Association between trace elements in serum from bipolar disorder and schizophrenia patients considering treatment effects

BackgroundImbalances in metal concentrations have been suggested to contribute to the pathophysiology of different brain disorders, such as bipolar disorder (BD) and schizophrenia (SCZ).ObjectivesThe aim of this exploratory study is to evaluate the association between the concentrations of macro/trace elements in serum from BD and SCZ patients considering the effects from different treatments.MethodsEleven subjects with SCZ, seven with BD treated with lithium (BDL) and eight subjects with BD treated with other medications except lithium (BDN) were recruited for the study, as well as eleven healthy controls (HC). Serum concentrations of eleven macro/trace elements (Se, Zn, Fe, K, Ca, Mg, P, Al, Cu, Mn, and Ni) were determined using inductively coupled plasma mass spectrometry (ICP-MS).ResultsSe and Zn concentrations were significantly lower for patients with SCZ and BD in comparison to HC by one-way ANOVA test. Moreover, serum concentrations for Fe were significantly higher (p < 0.05) in BDN (548 ± 92 μg L⁻¹) and SCZ (632 ± 279 μg L⁻¹) in comparison to HC (421 ± 121 μg L⁻¹). A significant negative correlation was reported between Se and Fe in BDL group (r = −0.935, p < 0.05). In addition, a significantly higher Cu/Zn ratio was determined in SCZ group against HC (ratio = 2.4, p = 0.028).ConclusionsThe obtained results suggest that the imbalance in Fe concentrations is an effect of BD treatment. Lithium is supposed to have an antagonist effect for Se in BDL patients. A negative correlation reported between Fe and BMI in SCZ group could be related to antipsychotic treatment and the Cu/Zn ratio reported could be considered as a suggesting parameter to relate oxidative stress to SCZ. Future studies including larger number of patients with SCZ and BD before and after treatment are necessary to confirm the investigative results presented herein.     

Profiling of serum and tissue high abundance acute-phase proteins of patients with epithelial and germ line ovarian carcinoma

Background  

Acute-phase response involves the simultaneous altered expression of serum proteins in association to inflammation, infection, injury or malignancy. Studies of the acute-phase response usually involve determination of the levels of individual acute-phase serum proteins. In the present study, the acute-phase response of patients with epithelial (EOCa) and germ-line (GOCa) ovarian carcinoma was investigated using the gel-based proteomic approach, a technique which allowed the simultaneous assessment of the levels of the acute-phase serum high abundance proteins. Data obtained were validated using ELISA and immunostaining of biopsy samples.     

Improved Detection of Common Variants Associated with Schizophrenia and Bipolar Disorder Using Pleiotropy-Informed Conditional False Discovery Rate

Several lines of evidence suggest that genome-wide association studies (GWAS) have the potential to explain more of the “missing heritability” of common complex phenotypes. However, reliable methods to identify a larger proportion of single nucleotide polymorphisms (SNPs) that impact disease risk are currently lacking. Here, we use a genetic pleiotropy-informed conditional false discovery rate (FDR) method on GWAS summary statistics data to identify new loci associated with schizophrenia (SCZ) and bipolar disorders (BD), two highly heritable disorders with significant missing heritability. Epidemiological and clinical evidence suggest similar disease characteristics and overlapping genes between SCZ and BD. Here, we computed conditional Q–Q curves of data from the Psychiatric Genome Consortium (SCZ; n = 9,379 cases and n = 7,736 controls; BD: n = 6,990 cases and n = 4,820 controls) to show enrichment of SNPs associated with SCZ as a function of association with BD and vice versa with a corresponding reduction in FDR. Applying the conditional FDR method, we identified 58 loci associated with SCZ and 35 loci associated with BD below the conditional FDR level of 0.05. Of these, 14 loci were associated with both SCZ and BD (conjunction FDR). Together, these findings show the feasibility of genetic pleiotropy-informed methods to improve gene discovery in SCZ and BD and indicate overlapping genetic mechanisms between these two disorders.     

Association of long non-coding RNAs NEAT1, and MALAT1 expression and pathogenesis of Behçet's disease among Egyptian patients

Behçet's disease (BD) is a chronic inflammatory disease. Immunological defects have been shown to play a significant role in the progression of BD. The serum levels of two long non-coding RNAs (lncRNAs), NEAT1 and MALAT1, were examined in patients with BD to identify their role in the disease pathogenesis. Both lncRNAs were mentioned as essential regulators of innate immune responses and have a crucial role in inflammatory diseases. Fifty patients with BD and a similar number of control individuals were involved in our study. At enrollment, data was collected from patients and controls, and the disease severity in active cases was determined using the Behçet's Disease Current Activity Form (BDCAF). Levels of the two studied biomarkers in the serum, NEAT1 and MALAT1, were investigated by quantitative RT-PCR (qRT-PCR). NEAT1 levels were significantly turned down in BD patients (fold changes = 0.77, p = 0.0001) and correlated negatively with the BDCAF (r = ?0.41; p = 0.003). On the other hand, the MALAT1 levels were significantly up-regulated in BD patients (fold changes = 2.65, p = 0.003). Serum levels of NEAT1 were significantly decreased in patients with active states than in stationary cases (0.387 versus 1.99, respectively; p = 0.01) and compared with controls (p = 0.001). Also, NEAT1 levels were significantly increased in patients with stationary states compared to controls (p = 0.03). There was a positive association between NEAT1 and MALAT1 levels among BD patients (r = 0.29, p = 0.04). Our findings demonstrate a possible role of NEAT1 and MALAT1 in the pathogenesis of BD.     

Specific subcellular changes in oxidative stress in prefrontal cortex from patients with bipolar disorder

Previously, we found decreased mitochondrial complex I subunits levels and increased protein oxidation and nitration in postmortem prefrontal cortex (PFC) from patients with bipolar disorder (BD) and schizophrenia (SCZ). The objectives of this study were to replicate our findings in an independent sample of subjects with BD, and to examine more specifically oxidative and nitrosative damage to mitochondrial and synaptosomal proteins and lipid peroxidation in myelin. We isolated mitochondria, synaptosomes, and myelin using a percoll gradient from postmortem PFC from patients with BD, SCZ, and healthy controls. Levels of mitochondrial complex I and III proteins, protein oxidation (carbonylation), and nitration (3‐nitrotyrosine) were assessed using immunobloting analysis. Lipid peroxidation [lipid hydroperoxides (LPH), 8‐isoprostane (8‐Iso), 4‐hydroxy‐2‐nonenal (4‐HNE)] were measured using colorimetric or ELISA assays. We found decreased complex I subunits levels in BD subjects compared with control (CTL), but no difference in complex III subunits. Carbonylation was increased in synaptosomes from BD group while 3‐nitrotyrosine was increased in mitochondria from BD and SCZ groups. 8‐Iso was found increased in the BD group while 4‐HNE was increased in both SCZ and BD when compared with controls with no differences in LPH. Our results suggest that in BD mitochondrial proteins are more susceptible to potentially reversible nitrosative damage while more longstanding oxidative damage occurs to synaptic proteins.

     

Peripheral profiling analysis for bipolar disorder reveals markers associated with reduced cell survival

Little is known about the molecular factors that are altered in remitting bipolar disorder (BD) patients. We carried out proteome profiling of peripheral blood mononuclear cells (PBMCs) and serum from BD patients who were not experiencing mania or major depression (euthymia) compared to matched healthy controls using liquid chromatography–mass spectrometry (LC‐MS^E) and Multi‐Analyte Profiling (Human Map^®) platforms. This resulted in the identification of approximately 60 differentially expressed molecules involved predominantly in cell death/survival pathways. In PBMCs, this was manifested in cytoskeletal and stress response‐associated proteins, whereas most serum analytes were associated with the inflammatory response. The predicted effect of serum analytes on physiological systems was tested by treating PBMCs with serum obtained from the same patients, resulting in reduced cellular survival. These preliminary results suggest that BD patients carry a peripheral fingerprint that has detrimental effects on cell function and that could be used to distinguish BD patients from healthy controls despite being in a remission phase. It is hoped that additional studies of BD patients in the manic and depressed stages could lead to the identification of a molecular fingerprint that could be used for predicting episodic switching and for guiding treatment strategies.     

Proteomic investigation of falciparum and vivax malaria for identification of surrogate protein markers

This study was conducted to analyze alterations in the human serum proteome as a consequence of infection by malaria parasites Plasmodium falciparum and P. vivax to obtain mechanistic insights about disease pathogenesis, host immune response, and identification of potential protein markers. Serum samples from patients diagnosed with falciparum malaria (FM) (n?=?20), vivax malaria (VM) (n?=?17) and healthy controls (HC) (n?=?20) were investigated using multiple proteomic techniques and results were validated by employing immunoassay-based approaches. Specificity of the identified malaria related serum markers was evaluated by means of analysis of leptospirosis as a febrile control (FC). Compared to HC, 30 and 31 differentially expressed and statistically significant (p<0.05) serum proteins were identified in FM and VM respectively, and almost half (46.2%) of these proteins were commonly modulated due to both of the plasmodial infections. 13 proteins were found to be differentially expressed in FM compared to VM. Functional pathway analysis involving the identified proteins revealed the modulation of different vital physiological pathways, including acute phase response signaling, chemokine and cytokine signaling, complement cascades and blood coagulation in malaria. A panel of identified proteins consists of six candidates; serum amyloid A, hemopexin, apolipoprotein E, haptoglobin, retinol-binding protein and apolipoprotein A-I was used to build statistical sample class prediction models. By employing PLS-DA and other classification methods the clinical phenotypic classes (FM, VM, FC and HC) were predicted with over 95% prediction accuracy. Individual performance of three classifier proteins; haptoglobin, apolipoprotein A-I and retinol-binding protein in diagnosis of malaria was analyzed using receiver operating characteristic (ROC) curves. The discrimination of FM, VM, FC and HC groups on the basis of differentially expressed serum proteins demonstrates the potential of this analytical approach for the detection of malaria as well as other human diseases.     

Genome-wide pathway analysis of a genome-wide association study on psoriasis and Behcet’s disease

The aim of this study was to identify candidate causal single nucleotide polymorphisms (SNPs) and candidate causal mechanisms of psoriasis and Behcets’s disease (BD) and to generate an SNP → gene → pathway hypothesis. A psoriasis genome-wide association study (GWAS) dataset that included 436,192 SNPs in 1,409 psoriasis cases and 1,436 controls of European descent and a BD GWAS dataset that contained 310,324 SNPs in 1,215 BD cases and 1,278 controls were used in this study. Identify candidate causal SNPs and pathways (ICSNPathway) analysis was applied to the GWAS datasets. ICSNPathway analysis identified 15 candidate causal SNPs and 28 candidate causal pathways. The top five candidate causal SNPs were rs1063478 (P = 1.45E−10), rs8084 (P = 2.20E−08), rs7192 (P = 5.18E−08), rs20541 (P = 5.30E−06), and rs1130838 (P = 5.65E−06), which with the exception of rs20541 [interleukin (IL)-13] are at human leukocyte antigen (HLA) loci. These candidate causal SNPs and pathways provided ten hypothetical biological mechanisms. The most strongly associated pathway concerned HLA. When HLA loci were excluded, ICSNPathway analysis provided one hypothetical biological mechanism. rs20541 (non_synonymous_coding) → IL-13 → dendritic cell involvement in the regulation of Th1 and Th2 development, and the GATA3 pathway. ICSNPathway analysis identified four candidate causal SNPs, eleven candidate causal pathways, and three hypothetical biological mechanisms. One of them was as follows: rs2072895 (non_synonymous_coding & splice-site) and rs2735059 (non_synonymous_coding) → HLA-F → type I diabetes mellitus, antigen processing and presentation, and autoimmune thyroid disease. The application of ICSNPathway analysis to GWAS dataset of psoriasis and BD resulted in the identification of candidate causal SNPs and candidate pathways that might contribute to psoriasis susceptibility.     

Association and linkage analysis of RGS4 polymorphisms with schizophrenia and bipolar disorder in Brazil

Linkage and association studies in five independently ascertained samples have suggested that polymorphisms of the regulator of G-protein signaling 4 (RGS4) may confer risk for schizophrenia (SCZ). Suggestive evidence for association with bipolar disorder (BD) has also been presented. However, the associated alleles and haplotypes have differed among the samples. Data from other independent samples may clarify the putative associations. Hence, we investigated an independent, ethnically diverse Brazilian population comprising patients with SCZ (n=271) or BD1 (n=306), who were contrasted with 576 community-based controls. Parents of 49 SCZ cases and 44 BD cases were available for transmission disequilibrium tests (TDTs). Four RGS4 single-nucleotide polymorphisms (SNPs) 1, 4, 7 and 18 putatively associated with SCZ were investigated. In the SCZ samples, significant case-control differences were not observed for individual SNPs or haplotypes, though the TDT suggested transmission distortion similar to that observed in the initial report. For the BD sample, case-control comparisons revealed no significant differences for individual SNPs, but an omnibus test suggested differences in the overall distribution of haplotypes bearing all four SNPs (SNP-EM Omnibus likelihood ratio test; P=0.003). The TDT revealed over-transmission of allele A at SNP7 (P=0.016), as well as haplotypes incorporating this allele. However, global tests incorporating all haplotypes yielded only suggestive trends for association (P=0.19). In conclusion, association with SCZ was not detected in the present analyses. The failure to detect an association may be related to inadequate power or to confounds related to ethnic admixture. Suggestive associations with BD detected here require further investigation in a larger sample.     

Resveratrol affects in vitro rumen fermentation,methane production and prokaryotic community composition in a time- and diet-specific manner

This study aimed to investigate the effect of resveratrol on methane production, rumen fermentation and microbial composition under high-concentrate (HC) and high-forage (HF) diets using the in vitro fermentation system. A total of 25 mg of resveratrol was supplemented into 300 mg of either HC or HF diet. Methane production, total volatile fatty acid (VFA) concentration, molar proportion of VFA, metabolites of resveratrol and prokaryotic community composition were measured after 12 and 24 h of in vitro fermentation. Resveratrol reduced methane production (ml per mg of dry matter degraded) by 41% and 60% under both HC and HF diets (P < 0.001), respectively, and this result could be associated with the lower abundance of Methanobrevibacter (P < 0.001) in response to resveratrol. The molar proportion of propionate was significantly higher in the resveratrol group only under the HC diet (P = 0.045). The relative abundance of 10 bacterial genera was affected by the three-way interaction of treatment, diet and time (P < 0.05). Resveratrol was partly converted to dihydroresveratrol after 24 h of fermentation, and its degradation could be associated with microbes belonging to the order Coriobacteriales. Our results suggest that multiple factors (e.g. diet and time) should be considered in animal experiments to test the effect of polyphenol or other plant extracts on rumen fermentation, methane emission and microbial composition.     

Association between two single nucleotide polymorphisms at corresponding microRNA and schizophrenia in a Chinese population

Numerous linkage and association studies have been performed to identify genetic predispositions to schizophrenic (SCZ) in different populations, but its genetic basis remains unclear. Some findings may provide a clue in understanding the association between abnormal immunity and SCZ. MicroRNA (miRNA) involves in regulating both schizophrenic and immunity as previous reported. And single nucleotide polymorphisms (SNPs) within miRNAs can change their characteristics, resulting in functional and/or phenotypic changes. So two SNPs (hsa-pre-mir-146a rs2910164 G>C and hsa-mir-499 rs3746444 T>C) at two miRNAs, were genotyped to demonstrate their association with susceptibility to SCZ. Polymorphisms were analyzed among 268 Chinese schizophrenic patients and 232 healthy controls by PCR-RFLP and validated by sequencing. No association was found between the two polymorphisms and SCZ either in cases or in controls. SCZ patients with family history showed significant increase of the G allele frequency of rs2910164 in comparison to those without (P = 0.018). The CC genotype frequency of rs3746444 was also higher in the patients having hallucinations than those without hallucinations (P = 0.012). In addition, patients carrying CC genotype of rs3746444 were more likely to be lack of motivation in comparison to normal controls (P = 0.042). Allele and genotype frequency of rs2910164 showed no significant difference between patients and normal subjects or between patients with and without clinical variables. Although patients carrying CC genotype of rs3746444 were found to be more likely to develop hallucination and individuals carrying C allele to lack motivation, there is lacking association between SCZ and the two SNPs at miRNAs, which may regulate immune response.     

A proteomic approach towards understanding crypoprotective action of Me2SO on the CHO cell proteome

Chinese hamster ovary (CHO) cell lines are the most widely used in vitro cells for research and production of recombinant proteins such as rhGH, tPA, and erythropoietin. We aimed to investigate changes in protein profiles after cryopreservation using 2D-DIGE MALDI-TOF MS and network pathway analysis. The proteome changes that occur in CHO cells between freshly prepared cells and cryopreserved cells with and without Me2SO were compared to determine the key proteins and pathways altered during recovery from cryopreservation. A total of 54 proteins were identified and successfully matched to 37 peptide mass fingerprints (PMF). 14 protein spots showed an increase while 23 showed decrease abundance in the Me2SO free group compared to the control. The proteins with increased abundance included vimentin, heat shock protein 60 kDa, mitochondrial, heat shock 70 kDa protein 9, protein disulfide-isomerase A3, voltage-dependent anion-selective channel protein 2. Those with a decrease in abundance were myotubularin, glutathione peroxidase, enolase, phospho glyceromutase, chloride intracellular channel protein 1. The main canonical functional pathway affected involved the unfolded protein response, aldosterone Signaling in Epithelial Cells, 14-3-3-mediated signaling. 2D-DIGE MALDI TOF mass spectrometry and network pathway analysis revealed the differential proteome expression of FreeStyle CHO cells after cryopreservation with and without 5% Me2SOto involve pathways related to post-translational modification, protein folding and cell death and survival (score = 56, 22 focus molecules). This study revealed, for the first time to our knowledge the proteins and their regulated pathways involved in the cryoprotective action of 5% Me2SO. The use of 5% Me2SO as a cryoprotectant maintained the CHO cell proteome in the cryopreserved cells, similar to that of fresh CHO cells.     

Comparative proteomics profiling of a phospholamban mutant mouse model of dilated cardiomyopathy reveals progressive intracellular stress responses

Defective mobilization of Ca2+ by cardiomyocytes can lead to cardiac insufficiency, but the causative mechanisms leading to congestive heart failure (HF) remain unclear. In the present study we performed exhaustive global proteomics surveys of cardiac ventricle isolated from a mouse model of cardiomyopathy overexpressing a phospholamban mutant, R9C (PLN-R9C), and exhibiting impaired Ca2+ handling and death at 24 weeks and compared them with normal control littermates. The relative expression patterns of 6190 high confidence proteins were monitored by shotgun tandem mass spectrometry at 8, 16, and 24 weeks of disease progression. Significant differential abundance of 593 proteins was detected. These proteins mapped to select biological pathways such as endoplasmic reticulum stress response, cytoskeletal remodeling, and apoptosis and included known biomarkers of HF (e.g. brain natriuretic peptide/atrial natriuretic factor and angiotensin-converting enzyme) and other indicators of presymptomatic functional impairment. These altered proteomic profiles were concordant with cognate mRNA patterns recorded in parallel using high density mRNA microarrays, and top candidates were validated by RT-PCR and Western blotting. Mapping of our highest ranked proteins against a human diseased explant and to available data sets indicated that many of these proteins could serve as markers of disease. Indeed we showed that several of these proteins are detectable in mouse and human plasma and display differential abundance in the plasma of diseased mice and affected patients. These results offer a systems-wide perspective of the dynamic maladaptions associated with impaired Ca2+ homeostasis that perturb myocyte function and ultimately converge to cause HF.     

Novel Effects of Hormonal Contraceptive Use on the Plasma Proteome

Background

Hormonal contraceptive (HC) use may increase cardiometabolic risk; however, the effect of HC on emerging cardiometabolic and other disease risk factors is not clear.

Objectives

To determine the association between HC use and plasma proteins involved in established and emerging disease risk pathways.

Method

Concentrations of 54 high-abundance plasma proteins were measured simultaneously by LC-MRM/MS in 783 women from the Toronto Nutrigenomics and Health Study. C-reactive protein (CRP) was measured separately. ANCOVA was used to test differences in protein concentrations between users and non-users, and among HC users depending on total hormone dose. Linear regression was used to test the association between duration (years) of HC use and plasma protein concentrations. Principal components analysis (PCA) was used to identify plasma proteomic profiles in users and non-users.

Results

After Bonferroni correction, 19 proteins involved in inflammation, innate immunity, coagulation and blood pressure regulation were significantly different between users and non-users (P<0.0009). These differences were replicated across three distinct ethnocultural groups. Traditional markers of glucose and lipid metabolism were also significantly higher among HC users. Neither hormone dose nor duration of use affected protein concentrations. PCA identified 4 distinct proteomic profiles in users and 3 in non-users.

Conclusion

HC use was associated with different concentrations of plasma proteins along various disease-related pathways, and these differences were present across different ethnicities. Aside from the known effect of HC on traditional biomarkers of cardiometabolic risk, HC use also affects numerous proteins that may be biomarkers of dysregulation in inflammation, coagulation and blood pressure.     

Gender and estrous cycle influences on behavioral and neurochemical alterations in adult rats neonatally administered ketamine

Neonatal N‐methyl‐D‐aspartate (NMDA) receptor blockade in rodents triggers schizophrenia (SCZ)‐like alterations during adult life. SCZ is influenced by gender in age of onset, premorbid functioning, and course. Estrogen, the hormone potentially driving the gender differences in SCZ, is known to present neuroprotective effects such as regulate oxidative pathways and the expression of brain‐derived neurotrophic factor (BDNF). Thus, the aim of this study was to verify if differences in gender and/or estrous cycle phase during adulthood would influence the development of behavioral and neurochemical alterations in animals neonatally administered ketamine. The results showed that ketamine‐treated male (KT‐male) and female‐in‐diestrus (KTF‐diestrus, the low estrogen phase) presented significant deficits in prepulse inhibition of the startle reflex and spatial working memory, two behavioral SCZ endophenotypes. On the contrary, female ketamine‐treated rats during proestrus (KTF‐proestrus, the high estradiol phase) had no behavioral alterations. This correlated with an oxidative imbalance in the hippocampus (HC) of both male and KTF‐diestrus female rats, that is, decreased levels of GSH and increased levels of lipid peroxidation and nitrite. Similarly, BDNF was decreased in the KTF‐diestrus rats while no alterations were observed in KTF‐proestrus and male animals. The changes in the HC were in contrast to those in the prefrontal cortex in which only increased levels of nitrite in all groups studied were observed. Thus, there is a gender difference in the adult rat HC in response to ketamine neonatal administration, which is based on the estrous cycle. This is discussed in relation to neuropsychiatric conditions and in particular SCZ. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 519–532, 2016     

The endogenous peptides of normal human serum extracted from the acetonitrile-insoluble precipitate using modified aqueous buffer with analysis by LC–ESI–Paul ion trap and Qq-TOF

Many peptides of biological or medicinal importance may be derived from proteolytic actions and are found at low concentrations in human blood fluids. Endogenous polypeptides from human serum were precipitated in acetonitrile and the precipitate was then selectively extracted with water modified by organic solvents and collected over C18 resin. Extraction of serum with C18 alone, and the acetonitrile supernatant or ultrafiltration collected over C18, served as controls. The samples were analyzed by SDS-PAGE, or C18 high pressure liquid chromatography with electrospray ionization using a Paul ion trap and Qq-TOF. Spectra were correlated without specifying an enzyme using the X!TANDEM or the Paragon algorithms. Multiple endogenous peptides from plasminogen, coagulation factors, collagens, serum amyloid, receptors, zinc finger/bromo peptide proteins, ryanodine receptor, calmodulin binding activator, erythroid differentiation factor, testes cancer antigen, extracellular matrix protein, myeloid/lymphoid leukemia 2 and many low abundance proteins were correlated by X!TANDEM with protein expect values of ～ E-16 or less. Proteins with binding sites for nucleic acids, phosphoinositides, and other cellular locations were also observed using the Qq-TOF and Paragon algorithm. Proteins with low expectation scores and overlapping peptides sequences were observed. The existence of these proteins in serum has been confirmed by tryptic digestion and LC–ESI–MS/MS. The presence of plasminogen, serum amyloid and zinc finger RNA binding proteins were confirmed by Western blot. There was agreement on the detection of endogenous peptides from low abundance proteins associated with the biology of cancer from the examination of the blood peptides by ion trap and Qq-TOF, tryptic digests of blood proteins, and Western blot.     

Serum copper and zinc levels in breast cancer: A meta-analysis

BackgroundMore and more studies have investigated the relationship between serum copper (Cu) and/or zinc (Zn) levels and breast cancer (BC). However, the results are inconsistent. It is unclear whether the serum Cu to Zn ratio (Cu/Zn) is associated with BC risk. Therefore, we evaluated serum Cu and Zn concentrations, and Cu/Zn in BC through meta-analysis.Materials and methodsStudies reporting serum Cu and/or Zn concentrations in BC patients and controls from 1991 to 2020 were identified from PubMed, CNKI, and Wanfang databases online. Based on a random effects model, summary standard mean differences (SMDs) and the corresponding 95 % confidence intervals (95 % CIs) were applied to compare the serum levels of Cu, Zn and Cu/Zn between BC patients and controls.ResultsThirty-six eligible studies involving 5747 female subjects were included. The present study illustrated that the BC patients had significantly higher serum Cu levels than healthy controls (HC) (SMD (95 % CI): 1.99(1.48, 2.49)) and patients with benign breast diseases (BD) (SMD (95 % CI): 0.99(0.38, 1.61)). However, Zn concentrations were statistically decreased in BC patients than HC (SMD (95 % CI): -1.20(-1.74, -0.66)) and BD (SMD (95 % CI): -1.13 (-1.73, -0.54)). Cu/Zn concentrations were remarkably increased in BC patients than HC (SMD (95 % CI): 2.75(1.79, 3.60)) and BD (SMD (95 % CI): 2.98(1.91, 4.05)) in some studies.ConclusionThe results show that elevated serum levels of Cu and Cu/Zn, as well as decreased Zn might be associated with increased risk of breast cancer. These three parameters have the potential to distinguish breast cancer from benign breast diseases.