Recent studies have investigated the circulating adipocyte fatty acid binding protein (FABP4), nesfatin-1, and osteocalcin (OC) concentrations in women diagnosed with gestational diabetes mellitus (GDM), but the findings prove to be conflicting. The objective of this research was to systematically assess the relationship of circulating levels of above adipokines with GDM.Pubmed, Embase, Web of Science, Cochrane library, OVID, and Scopus were performed to locate articles published up to January 31, 2020. Pooled standard mean differences (SMDs) with 95% confidence intervals (CIs), and 95% predictive intervals (PIs) were calculated by random-effects models to compare levels of adipokines between GDM cases and control groups. Cumulative and single-arm meta-analyses were also performed.Thirty-one studies comprising 4590 participants were included. No significant differences were found between GDM women and healthy controls in circulating nesfatin-1 levels . Nevertheless, circulating FABP4 and OC levels observed in GDM women outnumbered normal controls . The cumulative meta-analysis showed that the SMDs of circulating FABP4 and OC levels had stabilized between the two groups.Elevated circulating FABP4 and OC levels were observed in GDM women, but nesfatin-1 levels did not change, the PI of OC crossed the no-effect threshold. The results suggested that FABP4 is more suitable as a biomarker of GDM compared to OC in a future study, which is useful in identifying pregnant women who are likely to develop GDM and providing prompt management strategies. Based on the criteria of gestational diabetes mellitus (GDM) issued by the American Diabetes Association (ADA), GDM is diagnosed in the second or third trimester when no signs of overt diabetes are observed before pregnancy . With a The mechanism underlying the development of GDM remains to be illuminated ; howeverAdipocyte fatty acid binding protein 4 (FABP4), which is also termed as adipocyte FABP (A-FABP), falls into the category of the lipid-binding protein super-family with a high expression in adipocytes, which is crucial in glucose metabolism . FABP4 mNesfatin-1 consists of an 82-amino acid peptide originating from nucleobindin-2, predominantly expressed in specific areas of the hypothalamus, and is secreted in the peripheral tissues, such as adipocytes and human pancreatic beta-cells . Among tOsteocalcin (OC) has been defined as a bone-derived protein participating in bone metabolism , while rAlthough the potential roles of circulating FABP4, nesfatin-1, and OC in GDM have been the focus of research in recent decades, the results have been controversial due to different ethnicities, assay methods, and diagnostic/definition of GDM –21. TherThis study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement  and was Eligible studies were as follows: a) cross-sectional, case control, or clinical cohort design; b) provided detailed data with serum or plasma concentrations of FABP4, nesfatin-1, or OC in GDM patients and normal controls; and c) the articles were published in English or Chinese. In the case of duplicate studies in different databases, only one study was reserved referring to the author and title.Excluded points were as follows: a) review articles, case reports, letters, comments, and other non-original articles; b) research without precise information; and c) animal or cell culture (in vitro or ex vivo) studies.Data retrieval and quality assessment were performed in an dependent form by two authors (JS and CC). A spreadsheet database was collected to store suitable information, covering given names of the first authors, publication year, sample size of study, design type of research, diagnostic criteria of GDM, trimester of for adipokine assay, gestational body mass index (BMI), gestational age, and means and standard deviations of adipokine concentrations in the GDM and control groups.With respect to the quality assessment of the included studies, CC or cohort studies were evaluated by Newcastle-Ottawa quality assessment scale (NOS), consisting of 9 items; the quality assessment is available in Additional file The effect size of continuous data was calculated by the standard mean difference (SMD) because the included studies varied in the methodologies used when measuring concentrations of serum or plasma adipokines . Forest I2 tests (I2 = [(Q-df) / Q) × 100%], if an I2 exceeded 50%, indicating quite high statistical heterogeneity, then a random-effect model was selected to pool the findings; otherwise a fixed-effect model would be applied if the I2 was below 50%. The prediction interval (PI) was also used to interpret heterogeneity, reflecting the dispersion of the true effect sizes of the new studies. For calculation of the PI, the estimate size, M, the variance, SE, andτ2 are needed. The PI was calculated using the following formulae: LLpred = M - tα, k-2 × √(τ2 + SE2); and ULpred = M + tα, k-2 × √(τ2 + SE2). tα, k-2 is the (1-α/2) % percentile of the t distribution with a significance level, α, and k-2 degrees of freedom when k studies are included in the analysis [α was adopted at a significance level of 5% to calculate the 95% PI.Study heterogeneity, a problem arising during the analysis, was examined through the Cochrane Chi-square and analysis . In thisTo identify the source of heterogeneity, subgroup and meta-regression analyses were performed. Subgroup analyses classified by varieties of ethnicity, gestational age, gestational BMI, design type of study, ELISA kits, diagnostic criteria of GDM, and trimester of various adipokines measurement were performed. Subsequently, restricted maximum likelihood-based meta-regression analyses with random-effect model were conducted to evaluate the aforementioned potential factors accounting for heterogeneity.P value less than 0.05 was viewed to represent statistical significance (two-sided). In addition, a p-value < 0.10 was defined as significant publication bias for Egger’s regression test.The leave-one-out sensitivity analyses were used to evaluate the robustness of the characterizing result. Publication bias was detected through funnel plots, Egger tests, and the trim-and-fill method. All the analyses of the data processing were carried out by utilizing STATA software . Among the 806 articles retrieved, 31 were eligible; 14 were FABP4 studies , 26–36, The levels of FABP4, nesfatin-1, and OC were determined by enzyme linked immunosorbent assay (ELISA) in 27 studies, by electrochemiluminescence immunoassay (ECLIA) in three studies, and immunoradiography assays (IRMA) in one study. The NOS scores ranged from 6 to 8. The study characteristics are shown in Table P = 0.65; Fig. P < 0.01; Fig. P < 0.01; Fig. The overall pooled analysis indicated that no evident differences existed between GDM cases and healthy controls in regard to circulating nesfatin-1 levels , whereas the circulating FABP4 levels in the healthy controls were 16.04 ng/mL . The nesfatin-1 concentrations in the GDM cases were 4.56 ng/mL , whereas the levels of nesfatin-1 in the healthy controls were 5.02 ng/mL . The circulating OC levels in the GDM cases were 52.34 ng/mL , whereas the circulating OC levels in the healthy controls were 51.04 ng/mL .I2 = 96.90%, P < 0.001, Fig. I2 = 93.0%, P < 0.001; Fig. I2 = 89.4%, P < 0.001; Fig. Significant heterogeneity was found across the synthetic studies ; however, the predictive interval of the SMD for OC crossed the no-effect threshold. Thus, there was strong evidence to support that the FABP4 levels observed in GDM women outnumbered normal controls regarding the studied outcomes ; whereas, further analysis employing the trim-and-fill method indicated that this publication bias did not affect the estimates (SMD = 2.99, 95% CI, 2.28–3.69; Table Funnel plots manifested an asymmetric distribution of the studies involved Fig. a,c,e andIt was found that FABP4 concentrations observed in GDM cases surpassed those in healthy controls during the advanced stages of pregnancy. Available evidence showed that the serum FABP4 level was closely related to GDM. Zhang et al.  reportedWhy do adipocytes in women with GDM secrete superfluous levels of FABP4? Analyzing the results, the following factors were taken into consideration. First, FABP4 chiefly secreted by adipocytes, as well as released from the placenta in pregnant women . The serThe results of stratified analysis indicated that dissimilarities in the ELISA kits utilized in those diverse studies might have accounted for some degree of heterogeneity in the levels of FABP4. Multiple ELISA kits were available for the measurement of each adipokine, with different sensitivities and detection limits, leading to quite heterogenous results. Furthermore, a meta-regression for circulating FABP4 levels indicated that sample size also accounted for the high heterogeneity across studies.With respect to nesfatin-1, no remarkable differences could be observed in the levels of nesfatin-1 between GDM patients and healthy controls. Subgroup analysis indicated that nesfatin-1 displayed lower levels in Caucasian women suffering from GDM, but there were no differences in Asians, suggesting that geographic region may influence the serum nesfatin-1 levels. Indeed, people from various regions have diverse physical qualities, and genetic and environmental characteristics, and all of these may be linked to serum levels of nesfatin-1.In addition, in women diagnosed with GDM following the C&C and WHO criteria, circulating nesfatin-1 levels were lower than controls, but circulating nesfatin-1 levels were higher than controls when the pregnant women were diagnosed using IADPSG criteria. When women follow the ADA criteria, nesfatin-1 concentrations in GDM patients showed controversy. Three studies reported that the levels of circulating nesfatin-1 were lower than in controls, while four studies observed that nesfatin-1 levels outnumbered controls. Hence, it was thought that diagnostic standards of GDM may have impinged on the findings published previously. Similarly, subgroup analysis also found significant heterogeneity in nesfatin-1 concentrations in GDM that was correlated with the factor of ELISA kits.In the previous researches, the correlation between nesfatin-1 levels and BMI remained unclear , 37. TheBased on the pooled results, it is noted that both ucOC and tOC levels were clearly higher than controls. Unlike Martinez-Portilla et al. , the curThe stratified analysis suggested that Asian and Austrian patients, but not Australoid patients, had higher OC levels than healthy controls. In the subgroup ≤30 years of age, GDM patients had higher circulating OC than controls, indicating that a negative correlation exists between age and OC concentration in GDM. Moreover, FABP4 and OC levels were elevated in both second and third trimester, which indicated that occasion of measurement may not influence the relationship of FABP4 and OC concentrations with GDM. Consequently, it was assumed that GDM was described as a rise of FABP4 and OC, in line with findings supported by Ning et al.  and AbelFirst, this is the first registered meta-analysis on this area, the literature research was carried out systematically across multiple online databases, with a rigorous search strategy in detail. Second, numerous of studies were pooled from authoritative publications regarding FABP4, nesfatin-1, and OC concentrations with women in GDM, which improved the statistical power of this meta-analysis largely. Though high heterogeneity was observed, the cause of heterogeneity was analyzed deeply, such as subgroup, meta-regression, and random-model effects were conducted subsequently. In addition, the predictive interval of adipokines was calculated to provide support that the FABP4 is a biomarker of GDM because the value of no difference was excluded in the predictive interval .Third, cumulative meta-analyses proved that the association between FABP4, nesfatin-1, and OC concentrations was not changed in GDM cases and controls with the prolongation of time, indicating that the relationship has been stabilized. Furthermore, single arm meta-analyses were carried out to provide the precise point and interval estimation concentrations of FABP4 and OC in GDM cases and controls, which have not been clarified by former publications. Fourth, leave-one-out sensitivity analyses and trim-and-fill method demonstrated that the pooled results were reliable, suggesting that no publication bias was found.In the present study several limitations should be taken into consideration. First, high heterogeneity was found in this meta-analysis. Primarily, the heterogeneity between studies are likely due to measurement method, sample size, and different diagnostic criteria for GDM. In addition, circadian rhythms may substantially influence the observed outcomes of adipokine measurement. Oher factors such as physical activity, family history of GDM, smoking history, and alcohol consumption may also lead to the heterogeneity.Second, the majority of those studies adopted a case control study design. As a result, this may prove an association, but does not demonstrate a causal link between adipokines and GDM. In addition, the lack of included prospective cohort studies was also a defect of this research. Third, residual confounding bias was also a limitation of this study. The distribution of adipokines is often skewed, and a number of original studies have provided results as the median and interquartile range. Consequently, a non-symmetric distribution presented and the data were transformed into the mean and standard deviation, which may contribute to the residual confounding bias effect.In the future, a large-scale prospective multicentric cohort study shall be conducted to prove that the increased adipokines is one of the key actions that leads to the development of GDM. Moreover, the potential confounders, such as the concentrations of adipokines studied, ought to be tailored after standardized treatment. To improve predictive accuracy, the cut-off values and 95% CI should be assessed. Moreover, the diagnostic criteria of GDM should be unified to minimize heterogeneity. Furthermore, the levels of adipokines should be evaluated in conjunction with GDM criteria, and maternal demographic and clinical risk factors so as to establish a predictive model that can lend itself to the clinical practice.This meta-analysis explained the possible capacity that FABP4 and OC can play as potential biomarkers for the prediction and prompt detection of GDM. FABP4 and OC provide an effective screening and diagnostic tool for GDM because the screening and diagnostic standards for GDM are in discord. Hence, this finding is of clinical importance.Additional file 1. The search strategy in detail.Additional file 2. The NOS scale.


Background: Due to inconsistencies in epidemiological findings, there has been uncertainty regarding the association of lead compounds with brain tumors. We performed a meta-analysis of published case-control and cohort studies exploring lead compound exposure and brain tumor risk. (2) Methods: We searched PubMed, Embase®, and Cochrane to find eligible studies. Eighteen studies were selected for assessment of occupational exposure to lead compound and brain tumor. Pooled estimates of odds ratios (ORs) were obtained using random effects models. We assessed the differences through subgroup analysis according to tumor type, study design, measurements of exposure, and tumor outcome. Statistical tests for publication bias, heterogeneity, and sensitivity analysis were applied. (3) Results: Our systematic review and meta-analysis showed a not significant association with lead exposure and risk of benign and malignant brain tumors : 0.95–1.29). Including only malignant brain tumors, the risk of brain tumor was significantly increased . (4) Conclusions: This meta-analysis provides suggestive evidence for an association between lead compound exposure and brain tumor. In future studies, it will be necessary to identify the effect of lead compounds according to the types of brain tumor.(1)  Primary brain and central nervous system (CNS) tumors are uncommon but are among the most feared diseases. These tumors cause severe, complex symptoms and are usually incurable, seriously affecting the patient’s quality of life. The global age-standardized rate of brain and CNS cancers is 3.5 per 100,000 ; the global age-standardized mortality for primary malignant brain and CNS tumors is 3.2 for males and 2.3 for females per 100,000 ,5,6.Lead has been defined as a “probable human carcinogen” by the International Agency for Research on Cancer (IARC) and as a compound that is “reasonably anticipated” to be human carcinogen by the National Toxicology Programme (NTP), primarily based on lung and stomach cancers, but lead is also known to have some suggestive carcinogenic effects on kidney and brain ,6. A recLead is a well-known neurotoxin, especially in early childhood. Lead exposure to the developing nervous system can be more toxic than on a mature brain and can affect mental development and intelligence and have long-term consequences . In the There have been some cohort and case-control studies about the relationship between lead exposure and brain tumors. However, the results of these studies have been inconsistent. A study by Steenland et al. (2019) showed significant positive trends for malignant brain tumors with increasing lead exposure . On the To overcome the limitations of previous studies , we plan® [We followed the reporting standards for systematic reviews and meta-analyses of observational studies according to the MOOSE  protocol . Two tra® , and Coc®  databaseStudies meeting the following eligibility criteria were included: (1) the study was of a case-control study or cohort study design; (2) the study population was adult workers; (3) the study reported the effect size of brain tumors in lead-exposed workers; (4) excluded were reviews, essays, conference abstracts, letters, and commentaries; (5) when multiple publications from the same study population were identified, we included the most thorough and recent article describing the most up-to-date data. In the case of errata, the results of the study were replaced with modified values.Two authors (J.A. and M.Y.P.) independently extracted relevant data from the studies, including authors, year of publication, sex, study period, study population, definitions and measurements of occupational lead exposure, effect size, and confidence interval of the outcome results. All cases of inconsistencies in the extracted data were discussed and resolved with the rest of the author team. When there was missing or unclear information in the published article, we contacted the author via email and requested the information.Two authors (J.A. and M.Y.P.) independently conducted the risk of bias assessment of the included studies using the Newcastle–Ottawa scale . SimilarThe primary meta-analysis was conducted to assess the association between occupational lead exposure and brain tumor. To calculate the pooled odds ratios (ORs), if the studies were heterogeneous both clinically and statistically, we used the random effect model . RegardiWe conducted subgroup analyses to examine the impact of using research design (case-control study vs cohort), the exposure assessment method (job information vs blood lead (Pb) level), outcome , and reference category . Additionally, in cases where the results were given according to tumor type and sex, we also performed subgroup analysis.We calculated the effect size and conducted analyses based on Borenstein et al. . Pooled The risk of publication bias was determined by the funnel plot method and Begg’s test, which are appropriate when there are at least 10 studies included in a meta-analysis . Using twww.r-project.org), where the “meta” and “metaphor” packages were used to estimate the models and apply “trim and fill” and Begg’s test [All meta-analyses were performed in R software  of occupational lead exposure was 1.11 (95% CI: 0.95–1.29) . SensitiSubgroup analyses were carried out , and thePBegg = 0.8817), nor was there evidence of publication bias observed on visual inspection of funnel plot asymmetry across all of the studies  , with homogeneity ( = 0.67) . Sensiti = 0.67) .Similar to the meta-analysis on brain tumor, the subgroup results by research design and reference category did not show significant differences, while the subgroup results by exposure assessment method showed significant differences .Unlike the meta-analysis on brain tumor, the subgroup by cancer outcome also showed statistically significant differences. For brain cancer incidence, the effect size was larger than for brain cancer mortality .PBegg = 0.5699). No evidence for publication bias was observed on visual inspection of funnel plot asymmetry across all of the studies  by the IARC. However, the evidence that lead exposure is associated with brain tumor has been inconsistent. Our systematic review and meta-analysis showed a significant association with lead exposure and risk of malignant brain tumors. Including all benign and malignant brain tumors, the risk of brain tumor was slightly increased to a statistically non-significant level.Previous studies have suggested inconsistent results. Gerhardsson et al., Lam et al., and Wong et al. showed that CNS tumors were not significantly associated with lead exposure ,39,43. IIn these heterogeneous studies, some attempted to explain the results according to sex ,40,45,46In addition, studies of gene-environment interactions are getting more attention than in the past. The G177C polymorphism (rs1800435) of the d-amino-levulinic acid dehydratase (ALAD) gene has been reported as an effect modifier of lead exposure and was assessed in a study . HoweverRecent studies suggest that lead can cross the blood-brain barrier and concentrate in the brain parenchyma due to its ability to replace calcium ions . HistoriAfter absorption, lead is generally distributed to plasma, the nervous system, and soft tissues. In most studies, lead exposure resulted in micronucleus formation, chromosomal aberrations, and DNA damage in mammals .The mechanism by which lead causes brain tumor is unclear. It has been proposed that lead can facilitate the process of carcinogenesis by inhibiting DNA synthesis and repair and by interacting with binding proteins, hindering tumor suppressor proteins. Lead may also affect carcinogenesis through mechanisms involving oxidative damage, induction of apoptosis, and altered signaling pathways ,40,54,55In the subgroup analysis on exposure assessment method, significant differences were observed between the studies using blood lead level and the studies using job information. When we analyzed studies using blood lead level, significantly increased risks were identified in cases with all brain tumors as well as cases with malignant tumors only. When measuring lead exposure using job information, misclassification of subjects may occur, which can lead to underestimation of the risk. Moreover, there is potential bias from the patients’ subjective and selective recall of exposure. Therefore, we suggest that an objective measurement like blood lead level better reflects lead exposure, and this result also shows the association with brain tumors.In the subgroup analysis of malignant brain tumors, the risk for brain cancer incidence was significantly higher than that for brain cancer mortality. The cause of death may be classified as a complication of brain cancer, not brain cancer itself. This misclassification can also underestimate the risks .When performing subgroup analysis according to tumor subtypes, the risk of meningioma was slightly higher than that of glioma, although the difference between the two groups was not significant. The cause of this has not been studied yet. Although lead can cross the blood-brain barrier , this maWe conducted subgroup analyses according to various factors, including research design, exposure assessment method, and outcome. Moreover, by performing statistical tests of publication bias, we determined that there is no evidence of publication bias in this study, and sensitivity analysis did not modify the results. Our study also has limitations. The included studies were heterogeneous in their study design, measurements of exposure, and tumor outcomes. Nevertheless, we sought to identify differences through subgroup analysis according to tumor type, study design, measurements of exposure, and tumor outcome to overcome this limitation. The issues of including gray literature and non-English publications are other possible limitations in the literature search.In conclusion, this meta-analysis provides suggestive evidence for an association between lead compound exposure and brain tumor. We should pay attention to the risk of brain tumor associated with occupational lead exposure. Therefore, appropriate preventive strategies are needed for workers exposed to lead. Future studies evaluating the possible mechanisms of developing brain tumors and evaluating the risk according to brain tumor subtypes will be needed.


The relationship of MTHFR rs1801133 with hepatocellular carcinoma (HCC) has been extensively investigated. However, the findings were conflicting. Recently, more investigations have been conducted on the relationship of MTHFR rs1801133 with HCC. To obtain a more precise assessment on the effect of this non-synonymous variant to the development of HCC, a pooled-analysis was performed. This meta-analysis consisted of 19 independent case–control studies. By using the odds ratio (OR) combined with 95% confidence interval (CI), the relationship of MTHFR rs1801133 with HCC risk was determined. A total of 19 independent case–control studies were included. Finally, 6,102 HCC cases and 6,526 controls were recruited to examine the relationship of MTHFR rs1801133 with HCC risk. In recessive model (TT vs. CC/CT), the findings reached statistical significance . Subgroup analysis also found an association between MTHFR rs1801133 polymorphism and the decreased risk of HCC in hepatitis/virus related patients . Subgroup analyses indicated that extreme heterogeneity existed in Asian population, larger sample size investigation, hospital-based study and normal/healthy control subgroups. The shape of Begger’s seemed symmetrical. Egger’s linear regression test also confirmed these evaluations. Sensitivity analyses suggested that our findings were stable. In summary, our results highlight that MTHFR rs1801133 polymorphism decreases HCC susceptibility. The relationship warrants a further assessment.C677T , a non-synonymous variant of  In 2018, global cancer statistics estimated that liver malignancy was the fifth most frequent type of cancer incidence among men and the eleven most frequent type among women, about 596,574 and 244,506 new cases diagnosed worldwide, respectively  may contMethylenetetrahydrofolate reductase (MTHFR) locates in 1p36.3, which maps from 11785723 to 11806103 . MTHFR, a key enzyme, plays a vital effect in folate metabolism by the role of catalyzing the 5,10-methylenetetrahydrofolate  to 5-methyltetrahydrofolate (5-methylene-THF) irreversibly. In the conversion of homocysteine to methionine, 5-methylene-THF is a primary methyl donor . Using 2I metric and Q statistic, the heterogeneity among the eligible case–control studies was evaluated. If P < 0.10 or I2 > 50%, we defined that there was significant heterogeneity. Thus, the random-effect model was used  and source of control [hospital-based (HB) or population-based (PB) or NA]. We pooled seven case–control studies  and found an association between In some genetic models, heterogeneity was significant . SubgrouWe used Begger’s and Egger’s tests to identify the bias of publication among the included investigations. The shape of Begger’s test seemed symmetrical . Egger’sBy sequentially omitting an individual investigation, sensitivity analysis was carried out. This method is considered as a criterion for meta-analysis. The results indicated that the significance of the present study could not be altered by removing any case–control study , suggestMTHFR rs1801133 polymorphism may be associated with the development of HCC. However, the findings of the previous case–control studies were conflicting, with several investigations suggesting a potential relationship, whereas others did not support the correlation. In this investigation, to explore whether the MTHFR rs1801133 polymorphism was implicated in the etiology of HCC, we carried out a pooled-analysis of 19 eligible studies, which recruited 6,102 HCC cases and 6,526 controls. This meta-analysis indicated that the MTHFR rs1801133 polymorphism was a protective factor for the development of HCC in the overall comparison. Compared with the previous study, this pooled-analysis first confirmed the association of MTHFR rs1801133 polymorphism with a decreased risk of HCC.Accumulating investigations highlight that MTHFR rs1801133 polymorphism locates on 11796321 (NCBI Build 38) of Chromosome 1. Zhu and her/his colleagues first reported that MTHFR rs1801133 polymorphism might confer a risk to HCC [MTHFR gene might decrease the susceptibility of HCC [MTHFR gene could not alter the risk of HCC. Thus, the association of MTHFR rs1801133 polymorphism with the susceptibility of HCC was more conflicting. Here, we performed a pooled-analysis of nineteen eligible studies involving 6,102 HCC cases and 6,526 controls to explore the correlation of rs1801133 with the etiology of HCC. The results indicated that this SNP in MTHFR gene could be a protective factor for the occurrence of HCC. Two meta-analyses suggested that rs1801133 was not associated with HCC development [MTHFR rs1801133 polymorphism was associated with an increased risk of HCC [MTHFR rs1801133 polymorphism and decreased risk of HCC in hepatitis/virus related patients. Of late, in Asian population, some meta-analyses identified that MTHFR rs1801133 polymorphism decreased the risk of colorectal cancer [MTHFR rs1801133 C>T polymorphism  could promote the level of 5,10-methylene-THF for DNA synthesis, which might be protective to carcinogenesis. In the future, a functional study should be carried out to address how this Ala→Val substitution could decrease the risk of HCC.k to HCC . In addik to HCC . Howevery of HCC . And moselopment ,44. Othek of HCC . Comparek of HCC . It is wk of HCC , the merl cancer ,50. Somel cancer ,52 suggeHeterogeneity was identified in the overall comparison. In the present study, we conducted subgroup analyses to explore the major source among the eligible studies. Subgroup analysis suggested that major heterogeneity might be due to different populations, sample size, and characteristics of controls.Some potential limitations should be addressed in this pooled-analysis. First, only published investigations were eligible in our study. Thus, the number of included case–control studies might be inadequate. Second, for lacking of sufficient data, only crude ORs and CIs were calculated. Third, the controls in some of the case–control studies were hepatitis or virus related patients. Fourth, a recent investigation contained some subgroups, we treated them as independent case–control studies. However, in this literature, the same HCC group was used in different stratified analysis. Finally, our study did not focus on the gene–gene and gene–environment interactions.MTHFR rs1801133 polymorphism is a protective factor for the occurrence of HCC, especially in hepatitis/virus related patients. The relationship of MTHFR rs1801133 polymorphism with HCC risk warrants a further determination.In summary, the present pooled-analysis highlights that


Objectives: To evaluate the effects of the single-nucleotide polymorphism (SNP) rs1800795 in interieukin-6 (IL-6) gene on diabetic microvascular complications of Type 2 diabetes mellitus (T2DM), using statistical meta-analysis.Methods: Literature pertaining to the relationship between the SNP rs1800795 and microvascular complications of T2DM including diabetic retinopathy, diabetic nephropathy, diabetic neuropathy and foot disease was retrieved from PubMed, Web of Science Knowledge and SinoMed databases. Original information was analyzed using Stata 12.0, including meta-analysis statistics, test for heterogeneity, evaluation of publication bias and sensitivity. Subgroup analysis was conducted to assess the effect of specific factors on the corresponding results.P=0.767), an allelic genetic model , a heterozygote genetic model , a dominant genetic model , and a recessive genetic model  were included respectively. In the subgroup analysis by types of diabetic microvascular complications, we found no correlation between the SNP rs1000795 polymorphism and complications of T2DM in either the homozygote genetic model or the allelic genetic model (P<0.05).Results: In total, 14 eligible articles were obtained. The SNP rs1800795 in IL-6 gene is not correlated with risk of microvascular complications in T2DM. Among the original literature, a genetic model (OR = 1.071, 95% CI: 0.681–1.685, Conclusion: Our results demonstrate that rs1800795 polymorphism in IL-6 gene is not correlated with the susceptibility of microvascular complications of T2DM. Diabetes mellitus (DM) is a chronic metabolic disease. Over 382 million people worldwide have DM, the prevalence of Type 2 diabetes mellitus (T2DM) in children and adolescents is on the rising around the world, in parallel with the increase in the rate of obesity . DM mighThe single-nucleotide polymorphism (SNP) of IL-6 gene has attracted more and more attention recently. Significant sequence variation of IL-6 174G/C gene is widely distributed at varying serum IL-6 levels in genetically susceptible individuals , increasWe intended to summarize data on the correlation between SNP rs1800795 (174G/C) in IL-6 gene and the risk of microvascular complications including diabetic retinopathy, nephropathy, neuropathy, or foot disease in T2DM. In this field, we conducted a literature search in PubMed, Web of Science Knowledge and SinoMed databases for related studies from January 1, 2000 to December 1, 2019. The search terms used are: (1) ‘SNP’ OR ‘single gene polymorphism’ OR ‘mutation’; (2) ‘rs1800795’ OR ‘Interieukin-6’ OR ‘IL-6 174G/C’; (3) ‘type 2 diabetes’ OR ‘type 2 diabetes mellitus’ OR ‘T2DM’; (4) ‘diabetic retinopathy’ OR ‘diabetic nephropathy’ OR ‘diabetic neuropathy’ OR ‘diabetic foot disease’ OR ‘diabetic complications’ OR ‘diabetic microvascular complications’. We made an effort to contact authors if some relevant data were needed. We have also done a bibliographic search for any other relevant studies.http://prisma-statement.org/PRISMAStatement/Checklist).This meta-analysis was undertaken in accordance with PRISMA guidelines  single-nucleotide polymorphism rs1800795 in IL-6 gene 174G/C position was assessed; (2) the final outcome was T2DM with or without microvascular complications; (3) the number of different genotypes and risk of complications respectively were provided; (4) clear presentation of units for data; (5) studies were obtained by means of standard formula.Two investigators extracted the data independently, discrepancies were resolved by discussion.Overall, 14 independent original articles (from 2000 onwards) including 4934 subjects and 9868 genetic locus were retrieved, based on relevant data on the effects of IL-6 gene promoter polymorphism (G/C) at position-174 variations (SNP rs1800795) on frequencies in complications of T2DM.P values <0.05 were considered statistically significant. The chi-square test was utilized to assess the offset of frequencies of IL-6 polymorphisms from the expected values under the Hardy–Weinberg equilibrium (HWE) among T2DM patients with or without microvascular complications. Odds ratio (OR) was used as measure correlation between SNP rs1800795 in IL-6 gene 174G/C and risk of diabetic complications. The association between rs1800795 and the risk of diabetic complications was measured by the pooled OR with its corresponding 95% CI. We assessed the association between rs1800795 polymorphism and the susceptibility to complications of T2DM. The genetic models employed were exhibited as follows: the allelic genetic model (G vs. C), the homozygote genetic model (GG vs. CC), the heterozygote genetic model (GG vs. GC), the dominant genetic model (CC+CG vs. GG), and the recessive genetic model (CC vs. GG+GC) [Meta-analysis and statistical analyses were conducted using the statistical software Stata 12.2. Q test and I-squared index. If I-squared index was >50% and P value was <0.1, the study would be considered as significant heterogeneity, and in consequence the random-effected model would be used; On the contrary, if I-squared index was proved to be <50% with the P value of >0.1, the study would be considered as not of significant heterogeneity, and the fixed-effects model would be selected. To assess the impact of possible factors on pooled effect size and heterogeneity, subgroup analyses were performed.The statistical heterogeneity of the studies was calculated using the chi-square-based P<0.05 was considered as statistically significant. Sensitivity analysis was conducted to test the influence of methodological quality by removing any low-quality studies from the meta-analysis. It was performed to determine the effect of each individual research on the pooled outcomes. As a measurement tool for investigation the quality of studies, ‘leave one out’ was used to evaluate the influence of the respective data on the integrated data by excluding one single data set from the pooled analyses one at a time.Publication bias was assessed using the funnel plot method and Begg’s test, the level of Study quality was assessed using Newcastle–Ottawa Scale (NOS) ranging from a low of 0 to a high of 10 with the higher score representing higher quality. The cut-off values of NOS < or =5 suggested low-quality study while NOS >6 suggested high-quality study.Our study was intended to evaluate the relationship between the single-nucleotide polymorphism rs1800795 in IL-6 gene 174G/C and the susceptibility of diabetic microvascular complications in T2DM.We identified 20 databases from 14 studies with diabetic microvascular complications of T2DM including diabetic retinopathy, diabetic nephropathy, diabetic foot disease, and diabetic neuropathy that met the inclusion criteria of this meta-analysis . Figure P=0.767), an allelic genetic model , a heterozygote genetic model , a dominant genetic model , and a recessive genetic model , respectively , both the homozygote genetic model and the allelic genetic model, with a homozygote genetic model  and an allelic genetic model  in diabetic retinopathy, a homozygote genetic model  and an allelic genetic model  in diabetic nephropathy, a homozygote genetic model  and an allelic genetic model  in diabetic foot disease, and a homozygote genetic model  and an allelic genetic model  in diabetic neuropathy, respectively   . We usedP>0.1). There were no asymmetries in Funnel’s plots in the current analyses  has been established to play the role of inflammatory cytokine in the pathogenesis of T2DM. Dysregulation of IL-6 signaling and IL-6 itself has been implicated in the etiology of several autoimmune and inflammatory diseases including T2DM . The eleSNP rs1800795 -174G/C) of IL-6 gene in T2DM was first reported in 2003 showing that GG phenotype was a genetic determination of inflammation in the development of T2DM G/C of IL. In ordeP=0.767), an allelic genetic model , a heterozygote model , a dominant genetic model , and a recessive model , respectively. In the subgroup analysis by types of diabetic microvascular complications, we also found that rs1000795 polymorphism was independent of the susceptibility of the four complications mentioned above in T2DM patients (P>0.05), in both the homozygote genetic model and allelic genetic model. Our results were consistent with most other studies. The study of Rudofsky et al. [P=0.039), the author suggested that the -174 G>C polymorphism of the IL-6 gene might be an independent risk factor for diabetic nephropathy in Turkish T2DM. The limitation of the present study was that the sample was too small. The study of Chen et al. [Our results showed that there was no correlation between risk of diabetic microvascular complications in T2DM and a homozygote genetic model (OR = 1.071, 95%CI: 0.681–1.685, y et al.  did not y et al. . The stuy et al.  showed ty et al.  evaluaten et al.  also clan et al.  concluden et al. ,26. It iNumerous studies have provided clear evidence that IL-6 C-174G single-nucleotide polymorphism was a risk factor in Type 2 diabetes and contributed to higher serum interleukin-6 level among the participants ,28. We sIn summary, comprehensive meta-analysis was performed and revealed no correlation between the SNP rs1000795 in IL-6 gene and diabetic microvascular complications in patients with T2DM. The results obtained in our study suggested that screening SNP rs1800795 may be helpless in identifying the high risk of developing diabetic microvascular complications in patients with T2DM. However, our findings still need to be confirmed by further large sample, multicenter and high-quality studies to provide theoretical basis. Our conclusion requires updated meta-analysis with a large sample size.Our review has some limitations that should be mentioned. First, the methodological quality of the published literature should be noted, as only 12 of the 14 studies were categorized as high-quality ones . Second,


Bioscience Reports journal showed that growth differentiation factor 5 (GDF5) rs143383 genetic polymorphism increases the susceptibility of knee osteoarthritis (KOA), but previous studies’ results have debates about available data. Considering the availability of more recent data, we focus on clarifying the relationship of KOA and GDF5 rs143383 genetic polymorphism by a meta-analysis of case-control trial data.A few months ago, the The eligible studies from the time of database established to Oct. 2019 were collected from PubMed, Springer, Cochrane library, Web of Science, China National Knowledge Infrastructure (CNKI), and Wan Fang library. Odds ratios (OR) and 95% confidence intervals (CI) were used to estimate the association between these polymorphisms and KOA risk. The meta-analysis was completed by STATA 18.0 software.A total of 196 studies were collected, 16 of them included in final meta-analysis . There was significant association between GDF5 rs143383 polymorphism and KOA in all genetic models (for Allele model (C versus T): OR = 0.84 (95% CI = 0.76–0.91); dominate model (CC+CT versus TT): OR = 0.80 (95% CI = 0.72–0.90); recessive model (CC versus CT+TT): OR = 0.79 (95% CI = 0.68–0.92); heterozygote model (CT versus CC+TT): OR = 0.89 (95% CI = 0.80–0.97); homozygous model (CC versus TT): OR = 0.71 (95% CI = 0.60–0.85)). In the subgroup analysis, we obtained the results that there is no significance among Asians.GDF5 rs143383 genetic polymorphism increases the risk of KOA among Caucasians; CC genotype and C allele are protective factors for the susceptibility of KOA among Caucasians. Osteoarthritis (OA) is a chronic degenerative disease and is a very important factor for disability in worldwide –3. OA inBioscience Reports [Growth differentiation factor 5 (GDF5) rs143383 genetic polymorphisms is the association of the susceptibility of knee osteoarthritis reported in  Reports . GDF5 is Reports .http://www.crd.york.ac.uk/prospero/).Although the association of the risk of knee osteoarthritis and GDF5 rs143383 genetic polymorphisms has been described in several meta-analyses , severalThe eligible studies from the time of database established to Oct. 2019 were collected from PubMed, Springer, Cochrane library, Web of Science, China National Knowledge Infrastructure (CNKI), and Wan Fang. Two independent authors extracted the data and assessed case-control trial quality.In the meta-analysis, we made use of the Newcastle–Ottawa Scale in Epidemiology (NOS) group . The PubTwo researchers (Lei Peng and Jiping Lu) conducted eligible studies based on the above inclusion criteria and collected information on each eligible study according to the inclusion criteria. The following items were extracted: first author, year of publication, country, population, genotype distribution, Hardy–Weinberg equilibrium (HWE), case, and control size. To avoid the wrong data, the researchers will examine the collected data and make a conclusion through discussion. The quality of studies was evaluated by two independent investigators (Peng and Lu) based on the Newcastle–Ottawa Scale (NOS) for case-control studies . The stuχ2 test estimates deviation from HWE in the control group according to genotype distributions. Crude OR with their 95% CI was estimated and used to assess the strength of association between GDF5 rs143383 polymorphism and KOA. The pooled OR was calculated respectively for allelic effect of C versus T, homozygote comparison of CC versus TT, heterozygote comparison of CT versus CC+TT, recessive model (CC versus TT+CT) and dominant model (CC+CT versus TT). The significance of the pooled OR was determined by the Z-test (P ≤ 0.05). Q statistics (P < 0.10) indicated the evidence of heterogeneity was used to assess heterogeneity between studies. When significant heterogeneity was achieved (P < 0.10), the effect size of the study was combined with the random effect model; otherwise, the fixed effect model was used. Subgroup analysis was performed according to population, and sensitivity analysis was performed to determine the impact of individual studies on the aggregated results and to test the reliability of the results. The potential publishing bias was estimated by Begg’s funnel plot and Egger regression test. All cases were analyzed by STATA 18.0 software . The P values were bilateral. This study followed the PRISMA standard.Pearson’s Sixteen articles , 15–28, By comprehensive analysis, there is significant relationship between knee osteoarthritis and GDF5 rs143383 polymorphisms. Allele model (C versus T): OR = 0.84 (95% CI = 0.76–0.92); dominate model (CC+CT versus TT): OR = 0.80 (95% CI = 0.72–0.90); recessive model (CC versus CT+TT): OR = 0.79 (95% CI = 0.68–0.92); heterozygote model (CT versus CC+TT): OR = 0.88 (95% CI = 0.80–0.96); homozygous model (CC versus TT): OR = 0.88 (95% CI = 0.80–0.97). Overall analyses are showed in Table P < 0.05; CC+CT vs. TT: OR = 0.71–0.92, P < 0.05; CC vs. CT+TT: OR = 0.72–0.90, P < 0.05; CT vs. CC+TT: OR = 0.79–1.02, P < 0.05; CC vs. TT: OR = 0.80–1.02, P < 0.05). But in Asians, there is no significant correlation between knee osteoarthritis and GDF5 rs143383 polymorphisms among all genetic model. We did not carry on the subgroup analysis by sex, because previous meta-analysis study conclude sex factor is not significant between GDF5 rs143383 polymorphism and the risk of knee osteoarthritis. A more obvious significant association was exploited for CC vs. TT+CT  and C vs. T  in comparison with other models in Caucasians . Figure The stableness of the results is estimated by sensitivity analysis. The sensitivity analysis procedure is a single study deleted from the meta-analysis every time, but the results remain unchanged Fig. S. The BegIn the research article, we firstly found that GDF5 rs143383 polymorphisms affect the risk of knee osteoarthritis in Caucasian but not in Asian, including detailed data from 16 studies in 7997 cases and 12,684 controls. The final results are new observations in previous studies. When carrying on the funnel plot to analyze some bias, the results still are very stable and reliable.GDF5 is a member of bone morphogenetic proteins (BMP) family, which is located on chromosome 20q11.2 and spans 21.43 kb, from 34,042,573 to 34,021,146 and can form the earliest markers of joint morphology. BMP is an indispensable signal pathway molecule or protein in most kinds of bones –37. TherP < 0.001) and Asian populations  [P < 0.001) [On the one hand, previous literatures have said that GDF5 rs143383 polymorphisms C allele is a protective factor for the susceptibility of knee osteoarthritis among Caucasian populations  . On the Although previous meta-analysis literatures thought that high-expressed GDF5 rs143383(C/T) can reduce the risk of knee osteoarthritis, their limitations still remain. Firstly, Pan et al.’s meta-analysis has some shortcomings, including unmatching HWE studies in their meta-analysis . AlthougTo sum it up, our final results, paralleling to previous results, are more reliable by comprehensive collection and assessment of quality. Furthermore, the association between osteoarthritis and GDF5 is more clear than previous studies.Our article has found sufficient pieces of evidences to conclude that the risk of Caucasian’s knee osteoarthritis is the association with GDF5 rs143383 polymorphisms. To our knowledge, this result is the first discovery in which the risk of Asian knee osteoarthritis is not associated with GDF5 rs143383 polymorphisms by meta-analysis. The finding may indicate that GDF5 rs143383 polymorphism mutations are population specific. In the future, the potential study should increase more samples about knee osteoarthritis and more gene variants to precisely and comprehensively clarify the relationship between knee osteoarthritis and gene variants.Additional file 1: Fig. S1. Sensitivity analysis of the pooled ORs and 95% CI for the overall analysis.


P > 0.05). In conclusion, this meta-analysis demonstrated the effects of MetS on almost all the semen parameters and part of the circulating sex hormones, and MetS tended to be a risk factor for male infertility. Further larger-scale prospective designed studies were needed to confirm our findings.Previous studies were controversial in the effects of metabolic syndrome (MetS) on semen quality and circulating sex hormones, and thus we conducted a systematic review and meta-analysis to clarify the association. A systematic search was conducted in public databases to identify all relevant studies, and study-specific standardized mean differences (SMD) and 95% confidence intervals (CI) were pooled using a random-effects model. Finally, 11 studies were identified with a total of 1,731 MetS cases and 11,740 controls. Compared with the controls, MetS cases had a statistically significant decrease of sperm total count , sperm concentration , sperm normal morphology , sperm progressive motility , sperm vitality , circulating follicle-stimulating hormone , testosterone , and inhibin B , and a statistically significant increase of sperm DNA fragmentation  and mitochondrial membrane potential . No significant difference was found in semen volume, sperm total motility, circulating luteinizing hormone (LH), estradiol, prolactin and anti-Müllerian hormone (AMH) ( Metabolic syndrome (MetS) is a complex of clinical conditions characterized by abdominal obesity, dyslipidemia, hypertension and insulin resistance , 2. DespAs a collection of these features, MetS was thought to be involved in the pathogenesis of male infertility. The meta-analysis by Brand et al.  indicateThe databases of PubMed and Embase were searched for relevant studies published up to March 1st, 2020, using the key words: (“metabolic syndrome” OR “syndrome X” OR “insulin resistance syndrome” OR “metabolic X syndrome” OR “dysmetabolic syndrome” OR “reaven syndrome” OR “metabolic cardiovascular syndrome”) AND . We also reviewed the references of related studies and reviews for undetected studies. This study was approved by the ethics committee of Linyi People's Hospital (No. 2020006).Two authors (LZ and AP) reviewed the studies independently. The inclusion criteria were as follows: (i) focused on MetS cases and controls; (ii) any measurement of semen volume, total sperm count, sperm concentration, sperm normal morphology, sperm total motility, sperm progressive motility, sperm vitality, sperm DNA fragmentation or mitochondrial membrane potential (MMP); (iii) measurement levels were presented as mean or median with standard error (SD), 95% confidence interval (95% CI), range or inter-quartile range (IQR). The exclusion criteria were as follows: abstracts without full texts, reviews, case reports, animal studies, and studies in languages other than English.http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp).Two authors (LZ and AP) extracted the data by a standardized collection form. All differences were resolved by discussion. In each study, the following information was extracted: first author, publication year, study area, study population, diagnosis criteria of MetS, semen or sex hormone parameters, sample size per group, and the testing values of semen parameters and circulating sex hormones. For studies from the same area, we also reviewed the medical center and study time to exclude duplicate publications. The Newcastle-Ottawa Scale (NOS) was used to assess the methodological quality of included studies , sperm concentration , sperm normal morphology , sperm progressive motility , and sperm vitality   and sperm total motility in MetS cases . Furthermore, MetS cases had a statistically significant increase of sperm DNA fragmentation  and MMP .Compared with the controls, MetS cases had a statistically significant decrease of sperm total count  –4. ThereI2 = 97%, n = 6), testosterone , and inhibin B   and anti-Müllerian hormone (AMH) , and a weak increase of estradiol  in MetS cases.Compared with the controls, MetS cases had a statistically significant decrease of follicle-stimulating hormone (FSH)  , 6. TherSensitivity analysis showed that the results were robust in semen parameters. In the meta-analysis of circulating FSH, the result showed no statistical difference when omitting the study by Saikia et al.  Table S. In the Subgroup analyses were conducted on the study cohort, ethnicity and study area. Compared with the infertile cohort, MetS cases in the fertile cohort had a significantly higher incidence of a decrease in sperm total count and sperm progressive motility, FSH, testosterone and estradiol, and an increase in LH . ComparaCompared with the Caucasian cohort or the cohort from developed area, MetS cases from the non-Caucasian cohort or the cohort from developing area had a significantly higher incidence of the decrease in sperm concentration, sperm total motility, sperm progressive motility, FSH, and inhibin B . MetS teP = 0.122), sperm total count (P = 0.200), sperm concentration (P = 0.185), sperm normal morphology (P = 0.400), sperm total motility (P = 0.659), sperm progressive motility (P = 0.120), circulating FSH (P = 0.199), testosterone (P = 0.215), or LH (P = 0.293)  –S3.According to the World Health Organization (WHO), infertility had an incidence of 8~12% in childbearing couples worldwide, among which male infertility accounted for 40~50% . Along wThe mechanism has been not clarified, and currently many researchers indicate a central role of insulin resistance in the pathogenesis. Abnormal blood glucose could cause the impairment of multiple organs, including erectile and ejaculation disorders. In the meta-analysis by Pergialiotis et al.  the infeIn this meta-analysis, we found a decrease of sperm total count, sperm concentration, sperm normal morphology, sperm progressive motility, and sperm vitality and an increase of sperm DNA fragmentation and MMP, while no significant difference was found in semen volume and sperm total motility. Generally, MetS had a negative impact on the semen quality, just like diabetes and obesity , 36. On Sensitivity analysis indicated a relative stability for semen parameters, while FSH and testosterone turned statistically insignificant when omitting certain studies. MetS seemed to have more significant and stable effects on semen quality than sex hormones, which was consistent with our previous analysis. Second, for almost all the outcomes, the exclusion of a single specific study dramatically decreased the effect size, especially like Ehala-Aleksejev and Punab  (FM) in The subgroup analyses suggested more effects of MetS on the individuals from the fertile cohort, non-Caucasian cohort, or the cohort from developing area. This might contribute to less impact of MetS on the impaired reproductivity, and MetS had a stronger influence on the reproductivity of healthy individuals. Moreover, this was also consistent with the high incidence of male infertility in the Asian cohort and developing countries .Although this was the first meta-analysis to evaluate the effects of MetS on both semen quality and circulating sex hormones in men, several limitations in this study should be also considered. First, not all included studies had a large sample size. Second, all included studies were cross-sectionally designed, and prospective studies were needed to confirm our findings. Third, the protocol of our meta-analysis was not registered in the PROSPERO database. Fourth, obvious heterogeneity between studies was observed, although we conducted both sensitivity analysis and subgroup analysis to evaluate the stability of the results. We expected large-scale prospective designed studies in the future to overcome these limitations.In conclusion, this meta-analysis demonstrated the effects of MetS on almost all the semen parameters and part of the circulating sex hormones, and MetS tended to be a risk factor for male infertility. Further larger-scale prospective designed studies were needed to confirm our findings.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.LZ and AP conceived the manuscript, performed literature search, drafted and wrote the manuscript, contributed to manuscript revision during peer review process, and contributed to manuscript revision, read, and approved the submitted version. AP critically revised the first original draft and any other version of the manuscript before and after peer review process, and provided significant content contribution and English language support.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Backgrounds: Some studies have reported association of circulating fibrinogen with the risk of chronic obstructive pulmonary disease (COPD), and the results are conflicting. To yield more information, we aimed to test the hypothesis that circulating fibrinogen is a promising biomarker for COPD by a meta-analysis.Methods: Data extraction and quality assessment were independently completed by two authors. Effect-size estimates are expressed as weighted mean difference (WMD) with 95% confidence interval (95% CI).Results: Forty-five articles involving 5586/18604 COPD patients/controls were incorporated. Overall analyses revealed significantly higher concentrations of circulating fibrinogen in COPD patients than in controls . Subgroup analyses by COPD course showed that the degree of increased circulating fibrinogen in patients with acute exacerbations of COPD (AECOPD) relative to controls  tripled when compared in patients with stable COPD . By COPD severity, there was a graded increase in fibrinogen with the increased severity of COPD relative to controls  I, II, III, and IV: WMD: 13.91, 29.19, 56.81, and 197.42 mg/dl; 95% CI: 7.70–20.11, 17.43–40.94, 39.20–74.41, and −7.88 to 402.73, respectively). There was a low probability of publication bias.Conclusion: Our findings indicate a graded, concentration-dependent, significant relation between higher circulating fibrinogen and more severity of COPD. Chronic obstructive pulmonary disease (COPD) is an escalating public health problem that affected more than 174.5 million adults in 2015 worldwide . Given tIt is widely recognized that systemic inflammation is an important clinical feature of COPD ,6. Much To fill this gap in our knowledge and generate more information for future studies, we prepared a comprehensive meta-analysis of published observational studies to test the hypothesis that circulating fibrinogen is a promising biomarker for COPD, and if this hypothesis is confirmed, we further examined whether circulating fibrinogen is associated with the severity of COPD in a concentration-dependent fashion.We conducted this meta-analysis of observational studies in compliance with the requirements of the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement . The PRIA systematic electronic search of PubMed, EMBASE (Excerpt Medica Database), Cochrane Central Register of Controlled Trials, and Web of Science was conducted from inception to 25 June 2019 for publications that assessed the relationship between circulating fibrinogen and COPD. The key terms used for search included ‘fibrinogen’, ‘FIB’, ‘chronic obstructive pulmonary disease’, and ‘COPD’.Literature search was restricted to articles published in the English language from peer-reviewed journals. Additional articles were obtained via manually scanning the reference lists of relevant reviews and major original articles. Literature search was independently completed by two authors (B.Z. and W.N.), and divergences were resolved by discussion until a consensus was reached.Articles were included if they were observational case–control studies, and if they had mean or median values of circulating fibrinogen concentration in both COPD patients and controls, along with standard deviation or standard error or interquartile range or whole range. Articles were excluded if they lacked control groups, or if they published in form of reviews, case reports, case series, conference abstracts, letter to the editor, comments, or editorials.Two authors (B.Z. and W.N.) independently screened the titles and abstracts of all retrieved articles, and if necessary the full texts to assess their eligibility. If more than one article was published from the same or part of study participants, the article with the largest sample size was retained in the analysis. Any disagreement was discussed, and when necessary, adjudicated by a third author (Z.Z.).Data from qualified articles were independently extracted by two authors (B.Z. and W.N.), including surname of first author, year of publication, country where the study was conducted, sample size, study type, COPD and its stages, circulating concentrations of fibrinogen in both patients and controls, and necessary baseline characteristics, if available. Extracted data from the two authors were checked for consistency using κ statistic, and any divergences were resolved by a third author (Z.Z.).The quality assessment tool, the 9-star Newcastle–Ottawa Scale, was employed . This sc2 test and quantified by the inconsistency index (I2) statistic, which ranges from 0 to 100%. Heterogeneity is statistically significant if the probability of χ2 test is less than 10% or I2 is over 50%. To explore potential sources of heterogeneity, subgroup analyses were conducted according to COPD course (stable and acute exacerbations), COPD severity  I, GOLD II, GOLD III, and GOLD IV), smoking habit in controls, region, sample size and study type, and meta-regression analyses were further conducted to assess the confounding impact of age and gender.The STATA software Release 14.1  was used for statistical analyses. The difference in circulating fibrinogen concentration between COPD patients and healthy controls is expressed as weighted mean difference (WMD) and 95% confidence interval (95% CI) under the random-effects model using the DerSimonian and Laird method . HeterogCumulative analyses were done to assess the impact of first published study on subsequent studies and evolution of accumulated estimates over time. Influential analyses were used to assess the contribution of single study to overall estimate.Publication bias was evaluated by the Begg’s funnel plots and the Egger’s tests at a significance level of 10% . The triIn total, 298 potentially relevant articles were identified after literature search for observational studies on circulating fibrinogen and COPD. On the basis of titles and abstracts, 187 articles were excluded with obvious reasons, leaving 111 articles for further evaluation in full texts. Finally, there were 45 articles in this meta-analysis ,21–59, iShown in Using the 9-star Newcastle–Ottawa Scale system, the total score of qualified case–control studies ranged from 6 to 9 stars  (Supplementary Table S2).P<0.001), and there was strong evidence of between-study heterogeneity   .In view of the strong evidence of heterogeneity in overall analyses, it is necessary to explore possible causes by grouping studies according to COPD course, COPD severity, smoking habit in controls, sample size, and region, respectively.P<0.001, I2: 94.5%) tripled when compared with patients with stable COPD . By COPD severity .By COPD course A, the deseverity B, there P<0.001, I2: 89.3%) than smoking controls . By sample size, the difference in circulating fibrinogen concentration between COPD patients and controls was larger in studies with sample size <50   than in studies with sample size ≥ 50   B.Subgroup analyses by region are presented in Supplementary Figure S1.P>0.05) .Other sources of heterogeneity were further explored through meta-regression analyses by modeling age, female percentage, and pack-year of COPD patients, and none of these factors reached statistical significance . In influential analyses, the impact of any single study on overall effect-size estimates was non-significant .P=0.103). As reflected by filled funnel plot, there was an estimated ten missing studies required to make the Begg’s funnel plot symmetrical. After taking these ten missing studies into account, COPD patients still had a statistically significant higher concentration of circulating fibrinogen than controls .Shown in The aim of this meta-analysis was to examine the association of circulating fibrinogen with COPD and its severity by pooling the results of 45 published articles. The key finding of this meta-analysis suggests that a graded, concentration-dependent, significant relation exists between higher circulating fibrinogen, and more severity of COPD. To the best of our knowledge, this is thus far the first meta-analysis that has evaluated the concentration-dependent association of circulating fibrinogen with COPD severity in the literature.In human body, fibrinogen is mainly synthesized by the liver, and it is converted into fibrin by thrombin during blood coagulation . FibrinoAnother important finding is that there is a possible interaction between circulating fibrinogen and cigarette smoking in our subgroup analyses by smoking habit in controls, as we interestingly noticed that the difference in circulating fibrinogen concentration was more obvious when compared with non-smoking controls than with smoking controls. Cigarette smoking is an established risk factor for the development of COPD, and it is of added interest to know whether the contribution of cigarette smoking to COPD is mediated by elevated fibrinogen in circulation, which cannot be reliably investigated in the present meta-analysis due to the unavailable individual participant data. We agree further explorations on the interaction or medication impact of cigarette smoking on circulating fibrinogen are needed.The findings of this meta-analysis are susceptible to several possible limitations. First, language selection bias is possible, as we restricted literature search to the articles written in the English language. As estimated by McAuley and colleagues, the exclusion of gray literature from a meta-analysis may result in an overestimate of an association impact by an average of 12% . Second,Despite these limitations, our findings suggest a graded, concentration-dependent, significant relation between higher circulating fibrinogen and more severity of COPD. For practical reasons, circulating fibrinogen can be proposed as a promising biomarker and an early warning sign of the susceptibility to develop COPD in the future, as issued by the FDA , as wellClick here for additional data file.


Consequently, 38 case-control studies (from 27 citations) with 27,459 cancer cases and 25,151controls were included in the meta-analysis of the five most prevalent SNPs . In the XPO5 gene rs11077 SNP, the minor C allele significantly increased the risk of cancer , and a strong association between rs11077 SNP and cancer risk was also found in the dominant model . In addition, the minor GG genotype allele of the RAN gene rs3803012 SNP significantly increased the cancer risk . Statistically significant associations between rs3803012 SNP and cancer risk were also observed in the recessive model . Furthermore, the eQTL analysis revealed that rs11077 SNP was significantly correlated with XPO5 mRNA expression, which provided additional biological basis for the observed positive association. Our results suggest that XPO5 rs11077 may be a possible functional susceptibility locus for cancer risk.XPO5/RAN-GTP complex mediates the nuclear transport of pre-miRNAs in the miRNA processing system, its altered expression is indicated to be correlated with cancer risk. Several studies have inspected the association between XPO5 or RAN polymorphisms and the risk of various cancers, but the findings remain controversial. A Bayesian hierarchical meta-analysis was carried out to review and analyze the effect of XPO5 and RAN polymorphisms on cancer risk. The association was estimated by calculating the logarithm of odds ratio (Log OR) and 95% credible interval (95% CrI). The expression quantitative trait loci (eQTL) analysis was used for  MicroRNAs (miRNAs) are a highly conserved class of small, noncoding RNAs, which mediate post-transcriptional gene silencing During the miRNA maturing processing, the XPO5/RAN-GTP complex mediates the nuclear transport of pre-miRNAs, which are crucial components. XPO5, a member of the nucleo-cytoplasmic exportins, is related to the human export receptor that uses the Ran-GTPase to control cargo association Increasing evidence proposed shows that single-nucleotide polymorphisms (SNPs) in core components of miRNA biogenesis may impair or enhance miRNA processing efficiency or function, which can function as an oncogene or tumor suppressor To identify all potentially eligible publications, PubMed, PubMed Central (PMC), Web of science, Embase, China National Knowledge Infrastructure (CNKI), Chinese Wanfang databases, Wiley, Google Scholar, Cochrane, the Cochrane Central Register of Controlled Trials were searched, using a combination of the following keywords: 'XPO5/ exportin 5/ exp5/ RAN/ ARA24/ Gsp1/ TC4'; 'SNP/ polymorphism/ variation/ variant'; and 'tumor/ cancer/ carcinoma/ neoplasm'. The search was limited to articles published in English or Chinese through April 9, 2019. References of the relevant literature and review articles were also evaluated to identify all potentially eligible articles. This meta-analysis was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (Supplementary PRISMA 2009 Checklist) Eligible publications were selected based on the following inclusion criteria: (i) evaluation of genetic association between XPO5 or RAN and susceptibility to cancer; (ii) a case-control designed study; Articles meeting the following criteria were excluded: (i) reviews, meta-analyses, conference reports, or editorial articles; (ii) duplicate records; (iii) no available data to extract; (iv) the control subjects exhibited a departure from Hardy-Weinberg equilibrium (HWE).The following information was extracted by two reviewers independently and disagreement was solved through discussion: first author's name, publication year, country, ethnicity, cancer type, polymorphisms, sample size of cases and controls, genotype distribution, source of control groups (population-based (PB) or hospital-based (HB)), genotyping method, HWE in controls. If more than one type of cancer or multistage research was involved in a single article, data for each type of cancer was extracted independently. When the data in eligible articles was unavailable, we tried our best to contact the corresponding authors for original data. Quality assessment of articles was conducted using the Newcastle-Ottawa Quality Assessment Scale (NOS) In this meta-analysis, the following comparisons for XPO5 and RAN polymorphisms were evaluated in five common genetic models including allele model (V vs. W) , heterozygote model (WV vs. WW), homozygote model (VV vs. WW), dominant model (WV+VV vs. WW), and recessive model (VV vs. WW+WV).2τ) and their respective 95% credible intervals (CrIs) are estimated. The 95% CrI is the Bayesian equivalent for standard confidence intervals. In particular, the model supposes that the mean of the Log ORs has a low-informative normal distribution  and the variance of the Log ORs has a low-informative inverse-gamma distribution   I2 statistic, which is used to measure the total variation τ parameters, with darker shading corresponding to higher probability density. All the statistical analyses were calculated using “bayesmeta” R package (https://cran.r-project.org/web/packages/bayesmeta/index.html).The Bayesian meta-analysis is a Bayesian modeling method which determines the prior distribution with hierarchical prior distribution, and then does the statistical inference https://www.ncbi.nlm.nih.gov/geo) (GSE65373). Choosing hepatocellular carcinoma and breast cancer as representatives, we also downloaded mRNA sequencing datasets of 154 paired cancer tissue samples and normal adjacent tissue samples from The Cancer Genome Atlas (TCGA-LIHC and TCGA-BRCA) (https://tcga-data.nci.nih.gov/tcga/). A linear regression model was performed to evaluate the correlation between SNPs and specific mRNA expression levels. A paired t-test was used to test for the differences in gene mRNA expression levels between cancer tissue and adjacent normal tissue from the TCGA database. All analyses were performed using R (version 3.5.1).To validate the potential impact of the cancer risk SNP, we examined its association with the expression of corresponding genes using eQTL databases. The eQTL analysis was performed by using the genotyping and expression data of lymphoblastoid cells from 373 European individuals available in the 1000 Genomes Project The process of selecting eligible studies is depicted in Figure τ parameters. On the basis of the Bayesian hierarchical meta-analysis, XPO5 rs11077 and RAN rs3803012 SNPs were significantly associated with the risk of cancer , and we found that XPO5 rs11077 was significantly associated with XPO5 mRNA expression levels (P = 5.83E-07).To substantiate the associations between the identified SNPs (XPO5 rs11077 and RAN rs3803012 SNPs) and cancer risk, we performed the eQTL analysis to assess the associations between SNPs and corresponding mRNA expression levels. The eQTL analysis results of lymphoblastoid cell lines from 373 Europeans were visualized through the Geuvadis Data Browser   from Stranger et al. In the present study, a total of five SNPs in XPO5 and RAN genes were comprehensively reviewed and analyzed to estimate their associations with the risk of overall cancer by Bayesian hierarchical meta-analysis. Of these five SNPs, two  were analyzed for the first time. In contrast to the classical meta-analysis already performed with a fewer number of articles included Since the Bayesian hierarchical meta-analysis is much more sensitive and confers more precise estimation compared with classical meta-analysis, it is powerful suggested that rs11077 SNP of XPO5 and rs3803012 SNP of RAN are associated with cancer risk. Furthermore, eQTL analysis demonstrated that rs11077 SNP may influence the mRNA expression levels of XPO5. However, no associations were revealed amongst other studied SNPs in our meta-analysis, therefore future studies with a larger sample size are needed to determine their relationships.For the classical meta-analysis, when faced with extreme values or small research quantum, the accuracy of the results cannot be guaranteed and the correctness of its conclusions will be questionable XPO5 is a member of karyopherin β family related to human export receptor CRMI, and is responsible for nuclear export and stabilization to form mature miRNA to produce physiological effects RAN is a key member of the Ras superfamily of GTPases and is essential for translocation of pre-miRNAs from the nucleus to the cytoplasm through the nuclear pore complex in a GTP-dependent manner Despite these results, we encountered some limitations during our meta-analysis. Firstly, since we had a limited number of studies, we could not perform a subgroup analysis with respect to the ethnicity, source of control groups  and cancer type. Heterogeneity among different cancers may cause the real effects to be hidden when pooling all cancer types. Secondly, gene-environmental interactions which may alter cancer risk were not evaluated due to the lack of relevant data across the included studies. Thirdly, studies of XPO5 and RAN SNPs in the cancer predisposition field continue to emerge, which resulted in limited number of the relevant investigations.In view of all this, Bayesian hierarchical meta-analysis suggests a potential role of the miRNA biogenesis genes XPO5 (rs11077 A/C) and RAN (rs3803012 A/G) SNPs in cancer risk, supplying novel clues to identifying new biomarkers with cancer-forewarning function. Although we used publicly available genotyping and expression data to confirm the biological significance of the variant and suggest that XPO5 rs11077 may be a possible functional susceptibility locus for cancer risk, further high-quality research and functional evaluations are still warranted to validate our findings due to the limitations mentioned above.Supplementary tables.Click here for additional data file.


Background: It is well known that insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) rs4402960 polymorphism is associated with Type 2 diabetes mellitus, which has a shared genetic background with gestational diabetes mellitus (GDM). Previous studies have yielded controversial results about the link between IGF2BP2 rs4402960 polymorphism and GDM risk. Thus, a meta-analysis was performed to obtain more conclusive results.Methods: Clinical and genotype data were determined for 305 GDM and 1216 healthy participants recruited. Eligible studies were retrieved in PubMed, Web of science, EMBASE, and Scopus. Odds ratios (ORs) with 95% confidence intervals (CIs) were utilized to evaluate the relationship between IGF2BP2 polymorphisms and GDM susceptibility in five genetic models. The subgroup stratified analysis and trial sequential analysis (TSA) were performed.Results: In this case–control study, no significant association was revealed between IGF2BP2 polymorphism and GDM (P>0.05). When combined with the previous studies in the meta-analysis, there was no statistical association between IGF2BP2 polymorphism and GDM . No association was observed in five genetic models in each subgroup. TSA indicated sufficient proof of such null association in the overall population.Conclusions: This meta-analysis provides sufficient statistical evidence indicating null association between IGF2BP2 rs4402960 polymorphism and GDM risk. Gestational diabetes mellitus (GDM) is defined as glucose intolerance that occurs during pregnancy. The GDM is the most prevalent metabolic disorder during pregnancy with prevalence between 9.3% and 25.5%, which is attributed mainly to obesity, older maternal age, and a sedentary lifestyle . GDM resIGF2BP2) is part of the family of mRNA-binding proteins regulating insulin-like growth factor 2 (IGF2) translation. IGF2BP2 is located on chromosome 3q27. A previous animal study showed that IGF2 is involved in pancreatic function AAGATACTGATTGTGTTTGCAAACA. The reaction mix included 10 μl DNA, 25 μl master mix (Applied Biosystems), 2.5 μl probe, and 12.5 μl sterile water in a final volume of 50 μl. PCR conditions comprised an initial denaturing step at 95°C for 10 min, followed by 45 cycles of 92°C for 30 s, with a final extension at 60°C for 1 min. PCR plates were read on an ABI PRISM 7900 instrument (Applied Biosystems). Two authors (G.S. and G.Z.) independently reviewed the genotyping results and input data.IGF2BP2’. Original studies were eligible if they met the following criteria: (I) case-control studies; (II) literatures on associations between IGF2BP2 rs4402960 polymorphism and GDM; (III) results were denoted as odds ratio (OR) with 95% confidence intervals (CI). Original studies were ineligible if they: (I) were reviews, letters, or case reports; (II) did not contain outcomes which can be converted to OR and 95% CI; (III) included control group that was not involved with healthy women; (IV) were laboratory studies with animals. For duplicate publications, we only included the study with the largest sample size for analyses.Two examiners (J.L. and G.S.) independently searched for the significant studies in databases, including PubMed, Web of science, EMBASE, and Scopus on March 15, 2020. The search terms are the ‘gestational diabetes mellitus’, ‘polymorphism/variant/mutation/’, and ‘Two researchers (J.L. and G.Z.) carried out data extraction independently. If there were disagreements, they discussed and reached a consensus with the help from a third reviewer (TM). The data contained the first author, publication year, ethnicity, control source, genotyping method, genotype distribution in case and control groups. The Newcastle–Ottawa Scale (NOS) was used to assess the quality of all studies included. The NOS quality score ranges from 0 to 9 stars. Two authors independently assessed the quality of the studies included. Disagreements were resolved by discussion.IGF2BP2 rs4402960 polymorphism and GDM risk was assessed by calculating the OR with 95% CI. We calculated the OR by genotype and allele model comparisons of IGF2BP2 rs4402960 polymorphism between cases and controls. The P value for Hardy–Weinberg equilibrium (HWE) was calculated in the control group using the chi-square test. Heterogeneity was assessed by using the I2 statistics. If there was no heterogeneity (P>0.1 or I2<50%), a fixed-effects model was used to estimate the pooled OR; otherwise, a random-effects model was utilized. Subgroup stratified analysis was performed using genotyping method (TaqMan assay or PCR), ethnicity (Caucasian or Asian), and control source . Study effects, such as publication bias, were evaluated with Egger’s tests and a P value of < 0.1 was considered statistically significant for asymmetry. Sensitivity analyses were directed to assess the influence of individual study on the overall estimate. Statistical analyses were performed with Stata . The TSA  was conducted to maintain a 95% confidence interval, a 20% relative risk reduction, overall 5% risk of a type I error and 20% of the type II error (a power of 80%) in this study to reduce the risk of type I error.Chi-square test was used to compare Allele/genotype frequencies between GDM and control groups. The strength of association between P>0.05). There were significant differences between the two groups with respect to triglyceride, total cholesterol, and high-density lipoprotein cholesterol (P<0.05). There was no difference in genotype frequencies between GDM and controls groups in IGF2BP2. Meanwhile, there was no significant susceptibility for rs4402960 polymorphism with GDM risk within five genetic models . A total of 8346 subjects were involved, including 2720 GDM patients and 5626 healthy women. All P values of HWE were more than 0.05.About 64 potentially eligible studies were retrieved. After application of the criteria, six studies were kept . CharactIGF2BP2 rs4402960 polymorphism and GDM within five genetic models as shown in IGF2BP2 rs4402960 polymorphism and GDM risk. No association was observed in five genetic models in each subgroup  patients [IGF2BP2 rs4402960 polymorphism plays a role in pathogenesis of T2DM [TCF7L2 rs12255372 and MTNR1B rs10830963 [WFS1 rs10010131 and ABCA1 rs1800977 [nslation . IGF2BP2molecule . Previoupatients . Therefo of T2DM . T2DM an of T2DM . Several10830963  while ths1800977 ,19.IGF2BP2 rs4402960 polymorphism was associated with GDM risk [IGF2BP2 rs4402960 polymorphism with GDM [IGF2BP2 rs4402960 polymorphism on GDM risk, a meta-analysis of six previously published reports in combination with the present results of the case–control study was conducted. As far as we know, this is the first meta-analysis to date comprehensively quantified the association between the IGF2BP2 and GDM risk.Early studies showed that GDM risk ,12,20. TGDM risk ,21. Howewith GDM ,22. ResuZ-curve touches the trial sequential monitoring boundary, the futility boundary, or the required information size line, it shows firm evidence for such study. If not, additional studies are necessary to reach a consistent conclusion [However, meta-analysis has its potential limitation, resulting in spuriously overestimated (type I errors) or spuriously underestimated (type II errors) effects . As a conclusion .Z-curve crosses the traditional boundary using the Cho, Lauenborg, Wang, and Chon’s studies [Z-curve goes back to the zone between two traditional boundaries, then crosses the futility boundary and reaches the required information size line. Until now, there is sufficient evidence to support the null association between IGF2BP2 rs4402960 polymorphism and GDM risk. This trend of cumulative Z-curve explains the TSA advantage, which helps us avoid reaching a premature statistical significance conclusion [In our TSA results, the cumulative  studies ,12,20,25 studies ,26. Utilnclusion .There were limitations in the present study. First, the sample size in each subgroup was small. Second, there was no study that includes the Blacks or Hispanics.IGF2BP2 rs4402960 polymorphism and GDM risk.This meta-analysis provides sufficient statistical evidence indicating null association between Click here for additional data file.


To explore the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model application for predicting outcome of patients with metastatic renal cell carcinoma using targeted agents.We performed a literature review of 989 articles. The selecting process used preferred reporting items for systematic reviews and meta-analyses (PRISMA). All included studies were assessed by Newcastle-Ottawa scale. Results of individual studies were pooled using Stata 14.0 software.A total of 17 articles were included. Most articles provided univariate and multivariate analysis of IMDC model prognosis. Combined HRs were 1.58 (95% CI 1.34-1.82) and 3.74 (95% CI 2.67-4.81) for univariate PFS of intermediate to favorable and poor to favorable respectively. In the category of multivariate PFS, combined HRs were 1.27 (95% CI 0.99-1.56) and 2.29 (95% CI 1.65-2.93) with intermediate to favorable and poor to favorable respectively. Regarding univariate OS, combined HRs were 1.93 (95% CI 1.62-2.24) and 6.25 (95% CI 4.18-8.31) with intermediate to favorable and poor to favorable respectively. With multivariate OS, combined HRs were 1.32 (95%CI 1.04-1.59) and 2.35 (95%CI 1.69-3.01) with intermediate to favorable and poor to favorable respectively.In summary, analysis of currently available clinical evidence indicated that IMDC model could be applied to classify patients with metastatic renal cell carcinoma using targeted agents. However, different types of targeted agents and various areas could affect the accuracy of the model. There was also a difference in predicting patients' PFS and OS. Renal cell carcinoma (RCC) represents approximately 3% of all cancers, with the highest incidence occurring in western countries. Generally, during the last two decades, there has been an annual increase of 2% in incidence both worldwide and in Europe, leading to approximately 99, 200 new RCC cases and 39.100 kidney cancer-related deaths within the European Union in 2018 . IMDC moWe performed a literature review of articles published before June 31, 2019 using the PubMed, Web of Sciences and Embase Databases. The main search terms used were “metastatic renal carcinoma”, “prognosis”, “TKI”, “mTORi”, “sunitinib”, “sorafenib”, “pazopanib”, “axitinib”, “bevacizumab”, “everolimus”, “temsirolimus” et al. and their combinations. Additional references were identified from the reference list of each article. Two reviewers carried out this process independently. The selecting process using preferred reporting items for systematic reviews and meta-analyses (PRISMA)  statemenInclusion criteria:  patientsExclusion criteria:  cohort o2 statistic test to assess the heterogeneity between studies. I2 ranges are from 0% to 100% . When I2 <50% or Pheterogeneity >0.1, no obvious heterogeneity existed among the studies. To achieve a relatively conservative conclusion, the random-effects (RE) model was applied  and the forest plot is shown in The combined HR was 3.74 (95% CI 2.67-4.81) and the forest plot is shown in There were 7 articles , 19-21 IThe combined HR was 1.27 (95% CI 0.99-1.56) and the forest plot is shown in The combined HR was 2.29 (95% CI 1.65-2.93) and the forest plot is shown in In all 10 articles , 22-24 iThe combined HR was 1.93 (95% CI 1.62-2.24) and the forest plot is shown in The combined HR was 6.25 (95% CI 4.18-8.31) and the forest plot is shown in A total of 9 articles , 25, 26 The combined HR was 1.32 (95% CI 1.04-1.59) and the forest plot is shown in The combined HR was 2.35 (95% CI 1.69-3.01) and the forest plot is shown in IMDC model including six independent factors such as KPS <80%, time from diagnosis to treatment <1 year; hemoglobin <LLN, Calcium >ULN, Neutrophils <ULN, and Platelets >ULN was first set in 2009 . After iMost incorporated articles provide univariate and multivariate analysis of prognostic factors. For meta-analysis, univariate pooling can best reflect potential valuable prognostic factors despite the possibility of combining confounding factors leading to repetitive effects. Multivariate merging may be inherently heterogeneous due to the inconsistencies in the variables included in each article. Conversely, the statistically significant prognostic factors obtained through this combination may be able to withstand the challenges of different conditions and could be widely used.According to our analysis, IMDC model was able to classify patients to different risk group with various PFS and OS except in the category of intermediate to poor risk group for PFS (95% CI 0.99-1.56). Simultaneously, the combined HR was larger in the category of univariate analysis than those in the category of multivariate analysis. It possibly suggested that IMDC model was affected by other existing factors. In other words, it should be taken into account when the model is incorporated as one independent prognostic factor to reform a new prognostic model. In addition, we also explored the applicability of this model in different drugs and different populations. There are a variety of targeted drugs, and we have included studies that simply use sunitinib as a treatment, as well as a combination of sorafenib, pazopanib, and even mTORi, such as temsirolimus. Based on the subgroup analysis, IMDC model was reliable on the univariate analysis of PFS and OS and multivariate analysis of PFS limited in the poor to favorable risk group. Its applicability was not stable in the category of multivariate analysis of PFS located in the intermediate to favorable risk group and multivariate analysis of OS. When it came to the area targeted agents were used, various results existed in different conditions. IMDC model was reliable on the univariate analysis of PFS and OS and multivariate analysis of PFS and OS limited in the poor to favorable risk group both in Asia and other areas. It was not reliable in the category of multivariate analysis of PFS located in the intermediate to favorable risk group both in Asia and other areas. However, it could be used in the multivariate analysis of OS in Asia not in other area. There were two main explanations for the difference. On one hand, unstable results were concentrated on the intermediate to favorable risk group, indicating the classification was not accurate enough. On the other hand, PFS results were more stable than OS results, indicating that OS was easier to be affected by other factors other than targeted drug therapy. There was no doubt that the number of studies included is an important factor affecting the outcome. More high-quality clinical studies could provide more robust results.The findings of this systematic review should be considered in the context of the available evidence, which may be limited by selection bias and follow-up as reflected in the strength of evidence ratings. Due to there was not enough articles available, the application of the model for specific country or race was not explored. Meanwhile, most of the involved patients were ccRCC, the reliability of the model for nccRCC needed more studies to verify. Additionally, most articles used targeted agents as first line therapy except Keizman's, Auclin's and Kwon's articles , 16, 26,In summary, our analysis of currently available clinical evidence indicated that IMDC could be applied to classify patients with metastatic renal cell carcinoma using targeted agents. However, different types of targeted agents and various areas could affect the accuracy of the model. There was also a difference in predicting patients' PFS and OS. Based on the limitations of both the studies evaluated and our meta-analysis, further well-designed studies are needed to draw a more definite conclusion as to the clinical significance of IMDC model.