/L. After adjusting for all of the covariates, compared with participants with low (1st tertile, <103 µg/L)/medium (2st tertile, 103-124 µg/L) serum copper levels, participants with high serum copper levels (3rd tertile, ≥124 µg/L) had a 1.75-fold (95% CI, 1.05-2.92)/1.78-fold (1.19,2.69) increase in all-cause mortality, a 2.35-fold (95% CI, 1.04-5.31)/3.84-fold (2.09,7.05) increase in CVD mortality and a 0.97-fold (95% CI, 0.28-3.29)/0.86-fold (0.34,2.13) increase in cancer mortality. In addition, there was a linear dose-response association between serum copper concentration with all-cause and CVD mortality (P for nonlinear > 0.05). Conclusions: This prospective study found that serum copper concentrations were linearly associated with all-cause and CVD mortality in US adults. High serum copper levels is a risk factor for all-cause and CVD mortality.

Comparative Analysis of Tissue Copper Levels in Oral Submucous Fibrosis (OSMF) Patients.

Background: Oral submucous fibrosis (OSMF) is a recognized potentially malignant oral condition linked to the consumption of areca nut. Chewing areca nut has been shown to elevate soluble copper levels in mouth fluids. Materials and Methods: Participants: The study included a panel of 30 patients with OSMF from Rama Dental College, Kanpur, India, and 30 nonareca chewing individuals serving as controls. Tissue Sample Collection and Analysis: Buccal mucosal biopsies were obtained from both OSMF patients and controls. The tissue copper concentrations were quantified using mass absorption spectrometry (MAS). Additionally, energy-dispersive X-ray microanalysis (EDX) was employed to identify the presence and distribution of copper in the tissue. Statistical Analysis: Statistical comparisons were performed using appropriate methods, with a P-value of less than 0.05 considered statistically significant. Results: MAS analysis revealed that the mean tissue copper level was 6.2 ± 3.1 micrograms per gram (µg/g) in OSMF specimens (n = 30), slightly higher than the 4.5 ± 2.0 µg/g in the nonareca chewing controls (n = 30) (P = 0.1). EDX analysis showed distinct copper peaks in both the epithelium (22/23) and connective tissue (18/23) of OSMF specimens compared to control biopsies. These findings were corroborated by secondary ion mass spectrometry (SIMS) in a subset of samples. Conclusion: The study revealed higher copper concentrations in buccal mucosal tissue of OSMF patients from Rama Dental College, Kanpur, suggesting a potential connection between copper and the initiation of OSMF.

Copper's dual role: unravelling the link between copper homeostasis, cuproptosis, and cardiovascular diseases.

This graphic depicts the interplay between copper homeostasis and cuproptosis and their role in cardiovascular diseases. Copper is vital for cardiac mitochondrial function, while its dysregulation induces cuproptosis via Ferredoxin1 (FDX1) and lipoic acid synthase (LIAS). Cuproptosis is linked to myocardial ischemia/reperfusion injury, heart failure, atherosclerosis, and arrhythmias. Copper deficiency impacts atherosclerosis markers. Therapeutic interventions include copper chelators (e.g., ammonium tetrathiomolybdate), and oxidative phosphorylation inhibitors like elesclomol and copper ionophores (CuII(atsm), CuII(gtsm), and disulfiram). These interventions modulate intracellular copper, elevate NO, and reduce inflammatory cytokines, contributing to decreased cardiovascular diseases.

Copper and Melanoma Risk: Results from NHANES 2007-2018 and Mendelian Randomization Analyses.

Copper is an essential trace element obtained from food. There is a paucity of observational or prospective studies that have investigated the relationship between copper and melanoma risk. Copper serves as a cofactor for pivotal enzymes involved in mitochondrial respiration, antioxidant defense, and neurotransmitter synthesis. Undoubtedly, copper plays an indispensable role in the initiation and progression of tumors, particularly melanoma; however, further investigations are warranted to elucidate the underlying mechanisms linking copper and melanoma risk. Given the availability of dietary copper and serum copper data in the NHANES database, we conducted an investigation into the association between dietary copper intake and serum copper levels with melanoma risk. We enrolled 26,401 individuals with dietary copper data in the 2007-2018 NHANES database. To mitigate confounding variables, a propensity score matching (PSM) was performed. To assess the association between dietary copper intake and melanoma risk, we employed a multivariate logistic regression analysis before and after PSM. The restricted cubic spline analysis was utilized to determine whether there is a non-linear relationship between dietary copper intake and melanoma risk, with subgroup analysis conducted to determine beneficiaries. Then, those with blood copper data from the enrolled population with dietary copper intake were screened out, and subsequently, multivariate logistic regression models were subsequently constructed to investigate the association between serum copper levels and melanoma risk after PSM. Mendelian analysis was further utilized to validate the results of the NHANES database using serum copper as the exposure factor and melanoma as the outcome variable. The study found that melanoma risk was associated with dietary copper intake before and after PSM, demonstrated by multiple logistic regression. The relationship between dietary copper intake and melanoma risk was non-linear, with a reduced risk observed above approximately 2.5 mg/day, as shown by the RCS. The evidence suggests that an increased intake of copper is linked to a decreased risk of melanoma. To clarify the mechanism behind the increased risk of melanoma due to higher dietary copper intake, we analyzed the population data from the NHANES database on serum copper and dietary copper intake. Our results indicated that there is no causal relationship between serum copper and melanoma risk. Mendelian randomization analysis of multi-database data sources confirmed the conclusion of the NHANES database analysis. Dietary copper is a protective factor against melanoma, and serum copper or blood copper is not associated with melanoma risk. This suggests that serum or blood copper is not responsible for the protective effect of dietary copper intake on melanoma risk, and the mechanisms need to be further investigated.

The Association between Serum Copper and Bone Mineral Density among Adolescents Aged 12 to 19 in the United States.

Bone mineral density (BMD) is a key parameter widely used in the assessment of bone health. Although many investigations have explored the relationship between trace elements and BMD, there are fewer studies focused on serum copper and BMD, especially for adolescents. Using data extracted from the National Health and Nutrition Examination Survey, we applied a multiple-linear regression and smooth curve fitting to assess the relationship between serum copper and BMD. A total of 910 participants were finally included in this study. After adjusting for relevant covariates, serum copper was negatively associated with lumbar spine BMD (ß = -0.057, 95% CI: -0.109 to -0.005), trunk bone BMD (ß = -0.068, 95% CI: -0.110 to -0.026), pelvis BMD (ß = -0.085, 95% CI: -0.145 to -0.024), subtotal BMD (ß = -0.072, 95% CI: -0.111 to -0.033), and total BMD (ß = -0.051, 95% CI: -0.087 to -0.016) (p < 0.05). In quartile analysis, the highest level of serum copper was associated with decreased BMD when compared with those at the lowest quartile (p < 0.05). The stratified analysis revealed a significant interaction between age and the effects of serum copper on trunk bone BMD (p = 0.022) and pelvis BMD (p = 0.018). Meanwhile, the higher level of serum copper was negatively associated with BMD in males, and gender modified the relationship (p < 0.001). Future longitudinal studies will be necessary for a more definitive interpretation of our results.

The Correlation Between Serum Copper and Non-alcoholic Fatty Liver Disease in American Adults: an Analysis Based on NHANES 2011 to 2016.

Copper functions as an essential micronutrient influencing diverse metabolic processes in mammals, encompassing oxidative stress responses, lipid metabolism, and participation in enzymatic reactions. However, the impact of serum copper on non-alcoholic fatty liver disease (NAFLD) remains controversial. Our aim was to explore the precise correlation between serum copper and NAFLD in a large-scale population-based study. A total of 1377 participants from the National Health and Nutrition Examination Survey (NHANES) 2011-2016 were included in our study. The diagnosis of NAFLD and its progress to advanced liver fibrosis were based on serological indexes. One-way ANOVA, Kruskal-Wallis H test, and Chi-square test were used to access variations between quartiles groups of serum copper. We conducted multivariate-adjusted logistic regression models and subgroup analyses to investigate the association between serum copper and NAFLD, along with several metabolic diseases. Among the 1377 participants, 661 were diagnosed with NAFLD, and 141 of whom were classified into advanced liver fibrosis. Higher serum copper levels (≥ 21.00 µmol/L) were associated with an increased incidence of NAFLD (odds ratio (OR) = 2.07 (1.38-3.10), p < 0.001), as well as advanced liver fibrosis (OR = 2.40 (1.17-5.19), p = 0.025). Moreover, serum copper exhibited a positive correlation with hypertension, overweight, and abdominal obesity, all of which have been identified as risk factors of NAFLD. Additionally, female participants, under the age of 60, and with a higher body mass index (BMI) (> 24.9 kg/m2) emerged as the most vulnerable subgroup concerning the relationship between serum copper and NAFLD. In the U.S. population, a notable association has been identified, linking elevated serum copper to an increased susceptibility for both the onset and progression of NAFLD, along with several metabolic disorders associated with NAFLD. The adverse effects of excess copper warrant attention in the context of public health considerations.

Association between serum copper levels and stroke in the general population: A nationally representative study.

OBJECTIVES: The objective was to explore the association between serum copper levels and the prevalence of stroke. METHODS: Data were obtained from 3 consecutive National Health and Nutrition Examination Survey (NHANES) cycles (2011-2016). Weighted multivariable logistic regression analysis was conducted to evaluate the association between serum copper levels and self-reported stroke. RESULTS: A total of 5,151 adults met the inclusion criteria. A total of 181 (3.51%) stroke patients were identified. In comparison to individuals with serum copper levels in the lowest tertile (<16.4 µmol/l), those with levels in the middle tertile (16.4-19.8 µmol/l) had an odds ratio (OR) of 0.99 (95% confidence interval [CI]: 0.44-2.25), while those with levels in the highest tertile (>19.8 µmol/l) had an OR of 2.36 (95% CI: 1.01-5.52). Furthermore, each standard deviation (SD) increase in serum copper was found to be positively associated with the prevalence of stroke, with an OR of 1.44 (95% CI: 1.11-1.86). Dose‒response analysis showed a positive linear association between serum copper levels and stroke (Pnonlinearity=0.554). CONCLUSIONS: This cross-sectional study suggested a positive association between serum copper levels and stroke among American adults.

Association between serum copper levels and muscle mass: results from NHANES 2011-2016.

Copper is essential for various biological processes. However, excess copper has several adverse health effects. The effects of serum copper on muscle mass are poorly understood. This study aimed to investigate the association between serum copper levels and muscle mass in the US population. We utilized National Health and Nutrition Examination Survey (NHANES) data between 2011 and 2016 for analysis. Data on serum copper, muscle mass (measured using the appendicular skeletal muscle mass index (ASMI)), and covariates were extracted and analyzed. Weighted multivariate linear regression analyses and smooth curve fittings were performed to investigate the association between serum copper levels and ASMI. Subgroup analyses stratified according to age and sex were performed. In the presence of nonlinearity, threshold effect analysis was performed using a two-piecewise linear regression model. A total of 3860 participants were included in the final analysis. Serum copper levels were negatively associated with ASMI in the fully adjusted model. Furthermore, by comparing participants in the highest and lowest tertiles of serum copper levels, we found that the ASMI decreased by 0.292 kg/m2. In the sex-stratified subgroup analysis, we observed an inverse association between serum copper levels and the ASMI in both men and women. When stratified by age, the association remained significant among participants < 40 years of age, but not among those ≥ 40 years old. Smooth curve fitting revealed a nonlinear relationship between serum copper and ASMI, with an inflection point identified at 150.6 µg/dL. Our study revealed an inverse relationship between serum copper levels and muscle mass. This finding improves the current knowledge on the impact of serum copper on muscle loss and highlights the importance of serum copper homeostasis in muscle health.

Association Between the Serum Copper Levels and Environmental Tobacco Exposure on the Risk of Overweight and Obesity in Children: a Study Based on the National Health and Nutrition Examination Survey.

This study was to assess the individual effects of serum copper levels and environmental tobacco exposure and their joint effects on the risk of overweight and obesity among children and adolescents of 6 to 19 year olds. We analyzed cross-sectional data from 1849 children and adolescents participating in the National Health and Nutrition Examination Survey (NHANES) collected between 2011 and 2016. Environmental tobacco exposure was determined by cotinine levels. The serum copper level was divided into < median group and ≥ median groups according to the median of 109.81 µg/dL. The outcome was overweight/obese in children and adolescents. Weighted multinomial multivariate logistic regression models were used to assess the association of serum copper and cotinine levels, with the risk of overweight/obesity, and the joint effects on the risk of overweight and obesity among children and adolescents. The subgroup analyses based on age, gender, and household smoking status were conducted. Among 1849 children and adolescents, 332 children and adolescents had overweight BMI, and 450 children and adolescents had obese BMI. Higher serum copper levels were associated with the risk of obesity in children and adolescents (odds ratio (OR) 2.96, 95% confidence interval (CI) 1.39-6.31, P = 0.006). A positive association between increasing levels of cotinine levels and the risk of overweight (OR 1.83, 95% CI 1.16-2.87, P = 0.010) and obesity (OR 2.56, 95% CI 1.03-6.40, P = 0.044) in children and adolescents was observed. A remarkable association was found between higher serum copper in combination with higher cotinine levels and the risk of overweight (OR 3.23, 95% CI 1.19-8.83, P = 0.023) and obesity (OR 8.76, 95% CI 2.14-35.87, P = 0.003) in children and adolescents. The subgroup analyses revealed positive associations between high serum copper levels in combination with high cotinine levels and overweight and obesity in children and adolescents aged ≥ 12 years, of female sex, and without smoking family members. There may exist a joint effect of serum copper levels and environmental tobacco exposure on overweight/obesity among children and adolescents. These findings offer an insight that early weight control and reduction of tobacco exposure and the detection of serum copper levels may be important in reducing the risk of obesity in children.

Abnormalities in Copper Status Associated with an Elevated Risk of Parkinson's Phenotype Development.

In the last 15 years, among the many reasons given for the development of idiopathic forms of Parkinson's disease (PD), copper imbalance has been identified as a factor, and PD is often referred to as a copper-mediated disorder. More than 640 papers have been devoted to the relationship between PD and copper status in the blood, which include the following markers: total copper concentration, enzymatic ceruloplasmin (Cp) concentration, Cp protein level, and non-ceruloplasmin copper level. Most studies measure only one of these markers. Therefore, the existence of a correlation between copper status and the development of PD is still debated. Based on data from the published literature, meta-analysis, and our own research, it is clear that there is a connection between the development of PD symptoms and the number of copper atoms, which are weakly associated with the ceruloplasmin molecule. In this work, the link between the risk of developing PD and various inborn errors related to copper metabolism, leading to decreased levels of oxidase ceruloplasmin in the circulation and cerebrospinal fluid, is discussed.

Association between serum copper levels and risk of cardiovascular disease: A nested case-control study in the PREDIMED trial.

BACKGROUND AND AIM: Certain trace elements have been associated with increased cardiovascular risk. The aim of this study was to evaluate the association between serum copper (S-Cu) levels and the risk of a first event of cardiovascular disease (CVD) in a population of older adults with high cardiovascular risk. METHODS AND RESULTS: We conducted a case-control study nested within the PREDIMED trial. During a median follow-up of 4.8 years, a total of 207 incident cases diagnosed with CVD were matched for sex, age, and intervention group with 436 controls. Personal interviews, reviews of medical records, and validated questionnaires were used to assess known CVD risk factors. Biological serum samples were collected annually. Inductively coupled plasma mass spectrometry analysis was used to determine S-Cu levels. Adjusted odds ratios were calculated using multivariate conditional logistic regression models. All participants had S-Cu levels within the reference values, 750 µg/L to 1450 µg/L. Among men, but not among women, the mean S-Cu concentration was higher in cases 1014.1 µg/L than in controls 959.3 µg/L; (p = 0.004). In men, the multivariable-adjusted odds ratio for CVD was 2.36 (95% CI 1.07-5.20 for the comparison of the highest vs. the lowest quartile; p for trend = 0.02), in women, it was 0.43 (95% CI 0.11-1.70; p for trend = 0.165). CONCLUSION: In older Spanish men with high cardiovascular risk, a significant association was observed between high S-Cu levels, but still within the reference values, and an increased risk of a first event of CVD. Our findings suggest a sex difference in CVD risk and S-Cu levels. To confirm this relationship and to analyze the differences observed between men and women, further studies are needed.

Serum copper levels and risk of major adverse cardiovascular events: a systematic review and meta-analysis.

Background: Despite the fact that several studies have investigated the association between serum copper levels (S-Cu) and the risk of cardiovascular diseases, this relationship remains unclear. The aims of this study were to investigate the association between S-Cu and risk of major adverse cardiovascular events (MACE), including total stroke, ischemic stroke, hemorrhagic stroke, myocardial infarction and cardiovascular mortality, and identify potential sources of results heterogeneity. Methods: We carried out a systematic review and meta-analysis. The selection criteria were: (1) Observational studies (cohort studies, case-control studies and hybrid studies); (2) Studies containing quantitative data about the relationship between S-Cu and risk of MACE; (3) Estimating association measures; and (4) Studies written in English, French or Spanish. Overall pooled Odds ratio (pOR) and 95% confidence intervals (95% CI) of MACE for the highest vs. lowest S-Cu category were calculated using random-effects models. Results: Sixteen studies with a total of 41,322 participants were included in the meta-analysis: 10 prospective cohort studies, 5 nested case-control studies and 1 case-control study. Comparing highest vs. lowest category, high S-Cu levels were associated with total stroke (pOR: 1.49, 95% CI 1.22-1.82; I2 = 0%, p = 0.54), myocardial infarction (pOR: 1.31, 95% CI 1.17-1.46; I2 = 0.0%, p = 0.92) and cardiovascular mortality (pOR: 1.60, 95% CI 1.39-1.86; I2 = 0.0%, p = 0.54). Subgroup analysis showed that studies with a hybrid design had higher risks for cardiovascular mortality (pOR: 3.42, 95% CI 1.98-5.92) and ischemic stroke (pOR: 1.54, 95% CI 1.30-1.83). Conclusion: High S-Cu levels were associated with an increased risk of total stroke, myocardial infarction and cardiovascular mortality. Hybrid studies seems to modify the strength of the association between S-Cu and the risk of cardiovascular mortality and ischemic stroke. Systematic review registration: [https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022370782], identifier [CRD42022370782].

Association Between Serum Copper Levels and Urinary Incontinence in Adult Men.

Urinary incontinence (UI) is a major health burden to aging patients. The function of the trace element copper in male UI is unclear. To elaborate on the impact of serum copper levels on UI, we investigated the association between serum copper levels and UI using data from the National Health and Nutrition Examination Survey (NHANES), a cross-sectional survey of male participants aged 20 years old and older in the United States from 2011 to 2016. We performed weighted multivariable logistic and linear regression models to evaluate the association between serum copper levels and UI. Compared with serum copper levels in quartile 1 (Q1), serum copper levels in Q2 and Q3 were associated with stress urinary incontinence (SUI) after adjusting for all potential confounders (Q2, odds ratio [OR] = 0.292, 95% confidence interval [CI] = 0.093-0.920, P = 0.047; Q3, OR = 0.326, 95% CI = 0.113-0.937, P = 0.049). No significance was found between serum copper levels and other types of UI. Our findings revealed that the serum copper levels were inversely related to SUI in adult males. Race and education level might modulate this relationship. Further studies are warranted for validation.

The association between serum copper and obesity and all-cause mortality: the NHANES 2011-2016.

Excessive serum copper has multiple effects on human health, while the association between copper and obesity remains unclear. The objective of this study is to examine the associations of serum copper concentrations with obesity and adiposity measures, including body fat composition and distribution among adults in the USA. This analysis utilized data from the National Health and Nutrition Examination Survey (NHANES) (2011-2016). A total of 7285 adults aged 18 years or older who had serum copper measures were included in this cross-sectional study. Multi-linear regression and logistic regression were used to estimate the independent risky effect of copper on fat deposition and all-cause mortality. Moreover, these associations were analyzed in stratification analysis by gender, age, and physical activity (PA). Generally, we found that participants who were females, non-Hispanic Black, or with inactive PA tended to have a higher serum level of copper. In addition, we observed positive associations between serum copper and adiposity measurements. Furthermore, a serum copper level higher than 133.9 µg/dL was a risk factor for all-cause mortality, which doubled the odds ratio of all-cause mortality compared to the normal serum copper level. Serum copper was positively associated with fat deposition of whole body and regional parts, and all-cause mortality. Furthermore, the effects of copper on fat distribution were also significant and could be modified by age, gender, and PA.

Serum Copper-to-Zinc Ratio and Risk of Chronic Obstructive Pulmonary Disease: A Cohort Study.

PURPOSE: Serum copper (Cu), zinc (Zn), and Cu/Zn-ratio have emerged as ageing-related biomarkers. We sought to assess the association between Cu/Zn-ratio and chronic obstructive pulmonary disease (COPD) risk. METHODS: Serum Cu and Zn were measured using atomic absorption spectrometry in 2,503 men aged 42-61 years. RESULTS: During a median follow-up of 27.1 years, 210 COPD cases occurred. Serum Cu/Zn-ratio and Cu concentrations were linearly associated with COPD risk, whereas the relationship was curvilinear for Zn and COPD risk. A unit increase in Cu/Zn-ratio was associated with an increased COPD risk in multivariable analysis (hazard ratio, HR 1.81; 95% CI 1.08-3.05). The corresponding adjusted HR (95% CI) was 3.17 (1.40-7.15) for Cu. Compared to the bottom tertile of Zn, the HRs (95% CIs) were 0.68 (0.48-0.97) and 1.01 (0.73-1.41) for the middle and top tertiles of Zn, respectively. CONCLUSIONS: Increased serum Cu/Zn-ratio and Cu concentrations were linearly associated with an increased COPD risk in men.

Serum copper and the risk of cardiovascular disease death in Finnish men.

BACKGROUND AND AIMS: Copper (Cu) is a component of enzymes catalyzing oxidation-reduction reactions. With the persisting burden of cardiovascular disease (CVD), there is evident need to identify biomarkers and potential risk factors for CVD. We therefore examined the association between serum Cu levels and the risk of CVD death in Finnish men and across different body mass index (BMI) categories. METHODS AND RESULTS: This Finnish prospective study is based on 1911 men aged 42-60 years who were free of coronary heart disease at baseline. Cu concentrations (mg/l) were determined using atomic absorption spectrometer and categorized into quartiles (<1.0; 1 to <1.1; 1.1 to <1.21; ≥1.21). Participants were categorized into normal weight <25 kg/m2, pre-obesity 25-29.9 kg/m2, and obesity >30 kg/m2. The association between Cu and CVD death was analyzed using multivariable Cox regression models. During a median follow-up of 25.8 years, 358 CVD deaths occurred. The risk of CVD death increased continuously with increasing Cu levels (for non-linearity, p = 0.64). Using the first quartile as reference after adjustment for covariates, the hazard ratios (HR) (95% confidence interval (CI)) for CVD death for Cu concentrations in second, third and fourth quartiles were 1.45(1.05-2.01), 1.69(1.25-2.27), and 1.68(1.23-2.29), respectively. Obese men in the third quartile of serum Cu concentrations had highest risk of CVD death (HR (95%CI) 2.71(1.27-5.78)). CONCLUSION: Elevated serum Cu level was associated with increased risk of CVD death across all BMI categories in middle-aged and older Finnish men. Serum Cu may have prognostic implication for CVD mortality risk; however, further studies are needed.

Association between serum copper, zinc and their ratio and handgrip strength among adults: a study from National Health and Nutrition Examination Survey (NHANES) 2011-2014.

Evidence for the association between serum copper and zinc status and handgrip strength is very limited only in several observational studies with study participants of specific population or a narrower age range. The aim of this study was to evaluate the association between serum copper, zinc and their ratio and handgrip strength in the general population. This study included adult participants aged 20-80 years with complete data of serum copper and zinc status and handgrip strength from NHANES 2011-2014. Handgrip strength was calculated as the average of the maximum measure obtained in each hand with a grip strength dynamometer and corrected using BMI. Serum copper and zinc levels were measured using inductively coupled plasma dynamic reaction cell mass spectrometry, and their ratios were calculated. The multivariable linear regression and restricted cubic spline models were used. Serum copper level was inversely associated with BMI-corrected handgrip strength, and the beta coefficients (95% confidence intervals) comparing the second, third, and fourth to the lowest quartiles of serum copper level were - 0.17 kg (- 0.26; - 0.08), - 0.22 kg (- 0.32; - 0.13), and - 0.36 kg (- 0.44; - 0.28), respectively (P for trend < 0.001). Non-linear association was detected between serum copper level and BMI-corrected handgrip strength (P < 0.01). Consistent with serum copper, serum copper/zinc ratio was inversely associated with BMI-corrected handgrip strength. However, no significant associations were observed between serum zinc level and BMI-corrected handgrip strength (all P > 0.05). Higher serum copper level and copper/zinc ratios were significantly associated with lower handgrip strength. Further research is needed to address related issues.

Serum copper-to-zinc ratio and risk of incident pneumonia in caucasian men: a prospective cohort study.

Serum copper (Cu) and zinc (Zn), essential micronutrients that have important immunomodulatory and antimicrobial properties, are biomarkers of ageing. Serum Cu/Zn-ratio may be a more reliable marker for age-related degenerative conditions compared with serum Cu or Zn alone. We aimed to assess the association between Cu/Zn-ratio and the risk of incident pneumonia in a prospective cohort study. Serum levels of Cu and Zn were measured at baseline using atomic absorption spectrometry in 2503 men aged 42-61 years in the Kuopio Ischemic Heart Disease prospective cohort study. Hazard ratios (HRs) with confidence intervals (CIs) were calculated for incident pneumonia using Cox regression models. A total of 599 cases of pneumonia occurred during a median follow-up of 26.1 years. Serum Cu/Zn-ratio and Cu were each linearly associated with incident pneumonia. A unit increase in Cu/Zn-ratio was associated with an increased risk of pneumonia in analysis adjusted for potential confounders including C-reactive protein (HR 1.65; 95% CI 1.17-2.33). The corresponding adjusted HR (95% CI) was 2.04 (1.22-3.40) for serum Cu. The association between serum Zn and pneumonia was curvilinear. Compared to the bottom tertile of Zn, the multivariable adjusted HRs (95% CIs) for incident pneumonia were 0.68 (0.55-0.83) and 0.96 (0.79-1.16) for the middle and top tertiles of Zn, respectively. Further analysis in the same participants showed that Cu/Zn-ratio might be a stronger risk indicator for pneumonia than serum C-reactive protein. In middle-aged and older Finnish men, increased serum Cu/Zn-ratio and Cu concentrations are each linearly associated with an increased risk of incident pneumonia.

Serum Copper and Zinc Concentrations and Cognitive Impairment in Older Adults Aged 60 Years and Older.

Epidemiological evidence on serum zinc and copper and cognitive impairment in older adults are not consistent. Results on serum zinc and copper and cognitive impairment in older adults from the National Health and Nutrition Examination Survey (NHANES) have not been reported. Data on serum zinc and copper and cognitive impairment from individuals ≥ 60 years of age were obtained from the 2011-2014 NHANES. Serum zinc and copper concentrations were determined with inductively coupled plasma dynamic reaction cell mass spectrometry. Cognitive impairment was assessed with four cognitive tests: the Digit Symbol Substitution Test (DSST), the Animal Fluency (AF), the Consortium to Establish a Registry for Alzheimer's Disease Delayed Recall (CERAD-DR), and the Word Learning (CERAD-WL) tests. Compared with the lowest tertile of serum copper, the multivariate-adjusted odds ratios of scoring low on the AF were 0.86 (0.44-1.68) in tertile 2 and 0.46 (0.25-0.82) in tertile 3, and the inverse association was also found in women. No association was found between serum copper and the DSST, CERAD-DR, and CRAD-WL, respectively. Compared with the lowest tertile of serum zinc, the multivariate-adjusted odds ratios of scoring low on the DSST were 0.83 (0.37-1.90) in tertile 2 and 0.42 (0.22-0.80) in tertile 3, and the inverse association was also found in men. No association was found between serum zinc and the AF, CERAD-DR, and CRAD-WL, respectively. In conclusion, serum copper and zinc were associated with certain cognitive performance tests among older adults, and the causality deserves to be confirmed further.