Since obesity is an established risk factor of cancer, several studies have examined the association between SNPs near the MC4R gene and cancer risk, but the findings are inconsistent. The present study aimed to perform a meta-analysis to clarify the association between SNPs near MC4R and cancer risk.Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) near the MC4R rs17782313 SNP (or its proxy rs12970134) and cancer risk were included. The pooled odds ratios with 95% confidence intervals (CIs) were calculated using the random-effects model. And subgroup analysis by cancer type  was conducted for further investigate the association.The PubMed and Embase databases were searched for potentially eligible publications. All studies that evaluated the association between MC4R rs17782313 SNP was moderately associated with cancer risk . However, the subgroup analysis between different cancer types shows that rs17782313 is only associated with colorectal cancer but not the endometrial cancer and breast cancer. Risk factor in colorectal cancer was both significantly associated with rs17782313 with and without adjustment for body mass index; while the risk factor of the endometrial cancer and breast cancer were both not associated with the rs17782313 with and without adjustment for body mass index. There was no publication bias for the association between MC4R rs17782313 and cancer risk.A total of 6 eligible studies  were included in the present meta-analysis. The results indicated that MC4R rs17782313 and cancer risk.The present meta-analysis confirmed the moderate association between  Furthermore, subsequent studies have confirmed the positive association between SNPs in/near the MC4R gene and risk of obesity in populations with different races/ethnicities.–4In 2008, the genome-wide association studies (GWAS) reported that rs17782313 single nucleotide polymorphism (SNP) mapped 188 kb downstream of the MC4R gene have been found to be the main cause of human monogenic obesity, suggesting that the MC4R gene represents a compelling biological candidate. MC4R expression is also associated with risk of early-onset obesity, increased lean mass and bone mineral density, and enhanced linear growth. Two previous meta-analyses confirmed that the rs17782313 SNP near the MC4R gene was associated with risk of obesity and type-2 diabetes. It has been well-documented that obesity is the leading risk factor for many cancers. Therefore, it is important to determine whether MC4R SNPs are associated with cancer risk, which may help illuminate the potential biological mechanism between obesity and cancer development. To date, several studies have investigated the associations of MC4R SNPs with risk of cancer.–14 However, the findings have been contradictory.MC4R is a 332-amino acid protein encoded by a single exon on chromosome 18q22. The rare coding mutations in the MC4R gene and risk of cancer.The present study aimed to perform a systematic meta-analysis to clarify the association between the rs17782313 SNP (or its proxy) near the 22.1melanocortin 4 receptor OR MC4R) and (polymorphism OR variant OR variation OR genotype) and (cancer OR tumor OR carcinoma). The publication language was restricted to the English language. The reference lists of retrieved articles were also hand-searched. The literature search was updated as of September 10, 2019. Since this is a meta-analysis, ethical approval was waived.The PubMed and Embase databases were searched for potentially eligible studies. The following key words were used to search for eligible publications: MC4R rs17782313  with cancer risk;studies that determined the association of (2)studies that had case-control design;(3)studies that provided an odds ratio (OR) with 95% confidence interval (CI) with or without adjustments for BMI.The following information were extracted from each study:(1)name of the first author,(2)year of publication,(3)country of origin,(4)race/ethnicity of the study population,(5)number of cases and controls,(6)gender ratio,(7)mean age,(8)mean BMI,(9)cancer type,(10)the studied SNP, and(11)the determination of whether BMI was adjusted in the statistical model.Two authors independently reviewed the articles for compliance with the inclusion/exclusion criteria, resolved any disagreement, and reached a consistent decision after discussion with a third author, if necessary.2.3MC4R rs17782313 and cancer risk was determined by calculating the pooled OR and 95% CI under an additive genetic model. Z-test was used to determine the significance of the OR . Cochrane Q-test was conducted to assess the between-study heterogeneity.,16I2 represented the range for the degree of heterogeneity. A random-effects model (DerSimonian–Laird) was used to calculate the pooled OR when there was between-study heterogeneity (P ≤ .10 or I2 ≥ 50%). Otherwise, a fixed-effects model (Mantel–Haenszel) was used. Publication bias was assessed by Begg test and Egger test . The data were analyzed using STATA version 11.0 .The association between 33.1MC4R rs17782313 (or its proxy SNP rs12970134) in each included study was in Hardy-Weinberg Equivalent. The characteristics of the included studies are listed in Table Figure 3.2MC4R rs17782313 SNP risk allele was moderately associated with cancer risk  in an additive genetic model  or breast cancer   or Egger test (P = .275) before adjusting for BMI, as well as after adjusting for BMI .There was no publication bias for the 4MC4R gene and risk of cancer. The present meta-analysis revealed that the MC4R rs17782313 SNP is moderately associated with risk of cancer, without adjusting for BMI. However, this association disappeared after adjusting for BMI. It appears that the association between the MC4R gene SNP and cancer risk may be mediated through adiposity.To our knowledge, this is the first meta-analysis that investigated the association between a SNP near the FTO gene is one of the first loci identified for obesity risk by GWAS. A most recent meta-analysis conducted by Kang et al revealed that the FTO gene rs9939609 SNP was not significantly associated with risk of cancer, regardless of the adjustment for BMI. However, in the subgroup analysis, this variant moderately increased the risk of endometrial cancer and pancreatic cancer, which was mediated by adiposity. Similarly, the authors also found a significant association between the MC4R gene rs17782313 SNP and risk of cancer, which mediated through BMI. Notably, a recent large-scale study suggested that MC4R gene SNPs are not associated with risk of colorectal cancer, regardless of adjusting for BMI. However, that study did not focus on the rs17782313 SNP, which is the interest of the present study.Several previous GWAS have identified a large number of SNPs associated with obesity. The MC4R SNP and cancer risk remains unclear. Similar to the FTO gene, the MC4R gene is also highly expressed in the central nervous system, which regulates the energy metabolism. It was reported that MC4R may regulate food choice and intake, and energy expenditure through a distinct pathway.,21 However, further studies are needed to clarify the potential biological pathways through which these MC4R SNPs increase the risk of obesity and cancer.The mechanism underlying the association between the It is important to focus on an organ system, which might encompass two or more different cancer types . However, merely 6 studies met the inclusion criteria. Thus, an analysis that focused on an organ system could not be performed. In addition, it is also important to assess the association between SNPs and different endocrine-driven cancers. However, due to the unavailability of data, subgroup analysis was performed by cancer type .The present study had 2 strengths. First, the OR was extracted with 95% CI, with the adjustment of covariates from individual studies, to calculate the summary estimate, which represents an accurate estimate. Second, a total 6517 cancer cases and 16,886 healthy controls were included in the present meta-analysis, which greatly improved the statistical power. However, 2 limitations should be considered. First, although the total sample size was sufficiently large, merely 6 studies were included. In addition, the subgroup analysis by cancer type should be interpreted with caution due to the limited studies available for each cancer type. Second, there was a significant between-study heterogeneity in the meta-analysis, even although a random effects model was used to overcome this limitation. In addition, the further meta-regression analysis did not reveal any potential confounders that may explain the between-study heterogeneity.MC4R rs17782313 SNP and risk of cancer, which might be mediated by adiposity. Further studies are necessary to identify the causal variant near the MC4R gene, as well as the underlying mechanism between the MC4R gene SNP and risk of cancer.In summary, there might be an association between the Conceptualization: Zeng Tian, Hongjun Xie.Data curation: Xiaojiao Wang.Formal analysis: Xiaojiao Wang.Investigation: Zeng Tian.Methodology: Jing Zhao, Yu Kang.Supervision: Yu Kang.Validation: Jing Zhao.Visualization: Jing Zhao.Writing – original draft: Zeng Tian, Jing Zhao, Hongjun Xie.Writing – review & editing: Hongjun Xie.


The relationship between cancer with body mass index has been extensively reported. However, association between urinary cancers with these risk factors remains unclear, with existing reports showing conflicting findings. The current review, therefore, sought to clarify the latter association by assessing the methodological and reporting quality of existing systematic reviews on the subject.We will screen PubMed, EMBASE, and Cochrane Library databases for relevant literature and subjected the resulting articles to meta-analysis. We will adopt the AMSTAR and PRISMA checklists for assessing methodological, and reporting quality, respectively. The association between BMI and different urinary cancers will be estimated by computing the pooled relative risk (RR) and its 95% confidence interval (CI), which will be calculated from the adjusted RR, odds ratio, or hazard ratio, and 95% CI offered in the studies. Heterogeneity between studies will be assessed with the I statistic as a measure of the proportion of total variation in estimates that is due to heterogeneity, where I values of 25%, 50%, and 75% correspond to cut-off points for low, moderate, and high degrees of heterogeneity. The random effects model will be used as the pooling method when significant heterogeneity existed and the fixed effect model will be used when no heterogeneity was observed. Possible publication bias will be tested by Begg and Egger test.Our evidence synthesis will provide a new commentary on the current systematic review evidence for the association between BMI and the risk of different urinary cancers.CRD42019119459. For example, this type caused an estimated 1.3 million new cases and 359,000 deaths in 2018 alone, whereas bladder cancer accounted for 549,000 new cases and 20 million deaths worldwide. The incidence of bladder cancer  as well as mortality rate  are about four times  that of females. On the other hand, kidney cancer caused >400,000 new cases, and 170,000 deaths in the same year. These figures underscore the incidence and impact caused by the three types of cancers across the world,,3 although the underlying mechanism of their development remains unclear owing to limited evidence. Previous studies have suggested that cumulative effects of cigarette smoking, alcohol consumption, obesity, and genetic susceptibility may be risk factors for urinary cancer.,4 Accurate understanding of these risk factors is critical for the development of effective approaches for cancer prevention and treatment.Cancer is the second most deadly disease affecting human health worldwide.,6 In USA, Wang et al predicted a $48 to $66 billion increase per year in combined medical costs from common obesity-related diseases by 2030. Policymakers in the public health sector rely on high-quality evidence, generated by meta-analyses and SR, to formulate policies for the prevention and management of cancer. However, despite numerous SRs describing the relationship between cancer with overweight and obesity, over the past several decades, conflicting findings regarding the association of these risks factors with urinary cancers pose a challenge to accurate understanding of their epidemiology as well as the development of management approaches.–12Overweight and obesity are defined as excess body weight that causes many chronic diseases and increases the risk of death. The number of overweight and obese adults had risen to 2.1 billion in 2013, with direct costs resulting from obesity estimated to account for 0.7 to 2.8% of a country's total healthcare expenditures.In the current study, we sought to generate more comprehensive and robust evidence of the relationship between the urinary cancers with obesity and overweight using a meta-analysis of published literature.22.1This overview was registered by the International prospective register of systematic reviews (PROSPERO), number CRD42019119459.2.2Two reviewers will independently search the PubMed, Cochrane Library, and Embase databases. The search was limited to articles written in English and used the following search terms: BMI, obesity, cancer, carcinoma, neoplasm, meta-analysis, and SRs. A detailed description of the PubMed search strategy is presented in the Data S1.2.3Studies will be included if:(1)SRs or meta-analysis associated obesity, and overweight with urinary cancer;(2)SRs or meta-analysis associated increase in BMI with urinary cancer;(3)articles were published in English;(4)latest article was included when SRs or meta-analysis had been updated.Studies were excluded if:(1)they were only abstracts and/or letters;(2)SRs and meta-analysis examined the association between BMI increase and prognosis, survival or recurrence of urinary cancers;(3)protocols of SRs and meta-analysis or methodological articles;(4)SRs without meta-analysis.2.4The retrieved articles were first imported into EndNote X7 software, then titles and abstracts independently selected by two reviewers. The reviewers thereafter retrieved full texts of potentially eligible studies and independently subjected them to the aforementioned criteria. Any disagreement was discussed with a third reviewer. The 2 reviewers independently extracted the following characteristic from each study: first author's name, year of publication, funding, number of reference test, name of database, country of first author, the epidemiological study design (case-control or cohort), number of cases, features of the urinary cancers, summary effects between BMI and cancer risk (at 95% CI), and the number of included studies.2.5,14 To assess the reporting quality of included SRs and meta-analyses, we will use the PRISMA checklist, which comprises 27 items. To show the degree of compliance, total PRISMA scores will be calculated by summing 1 point for “Yes” , 0.5 points for “Partial”  and “Cannot answer” (limited information), 0 point for “No” (noncompliance). The SR and meta-analysis will be regarded low quality if PRISMA scores are below 15 points, moderate if they recorded 15.0 to 21.0 points, and high if >21.0 points are recorded.,16 Quality assessment of the included SRs and meta-analyses will be independently performed by two authors (JYS and LLS), and any disagreements between them will be discussed with a third author (JHT).To assess methodological quality, we will use the AMSTAR checklist, which comprises 11 items. Total AMSTAR scores will be denoted as 1 point for “Yes” (item/question fully solved), no point for “No” (item/question not solved), or “partial answer” (item not fully solved). Obvious, moderate and minimal flaws will be defined using <4, 5–8, and <9 points, respectively as previously described.2.6 A condition is considered normal if a BMI of 18.5–24.9 kg/m2 was recorded, overweight for 25 to 29.9 kg/m2, and obesity for BMI ≥ 30 kg/m2. We will also analyze each 1 kg/m2 and 5 kg/m2 increase in BMI according to previous protocols.,19 In addition, we will assesses the heterogeneity between studies using the I2 statistic. Specifically, we will adopt the fixed-effect model when I2 value was less than 50%, and the random-effect model for an I2 value greater than 50%. Possible publication bias will be tested by Begg and Egger test. Furthermore, we will analyze indirect comparisons of the outcomes across the meta-analyses. Statistical analyses will be performed using STATA software , with values that have P ≤ .05 considered statistically significant. Bubble diagram will be constructed to visualize the methodological quality and the quality of included literature.We will calculate pooled RRs (at 95% CI) from included SRs and meta-analysis  records using the fixed effects model or random-effects model.3Methodological and reporting quality of meta-analysis and SRs are crucial to public health and clinical decision making. Despite numerous studies analyzing cancer risk factors, no consensus has been reached regarding the relationship between different urinary cancer with obesity and overweight. In the current study, we sought to generate more comprehensive and robust evidence of the relationship between the urinary cancers with obesity and overweight using a meta-analysis of published literature.We express our thanks to Jinhui Tian for the assistance with the design of the protocol.JS and LLS conceived the idea for this study; JS, XJ, YG, and WLZ drafted the protocol. All authors approved the article in its final form.Writing – original draft: Jiyuan Shi.


EGLN2 4-bp insertion/deletion (ins/del) polymorphism (rs10680577) and many cancers. However, up to date, no study has inspected the impact of rs10680577 polymorphism on prostate cancer (PCa) risk. This case-control study was achieved on 170 pathologically confirmed PCa patients and 196 cancer free men to inspect whether rs10680577 variant is related to the risk and clinicopathological features of patients with PCa. Genotyping was performed by mismatched polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The findings did not support an association between the variant with the risk and clinicopathological characteristics of PCa patients. When we pooled our results with six preceding studies, the findings suggested that rs10680577 variant significantly augmented the risk of overall cancer in heterozygous , homozygous , codominant , and allele  genetic models. Additional well designed studies with larger sample sizes are necessary to confirm our findings.Several studies have evaluated the association between  Prostate cancer (PCa) is one of the most common cancer among men globally . The precise mechanisms underlying PCa development is largely unknown. Mounting evidence suggests that genomic and environmental factors play a role in development and progression of PCa . Small insertions/deletions (indels), the second most common form of genetic variations in human genome, have been linked to cancer development . EGLN2 (Egl nine homolog 2) gene which is located on chromosome 19 (19q13.2) encodes prolyl hydroxylases 1 (PHD1) . Hypoxia, a main characteristic of solid tumors, leads to alterations of gene expression in tumor cells to adapt to the hypoxic environment . The hypoxia-inducible factor 1 (HIF-1), a key transcriptional activator is induced by hypoxia . The HIF-1 plays a critical role in the development of solid tumors and in coordinating the cellular response to hypoxia and oxygen homeostasis . The level of HIF-1 is tightly regulated by three PHDs  . In normoxia condition HIF is hydroxylated at specific residues by PHDs which uses oxygen as a substrate. Hydroxylated HIF binds to a protein called Von Hippel Lindau protein (VHL) for its degradation, while in hypoxic situation, stabilization and nuclear translocation occur, leading to oncogenes activation . rs10680577) and susceptibility to various cancer comprising breast cancer , colorectal cancer , gastric cancer , hepatocellular carcinoma (HCC) , and lung cancer , As far as we know, there is no data concerning the impact of EGLN2 4-bp ins/del polymorphism on PCa susceptibility. Consequently, the current study aimed to assess the impact of this variant on PCa development. Several studies investigated the correlation between EGLN2 4-bp ins/del polymorphism . The study was approved by the Zahedan University of Medical Sciences ethics committee and all participants were asked to provide their written informed consent. Whole blood samples were collected in EDTA tube, and genomic DNA was purified by salting out method.Genotypingrs10680577) polymorphism was done by mismatch polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) as described previously . The forward and reverse primers were 5`-CCGTTATAAAAGATACTTATGTAAATCAC-3` and 5`-TTGGAATCAAGTGGCGTCG-3`, respectively. PCR was achieved using Prime Taq Premix  and the PCR products were digested by AleI restriction enzyme. The del allele digested and created 224 and 31 bp fragments, whereas the ins allele remained undigested (259 bp).Genotyping of EGLN2 4-bp ins/del  and 95% confidence intervals (95% CIs) was estimated by logistic regression analysis. P value < 0.05 was considered statistically significant. All analyses were conducted with SPSS 22 statistical package. The χPooled analysis Pooling of our outcomes with six previous published studies was done using STATA 14.1 software. Electronic databases were searched for all articles describing the relationship between EGLN2 4-bp ins/del polymorphism and cancer susceptibility. The characteristic of study included into pooled analysis is shown in The study group consisted of 170 histologically confirmed PCa (mean age: 61.2±6.6 years) and 196 cancer free men (mean age: 64.5±8.9 years). Statistically significant difference was observed between cases and controls groups regarding age (p<0.05). The frequency distribution of genotype and allele is shown in The relationship between the variant and clinicopathological features such as age, stage, prostate specific antigen (PSA) level, Gleason score, perineural invasion, and surgical margin were determined . The resMain pooled analysis results The pooled results with six previous published studies support an association between 4-bp ins/del polymorphism of EGLN2 and cancer susceptibility. The variant positively associated with overall cancer susceptibility in heterozygous , homozygous , codominant , and allele  inheritance model .Heterogeneity between the studies comprised in the pooled analysis is indicated in Begg’s funnel plot and Egger’s test noticed no publication bias in all genetic models except in dominant .We executed sensitivity analysis to evaluate the influence of each study on the overall estimate. The pooled ORs were not substantially changed except in homozygous model, indicating that the present pooled analysis is stable and reliable.Prolyl hydroxylases 1 (PHD1) encoded by EGLN2 gene is involved in the catalyze degradation of HIF-1 by prolyl hydroxylation of specific residues. Several studies examined the role of EGLN2 4-bp ins/del polymorphism and the risk of some cancers . In the current study, for the first time, we inspected the correlation between EGLN2 4-bp ins/del polymorphism with the risk and clinicopathological characteristic of PCa. Our findings revealed no association between this variant and susceptibility as well as clinicopathological features of PCa patients. Furthermore, pooled analysis of our outcomes with six previous published studies indicated a significant association between the variant and risk of overall cancer in heterozygous, homozygous, codominant, and allele genetic models.Long non-coding RNAs (lncRNAs), a class of non-coding transcripts longer than 200 nucleotides, are involved in epigenetic, transcriptional and post-transcriptional regulation of gene expression . Growing evidence revealed that dysregulation expression of lncRNA contributes to the development and progression of various cancer for their function as proto-oncogene or anti-oncogene . (rs10680577) is within PERT-lncRNA . As rs10680577 variant is positioned within the RERT-lncRNA, it is reasonable that this variant may influence the expression level of RERT-lncRNA by affecting its folding structures. Recently, Zhu et al., (2018) reported that 4-bp ins/del polymorphism (rs10680577) affect the expression of EGLN2 and PERT-lncRNA. They found that the ins/del+del/del genotype carriers had increased expressions level of RERT-lncRNA as well as EGLN2. RERT-lncRNA, with 2,849 base pairs in length, is located within the proximal promoter of EGLN2, and a 4-bp ins/del polymorphism In conclusion, our findings proposed that EGLN2 4-bp ins/del polymorphism was not correlated with susceptibility and clinicopathological features of PCa in an Iranian population. Pooled analysis of our findings with previously published studies designated that 4-bp ins/del variant significantly augmented the risk of overall cancer.


Background: Studies suggest that neuron-specific enolase (NSE) levels in the cerebrospinal fluid (CSF) and serum play an important role in childhood epilepsy. However, these investigations remain controversial due to inconsistent clinical results. The present study aimed to quantitatively summarize and assess whether CSF and serum NSE levels are associated with epilepsy in children.Methods : A systematic search of the Harvard Hollis+, Clinicaltrials, Open Gray, China National Knowledge Infrastructure, and Wanfang databases was performed. Studies investigating NSE and epilepsy were identified and retrieved. Original studies with data overlapping those from other investigations and those lacking the necessary data were excluded. The included studies were extracted and synthesized, and data were analyzed using a random-effects model in R Studio and Comprehensive Meta-Analysis version 3 .Results: Random-effects meta-analysis of 26 studies, including 1,360 patients, and 1,256 healthy control, revealed that childhood epilepsy exhibited meaningfully increased CSF and serum levels of NSE compared with controls . No single study meaningfully influenced the overall association between CSF and serum levels of NSE and epilepsy after sensitivity analysis. Subgroup analyses according to sample source and assay type revealed a significant association between NSE levels and epilepsy. Stratified analysis confirmed that NSE levels were significantly correlated with the severity of neurological compromise. Metaregression analyses revealed that sample size, mean age, and sex may contribute to effect-size reductions; however, sample source, assay type, and country did not moderate effect size. Funnel plots constructed using the trim-and-fill method confirmed that the outcome of the meta-analysis could not be due to publication bias.Conclusion: The results demonstrated that childhood epilepsy exhibits significantly elevated levels of NSE in the CSF and serum, thus strengthening the association between increased NSE levels and epilepsy. Biomarksy) WHO, . This issy) WHO, , and presy) WHO, . Cellulasy) WHO, .Neuron-specific enolase (NSE), a glycolytic enzyme found in the brain, is released from the neuronal cytoplasm and neuroendocrine cells. Neuron-specific enolase levels can be used as an index of neural maturation, which exist as γγ- and αγ-dimers  statement , and sample sizes were extracted by two independent researchers. Information regarding potential moderator analyses of study type, region (country), publication year, mean age, diagnosis, sex distribution [male (%)], medication, disease duration, sample source, and assay type was also collected .g value, which is an unbiased ES that provides a correction factor to adjust for sample size. Random-effects models were used to assess ES, and 95% confidence interval (CI) to evaluate the statistical differences in the pooled ES. Random-effect models are more conservative because they generate a wider CI if there is high heterogeneity between and/or among studies. Sensitivity analysis was performed using a “leave-one-out”  RStudio,  and Comput” CMA,  method tI2 statistic, with I2 values of 25, 50, and 75% indicating low, moderate, and high heterogeneity, respectively. The potential moderating effects of study heterogeneity was assessed using metaregression analyses, including sample size, mean age, sex, sample source, assay type, and country. Subgroup analyses were undertaken according to sample source and assay type.Between-study heterogeneity was assessed using the Cochran Q test and the Publication bias was evaluated using funnel plots and CMA version 3, and statistical significance was assessed using Egger's test. Publication bias was examined using the trim-and-fill method, and the potential effect of publication bias was evaluated using a classic fail-safe N test, which calculates the number of missing studies.The systematic search retrieved 430 studies from the English language databases , 233 from the Chinese databases (CNKI and Wanfang), and four dissertations from CNKI. Abstracts of the retrieved articles were reviewed to evaluate their eligibility for full-text review. Thirty-two studies were selected for full-text analysis, which, after careful scrutiny, resulted in the exclusion of six studies due to a lack of necessary data ; P < 0.001] (g = 2.005 (95% CI = 1.169–2.840); P < 0.001] (g = 1.932 (95% CI = 1.189–2.675); P < 0.001] in childhood epilepsy  = 26; I2 = 96.714; P < 0.001].Random-effects meta-analysis was performed on the 26 included studies to generate a forest plot, which revealed that childhood epilepsy exhibited significantly increased CSF and serum levels of NSE compared with HCs [Hedges' < 0.001] . Neuron-< 0.001] , as wereepilepsy . Sensitiepilepsy . Howeverg = 2.194 (95% CI = 1.232–3.162), P < 0.001; Hedges' g = 2.455 (95% CI = 1.807–3.102), P < 0.001; and Hedges' g = 0.710 (95% CI = 0.082–1.337), P < 0.027, respectively] , ECLIA , enzyme immunoassay , and RIA . Subsequently, sample source subgroup analysis indicated a significant association between NSE levels in the CSF and epilepsy in children  (g = 1.932 (95% CI = 1.189–2.675); P < 0.001]. High heterogeneity between studies was still observed in studies in which CSF was the sample source  and from serum . Furthermore, the pooled Hedges' g values for epileptic type subgroup analysis according to generalized seizures  groups.To investigate possible explanations for the high heterogeneity, subgroup analyses were performed to explore potential methodological and clinical moderators. Subgroup analysis according to assay type, such as enzyme-linked immunosorbent assay (ELISA)  that could explain the high heterogeneity in the meta-analysis. Sex (P = 0.037). To adjust for funnel plot asymmetry, the trim-and-fill method was used in the meta-analysis, which yielded a Hedges' g = 0.6779 (95% CI = 0.106–1.250) , further supporting that the significant association between NSE levels and epilepsy demonstrated in the meta-analysis could not to be due to publication bias.Visual inspection of the funnel plots revealed that the distribution of dots appeared to be non-symmetric, suggesting that there was a possibility of publication bias among studies , which w6–1.250) , confirmNeuron-specific enolase is released into the CSF and blood following impairment to the integrity of the blood-brain barrier and neuronal cell structural damage. Increases in NSE levels have been observed soon after brain injury and are followed by a sustained peak 48 h after injury  results of craniocerebral injury, thereby reducing the number of CT examinations and guiding treatment. Although publication bias among studies was revealed by funnel plots and Egger's tests, our analyses using the trim-and-fill method suggested that the significant association between NSE levels and epilepsy in our meta-analysis was unlikely to be caused by publication bias.Large heterogeneity between studies was found in the present meta-analysis; however, sensitivity analysis indicated that no individual study could fully explain this heterogeneity. Subgroup analyses of study type, sample source, and assay type revealed a statistically significant association between NSE levels and epilepsy, although the high heterogeneity remained, and none of subgroups with relevant categorical variables fundamentally reduced or explained the heterogeneity. Stratified analysis confirmed that NSE levels were significantly correlated with clinical severity, and the ES value varied significantly according to different disease severities , as previously reported in the literature . Moreover, we attempted to adjust for more possible confounders; however, none of the relevant methodological and biological variables that we checked could explain the heterogeneity. Second, although we performed stratification analysis according to disease severity and type of epilepsy, only six studies provided detailed data regarding generalized or focal seizures. Furthermore, we did not perform stratification analysis of the pharmacological history of the patients due to a lack of data and studies, although some studies have reported pharmacological history in childhood epilepsy (Maiti et al., Further investigations of NSE levels and the influence of relevant confounding factors are needed to understand the molecular mechanisms driving changes in NSE levels in patients with epilepsy. Integrating electroencephalography and neuroimaging, molecular and cellular biomarkers, genomic information, and clinical information will be important in this regard.This study provided supportive evidence that CSF and serum levels of NSE are significantly elevated in childhood epilepsy, which is helpful for early diagnosis, evaluation of therapeutic effects, prognosis, and crucial medical interventions for epilepsy.Y-JH: study conception and design. SL and R-ZM: data collection. R-ZM, SL, and Y-JH: analysis or interpretation of data. All authors drafted the manuscript, critical revision, and read and approved the final manuscript.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.


ADRB3 Trp64Arg polymorphism may regulate adipokines and play an essential role in lipids metabolism. This study aims to clarify the associations of ADRB3 Trp64Arg polymorphism with plasma adipokines and lipid levels.Recently, some studies claim that adipokines may modulate plasma lipids. More interestingly, the Twenty-two studies (5527 subjects) and 121 studies  were respectively identified for the association analyses of adipokines and lipids. Standardized mean difference (SMD) and 95% confidence interval (CI) were used to estimate the strength of the Trp64Arg variant in adipokines and plasma lipids. All results were recalculated after eliminating the studies with heterogeneity.The carriers of the C allele  had higher levels of leptin and lower levels of adiponectin than the non-carriers. The carriers of the C allele had higher levels of triglycerides (TG), total cholesterol (TC), and lower levels of high-density lipoprotein cholesterol (HDL-C) than the non-carriers. Subgroup analysis certified an ethnicity (Asians), disease status (obesity), and gender  specific association. Sensitivity analysis indicated that the analysis results were robust and stable. Meta-regression indicated that obesity was related to adiponectin.The C allele carriers of Trp64Arg polymorphism had a slight but significant influence on lipid levels, and the remarkable effects specific existed in obese Asian women. The associations of Trp64Arg polymorphism with dyslipidemia may partly be mediated by the effect of this polymorphism on adipokines. The association of Trp64Arg polymorphism with obesity may partly be mediated by the effect of this polymorphism on adipokines. The C allele carriers had abnormal levels of adipokines and lipids, and it indicated that the Trp64Arg polymorphism might represent a genetic risk factor for coronary artery disease (CAD). CAD obtains the highest mortality and disability rate in most of the developed and developing countries. CAD is triggered by multiple genetic and environmental risk factors. Among these risk factors, the abnormal levels of adipokines , 2 and lADRB3 gene is located on the long arm of human chromosome 8 (8p11.1–12), and it contains two exons and one intron. The Trp64Arg polymorphism  is the only function mutation of the ADRB3 gene, located in exon one and caused by substitution from thymine (T) to cytosine (C). Previous studies have reported that the ADRB3 gene might regulate the expression levels of adipokines . (3) The studies have offered the mean adipokines or lipids with standard deviation (SD) by genotypes. (4) The studies have provided the allele or genotype frequencies of the Trp64Arg polymorphism. (5) The language of included studies is restricted to English and Chinese. The exclusion criteria for this study are as below: (1) Studies not related to Trp64Arg polymorphism; (2) studies do not offer genotype or allele frequencies; (3) studies present invalid data; (4) pedigree studies; (5) overlapping studies; (6) abstract, review, systematic review, meta-analysis, and animal studies.According to a pre-piloted data extraction form and the pre-specified selection criteria, two researchers independently extracted the data from each eligible study. Results were compared, and divergences about data extraction were settled by consensus. If crucial data were absent from included studies, e-mail, or telephone would be used to acquire these data. From each eligible study, the following data were extracted: the first author’s name, the publication year, language, country, ethnicity, disease status, gender, genotype counts, total sample size, and mean plasma levels of adiponectin, leptin, and lipids with SD by genotypes.P-values less than 0.05 were considered to be statistically significant. The Chi-square test estimated the Hardy–Weinberg equilibrium (HWE) among control subjects. Publication bias was tested by Begg’s funnel plot and Egger’s test [All the tests were performed by STATA software . r’s test . SMD witr’s test . GalbraiThe initial search of the databases yielded 2568 studies. Two thousand two hundred and ninety-seven studies were excluded by its contents. Then 167 studies were reevaluated by the inclusion criteria. Forty-five studies were further excluded due to the following reasons: twenty-five studies offered data of other polymorphisms, ten studies offered invalid data, five studies had subjects overlapping with other publications, and five studies were based on pedigree analysis. Finally, 122 studies were included for this systematic review  and HDL-C . Also, the disease status . However, no confounding factors , TC , and LDL-C .Univariate and multivariate meta-regression analysis was also conducted to explore sources of heterogeneity among the included studies. Furthermore, the analyses revealed that the total sample size Table S was a sis Table S was a sis Table S-S9 explaIn association analysis of the Trp64Arg polymorphism with plasma adipokines and lipids levels, a sensitivity analysis was conducted by calculating all results again after omitting every single study. Interestingly, the analysis results of adipokines and plasma lipids did not change substantially after omitting these studies, which indicated that the analysis results were robust and stable.P = 0.90 for leptin, 0.68 for adiponectin, 0.89 for TG, 0.28 for TC, 0.39 for LDL-C, 0.37 for HDL-C, respectively).Begg’s test and Egger’s test were used to evaluating the publication bias of the included studies, and no publication bias was detected  gene knock-out mice. Their data suggest that the ADRB3 gene may trigger dyslipidemia by regulating the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9) gene and LDL receptor (LDLR) gene. It is widely known that both PCSK9 and LDLR are lipid metabolism-regulated genes, thereby the Trp64Arg polymorphism may indirectly affect plasma lipids levels by regulating lipid metabolism-regulated genes expression. Thirdly, whereas both leptin [Several possible mechanisms can be proposed to explain the relationship between the e tissue , 41 intoe tissue , 39 wille tissue  have conh leptin –12 and ah leptin –15 are rh leptin –9. This In the present meta-analysis, the significant effects of the Trp64Arg variant on lipid levels were only in Asians Table , Table 4Several strengths of the present meta-analysis should be put forward. Firstly, the present meta-analysis had the sufficiently high statistical power to examine the associations of the Trp64Arg polymorphism with adipokines and plasma lipids in a large sample size, which would increase the reliability of the calculated results. Secondly, the calculated results were obtained after excluding the studies with heterogeneity, which would undoubtedly contribute to drawing some scientific and precise conclusions in the present meta-analysis. Thirdly, the multi-level analyses were performed by ethnicity, disease status, gender, healthy subjects, and children subjects, which would undoubtedly be beneficial to generate some comprehensive and diversified results in this present study. The main limitation of the present meta-analysis was that multiple genetic and environmental factors triggered dyslipidemia. However, the interactions between Trp64Arg polymorphism and other genetic or environmental factors on plasma lipids have not been investigated in this work due to the lack of original data.The C allele carriers of Trp64Arg polymorphism had a slight but significant influence on lipid levels, and the remarkable effects specific existed in obese Asian women. The associations of Trp64Arg polymorphism with dyslipidemia may partly be mediated by the effect of this polymorphism on adipokines. The association of Trp64Arg polymorphism with obesity may partly be mediated by the effect of this polymorphism on adipokines. The C allele carriers had abnormal levels of adipokines and lipids, and it indicated that the Trp64Arg polymorphism might represent a genetic risk factor for CAD.Additional file 1 Table S1. Characteristics of the included studies in this systematic review of plasma adipokines and lipids levels for the ADRB3 Trp64Arg polymorphism. Table S2. Plasma adipokines levels by the genotypes of the ADRB3 Trp64Arg polymorphism. Table S3. Plasma lipids levels by the genotypes of the ADRB3 Trp64Arg polymorphism. Table S4. Meta-regression analysis explores the sources of heterogeneity of plasma triglycerides (TG) levels. Table S5. Meta-regression analysis explores the sources of heterogeneity of plasma high-density lipoprotein cholesterol (HDL-C) levels. Table S6. Meta-regression analysis explores the sources of heterogeneity of plasma adiponectin levels. Table S7. Meta-regression analysis explores the sources of heterogeneity of plasma leptin levels. Table S8. Meta-regression analysis explores the sources of heterogeneity of plasma total cholesterol (TC) levels. Table S9. Meta-regression analysis explores the sources of heterogeneity for circulating low-density lipoprotein cholesterol (LDL-C) levels. Supplementary References: The reference list of the included studies in this systematic review.


Several associations between non‐genetic biomarkers and colorectal cancer (CRC) risk have been detected, but the strength of evidence and the direction of associations are not confirmed. We aimed to evaluate the evidence of these associations and integrate results from different approaches to assess causal inference. We searched Medline and Embase for meta‐analyses of observational studies, meta‐analyses of randomized clinical trials (RCTs), and Mendelian randomization (MR) studies measuring the associations between non‐genetic biomarkers and CRC risk and meta‐analyses of RCTs on supplementary micronutrients. We repeated the meta‐analyses using random‐effects models and categorized the evidence based on predefined criteria. We described each MR study and evaluated their credibility. Seventy‐two meta‐analyses of observational studies and 18 MR studies on non‐genetic biomarkers and six meta‐analyses of RCTs on micronutrient intake and CRC risk considering 65, 42, and five unique associations, respectively, were identified. No meta‐analyses of RCTs on blood level biomarkers have been found. None of the associations were classified as convincing or highly suggestive, three were classified as suggestive, and 26 were classified as weak. For three biomarkers explored in MR studies, there was evidence of causality and seven were classified as likely noncausal. For the first time, results from both observational and MR studies were integrated by triangulating the evidence for a wide variety of non‐genetic biomarkers and CRC risk. At blood level, lower vitamin D, higher homeostatic model assessment‐insulin resistance, and human papillomavirus infection were associated with higher CRC risk while increased linoleic acid and oleic acid and decreased arachidonic acid were likely causally associated with lower CRC risk. No association was found convincing in both study types. The identification of specific biomarkers related to colorectal cancer (CRC) risk is essential to understand cancer aetiology and mechanisms of progression. This is the first time that evidence of associations between a wide range of non‐genetic biomarkers and CRC risk from a huge number of epidemiological workswere evaluated. Three associations detected from meta‐analyses of observational studies were classified as suggestive, three and seven associations detected from Mendelian randomisation studies were classified as evidence of causality and likely non‐causal respectively. As no meta‐analyses of RCTs on non‐genetic biomarkers were identified, we included meta‐analyses of RCTs (1 January 2010 to 14 June 2019) on micronutrient intake as proxies of micronutrient blood levels. Systematic reviews without meta‐analyses were excluded. Meta‐analyses of observational studies on non‐genetic biomarkers and CRC risk published before 2010 had been previously reviewed in a published umbrella review.2.2R2), and the approximate statistical power (where presented).One investigator extracted information from each eligible study and two other investigators checked the extracted data. A fourth investigator was involved to judge any discrepancies. For meta‐analyses of observational studies, we extracted the first author, year of publication, number of studies considered, epidemiological study design, biomarker details, outcome, and study population. We also recorded the study‐specific relative risk estimates , details of the applied statistical models, correspondent confidence intervals, and number of cases and participants. For meta‐analyses of RCTs on micronutrient intake, we further extracted the dose and duration of supplementation, number of events, and type of intervention in the control group. For MR studies, we extracted: the exposure, study design, effect estimate unit, sample size, population ethnicity for both exposure and outcome groups, main MR estimate and any sensitivity analyses for the associations of genetic instruments with the exposure and outcome, total variance level explained by the genetic instrument assuming an additive model  estimator could give an accurate result when between‐study heterogeneity is large but the number of studies is not small.2 value and its 95% prediction interval.P < .1 as the threshold.For the meta‐analyses of observational studies, we re‐estimated the summary effect size and its confidence interval. As the most commonly used DerSimonian and Laird (DL) estimator tends to underestimate the 95% CI when less than 10 studies are included,Stata version 14.0 and “metafor” packageP values were used.in R 3.5.1 were used for statistical analysis. Two‐tailed 2.4P ≤ .05), and effect size. The most recent meta‐analysis with the largest number of prospective studies was retained for further analysis. The most recent MR study (unless a previous MR study employed a stronger genetic instrument and/ or had a larger sample size at the outcome arm) was retained for further comparison.If there were more than one meta‐analysis of observational studies or more than one MR study investigating the association between the same biomarker and CRC risk, we compared the direction, level of statistical significance (P ≤ .05). All associations explored in meta‐analyses of observational studies and/ or MR studies are presented in an evidence triangulation plot.If we identified meta‐analyses of observational studies and MR studies investigating the same biomarker, we compared the direction and level of statistical significance .P < .05), pre‐estimated power (Power ≥ 0.8 regarded as sufficient), and evidence of bias due to directional pleiotropy  by using the HKSJ meta‐analysis estimator  had a 95% prediction interval that excluded null, 14 (48%) had more than 1000 cases, 13 (45%) had no obvious large heterogeneity (I2 < 50%), 20 (69%) were not subject to small‐study effect or excess significance bias  were statistically significant . After removing the overlapping MR studies, 42 biomarkers were retained for analysis , fatty acid/lipid metabolism biomarkers n = 30), inflammatory markers (n = 4), protein/amino acid (n = 9), insulin‐related markers (n = 4), and other biomarkers (n = 2) Table . Nine  were classified as suggestive and 26 as weak.Twenty‐nine biomarkers were associated with CRC risk at The association between vitamin D concentration and CRC risk was classified as suggestive (Class III) and indicated that a higher blood concentration of vitamin D was associated with a 33% decrease in CRC risk. This result was consistent among all eight overlapping meta‐analyses.A statistically significant association between diabetes and CRC risk has been previously identified by an umbrella review published in 2014.Interestingly, seven different types of pathogenic microorganisms were found to be related to CRC risk, but most of the evidence was classified as weak due to small number of cases. Only HPV showed a suggestive association with CRC risk. HPV is a non‐enveloped double‐stranded DNA virus with more than 170 types. Twelve of these types are considered as causal risk factors for cervical cancer (known as high‐risk HPV types) by IARC Monographs.P‐value threshold of convincing evidence, and of these three were based on evidence from less than 1000 cases, three did not have a statistically significant P‐value for their largest component study and for one there was evidence of small study effect bias and excess significance bias. Despite weak evidence after applying the predefined credibility criteria, we cannot ignore the clinical importance of these associations. Notably, most (85%) of the overlapping studies agreed on the direction of effect estimate and over half (60%) agreed on both the direction and statistical significance.Overall, meta‐analyses of observational studies indicated weak associations between non‐genetic biomarkers and CRC risk. In this review, only seven of 65 associations fulfilled the 4.2Almost half of the biomarkers identified from MR studies were biomarkers of fatty acid/lipid metabolism. Most of the detected MR studies had insufficient power (<0.8). There were nine MR studies that reported statistically significant results. After retaining the largest MR study for each biomarker and applying the predefined assessment criteria, we found evidence that high blood levels of linoleic acid and oleic acid and low blood levels of arachidonic acid were associated with low CRC risk. Conversely, LDL‐cholesterol, omega‐6 polyunsaturated fatty acids (n‐6 PUFAs), total cholesterol, selenium, vitamin B12, telomere length, and adiponectin were not found to be associated with CRC risk.n‐3 and n‐6 PUFAs are essential fatty acids and cannot be produced in the human body.Overall, we found that there was either lack of evidence or that the credibility of evidence varied across the three different study designs. For instance, evidence detected from meta‐analyses of observational studies was not confirmed by MR studies or meta‐analyses of RCTs on supplementary micronutrients . This may be either due to differences in the study designs  or due to their inherent distinct limitations and biases. Conversely, four “likely noncausal” associations identified from MR studies also were reported as negative results by meta‐analyses of observational studies, that is, selenium, total cholesterol, LDL‐cholesterol, and telomere length.5This umbrella review presents for the first time, integrated evidence from meta‐analyses of observational studies, MR studies, and RCTs with the aim to improve our understanding of the associations between non‐genetic biomarkers and CRC risk. Each of the included studies have different strength and limitations and, if consistent, could strengthen our confidence in findings.6This umbrella review represents a comprehensive summary and evidence triangulation of a wide range of CRC risk‐associated non‐genetic biomarkers. In conclusion, we report and classify the evidence for non‐genetic biomarkers detected from meta‐analyses of observational studies, MR studies, and meta‐analyses of RCTs. Convincing evidence of a clear role of a non‐genetic biomarker in CRC risk has not been detected from meta‐analyses of observational studies. From MR studies, a likely causal increased CRC risk with arachidonic acid and a likely causal decreased risk with linoleic acid and oleic acid were suggested. Conversely, seven biomarkers  are likely noncausal. Four  of these seven biomarkers have consistent results  from MR and meta‐analyses of observational studies.None declared.ET conceived this study. XZ and DG conducted the literature search. XZ and TY conducted literature screening. XZ extracted the data. YH, GM, and DG checked the extracted data. XZ analyzed the data and draft the manuscript. All authors interpret the data, revised the manuscript, and approved the final version. ET is guarantor.Not required.Table S1‐S8Click here for additional data file.


Previous studies evaluated the association of IL-4 C33T polymorphism and risk of bronchial asthma but failed to establish a consistent conclusive association. In the present meta-analysis, we intend to define a more reliable estimate of the association in the presence of filling published literature.2 statistics were used to evaluate the degree of heterogeneity between studies.An exhaustive search in Web of Science, Scopus, and PubMed databases was performed to identify all relevant publications before September 2020, and 24 publications (28 studies) with 6587 cases and 8408 controls were included in final analysis. The association between polymorphism and risk of asthma were measured by Odd ratios (ORs) and 95% confidence intervals (CIs). Moreover, Cochran’s Q and the IIn the overall study populations, a significant positive association was detected under all genotype models and announced the IL-4 C33T polymorphism as a potential risk factor in the pathogenesis of asthma. In the subgroup analysis by age, a significant association between IL-4 C33T polymorphism and risk of asthma in different age groups was identified in allelic model, which highlighted the predisposing role of the T allele for the asthma risk in all three age groups. Furthermore, the results of subgroup analysis by continent were heterogenous. Accordingly, IL-4 C33T polymorphism was a risk factor in Europeans , Americans  and Asians . Finally, the ethnicity-specific analysis disclosed a significant association between IL-4 C33T polymorphism and asthma risk in Caucasians , while this association was not significant in African-Americans.This study suggests that IL-4 C33T polymorphism potentially acts as a risk factor for asthma in different ethnicities and age groups. Asthma is a chronic, complex respiratory disorder in which allergen-triggered inflammatory reactions in the airways contribute to the development of symptoms, including breathlessness, cough, wheezing, and dyspnea. It has been estimated that asthma affect about 300 million people in the world . PrognosWe carried out this meta-analysis by following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement . Since oA comprehensive systematic search was applied through three major databases  to find all potential publications considering the association between IL-4 C33T polymorphism and asthma risk released before September 2020. We searched (“asthma” [Mesh] OR “asthmatic”) AND (“interleukin-4” OR “IL-4” OR “interleukin 4”) AND (“single nucleotide polymorphism” OR “SNP” OR “polymorphisms” OR “mutation” OR “variation”), as main key words. Besides, cross reference check of review studies were screened for additional relevant papers.Initial search strategy yield 1873 studies that exported to Endnote X8. The duplicate studies which were common among databases were removed and title and abstract of remain studies were reviewed by two investigators. In cases that we could not categorize retrieved studies by title and abstract, full-text verification was performed. Eventually, studies considered eligible if met the following criteria: 1) publications that evaluate the association between IL-4 C33T polymorphism and the risk of asthma; 2) publications with extractable data to estimate odds ratios (ORs) and 95% confidence intervals; 3) publications that report genotype or allele distributions of case and controls. Duplicate articles, review articles, editorials, case reports, book chapters, republished data, comments, and studies with insufficient data after contacting with authors were all excluded. The usage of these criteria results in 24 eligible paper for the meta-analysis.Two researchers independently and according to a standard checklist extracted requisite data including: the first author family, country of origin, ethnicity, number of subjects in the case and the control groups for each gender, mean or range of age, applied genotyping method, distribution of alleles in cases and controls, journal and year of publication. The methodological quality of included study was scored using the Newcastle-Ottawa Scale (NOS) criteria . AccordiP value> 0.10, no heterogeneity vs. Q-statistic P value< 0.10, significant heterogeneity) and the I2 test   and recessive model ) Fig. In this group, we stratified included publications into three groups including: adult (8 articles), children (7 articles) and mixed . Overall, the results rejected significant association between IL-4 C33T polymorphism and risk of asthma in different age group except for allelic model [adults , recessive model , allelic model  and CC vs. TT . Moreover, there was a significant association between IL-4 C33T polymorphism and risk of asthma in American population under dominant model , allelic model , and CT vs. TT model . Eventually, Significant positive association was revealed in Asians just in recessive model , and allelic model  Fig. Our included studies performed in Asia (15 articles), Europe (4 articles), America (4 articles), and Oceania (1 article). Since there was only one study for Oceania, we exclude it. The final findings indicated strong significant association between IL-4 C33T polymorphism and asthma risk in European population across dominant model , recessive model , allelic model ,and CC vs. TT model  but not CT vs. TT model . However, there was no significant association between IL-4 C33T polymorphism and risk of asthma in American-African population across all genotype models Fig. Finally, we stratified eligible articles according ethnicity including Caucasians (20 articles), and African-Americans (4 articles). The results showed significant association between IL-4 SNP C33T) and asthma risk in Caucasians under dominant model  involving 6587 cases and 8408 controls, we systematically assessed the relationship between IL-4 C33T polymorphism and asthma susceptibility. Cumulatively, the result illustrated IL-4 C33T polymorphism as a risk factor in the pathogenesis of asthma. The result indicated that the presence of T allele across different genetic models increased asthma risk by 10 to 21%. In the subgroup analysis by age, the results rejected the significant association between IL-4 C33T polymorphism and risk of asthma in different age groups except for allelic model, which highlighted the predisposing role of the T allele for the asthma risk in all three age groups. Subgroup analysis by continent revealed a significant association between IL-4 C33T polymorphism and asthma risk in the European population. In the Asian population, there was a significant association between IL-4 C33T polymorphism and the risk of asthma under recessive and allelic models. In contrast, the American population showed a significant association under dominant and allelic models.Additionally, subgroup analysis was conducted according to ethnicity; the results showed a significant association between IL-4 C33T polymorphism and asthma risk in Caucasians under all models except CT vs TT model. While, no significant association between IL-4 C33T polymorphism and the risk of asthma in the American-African population were detected.It should be noted that our results are not in agreement with those of Liu et al.  meta-anaThe main reason for these discrepancies raised could be from the fact that Liu and colleagues included 18 studies with 5523 cases and 5618 controls. However, our meta-analysis encompasses 28 studies including 6587 cases and 8408 controls from different ethnicities and continents.The C33T single nucleotide polymorphism is detected on the 5′ untranslated regions (UTR) of the IL-4 gene . The 5′ Heterogeneity and publication bias, which may affect the results of meta-analyses, should always be considered. The result of this study did not show significant heterogeneity. Moreover, there was no significant publication bias in the overall population and subgroup analysis under all genetic models. Consequently, heterogeneity and publication bias did not appear to have inclined the results. Sensitivity analyses were also performed. There was a little variation of the estimates after exclusion of a single study and the significance of the pooled ORs was not affected proposing the consistency of this result.The current study had some limitations. First, most included articles were from the Asia continent with Caucasian race and there was no study from Africans; accordingly, the results of this meta-analysis may not be appropriate to Africans. Second, in some studies, the diagnostic criteria and asthma phenotype were not clearly determined; while the asthma diagnostic criteria were primarily based on physical examination, clinical history, and pulmonary function tests (PFT), there did exist a little dissimilarity among studies. Third, the overall results were based on unadjusted estimates; a more precise evaluation should be accompanied when all singular raw data are accessible, which would facilitate the adjustment by other potential co-variants such as; age, gender, obesity, environmental factors, smoking status, and other lifestyles. Fourth, due to a lack of extractable data, we failed to address gene-environment and gene-gene interactions. In contrast to these limitations, two main strengths of our meta-analysis include; Firstly, a large number of patients and the healthy individuals were pooled from various studies, which considerably augment the statistical power of the meta-analysis. Secondly, no evidence of publication biases was identified, representing that the whole collected data may be unbiased.Taken together, this study suggests that IL-4 C33T polymorphism potentially acts as a risk factor for asthma in different ethnicities and age groups. Nevertheless, large sample studies from different continents and races with homogeneous asthmatic patients and well-matched healthy subjects are still needed. Furthermore, gene-environment and gene-gene interactions should also be regarded in future studies. With taking these factors into account in future studies, it would ultimately lead to our comprehensive and better understanding of the association between the IL-4 C33T polymorphism and asthma susceptibility.


LTF, ENAM, and AMELX polymorphisms with dental caries susceptibility.This meta-analysis evaluated the association of We searched the Scopus, PubMed/Medline, Web of Science, and Cochrane Library databases to retrieve articles published by October 2019. Review Manager 5.3 software was used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs). The results of publication bias tests were retrieved by Comprehensive Meta-Analysis 2.0 software.LTF, 11 ENAM, and 11 AMELX polymorphisms). Of all polymorphisms, there was a significant association only between ENAM rs3796704 polymorphism and dental caries susceptibility. Both ENAM rs3796704 and AMELX rs17878486 polymorphisms had a significant association with dental caries risk in the Caucasian ethnicity and the studies including caries-free control group.A total of 150 relevant records were identified; out of which, 16 were entered into the analysis , and AMELX  polymorphisms and dental caries susceptibility.The results of this meta-analysis showed that the G allele and the GG genotype of  ENAM rs3796704 polymorphism and the risk of dental caries.1. There was an association between LTF (rs1126478), ENAM (rs1264848 and rs3796703), and AMELX  and dental caries susceptibility.2. There was no association between polymorphisms of lactotransferrin (LTF), enamelin (ENAM), and amelogenin X (AMELX). The rs1126478 polymorphism of LTF  produces a shift from arginine to lysine at amino acid position 47 in the antimicrobial region, and presents transcriptional activation activity  and the GG genotype ) of ENAM rs3796704 had an elevated risk in the case group compared with the control group. In addition, the funnel plots of each polymorphism are presented in the ENAM rs3796704 polymorphism and dental caries susceptibility.Table ENAM rs3796704 had an elevated risk in the case group compared with the control group in the Caucasian ethnicity; whereas in studies with a caries-free control group, the G allele and GG genotype had an elevated risk in the case group compared with the control group. In addition, the T allele, and TT and CT genotypes of AMELX rs17878486 polymorphism had an elevated risk in the case group compared with the control group in mixed ethnicity and studies with a caries-free control group. Therefore, there was a significant association between both polymorphisms of ENAM rs3796704 and AMELX rs17878486 and dental caries susceptibility in the Caucasian ethnicity and studies including caries-free individuals as the control group.Table AMELX rs17878486 because the outlier data and the results illustrated that by deleting this study, the CT  and CT + TT  genotypes in dental caries patients were significantly superior to controls and with a low heterogeneity, respectively  and also T vs. C and CT + TT vs. CC models of AMELX rs2106416 polymorphism (Begg’s test: P < 0.05).Both Egger’s and Begg’s tests were done on the previous pooled analyses with a minimum of three studies Fig. . The resLTF, ENAM, and AMELX and the risk of dental caries. The findings showed that ENAM rs3796704 polymorphism had an increased risk in the case group compared with the control group especially in the Caucasian ethnicity and studies with caries-free individuals as the control group.The effect of environmental risk factors  and geneLTF polymorphisms differs among various ethnicities [LTF rs1126478 polymorphism. However, none of them found any association between this polymorphism and dental caries susceptibility. In addition, the subgroup analysis in this meta-analysis did not find any association between this polymorphism and dental caries risk. Thus, we can exclude LTF rs1126478 polymorphism as a risk factor for dental caries; however, more accurate confirmation of results requires further research through larger studies on different ethnicities.The prevalence of nicities . The gennicities . Four stnicities , 20, 24 AMELX aberration predominantly causes mineralization defects and congenital disorders such as amelogenesis imperfecta [AMELX rs946252, AMELX rs17878486, AMELX rs6639060, and AMELX rs2106416 polymorphisms, none of them was associated with the risk of dental caries. However, the sensitivity analysis revealed that AMELX rs17878486 polymorphism could be a risk factor for dental caries but the ethnicity and type of selected controls were the effective factors on the association between AMELX rs17878486 polymorphism and risk of dental caries. In addition, two studies included in our meta-analysis [AMELX rs17878486 polymorphism and dental caries susceptibility. Therefore, it may point to the role of AMELX rs17878486 polymorphism in development of dental caries more than others.AMELX is the most significant factor for development of normal enamel  and AMELperfecta . Therefoperfecta . In our analysis , 15 showENAM gene may also play a role in enamel formation [ENAM polymorphisms included in this meta-analysis, one study on Saudi patients [ENAM rs1264848 polymorphism and another study on Polish children [ENAM rs1264848 polymorphism in dental caries, which was confirmed by Abbasoğlu et al., in their study on Turkish children [ENAM rs3796704 polymorphism and another study [ENAM rs3796703 polymorphism in dental caries patients compared with controls. One research [ENAM rs3796704 and risk of dental caries. Bayram and colleagues [ENAM polymorphisms may affect the development of enamel and these effects may be different between primary and permanent dentitions.ormation  and any ormation . Among spatients  reportedchildren  showed tchildren . Also, ochildren  reporteder study  showed aresearch  reportedlleagues  showed tSmall number of studies included in each analysis and different DMFT scores for selecting the cases and controls between the studies were two important limitations of the present meta-analysis. However, in most analyses, the heterogeneity was low and there was no publication bias.ENAM rs3796704 polymorphism were associated with an elevated risk of caries in the case group compared with the control group. But there was no association between LTF rs1126478, ENAM rs1264848, ENAM rs3796703, AMELX rs946252, AMELX rs17878486, and AMELX rs2106416 polymorphisms and dental caries susceptibility. However, subgroup analysis showed an association between ENAM rs3796704 and AMELX rs17878486 polymorphisms and dental caries susceptibility in the Caucasian ethnicity and studies including caries-free individuals as the control group. In addition, sensitivity analysis showed an increased risk of AMELX rs17878486 polymorphism in the case group compared with the control group. The future analyses with more cases in various areas should have focused on possible effects of gene-environmental interactions on caries experience.The findings of this meta-analysis confirmed that the G allele and the GG genotype of Additional file 1.


Geriatric nutritional risk index (GNRI) might predict the all-cause mortality in patients with heart failure (HF). We performed a meta-analysis to evaluate the correlation between GNRI and all-cause mortality in patients with HF.We searched the PubMed, Medline, Cochrane Library, and Embase databases for clinical trials investigating the association between GNRI and all-cause mortality in patients with HF, having the primary endpoint as all-cause mortality.In total, nine studies involving 7,659 subjects were included in the systematic review and meta-analysis. The results indicated that major risk and moderate risk GNRI (GNRI<92) was associated with an increased risk of all-cause mortality in elderly patients with HF . Low risk GNRI (GNRI<98) group predicted all-cause mortality in elderly HF patients  when compared with the high GNRI value group. A subgroup analysis indicated that the relationship between GNRI and HF might differ based on the subtype of heart failure.GNRI is a simple and well-established nutritional assessment tool to predict all-cause mortality in patients with HF. Heart failure (HF) is associated with high morbidity and mortality. Approximately 1-2% of adults have HF, and the incidence increases to 10% among people aged above 70 years . The allThe objective of our meta-analysis was to investigate the relationship between GNRI and all-cause mortality among patients with HF.We searched for articles in PubMed, Medline, Embase, and the Cochrane Library published up to November 15, 2019, without language restrictions. The following MESH terms or text words were used for our search: HF, GNRI, malnutrition, and mortality. Completed trials among human beings whose abstracts or full texts were available were selected.The GNRI was calculated from the serum albumin and BMI:2GNRI=14.89* serum albumin (g/dl) +41.7*BMI/22 kg/mThe cut-off values of GNRI were based on the report by Bouillanne et al. . They deTwo investigators independently reviewed the title and abstracts of all potentially eligible studies reporting the effect of GNRI on all-cause mortality in patients. Two researchers independently extracted the data using standardized data extraction forms and the defined eligibility criteria. Disagreements were solved by consensus. To ensure the reliability of the studies, the following criteria were used for the selection: a) Adults patients with HF, b) GNRI available and associated with all-cause mortality, c) cut-off GNRI value of 92, The following studies were excluded: a) overlapping or duplicate reports, b) Non-human experiments, c) The cut-off value not meeting our defined criteria.After removing all duplicate citations, two researchers extracted all the outcome data independently. The following data were extracted: publication characteristics, study regions, follow-up duration, BMI, GNRI, serum albumin, and all-cause mortality/CV events. The quality of the studies selected was scored by two reviewers using Newcastle-Ottawa Scale (NOS). We considered studies as high quality if they had a score of more than six.All data were analyzed using STATA statistical software (version 14.0). Results are presented as mean±x when normally distributed and as median and interquartile range otherwise. Heterogeneity between the studies was evaluating the Cochrane’s Q and I2 tests. A fixed-effect model was used in the absence of significant heterogeneity (I2<50%), else the random effect model was used. Publication bias in studies with different samples size was assessed by Egger’s funnel plots. We considered two-sided probability values of <0.05 as statistically significant.Initially, a total of 47 articles were selected from the primary search in the major databases. After screening the title and abstracts, 31 articles were excluded. Finally, nine studies published from 2013 to 2019 were selected -19. The p<0.01, random effect, p<0.01, random effect) compared to the high GNRI group , low or no risk (GNRI≥92). The pooled outcome for the low GNRI group showed a 1.59 (95%CI 1.37-1.85) times higher risk compared with the high GNRI group , we conducted four subgroup analyses based on the study region , sample size (>500 and ≤500), age (>75 years and ≤75 years), follow-up duration (>2 years and ≤2 years), and type of heart failure . When grouped by study region, GNRI predicted the all-cause mortality in Western countries  (Due to extreme heterogeneity between the studies (I effect) ,15-16 as effect) -14,17-19 effect) ,14-15 an effect) ,16,18-19 effect) ,15,17-18 effect) ,15,17-18 effect) ,14-16,19 effect) -12,19, wSensitivity analysis indicated that some included studies led to heterogeneity in the meta-analysis . The subHF is a growing health problem and is associated with high mortality. In patients with HF, malnutrition is common due to the change in systemic metabolism, the increase of body consumption and the dysfunction of gastrointestinal. A previous study indicated that approximately one-third of the patients with HF had accompanying malnutrition  and thatThe Geriatric Nutritional Risk Index (GNRI) is an-elderly-specific index that has been proposed to assess the nutrition-related risk of morbidity and mortality for elderly patients.Some studies demonstrated that low GNRI was associated with an increased risk for cancer and other diseases ,20. Our p<0.05). A further analysis involving 5206 subjects demonstrated that even a low risk of malnutrition (<98) was associated with an increased risk of all-cause mortality in patients with HF, which was in line with previous studies. Mastatoshi et al. also reported that low GNRI was strongly associated with increased CV events and re-hospitalization due to HF.The present study indicated that GNRI was associated with an increased risk for all-cause mortality in patients with HF. Patients in our study were divided into two groups, low GNRI (<92) indicating moderate to serve malnutrition, and high GNRI (≥92) indicating low or no risk of malnutrition. Our meta-analysis indicates that low GNRI predicted all-cause mortality in patients with HF , while patients in the other studies were elderly (≥65 years old). The result demonstrated that an association between low GNRI and poor prognosis in patients with HF was seen at all ages. In the analysis by subtype of HF, the significance of GNRI in predicting all-cause mortality in acute HF was low, while it was high in chronic HF. Thus, low GNRI might be better in predicting all-cause mortality in chronic heart failure than acute heart failure, especially in HFpEF.There was some heterogeneity in our study; we conducted some subgroup and sensitivity analyses to detect the origin of the heterogeneity. The subgroup analysis indicated the type of HF as the main cause of heterogeneity. The included studies comprised patients with acute heart failure, HFpEF, HFrEF, and mixed type of heart failure, which might lead to some heterogeneity. However, the limited number of studies precluded a more detailed analysis of classification.2 in one study, while it was below 28 kg/m2 in others. GNRI might underestimate malnutrition in overweight patients. Moreover, different nutrition-related risk results might be seen with different assessment methods, such as CONUT or PNI. Hence, future studies should focus on a better method to estimate the nutrition in HF patients.GNRI was calculated from serum albumin and BMI, and was a more useful parameter for predicting mortality than BMI and serum albumin in HF. Seven of the included studies reported BMI, of which the mean BMI was above 28 kg/mTo the best of our knowledge, this is the first meta-analysis that analyzed the association between GNRI and all-cause mortality in patients with HF. However, there are several limitations of the present systematic review and meta-analysis. First, some of the included studies had a small sample size in the low GNRI group, which could have affected the results. Second, studies that lacked information concerning the GNRI and mortality were excluded from the analyses. Third, the number of women enrolled was lower than men, which might have influenced the results. The population in studies from Eastern countries was entirely from Japan, which might have influenced some results. Besides, all the included studies were observational studies, which can influence the accuracy of the study. Despite these limitations, GNRI could be an effective marker in predicting the risk of mortality in HF.In elderly patients with HF, GNRI is a simple and well-established nutritional assessment tool that can help in predicting all-cause mortality. More studies should focus on GNRI and the subtype of HF and suggest methods to improve malnutrition in patients with HF.Dong CH and Chen SY designed and conceived this study. Dong CH and Chen SY completed data collection and manuscript writing. Pan J participated in data analysis and manuscript preparation. Zeng HL and Yang B provided important suggestions for article revision. Chen SY approved the final version of the manuscript.


Methionine synthase gene with the susceptibility to prostate cancer (PCa). Nevertheless, the conclusions remain divergent. We performed a systemic analysis with odds ratios (ORs) and 95% confidence intervals (95% CIs) to assess Methionine synthase rs1805087 A/G variant and PCa risk. Furthermore, we utilized in silico analysis to investigate the relationship between Methionine synthase expression and the overall survival (OS) time. Totally, 10,666 PCa patients and 40,750 controls were included. We observed that Methionine synthase rs1805087 A/G variant is associated with an elevated risk of PCa . During stratified analysis, similar results were obtained in Asian populations, hospital-based, high quality studies and that with large sample size. Moreover, in silico analysis indicated the Methionine synthase expression is down-regulated in both young and old PCa subjects (P < 0.05). Compared with the normal subjects, the down-regulated expression of Methionine synthase was found in PCa cases with Gleason score 6 to 9. Our study showed that Methionine synthase rs1805087 A/G variant may be associated with susceptibility of PCa, especially in Asian populations, hospital-based studies and that with high quality and large sample size. Furthermore, Methionine synthase rs1805087 A/G variant may be related to the prognosis of PCa.Previous studies have investigated the association of the rs1805087 A/G variant of  Although the incidence and mortality rate of PCa in Asian populations is lower than that in Western countries2, they have been increasing remarkably in recent years3. In China, the overall incidence is also increasing. PCa has become the most common solid tumor in urban male individuals. Therefore this highlights the need of strategies to prevent advanced PCa5. Up to now, various factors, such as age, hormone exposure and gene mutations, have been proved to be correlated with the development of PCa7. Particularly, growing evidence has indicated that genetic factors may play a crucial role in the etiology of PCa. For instance, the susceptibility of PCa would be increased around two to fivefold in patients suffering from Lynch syndrome. This disease is caused by gene mutations including PMS2 (Postmeiotic segregation increased—2) and MLH1 (Mutl homolog—1)10.Prostate cancer (PCa) remains the most commonly occurring non-cutaneous carcinoma. It can be considered as the leading cause of cancer-related deaths among men in Western countries12. Methionine synthase is located on chromosome 1 (1q43) and with 34 exons. It encodes a core enzyme in folate pathway with 1,265 amino acids (molecular weight 140.5 kDa)13. Methionine synthase rs1805087 A/G variant is the most common mutation. It can lead to an aspartic acid to glycine transition at position 919 of the polypeptide chain16. Previous researches have indicated that this variant is involved in DNA methylation and elevation of homocysteine levels, therefore regulating the enzymatic activity of Methionine synthase17. The association of Methionine synthase rs1805087 A/G variant with susceptibility to PCa was investigated by several studies; however, their conclusions were divergent. In 2009, a systemic analysis evaluated the association between Methionine synthase rs1805087 A/G variant and susceptibility of PCa; nevertheless, they indicated no significant effects of this mutation on PCa risk18. From then on, another research assessed the association between this polymorphism and PCa susceptibility in Han Chinese population. They revealed that Methionine synthase rs1805087 A/G polymorphism was independently associated with PCa by down-regulating the potential of methylation19. The aim of the present study was to explore the association between Methionine synthase rs1805087 A/G variant and PCa susceptibility in larger sample size using multiple analyses to acquire convincing conclusion32.Previous studies have shown that folate metabolizing genes play a central role in carcinogenesis. They are involved in the process of DNA repair and methylationWe conducted a comprehensive literature search according to EMbase, PubMed, Google Scholar, Web of Science, and Chinese SinoMed databases. The keywords are as follows: (MTR OR METH OR methionine synthase) AND (variant OR single nucleotide polymorphism) AND (prostate cancer OR tumor) . In addition, the reference lists of reviews or supplementary material of source documents were also retrieved for further research.Methionine synthase rs1805087 A/G polymorphism; (b) containing adequate information for all genotypes; and (c) case–control studies. Furthermore, studies should be removed if: (a) no control population was included; (b) research focuses on other diseases rather than cancer; (c) repeated previous publications.Studies were enrolled in our analysis according to the following criteria: (a) evaluating the relationship between PCa and Methionine synthase rs1805087 A/G variant. On the other hand, the D-allele is a wild type and considered to be a low-risk allele. Five genetic models were selected in the current study: allelic comparison , homozygote model (GG vs. AA), heterozygote comparison (GA vs. AA), dominant contrast (GG + GA vs. AA), and recessive model (GG vs. GA + AA).Relevant data were independently screened by two of the authors according to the selection criteria. The quality assessment of the included studies was investigated by Newcastle–Ottawa Scale (NOS). The NOS score ranges from 0 to 9 stars. A research can be considered as high-quality if it obtained seven or more stars. The following items were extracted: the first author’s name, publication year, race, source of control, score of NOS, genotype frequency, age range, Hardy–Weinberg Equilibrium (HWE) of cases and controls, sample size, and method. G-allele is a minor allele (mutated gene) for Methionine synthase rs1805087 A/G variant and risk of PCa was assessed by odds ratios (ORs) and 95% confidence intervals (CIs). We adopt Z-test to measure statistical significance of ORs. Assumption of heterogeneity was calculated by Chi-square-based Q-test. Fixed-effect model (Mantel–Haenszel method) was used when P value of Q-test was more than 0.05; otherwise, the random-effect model was used34. Subgroup analyses were conducted by race, sample size of case, quality assessment, and source of controls. P value for HWE was evaluated by web-based program (https://ihg2.helmholtz-muenchen.de/cgibin/hw/hwa1.pl) 35. P value > 0.05 revealed an HWE balance. Sensitivity analysis was adopted to explore the effect of single study on the OR by sequential exclusion of individual study36. I2 value < 50% indicates no statistical heterogeneity among studies. We used the Begg's funnel plot and Egger's test to evaluate the publication bias38. P > 0.05 indicates no statistical significance. All the statistical process was conducted using software STATA v11.0 .The strength of relationship between 42. The written informed consent was required from each participant. The above study protocol has been approved by ethics committee of the Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University and Affiliated Hospital of Jiangnan University. IHS was used to test the Methionine synthase expression in PCa cases enrolled in our centers. We incubated the paraffin section of PRAD in hydrogen peroxide (1%), and then washed it in phosphate buffer saline (PBS). Goat serum was utilized to block binding of non-specific proteins. These sections were incubated with anti Methionine synthase antibody at 1:200. Immunoreactive site was brown using diaminobenzidine. All methods in the present study were conducted in accordance with the relevant guidelines and regulations.Totally, 200 pathologically confirmed PCa patients were enrolled from our centers. Distribution of characteristics of these patients has been listed in our previous studyMethionine synthase in PCa and control counterparts (https://gemini.cancer-pku.cn/) 39. We also used The Cancer Genome Atlas (TCGA) samples to investigate the expression in PCa based on patients’ age, Gleason score, and nodal metastasis status. This database contains expression profiles of 52 PCa subjects and 496 controls . We evaluated the effects of Methionine synthase rs1805087 A/G variant by SNAP tool (https://rostlab.org/services/snap/). String online server was also employed to assess the network of Methionine synthase interaction (https://string-db.org/) 47.We employed the online database to explore the expression of The present study was approved by ethics committee of the Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University and ethics committee of Affiliated Hospital of Jiangnan University.https://www.ncbi.nlm.nih.gov/snp). In Global, G = 0.2118; Europeans, G = 0.1961; Americans, G = 0.1890; Africans, G = 0.2679; East Asians, G = 0.1098; Ashkenazi Jewish, G = 0.1660; and Others, G = 0.2123 , but not in low quality studies  . TGCA database40 showed evidence that the expression of Methionine synthase in PCa cases with Gleason score 6 to 9 was lower than that in normal subjects (P < 0.05, Fig. Methionine synthase expression was both down-regulated in PCa patients with and without lymph node metastasis (P < 0.05, Fig. Methionine synthase rs1805087 A/G variant could impact the protein expression, we used SNAP tool to predict the mutation of Methionine synthase (Fig. Methionine synthase rs1805087 A/G variant is deleterious and effect (Fig. Homo sapiens. The top 10 proteins are: MTRR: Methionine synthase reductase; MTHFR: Methylenetetrahydrofolate reductase; MMADHC: Methylmalonic aciduria and homocystinuria type D protein, mitochondrial; CBSL: Cystathionine beta-synthase-like protein; MMACHC: Methylmalonic aciduria and homocystinuria type C protein; CTH: Cystathionine gamma-lyase; AHCY: Adenosylhomocysteinase; SHMT1: Serine hydroxymethyltransferase; MAT1A: S-adenosylmethionine synthase isoform type-1; MTHFD1: Methylenetetrahydrofolate dehydrogenase (Fig. Methionine synthase expression in PCa tissues, we adopted IHS to assess its expression among PCa participants in our hospitals. Compared with the earlier stage, the down-regulated expression of Methionine synthase was found in more advanced PCa participants (stage >  = T3b versus =  < T2c, P < 0.05, Fig. We employed in silico tool to investigate the expression of P = 0.066; GA vs. AA: t = 2.03, P = 0.064; GG vs. AA: t = 1.95, P = 0.073; GG + GA vs. AA: t = 2.06, P = 0.060; and GG vs. GA + AA model: t = 1.92, P = 0.077.The sensitivity analysis was conducted to investigate the effect of individual study on the OR. As described in Fig. 42. PCa remains one of the most commonly occurring carcinomas among men in Western countries. It has been clarified that several risk factors, such as family history, hormone exposure, lifestyle, may be associated with susceptibility of PCa46. Previous articles showed that Methionine synthase may be involved in the development of PCa29. However, the assoiation between Methionine synthase rs1805087 A/G variant and PCa risk remains ambiguous. For instance, a case–control study based on Iran descendants found that Methionine synthase rs1805087 A/G variant could influence stability and activity of its expression22. This polymorphism might be related to PCa risk in male individuals. However; another researchers did not indicate similar conclusions26. A meta-analysis conducted 10 years ago revealed no significant associations between Methionine synthase rs1805087 A/G variant and PCa risk18. From then on, more and more researchers ascertained their results in different populations26. Hence, in our systemic analysis, all eligible studies based on the inclusion criteria were summerized to ascertain a precise conclusion on the association between Methionine synthase rs1805087 A/G variant and PCa risk. Totally, 10,666 PCa patients and 40,750 controls were included to investigate the Methionine synthase polymorphism.Identification of genetic mutations that related to susceptibility of carcinoma is useful to predict cancer risk and reveal the pathogenesis of various tumorsMethionine synthase rs1805087 A/G variant and susceptibility of PCa under three genetic models. The conclusions acquired from our study were: person carrying the Methionine synthase G-allele may have an increased PCa risk. In stratification analysis by race, we observed similar positive results in Asian populations. Methionine synthase rs1805087 A/G variant might elevate PCa susceptibility as seen in high quality studies, hospital-based studies, and that with large sample size. Furthermore, we used online gene expression mini-database to investigate Methionine synthase expression in PCa and control counterparts. We found that Methionine synthase expression is down-regulated in both young and old PCa subjects. Compared with the normal subjects, the down-regulated expression of Methionine synthase was found in PCa cases with Gleason score 6 to 9, which was consistent with results of our IHS analysis. We also evaluated whether the Methionine synthase expression level influence the PCa patients' OS time. PCa patients with high Methionine synthase expression may have a shorter OS time in the first 5 years. However, with the passage of time, this positive relationship would not be statistically significant. In addition, we used SNAP tool to evaluate the variation of Methionine synthase. The mutation score is 3, which indicate that Methionine synthase rs1805087 A/G variant is deleterious and effect.In our analysis, 15 case–control studies were included. The overall results revealed a positive association between Methionine synthase rs1805087 A/G variant and PCa susceptibility, there are some limitations that should be considered. To start with, only three Asian studies involving Methionine synthase rs1805087 A/G variant and PCa risk were retrieved, which indicates that the total participants count for Asian population remains relatively low for more comprehensive analysis. Second, all included case–control studies were retrospective, which may cause selection bias during the process of analysis. Third, lacking of some original data such as family history, lifestyle, and smoking exposure, may limit the efficacy to further calculate adjusted OR. Fourth, studies with only English or Chinese language were included; therefore, some articles written in other languages may be missing, which may cause some bias in risk estimation. In spite of the limitations, there are several advantages in our analysis. First, HWE is very significant while evaluating genetic variations. P value for HWE is more than 0.05 in most of the included studies, which shows that the conclusion from the included studies is very stable. Second, studies with larger sample size particularly improved the statistical efficiency. Third, we indicated no publication bias while evaluating Methionine synthase rs1805087 A/G variant, so the conclusions of the present analysis are more convincing. As described in Fig. Methionine synthase in Homo sapiens. Nevertheless, there is not enough research on their further mechanism in PCa. Further researches are warranted to explore the interactions in more details.Although considerable resources have been generated to evaluate association between Methionine synthase rs1805087 A/G variant is associated with PCa susceptibility, especially in Asian descendants, hospital-based studies, high quality studies and that with large sample size. Moreover, Methionine synthase rs1805087 A/G variant may be related to the prognosis of PCa. Further studies containing more information such as lifestyle and smoking exposure, are warranted to assess this association in details.Taken together, our study indicated that All the data analyzed in the present study is included in the manuscript.Supplementary file1.