P < 0.001) and multivariate  analyses. Likewise, a similar result was found in different subgroups of the patient source, cancer type, test method, sample source, miR-200 component, and sample size. However, no association of miR-200 family was detected with recurrence- or relapse-free survival (RFS) , progression-free survival (PFS) , and disease-free survival (DFS) . Our findings have provided convincing evidence that miR-200 family overexpression suggested poor prognosis of various cancer types, which efforts may raise the potential use of miR-200 family for cancer prognosis in clinical practice.The correlation between miR-200 family overexpression and cancer prognosis remains controversial. Therefore, we conducted a systematic review and meta-analysis by searching PubMed, Embase, Cochrane Library, China Biology Medicine disc (CBM), and China National Knowledge Infrastructure (CNKI) to identify eligible studies. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to evaluate the strength of the correlations. Additionally, different subgroup analyses and publication bias test were performed. Eventually, we analyzed 23 articles that included five tumor types and 3038 patients. Consequently, high expression of miR-200 family in various tumors was associated with unfavorable overall survival (OS) in both univariate (HR = 1.32, 95% CI: 1.14–1.54,  MicroRNAs (miRNAs) are evolutionarily conserved, endogenous small noncoding, and single-stranded RNAs of 18–22 nucleotides in length. They often negatively regulate gene targets by translational inhibition or mRNA degradation , 4. miRNInterestingly, the miR-200 family is a typical and most extensively studied example in functional miRNAs. The miR-200 family, composed of five miRNA sequences  and located in two clusters in the genome, is involved in the epithelial to mesenchymal transition (EMT) through regulation of E-cadherin expression via suppression of ZEB1 and ZEB2 , 8. ReceThe PRISMA statement was used to conduct the current meta-analysis . No patiLiterature resources including PubMed, Cochrane Library, Embase, CBM, and CNK were introduced to search eligible studies, by using the terms “microRNA OR miRNA OR miR-200 OR miR-141 OR miR-429 OR miR-200 family OR miR-200 cluster,” “survival OR prognosis OR prognostic,” and “cancer OR tumor OR tumour OR neoplasm OR neoplasma OR neoplasia OR carcinoma OR cancers OR tumors OR tumours OR neoplasms OR neoplasmas OR neoplasias OR carcinomas.” Last search of current investigation was updated on November 25th, 2017. Additionally, the publication language was only limited to English and Chinese. In case of omission, we identified the reference lists of the relevant articles and reviewed articles to seek for the potentially relevant studies. Conventionally, we have not contacted the corresponding authors even if the relevant data were unavailable.Studies complied with the following criteria could be identified: (1) clinical study about the association of miR-200 family with cancer prognosis and (2) relevant data of the hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) to evaluate its associations were available. Studies which met the following four criteria were excluded: (1) the available data regarding associations was absent; (2) similar or duplicate study ; (3) other types of articles such as reviews or abstracts; and (4) studies involved with cell lines or animal models.In the light of inclusion and exclusion criteria, we extracted the relevant data from each eligible study. If disagreements were noticed, we are clearly open to discussion by each other (Wen Liu and Kaiping Zhang) or reviewed by a third author (Pengfei Wei). The data on first author, publication year, study country, age, cancer type, miRNA category, sample source, sample size, follow-up time, test method, survival outcome, analysis method, HR (95% CI), and the cut-off value were extracted. We have not contacted any author of the original researches even if the essential information could not be available. Besides, patient sources came from Asia, Europe, and North America. Sample sources were stratified into tissue, blood, formalin-fixed and paraffin-embedded (FFPE), and tissue microarray (TMA). Test methods included TaqMan, in situ hybridization (ISH), and reverse transcription polymerase chain reaction (RT-PCR). Sample sizes were separated into ≥100 and <100. Cancer types included epithelial ovarian cancer (EOC), breast cancer (BC), nonsmall cell lung cancer (NSCLC), gastric cancer (GC), and colorectal cancer (CRC). Analyses methods were divided into univariate analysis and multivariate analysis. Patients' prognostic outcomes included overall survival (OS), relapse-free survival (RFS), progression-free survival (PFS), and disease-free survival (DFS).Q and I2 test across studies  [I2 > 50% or P < 0.01 for Q test), we used random-effects (DerSimonian and Laird method) model [P value less than 0.05 indicated that there was a bias of the study [We have explored the association of miR-200 family with cancer prognosis by applying Review Manager software  and Stata software . HR and 95% CI were collected for assessing the prognostic value of high expression of miR-200 family in various cancers. Meanwhile, the heterogeneity has been assessed via chi-square-based d) model . Otherwid) model . One-wayhe study . AdditioConsequently, 23 studies consisted of 3038 samples satisfied the eligible criteria –38 Figu.The principal characteristics of the eligible studies were summarized in Among these studies, Cheng's study was involved with three different cohorts of Tianjin cohort, TexGen cohort, and all cohort . Zhu et P < 0.001)  . Besides< 0.001) .P < 0.001)  . Likewis< 0.001) .P = 0.47; multivariate: HR = 1.07, 95% CI: 1.00–1.14, P = 0.07)    , PFS (un = 0.32) , and DFS = 0.90) .I2 from 75.1% to 73.3%), while the pooled results remained unchanged . Likewise, as shown in I2 from 85.1% to 80.4%), and the pooled results remained unchanged  after excluding the aforementioned study [Each single included study was deleted at a time to assess the specific effect of the individual data on the pooled HRs, and one-way sensitivity analysis suggested that most pooled results were relatively stable. Among them, the pooled results of OS, RFS, and PFS in both univariate analysis and multivariate analysis were shown in Figures ed study .P = 0.028) and multivariate analysis (P < 0.001). However, no publication bias was found in meta-analysis of RFS , PFS , and DFS .Begg's funnel plot indicated that there was a significant publication bias in meta-analysis of OS under both univariate analysis , and miR-141 and miR-200c on chromosome 12 (12p13.31). Deregulation of the miR-200 family of microRNAs has been involved in cell plasticity, apoptosis, molecular subtype, oestrogen regulation, control of the growth and function of stem cells, and regulation of the downstream transcriptional program that mediate distant metastasis . Cancer To date, studies focused on the association of high expression of the miR-200 family with cancer prognosis have yielded conflicting results. Notably, small sample-sized studies lacking statistical power often have resulted in apparently contradicting conclusions. Meta-analysis is a useful tool for providing convincing evidence as it could present inconsistent results from different studies to get a relatively precise result. As far as we know, the current meta-analysis is the first try to comprehensively assess the correlation of miR-200 cluster high expression with cancer prognosis. We have explored the potential associations in overall population and the corresponding subgroups. Consequently, of particular interest is the finding of significant correlation between high expression of miR-200 cluster and poor OS by two different statistical methods. Likewise, a similar result was found in different subgroups. However, no association of miR-200 family was detected with RFS/PFS/DFS.In the current meta-analysis, significant heterogeneity was found, which required careful interpretation and searched for influencing factors by further subgroup analyses. Consequently, impact of ethnicity, detection methods, cancer types, sample size, and sample source on prognosis in patients was considerable, which should be taken into consideration when evaluating the prognosis of cancer for patients. Some potential or undiscovered factors including adjustment for surgery, radiation, chemotherapy, socioeconomic status, and tumor characteristics should not be ignored. Moreover, there was a significant publication bias in meta-analysis of OS under both univariate analysis and multivariate analysis, suggesting that only published studies in English and Chinese might not provide so sufficient evidences. As for RFS/PFS/DFS, we did not perform subgroup analyses due to relatively fewer eligible studies. Although the studies regarding various tumors without a consistent cut-off value may influence the ultimate results and the heterogeneity suggested that potential or undiscovered factors might be ignored, a certain relationship of high expression of the miR-200 family in cancer prognosis was found in the current study.In summary, the current study is the first original meta-analysis to address the correlation between miR-200 family expression and prognosis for cancer patients. A significant correlation was explored in overall population as well as the corresponding subgroups. Concretely, it presented that miR-200 family overexpression might be associated with poor OS to some extent, while no association was detected between high miR-200 family expression and RFS/PFS/DFS. In the future, detailed investigations comprising large cohort size from multicenter are required to confirm our conclusions.


To analyze the association between glutathione S-transferases polymorphisms and the risk of cervical lesions.Case-control studies focusing on the association between glutathione S-transferase polymorphisms and the risk of cervical lesions were collected from the PubMed, Web of Science, Cochrane Library, Embase, Medline, CNKI, VIP and Wanfang databases from inception to August 2018. Pooled odds ratios and 95% confidence intervals were employed to evaluate the strength of the association. Subgroup analysis and sensitivity analysis were used to test the potential discrepancy and robustness, respectively.GSTP1, 27 studies contained information about GSTM1, and 22 studies contained information about GSTT1. Our results supported that there was no statistical association between GSTP1 polymorphism and the risk of cervical lesions . The GSTM1 null variant showed increased susceptibility to cervical lesions . Subgroup analysis revealed that the GSTM1 null variant caused cervical lesions among HPV infection cases  and among the Chinese and Indian populations . The GSTT1 null variant increased the risk of cervical lesions in smokers . The GSTT1 null genotype was also related to high-grade intraepithelial neoplasia (HSIL) and cervical cancer risk .A total of 30 studies comprising 3961 patients and 4726 healthy controls satisfied the inclusion criteria. Of these, 6 studies contained information about GSTM1 null variant caused cervical lesions, especially among HPV infection cases and among the Chinese and Indian populations. The GSTT1 null variant increased the risk of cervical lesions in smokers and was also related to HISL and cervical cancer risk.The  Human papillomavirus (HPV) is considered a major factor in cervical cancer. Other co-factors are also important in cervix carcinogenesis, including immune suppression, cigarette smoking, parity, and oral contraceptive use.Cervical cancer ranks fourth for both incidence and mortality rates in women, with an estimated 570,000 cases and 311,000 deaths in 2018 worldwide. In lower human development index (HDI) regions, it is the second most frequently diagnosed cancer and the second leading cause of cancer death. Studies have shown that genetic variations in GSTs affect human phase II detoxification enzymes, thereby altering their ability to detoxify various exogenous and endogenous active species.Glutathione S-transferases (GSTs) are a family of phase II enzymes that are responsible for the metabolism of various xenobiotics and carcinogens by catalyzing the conjugation of glutathione to electrophilic compounds.GST genetic variants were related to the risk of several cancers, such as breast, lung, prostate, bladder, and nasopharyngeal cancer risk. However, the results were controversial regarding whether GST polymorphisms would lead to the development of cervical lesions, so we conducted this meta-analysis about the relationship between GST genetic variants and cervical lesions risk.Previous studies revealed that the 22.1We searched the Cochrane Library, Embase, Medline, PubMed, Web of Science, CNKI, Wanfang, and VIP databases by the following search terms: Glutathione Transferase[Mesh] or GST∗, glutathione S-transferase pi[Mesh] or GSTP1, glutathione S-transferase M1[Mesh] or GSTM1, glutathione S-transferase T1[Mesh] or GSTT1, polymorphism∗/variant∗/mutation∗/SNP, Uterine Cervical Neoplasm [Mesh]/cervix cancer/cervical cancer/cervical neoplasm∗/cervical carcinoma∗, and the combinations of these. In addition, we searched the reference lists of all identified articles manually to acquire more data.2.2GST gene polymorphisms (GSTP1/GSTM1/GSTT1) and the risk to cervical lesions; human study subjects; case-control studies; available and sufficient genotype distribution data to calculate odds ratios (ORs) and corresponding 95% confidence intervals (CIs); and diagnoses based on cervical biopsy pathology or cytology. Besides, if there were duplicate studies, the most complete one was reserved. Otherwise, the article was excluded if it did not satisfy the criteria above.Studies included needed to meet the following criteria: regarding on the association between 2.3 We gathered characteristics from all satisfied records: the first author, publication year, ethnicity, total numbers of cases and controls, source of controls, genotyping method.Two investigators extracted relevant data from all the eligible studies independently. A third reviewer was invited to participate in the work when some disagreement occurred; consensus was ultimately reached by discussion. According to the 4th WHO Women's Genital Tumor Classification Guidelines, we defined cervical lesions as cervical cancer, high-grade intraepithelial neoplasia (HSIL), and low-grade intraepithelial neoplasia (LSIL). LSIL was equivalent to cervical intraepithelial neoplasia (CIN) grade 1, and HSIL included most amount of CIN2 and all CIN3 cases.2.4GSTs polymorphic variants and cervix lesions. A Z-test revealed statistical significance when P < .05. I2 and Q statistic were applied to detect heterogeneity among different studies. There was no heterogeneity if I2 < 50% and P > .1 and a fixed effect model was used, otherwise we thought heterogeneity existed in the incorporated populations and a random effect model was used instead. Subsequently, we conducted a subgroup analysis according to HPV infection status, cigarette smoking, degree of cervix lesions, and ethnicity. Hardy-Weinberg equilibrium (HWE) was evaluated by chi-square test with P < .05 indicating a deviation from HWE. Sensitivity analysis was employed to estimate stability of the meta-analysis results by deleting all the studies one by one. Additionally, a Begg funnel plot and an Egger test were used to evaluate publication bias. The statistical analyses were performed using RevMan 5.3 (Cochrane Collaboration) and STATA 12.0  software.Using the ORs and 95% CIs to assess the degree of association between 33.1GST polymorphisms, 20 were review papers or meta-analyses, 8 records were deleted for other reasons. We downloaded the remaining 38 articles as full-text reports and reviewed them carefully. Four records were excluded for containing duplicate samples, and the data were not available in other 4 studies. Finally, 30 case-control studies containing 3961 cases and 4726 controls were included, among which 6 studies were about GSTP1, 27 articles were on GSTM1, and 22 studies focused on GSTT1   Fig. .GSTM1 involving 3383 cases and 3652 controls. The results showed that the GSTM1 null allele was related to an increased risk of cervical lesions  , thus, a random-effect model was employed. In addition, we conducted subgroup analysis based on HPV infection status, smoking status, degree of cervical lesions, ethnicity. The results presented in Table GSTM1 null variant was related to an increased risk of cervical lesions among HPV positive cases  , and Chinese and Indian populations , but was not related to the degree of cervical lesions  . In addition, the GSTT1 null variant was related to HISL and cervical cancer  but was not related to LSIL  Fig. . Conside3.3GST genetic variants . In consideration of this, we used a random effect model for the meta-analysis. Additionally, subgroup analysis stratified by HPV infection status, cigarette smoking, degree of cervical lesions, and ethnicity was performed to eliminate heterogeneity. Heterogeneity was clearly decreased in the ethnicity subgroup. This indicated that ethnicity might be a confounding factor and heterogeneity source, while the pooled ORs were substantially robust.As presented in Tables GST variants, indicating that the meta-analysis was robust and stable   Fig. .4Cervical cancer is an outcome of virus-induced carcinogenesis. HPV is the primary etiology of cervical carcinogenesis but all HPV infections do not result in cervical cancer. Tobacco use, immune system function, use of oral contraceptive, number of sexual partners all modify the outcome of cervix lesions. GSTs catalyzed the conjugation of glutathione to electrophilic substrates, which resulted in the enhanced renal clearance and reduced carcinogenic load from the cell.GSTs play an important role in protecting cells from oxidative damage and in modulating the induction of other enzymes and proteins in response to DNA damage, therefore, they are important for maintaining genomic integrity.GSTP1 G/A single nucleotide polymorphism caused valine  took the place of isoleucine (Ile) at codon 105, resulting in decreased enzymatic activity and low ability to metabolize certain xenobiotics and carcinogens. Biochemical studies indicated that the GSTP1 AA genotype was 2 to 3 times less stable and might be associated with the risk of gynecological cancer. However, our results supported that GSTP1 AA genetic variant was not associated with the risk of cervix lesions, which was consistent with Zhao finding. This might be attributed to an insufficient sample size.The GSTM1 and GSTT1 genotypes, some studies indicated that the GSTM1 null or GSTT1 null variants contributed to cervical cancer susceptibility, while some studies showed that the 2 variants were not associated with cervical carcinogenesis. Our results supported that the GSTT1 null variant increased the risk of cervical lesions in smokers. The GSTT1 null genotype was also related to HISL and cervical cancer risk. The GSTM1 null variant increased susceptibility to cervical carcinogenesis. Subgroup analysis revealed that the GSTM1 null variant caused cervical lesions among HPV infection cases and among the Chinese and Indian populations. This implied that there were differences in ethnicity and environment. In addition, it elevated the risk of cervical lesions among women who were not smoking, which implied that the GSTM1 null genotype might be a risk factor independent of cigarette smoking.With regard to the GST null genotype resulted in complete loss of the ability of the enzyme to bind genotoxic substrates. This leads to decreased detoxification ability, a reduction in the metabolic rate of intracellular toxic substances, and increased malignant transformation of cells, which thereby promoted tumorigenesis. Several studies on the relationship between GST polymorphisms and cervical cancer risk were conducted. Compared with those studies, our meta-analysis included additional qualified studies to evaluate the association and therefore obtained more persuasive conclusions. Additionally, the study included the association of GSTP1, GSTM1, and GSTT1 genetic variants on cervical lesion risk, while previous studies were based on only one or two of the three variants. Moreover, to eliminate the effects of co-factors, we performed subgroup analysis stratified by HPV infection status, cigarette smoking, degree of cervical lesion and ethnicity. Thus, our findings provide stronger evidence for the association between GST genetic variants and cervical lesions.A previous study demonstrated that the GSTP1 genetic variant. Second, the incidence of cervical cancer is highest in sub-Saharan Africa, Latin America, the Caribbean, and Melanesia, where people of African origin account for the majority of the population. However, there were no statistics and studies of interest focused on women of African descent. This caused bias in the relationship, which is concerning. Additionally, although we considered the effect of age on our conclusions and attempted to perform a subgroup analysis, inconsistent age grouping of the included studies prevented us from conducting a subgroup analysis stratified by age. Last but not least, GSTP1, GSTM1, and GSTT1 all belonged to the glutathione S-transferase family, playing an important role in protecting cells from oxidative damage and in metabolizing various carcinogens. As reported, the combination of the GSTM1 null, GSTT1 null, and GSTP1 AA genotypes was associated with an increased risk of gynecological cancer, while the GSTs alone were not. Therefore, gene–gene interactions are likely more appropriate to assess disease risk than individual genes. In our meta-analysis, there was no association study between gene–gene interactions and the risk of cervical lesions. Future studies containing more comprehensive information are needed to obtain more reliable conclusions.There are some limitations to our study. First, the small sample size was insufficient to support our results regarding the 5GSTP1 AA genotype was not associated with the risk of cervical lesions. The GSTM1 null variant caused cervix lesions, especially among HPV infection cases and among the Chinese and Indian populations. GSTT1 null variant increased the risk of cervical lesions in smokers and was also related to HISL and cervical cancer risk. Additional large, well-designed case-control studies are needed to authenticate these results.In general, the Conceptualization: Sijuan Tian, Li Zhang, Ting Yang.Data curation: Sijuan Tian, Xiaofeng Yang, Li Zhang, Juan Zhao, Meili Pei, Yang Yu, Ting Yang.Formal analysis: Sijuan Tian, Xiaofeng Yang, Li Zhang, Juan Zhao, Yang Yu, Ting Yang.Funding acquisition: Xiaofeng Yang, Juan Zhao, Ting Yang.Investigation: Sijuan Tian, Xiaofeng Yang, Juan Zhao, Meili Pei, Yang Yu, Ting Yang.Methodology: Sijuan Tian, Xiaofeng Yang, Juan Zhao, Meili Pei, Yang Yu, Ting Yang.Project administration: Sijuan Tian, Xiaofeng Yang, Li Zhang, Ting Yang.Resources: Ting Yang.Software: Sijuan Tian, Ting Yang.Supervision: Ting Yang.Validation: Ting Yang.Visualization: Sijuan Tian, Ting Yang.Writing – original draft: Sijuan Tian, Ting Yang.Writing – review & editing: Sijuan Tian, Ting Yang.


Several reports were published on the relationship between the vascular endothelial growth factor (VEGF) -2578C > A gene polymorphism and lung cancer risk; however, the results are debatable. This meta-analysis was conducted to assess the relationship between VEGF -2578C > A gene polymorphism and lung cancer risk.The associated literatures were identified on the 1st of September 2018 from CBM-disc  and PubMed.P = 0.003; CC genotype: OR = 0.72, 95% CI: 0.54–0.95, P = 0.02; Asians: A allele: OR = 1.33, 95% CI: 1.15–1.55, P = 0.0002; CC genotype: OR = 0.68, 95% CI: 0.50–0.93, P = 0.01). However, VEGF -2578C > A gene polymorphism was not associated with the risk of lung cancer in Caucasians.A total of 14 reports were recruited into our meta-analysis to assess the association between VEGF -2578C > A gene polymorphism and lung cancer susceptibility. There was a marked association between VEGF -2578C > A A allele / CC genotype and lung cancer risk in overall and Asian populations (overall populations: A allele: OR = 1.26, 95% CI: 1.08–1.46, VEGF -2578C > A A allele / CC genotype is associated with the lung cancer susceptibility in Asians and in overall populations. Lung cancer is a cancer with less than 15% survival rate and is a leading cause of patients’ death worldwid e. It is aSome genes were found to be associated with the risk of lung cance r–8. The vSeveral reports were published on the relationship between VEGF -2578C > A gene polymorphism and lung cancer susceptibility. We conducted this meta-analysis to evaluate the association between VEGF -2578C > A gene polymorphism and the risk of lung cancer.The relevant literature was searched and included using the electronic databases of CBM-disc  and PubMed on September the 1st, 2018. The retrieval strategy of “ AND (lung cancer OR lung carcinoma) AND (polymorphism OR polymorphisms)” was entered into the databases. The additional literature was obtained from cited references in recruited studies.(1) Patients outcomes must be lung carcinoma; (2) There should be two comparison groups (lung cancer group vs control group); (3) The studies should show data for VEGF -2578C > A genotype distribution.(1) Editorials and review articles; (2) Case reports; (3) Preliminary outcome not on VEGF -2578C > A gene polymorphism or lung cancer; (4) Studying the role VEGF gene expression in cancers; (5) Multiple publications.The data was searched and extracted by two investigators that were independent from each eligible study. The investigators analyzed the data based on the first author’s surname, location of the performed study, year of publication, the number of cases and controls for VEGF -2578C > A genotypes and the control source of the control group. Disagreements were resolved by discussion.P value for the heterogeneity test was less than 0.1, a random effects model was applied. Otherwise, the pooled statistic was counted using the fixed effects model. Odds ratios (OR) were used to express the dichotomous data, and 95% confidence intervals (CI) were also counted. A P value of less than 0.05 was regarded as the pooled OR, to be notably significant. I2 was applied to detect the heterogeneity among the included investigations. According to the source of the controls, sensitivity analysis was also performed . Stata 11.0 was used to test the publication bias. The Begg tes t[P < 0.1 was considered significant), when the sample size of included studies was more than ten.Revman 5  was applied to calculate the data extracted from each literature. When the egg tes t and the egg tes t were appA total of 14 studie s on the aP = 0.003, Fig. P = 0.18, Fig. P = 0.02, Fig. VEGF -2578C > A A allele and CC genotype were associated with lung cancer risk; however, the AA genotype was not found in overall populations . In the sensitivity analysis using population-based, the VEGF -2578C > A A allele and CC genotype were associated with lung cancer risk; however, the AA genotype was not , and Asians .No publication bias was found for the overall populations ; however, A allele was a negative gene allele. The AA genotype was not associated with lung cancer risk, which might due to the small sample size of included studies, and therefore, more studies should be conducted to confirm this result. Nevertheless, the results for the Caucasian population were less robust, also due to the small number of included studies. Additional studies should be performed to confirm this result.In the sensitivity analysis by the controls source, we found that, in the sensitivity analysis using the population-based control, the VEGF -2578C > A A allele / CC genotype was associated with lung cancer susceptibility. However, in the sensitivity analysis using the hospital-based control, VEGF -2578C > A gene polymorphism was not associated with lung cancer susceptibility.Publication bias was also analyzed, and we found that there was no publication bias for overall and Asians populations. This suggests that the conclusion from our meta-analysis was robust. However, additional well-designed studies should be performed to confirm this result in the future.In a previous study, Deng et al . recruiteIn the test of publication bias, two points were located on or out of scope, indicating publication bias. We deleted the two studies and conducted a further meta-analysis, and found the results were similar.The results in our study support that VEGF -2578C > A A allele / CC genotype was associated with lung cancer susceptibility in overall and Asian populations. However, additional well-designed investigations of this association are required to confirm these results.


Compared to the GG and GA genotypes, mothers who carried the AA genotype exhibited higher PTB risk  after adjusting for covariates. The meta-analysis confirmed this association under the recessive model , and also pointed out the protective effect of BsmI polymorphism against the risk of PTB under the allelic  and recessive  models. Our results suggest the association between some maternal VDR polymorphisms with neonatal anthropometric measures and the risk of PTB.The effect of vitamin D receptor gene (VDR) polymorphisms on adverse pregnancy outcomes—including preterm birth (PTB), low birth weight and small for gestational age—is currently under debate. We investigated 187 mother-child pairs from the Italian “Mamma & Bambino” cohort to evaluate the association of maternal VDR polymorphisms—BsmI, ApaI, FokI and TaqI—with neonatal anthropometric measures and the risk of PTB. To corroborate our results, we conducted a meta-analysis of observational studies. For the FokI polymorphism, we showed that gestational duration and birth weight decreased with increasing number of A allele ( Adverse pregnancy outcomes continue to be major Public Health problems in spite of improvements in health care ,2,3. AmoOverall, vitamin D is crucial for the maintenance of adult health  and its In this scenario, increasing interest concerns the effect of genetic variants affecting vitamin D metabolism and functions. Vitamin D activity is mediated by the vitamin D receptor (VDR), a nuclear receptor which acts as a high-affinity ligand-activated transcription factor . VDR genIn the present study we used data and samples from this cohort to evaluate the association of maternal VDR polymorphisms  with neonatal anthropometric measures and the risk of PTB, even considering dietary intake of vitamin D. Then, we carried out a systematic review evaluating the effect of VDR polymorphisms on PTB risk and on neonatal anthropometric measures. Finally, we corroborated our results by pooling them with those reported by previous studies through a meta-analysis.http://www.birthcohorts.net). During the prenatal genetic counselling, at gestational week 4–20 (mean = 16 weeks), pregnant women referred to the Azienda Ospedaliera Universitaria “Policlinico-Vittorio Emanuele”, Catania  were invited to participate. This study was carried out in accordance with the Declaration of Helsinki and the protocol was approved by the ethics committee of the involved institution. All subjects were fully informed of the purpose and procedures and gave written informed consent. In this cohort, information on sociodemographic and lifestyle data are collected by trained epidemiologists using a structured questionnaire. Educational level is classified as low  and high . Women are also classified as employed or unemployed (including students and housewives). Smoking status is classified as no smoking (including ex-smokers) and current smoking. Pre-pregnancy body mass index (BMI) is calculated as weight (kg) divided by height (m2), based on criteria from the WHO [The “Mamma & Bambino” cohort is an ongoing Italian birth cohort designed to explore the effect of preconception, perinatal and early life exposure on maternal and infant health  and macrosomia (birthweight ≥ 4.0 kg); birthweight for gestational age was defined as SGA, AGA or LGA according to sex-specific national reference charts . Mother-Maternal DNA was extracted from peripheral blood samples using QIAamp DNA Mini Kit according to the manufacturer protocol . VDR polymorphisms were genotyped using the following commercially available TaqMan SNP Genotyping Assays : ApaI rs7975232 (C_28977635_10), TaqI rs731236 (C_2404008_10), BsmI rs1544410 (C_8716062_10), FokI rs2228570 (C_12060045_20). All reactions were performed in triplicate on the QuantStudio™ 7 Flex Real-Time PCR System  deploying conditions set by the manufacturer. Allele determination was carried out using QuantStudio™ 7 Flex System Software .http://ndb.nal.usda.gov/) adapted to the Italian food consumption. The use of multimineral/multivitamin supplements containing vitamin D was recorded, but the vitamin D intake was based only on food sources, as the FFQ was not designed to ascertain the quantification of vitamin D intake by supplementation.Vitamin D intake was assessed by a validated 95-item semi-quantitative Food Frequency Questionnaire (FFQ) as described elsewhere . In briep values < 0.05 were considered statistically significant.Statistical analyses were conducted using SPSS software . Descriptive statistics were used to characterize the study population, using frequency, mean and standard deviation (SD), or median and interquartile range (IQR). The Chi-square test was performed to determine if geno-type distributions in mothers with full-term delivery were deviated from the Hardy-Weinberg Equilibrium (HWE). Prior to analysis, the normal distribution of all variables was checked using the Kolmogorov-Smirnov test. Based on skewed distribution, comparisons of maternal and infant quantitative variables across VDR genotypes were analysed using the Mann-Whitney U test or the Kruskal-Wallis test. Categorical variables were compared using the Chi-squared test. Linear and binary regression models were applied to evaluate the associations of VDR polymorphisms with primary and secondary outcomes, using the non-mutated genotypes as reference. Regression models were adjusted for age, smoking, educational level, employment status, pre-gestational BMI, GWG, vitamin D intake, use of vitamin D supplements, type of delivery and parity. Post-hoc statistical power analysis was performed using Epi Info™ software . All statistical tests were two-sided, and Two of the Authors carried out a systematic literature search in the PubMed-Medline and Web of Science databases to identify relevant epidemiological studies, investigating the association of BsmI, ApaI, FokI and TaqI polymorphism with neonatal anthropometric measures and incidence of PTB, LBW and SGA births. The search strategy comprised the terms (Vitamin D receptor OR VDR) AND (variation OR polymorphism OR mutations OR SNP) AND . The databases were searched from inception to February 2018 without language restriction; abstracts and unpublished studies were not included. Moreover, the reference lists from selected articles, including relevant review papers, were searched to identify all appropriate studies. The preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines were followed.Two of the Authors independently assessed the retrieved articles and any inconsistencies were resolved through discussion. Studies included were consistent with the following criteria: (i) observational studies or randomized control trials (RCTs) (ii) on pregnant women of any gestational age (iii) without pregnancy complications, (iv) focusing on the association of FokI, ApaI, TaqI and BsmI VDR polymorphisms with PTB, LBW, and SGA. Moreover, (v) studies were selected if they provide sufficient information on the numbers or genotype frequencies in cases and controls in order to estimate odds ratios (ORs) and 95% confidence intervals (95% Cis). By contrast, the exclusion criteria were as follow: (i) systematic reviews or meta-analyses; (ii) abstracts and unpublished studies; (iii) studies with insufficient or lack of data to estimate ORs and 95% CIs, after attempting to contact the corresponding authors via e-mail; (iv) investigating the association with other VDR polymorphisms (v) or with other adverse pregnancy outcomes; (vi) studies with no control group.p-values for HWE in controls. If additional data were needed, the Authors of retrieved articles were contacted. Primary outcome was PTB since lack of data and inconsistency of reported outcomes avoided the quantitative analysis for birthweight, birth length, LBW and SGA.Two of the Authors independently extracted the following information: first Author’s last name, year of publication, country where the study was performed, ethnicity and number of participants, sample type, phenotype of the cases evaluated, genotyping method, genotype distributions in cases and controls, and p < 0.1. As the Q test only indicates the presence of heterogeneity and not its magnitude, we also reported the I2 statistic, which estimates the percentage of outcome variability that can be attributed to heterogeneity across studies. An I2 value of 0% denotes no observed heterogeneity, whereas, 25% is “low”, 50% is “moderate” and 75% is “high” heterogeneity [p < 0.05 was considered statistically significant, and all tests were 2-sided. All statistical analyses were performed using the Review Manager software .Strength of association between VDR polymorphisms and PTB was estimated as ORs (95% CIs) under the allelic model (2 vs. 1), the dominant model (22 and 12 vs. 11) and the recessive model (22 vs. 11 and 12). The significance of pooled OR was determined by the Z test. Heterogeneity across studies was measured using the Q test, considering significant statistical heterogeneity as ogeneity . We alsoogeneity . Accordiogeneity ,56. Excen = 17; 9%) and full-term delivery . No differences were evident for maternal socio-demographic characteristics, pre-gestational BMI, GWG, use of vitamin D supplements and lifestyle. As expected, PTB new-borns exhibited lower birth length  and weight , with a higher proportion of underweight compared to full-term new-borns .From the “Mamma & Bambino” cohort, 187 women aged 15–50 years (median = 37 years) were enrolled at a median gestational age of 16 weeks (IQR = 4). According to pre-gestational BMI and GWG we identified 30.9% and 27.1% who exhibited reduced or excessive GWG, respectively. In general, gestational duration was 39 weeks (IQR = 2) and 55.1% of deliveries were natural. Median birth length and weight were 50.0 cm (IQR = 2) and 3.2 Kg (IQR = 0.6), respectively. Approximately 8% of new-borns were underweight while 7.5% was diagnosed with macrosomia. According to sex-specific national reference charts , most ofp = 0.020). However, we failed in confirming this difference after adjusting for covariates. The comparison of maternal and neonatal characteristics across FokI genotypes showed that gestational duration and birth weight decreased with increasing number of A allele . Accordingly, the proportion of PTB increased with increasing number of A allele , whereas no statistically significant differences were reported for BsmI, ApaI and TaqI (p = 003) and in the multivariable-adjusted models . Particularly, compared to the GG and GA genotypes, mothers who carried the AA genotype exhibited a higher PTB risk both in the age-adjusted  and in the multivariable-adjusted models .and TaqI B. In linThe detailed steps of study selection are given as a PRISMA flow diagram in n = 4) [n = 6) [n = 4) [n = 1) [A total of 5 studies were from European countries ,38,40,42n = 4) ,33,34,36n = 4) , LBW [35n = 4)  as priman = 4) ,40,41,42n = 4) ,33,37, rn = 4) ,41, BsmIn = 4) ,40,41,42n = 4) ,40 and Tn = 4) ,40. The  [n = 6) ,40,42, f [n = 4) ,33,37,41In 2011, Swamy and colleagues conducted a prospective study on 615 pregnant women, evaluating the effect of 38 VDR polymorphisms on several birth outcomes. In brief, they showed that 8 of 38 SNPs examined—including ApaI—were significantly associated with birth weight in black but not in white women . In the Manzon and colleagues genotyped VDR polymorphisms in both maternal and cord blood samples of 33 PTB and 98 full-term delivery . In lineI2 statistics showed no significant heterogeneity across studies under the allelic , dominant  and recessive  models. Using the fixed effect model, the meta-analysis showed no association of ApaI with PTB under the allelic model , dominant  and recessive model   .I2 statistics showed no significant heterogeneity across studies under the allelic , dominant  and recessive  models. Using the fixed effect model, the meta-analysis showed a significant negative association with PTB under the allelic  and recessive  models. By contrast, no statistically significant association was evident under the dominant model   .I2 statistics showed significant heterogeneity across studies under the allelic , dominant  and recessive models . Using the random effect model, the meta-analysis showed a significant association with PTB under the recessive model . By contrast, pooled ORs under the allelic  and dominant  models were not statistically significant , dominant  and recessive  models. Using the fixed effect model, the meta-analysis showed no significant association with PTB under the allelic , dominant , and recessive  models , BsmI , FokI , and TaqI .For the TaqI polymorphism we pooled our results with those reported by Baczyńska-Strzecha et al. and Rosenfeld et al. ,34. The ) models . OverallIn the present study, we used data from the “Mamma & Bambino” cohort to evaluate the effect of VDR polymorphisms on neonatal anthropometric measures and on the risk of PTB. Interestingly, we observed that maternal FokI polymorphism affected both gestational duration and birth weight, which decreased with increased number of the mutated allele (A). This is consistent with Workalemahu and colleagues that demonstrated, for the first time, that birth weight decreased with increasing number of A allele . In lineThe mechanistic link between VDR expression and foetal outcome is still unclear. Calcitriol is the major active ligand of VDR. The ligand-bound VDR forms a heterodimer with nuclear retinoid X receptor (RXR) , which rFinally, in future studies the effects of other single nucleotide polymorphisms in genes encoding for key components of the vitamin D metabolism pathway—such as genes involved in cholesterol synthesis (DHCR7), hydroxylation , and vitamin D transport (GC) that influence vitamin D status ,65 shoulIn conclusion, we provide novel evidence and a meta-analysis about the effect of VDR polymorphisms on birth weight and gestational duration, identifying a group of women at risk of PTB.


P < .05). For rs1801157 in subgroup analysis the association was significant in Asian populations . For rs712, subgroup analysis revealed a significant  and borderline  association in Chinese and Czech populations, respectively. The minor allele of rs17281995 increased risk of CRC in different genetic models (P < .05). Finally, rs5275, rs4648298, and rs61764370 did not show significant associations. In conclusion, minor allele of rs3025039, rs3212986, and rs712 polymorphisms increases the risk of CRC in the East Asian population, and heterozygote model of rs731236 polymorphism shows protective effect in the Middle East population. In Europeans, the minor allele of rs17281995 may increase the risk of CRC, while rs712 may have a protective effect. Further analysis based on population stratifications should be considered in future studies.Genetic variations in miRNAs binding site might participate in cancer risk. This study aimed to systematically review the association between miRNA‐binding site polymorphisms and colorectal cancer (CRC). Electronic literature search was carried out on PubMed, Web of Science (WOS), Scopus, and Embase. All types of observational studies till 30 November 2018 were included. Overall 85 studies (21 SNPs) from two systematic searches were included analysis. The results showed that in the Middle East population, the minor allele of rs731236 was associated with decreased risk of CRC (heterozygote model: 0.76 [0.61‐0.95]). The minor allele of rs3025039 was related to increased risk of CRC in East Asian population . Results for rs3212986 were significant in overall and subgroup analysis . The results have shown that these polymorphisms can serve as genetic biomarkers of CRC, and their roles were exclusively related to population stratifications. It is strongly recommended that further studies should be performed to display the effect of population stratifications. It has been recognized as the second and third common cancers in females and males, respectively.Some risk factors of CRC including diet and smoking could be modified in contrast to genetic factors.Polymorphisms in miRNA‐binding sites may also alter the risk and survival of a variety of human complex diseases including CRC.Because of importance and economic burden of CRC, and regarding the significant role of miRNA‐binding site polymorphisms on CRC according to the previous studies besides lack of a systematic review on this subject, the necessity of such study on association between miRNA‐binding site polymorphisms and CRC, as prognostic markers, is quite clear. For this purpose, the main objective of the current systematic review was to explore and reveal the association of 3'UTR and miRNA‐binding site polymorphisms with the risk of CRC. The secondary specific objective was to determine the effect of ethnicity on these associations.2The methods of this study have been developed according to the PRISMA‐P 2015 checklist.2.1This study imposed a restriction on the study design. Observational studies , describing the association between miRNA‐binding site polymorphisms and CRC, were eligible for inclusion. Primary documents will be screened according to the PECO criteria  and objectives of this study. Studies with deviation from Hardy‐Weinberg equilibrium2.2Polymorphisms in miRNA‐binding sites have been reported to be associated with cancers.2.3In order to identify the relevant papers on miRNA‐binding site polymorphisms and colorectal cancer, online systematic search (electronic searches) of literature was performed in PubMed, Embase, Scopus, and Web of Science. We developed PubMed search syntax, as the main database, this syntax was adapted to other database. PubMed search syntax was performed by combined medical subject headings (MeSH), Emtree terms, keywords of related papers, also free text words. Key search terms were “colorectal neoplasms,” “miRNA,” “Polymorphism, Single Nucleotide,” and their equivalents Table . To iden2.42.4.1Screening and eligibility checking was performed in three following steps. First, duplicate documents were removed. Second, for screening, two reviewers independently scrutinize remaining documents by checking title and/or abstract. Third, full texts' eligibility was independently scrutinized by two reviewers. Any disagreements between two reviewers were resolved by consensus strategy and third‐person strategy.2.4.2A data extraction form was created and then piloted by two reviewers. This form included the following data: the name of first author, country of study, year of publication, study design, age, gender, ethnicity, names of 3'UTR or binding site SNPs, genotyping methods, minor allele frequency (MAF), HWE, sample size, matching criteria (such as age and sex), source of controls , odds ratio (OR), confidence interval (95% CIs), and other related raw data. In the next step, two reviewers independently extracted data based on the extraction form. Disagreements were resolved by strategies listed above.2.52.5.1P < .05 is statistically significant) and the I2 statistic in forest plots. We used the following guide to interpret the amount of heterogeneity: I2 < 25% = low heterogeneity; 25 ≥ I2 < 50% = moderate heterogeneity; 50 ≥ I2 < 75% = sever heterogeneity; 75% ≥ I2 = highly sever heterogeneity.Meta‐analysis was performed by using R (3.5.2). Odds ratio and 95% CI were used to investigate the associations between each polymorphism in miRNA‐binding site and CRC. The meta‐analysis was performed based on different genetic models , homozygous model (AA vs aa), heterozygote model (Aa vs aa), AA vs Aa model, dominant model (AA + Aa vs aa), recessive model (AA vs Aa + aa), and overdominant model (Aa vs AA + aa)). All included studies were at the risk of various types of heterogeneity. For exploring possible sources of heterogeneity, included studies were divided according to the type of polymorphisms. For each polymorphism, if sufficient studies were included, subgroup analysis (based on ethnicity) was applied. Odds ratios were estimated by fixed effects model (FEM) or random effects model (REM), according to the heterogeneity level. Level of heterogeneity between primary studies was obtained by the Cochran's Q test . Sensitivity analysis was performed by the leave‐one‐out method.3In the systematic search, at the first stage we found 9221 documents, with 222 polymorphisms in 3′UTR and miRNA‐binding site of genes that were studied for the risk of CRC. Among them we included main polymorphisms in second search for meta‐analysis . Twenty‐five polymorphisms were included . Second search strategy applied for these polymorphisms, which contained 5170 documents. Finally, we included 54 studies on the role of 3′UTR polymorphisms and 52 studies on the role of miRNA‐binding site polymorphisms and risk of CRC for all the selected polymorphisms  no significant result for the risk of CRC was observed, but in subgroup analysis in Middle East population the results were significant in heterozygote (Tt vs TT) (0.76 [0.61‐0.95]) and overdominant models (Tt vs TT + tt) (0.75 [0.61‐0.92]), and borderline significance was observed in dominant model (tt + Tt vs TT) (0.81 [0.66‐1.00]) Figure .For rs3025039 in overall, there was no significant association, but subgroup analysis revealed significant results . In East Asian population, the allelic model (T vs C) (1.25 [1.01‐1.54]) significantly increased the risk of CRC and in dominant model (TT + TC vs CC) (1.29 [1.00‐1.66]) there was a trend towards significance Figure .In meta‐analysis for rs3212986, there were significant results in both overall and subgroup analysis in different genetic models , including homozygote model (TT vs GG) 1.76 (1.08‐2.86) Figure .Although we did not find any significant result for rs712 in overall models, subgroup analysis revealed significant and borderline association in Chinese and Czech populations, respectively, on six genetic models , including homozygote model (TT vs GG) in Chinese 2.51 (1.70‐3.69) and in Czech 0.85 (0.72‐1.01) populations Figure .The allele (A) of rs1801157 polymorphism increased risk of CRC in Asian population, while we did not find any significant results in Caucasian populations  and rs4648298 , we performed meta‐analysis according to three different subgroup analyses . The results in all different genetic models were not significant except dominant model (0.82 [0.70‐0.97]) in adenoma for rs5275, also the allelic model (C vs T) showed borderline association 0.92 (0.85‐1.00)  increased risk of CRC was observed in Asian population. This result is similar to previous meta‐analysis by Xu,We also found no significant association between rs712 and risk of CRC, in the overall meta‐analysis of five included studies. However, subgroup analysis revealed remarkable and completely different results in Chinese and Czech Republic populations. In Chinese, we observed a strong risk while in Czech population a protective effect was shown in all various models. There is one study similar to our results which confirm the increase risk of this polymorphism in Chinese population.In addition, our results (based on 10 eligible studies) showed that rs5275 was not related to the risk of CRC. While the minor allele of rs5275 may have a protective effect on the risk of adenoma. This polymorphism is located in COX‐2 gene at miR‐542‐3p target site. COX‐2 is usually overexpressed in colorectal adenoma patients,4.1Our study had several advantages: First, this is the first systematic review for evaluating the role of miRNA‐binding site polymorphisms on CRC susceptibility, and 25 polymorphisms were included in our pooled analysis. Second, to reduce the publication biases and include all relevant documents we carried out a systematic search on four common databases, as well as other sources such as references of relevant reviews. Third, there was no language bias, we included all relevant documents without any language restriction. Fourth, our study has high power and strength reliability because of our comprehensive and double search strategies and subgroup analyzing based on different ethnicity. Fifth, to reduce binding site false positive prediction, related to bioinformatics tools, we only included polymorphisms located in miRNA‐binding site or 3'UTR (stated at least in two of the included documents).There are also some limitations in our study. First, based on insufficient data, it was mandatory to exclude some relevant documents. Second, some polymorphisms had two or three included article. Third, CRC is a multifactorial disease and we only included genetic effect.5miRNA‐binding site polymorphisms in this meta‐analysis showed significant association with CRC in different populations. Interestingly, rs731236 polymorphism showed a significant association with CRC in Middle East population with a heterozygote advantage. The minor allele in the East Asian populations for rs3025039, rs3212986, and rs712, and also in Asian population for rs1801157, increased the risk of CRC. The minor allele of rs712 may have a protective effect on the risk of CRC in Czech populations, while rs17281995 showed risk effect in the European population. Finally, it can be concluded that these miRNA‐binding site polymorphisms play different roles on the risk of CRC in various populations which should be considered in data analysis and interpretation in the future studies.The authors declare that there is no conflict of interest. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file.


Gestational diabetes mellitus (GDM) is a common pregnancy complication, with complex disease mechanisms, and several risk factors may contribute to its onset. We performed an umbrella review to summarize the evidence from meta-analyses of observational studies on risk factors associated with GDM, evaluate whether there are indications of biases in this literature and identify which of the previously reported associations are supported by convincing evidence.We searched PubMed and ISI Web of Science from inception to December 2018 to identify meta-analyses examining associations between putative risk factors for GDM. For each meta-analysis we estimated the summary effect size, the 95% confidence interval, the 95% prediction interval, the between-study heterogeneity, evidence of small-study effects, and evidence of excess-significance bias.−6 under the random-effects model. Only four risk factors presented convincing evidence:, low vs. normal BMI (cohort studies), BMI ~30–35 kg/m2 vs. normal BMI, BMI >35 kg/m2 vs. normal BMI, and hypothyroidism.Thirty eligible meta-analyses were identified, providing data on 61 associations. Fifty (82%) associations had nominally statistically significant findings (P<0.05), while only 15 (25%) were significant at P<10The compilation of results from synthesis of observational studies suggests that increased BMI and hypothyroidism show the strongest consistent evidence for an association with GDM. Diet and lifestyle modifications in pregnancy should be tested in large randomized trials. Our findings suggest that women with known thyroid disease may be offered screening for GDM earlier in pregnancy. Gestational diabetes mellitus (GDM) is a common pregnancy complication, defined as glucose intolerance with onset or first recognition during pregnancy, in women without prior diabetes history prior to pregnancy., 2 DurinMeta-analyses of randomized clinical trials for GDM prevention that evaluated a range of dietary and lifestyle interventions during pregnancy, including diet and exercise, lifestyle advice, nutritional manipulation, and behavior modification, showed inconsistent findings, with some meta-analyses reporting significant deceased incidence of GDM –18, whilUnder the prism of the abundance of observational significant associations, we conducted an umbrella review of meta-analyses on risk factors for GDM. Using a standardized approach, we aimed to assess the credibility of those findings to identify which associations are with robust epidemiological evidence.This study was performed according to the guidelines for systematic reviews under the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).We conducted an umbrella review, which is a systematic collection and evaluation of multiple systematic reviews and meta-analyses performed on a specific research topic. An umbreTwo researchers (KG and SP) independently searched PubMed and ISI Web of Science from inception to 23 of December 2018 to identify meta-analyses of observational studies examining associations regarding risk factors for GDM. The search strategy used the keywords  AND . All identified publications went through a three-step parallel review of title, abstract, and full text, performed by KG and SP, based on predefined inclusion and exclusion criteria. We also screened the references of the retrieved articles for possible eligible papers. Any disagreement was resolved with discussion.We included meta-analyses of observational studies , which investigated risk factors for GDM. Meta-analyses were retained if they included at least three studies in which information was provided per included study on a measure of association, its standard error, the number of cases and the total population. We did not apply any language restrictions in the selection of eligible studies. We included only meta-analyses of epidemiological studies in humans. We excluded studies in which risk factors were used for screening, diagnostic, or prognostic purposes, or meta-analyses that examined GDM as a risk factor for other medical conditions. We also excluded studies on women with pre-existing type II diabetes. We excluded systematic reviews and meta-analyses of genetic risk factors, narrative reviews, letters to the editor, meta-analyses of Randomised Control Trials (RCTs), and systematic reviews without a quantitative synthesis of data. If an article presented meta-analyses on other pregnancy outcomes including GDM, we only extracted information on the latter. When more than one meta-analysis on the same research question was eligible, the meta-analysis with the largest number of component studies with data on individual studies’ effect sizes was retained for the main analysis to avoid duplication of the study populations.Data extraction was performed independently by two investigators , and in case of discrepancies, the final decision was reached by consensus, involving a third investigator, when necessary (EE). From each eligible meta-analysis, we extracted information on the first author, year of publication, the examined risk factors, the number of studies included, the study-specific relative risk estimates  along with the corresponding confidence intervals (CI). Also, we recorded the reported summary meta-analytic estimates using both fixed and random effect methods along with the corresponding confidence intervals, the total population, and number of cases for each study. We also recorded whether the selected meta-analyses applied any criteria to evaluate the quality of the included studies.For each meta-analysis, we re-calculated the summary effect and its 95% CI by using both fixed and random effect models., 33 We a2-based Cochran Q test and the I2 metric for inconsistency, which could reflect either diversity or bias. I2 metric ranges between 0% and 100% and quantifies the variability in effect estimates that is due to heterogeneity rather than sampling error. presented highly suggestive evidence for GDM.After applying our credibility criteria, four risk factors, low vs. normal BMI (cohort studies), BMI ~30–35 vs. normal weight, BMI >35 vs. normal weight, and hypothyroidism  presented convincing evidence for an association with GDM, supported by more than 1000 cases, P<10Nine risk factors were supported by suggestive evidence and twenty-seven associations presented weak evidence (P<0.05). An overall assessment of statistically significant associations for GDM is presented in In this umbrella review we evaluated the current evidence, derived from meta-analyses of observational studies on the association between various risk factors and GDM. Overall, from the 61 associations that have been examined, only a minority had strongly significant results with no suggestion of bias, as can be inferred by substantial heterogeneity between studies, small study effects, and excess significance bias. Four risk factors were supported by convincing evidence, including low vs. normal BMI (cohort studies), BMI ~30–35 vs. normal weight, BMI >35 vs. normal weight, and hypothyroidism. Another ten risk factors from various fields , achieved highly suggestive evidence for an association with GDM.It is well-known that maternal weight, as determined from pre-conception BMI, is critical on the development of insulin resistance and type II diabetes as well as GDM. This summary of observational studies shows that the more robust associations were related to overweight and obesity, as three out of four associations that met the criteria for convincing evidence and six out of ten highly suggestive associations were concentrated on maternal pre-pregnancy BMI and the risk of GDM. The association of low BMI vs. normal BMI was the only protective factor, which it was supported by convincing evidence for protection against GDM.Our findings further support the current guidelines regarding pregnancy weight, nutrition and activity, issued from the National Institute for Health and Clinical Excellence (NICE), the Institute of Medicine (IOM) and the American College of Obstetricians and Gynecologists (ACOG), which they accepted lifestyle change as an essential component of prevention and management of GDM.–79 NICE The observed association between obesity and GDM is biologically plausible. Normal pregnancy is characterized by a state of insulin resistance defined as an impaired response to insulin. This physiological insulin resistance also occurs in women with GDM on a background of chronic insulin resistance due to obesity to which the insulin resistance of pregnancy is partially additive. Obesity can cause major changes in maternal intermediary metabolism, where co-existing conditions associated with increased insulin resistance, higher serum lipids, and lower plasma levels of adiponectin, appear to play a central role to the development of GDM.–83The association between hypothyroidism, which includes both subclinical and overt hypothyroidism, and risk of GDM, was supported by convincing evidence. Increased levels of human chorionic gonadotropin (hCG) in the first trimester of pregnancy directly stimulate the thyroid gland to increase production of thyroid hormone, which leads in decreased secretion of thyroid stimulating hormone (TSH). Proposed−6), the proportion of significant associations decreased to 25%. Thirty-one (51%) associations had large or very large heterogeneity, while when we calculated the 95% prediction intervals, which further account for heterogeneity, we found that the null value was excluded in more than half of the associations. Only four of the assessed risk factors found to provide convincing evidence, indicating that several published meta-analyses of observational studies in the field could be susceptible to biases and the reported associations in the existing studies are often exaggerated.In the current umbrella review, we applied a transparent and replicable set of criteria and statistical tests to evaluate and categorize the level of existing observational evidence within in five broad areas with the goal to detect biases that work on a field-wide level. Although, 82% of the included meta-analyses report a nominally (P<0.05) statistically significant random-effects summary estimate, when stringent P value was considered  offer hints of bias, not definitive proof thereof, while the Egger test is difficult to interpret when the between-study heterogeneity is large. These tests have low power if the meta-analyses include less than 10 studies and they may not identify the exact source of bias., 41, 99 The present umbrella review of meta-analyses identified 61 unique risk factors for GDM. Our analysis identified four risk factors with convincing evidence and strong epidemiological credibility pertaining to hypothyroidism and BMI , BMI ~30–35 vs. normal weight, BMI >35 vs. normal weight). Diet and lifestyle modifications in pregnancy should be tested in large randomized trials. Our findings suggest that women with known thyroid disease could be offered screening for GDM earlier in pregnancy. As previously suggested, the use of standardized definitions and protocols for exposures, outcomes, and statistical analyses may diminish the threat of biases, allow for the computation of more precise estimates and will promote the development and training of prediction models that could promote public health.S1 TableNote: Y: Yes, N: No, CA: Cannot Answer. Item 1: Was an ‘‘a priori” design provided? Item 2: Was there duplicate study selection and data extraction? Item 3: Was a comprehensive literature search performed? Item 4: Was the status of publication  used as an inclusion criterion? Item 5: Was a list of studies (included and excluded) provided? Item 6: Were the characteristics of the included studies provided? Item 7: Was the scientific quality of the included studies assessed and documented? Item 8: Was the scientific quality of the included studies used appropriately in formulating conclusions? Item 9: Were the methods used to combine the findings of studies appropriate? Item 10: Was the likelihood of publication bias assessed? Item 11: Was the conflict of interest included?(DOCX)Click here for additional data file.S2 TableAbbreviations: Random effects, summary odds ratio (95% CI) using random effects model; Largest effect, odds ratio (95% CI) of the largest study in the meta-analysis; Egger, p-value from Egger's regression asymmetry test for evaluation of publication bias; P, p-value; NP, not pertinent, because the estimated is larger than the observed, and there is no evidence of excess of statistical significance based on the assumption made for the plausible effect size; BMI, Body Mass Index; GDM, gestational diabetes mellitus; PA, physical activity.* Summary random effects odds ratio (95% CI) of each meta-analysis, except for three meta-analyses  where the RR was used. † Summary fixed effects odds ratio (95% CI) of each meta-analysis, except for three meta-analyses  where the RR was used.‡ Odds ratio (95% CI) of the largest study in each meta-analysis, except for three meta-analyses  where the RR was used.§ P-value from the Egger regression asymmetry test for evaluation of publication bias|| I2 metric of inconsistency  and P-value of the Cochran Q test for evaluation of heterogeneity.≠ 95% Prediction Interval ¶ Observed number of statistically significant studies # Expected number of statistically significant studies using the summary fixed effects estimate of each meta-analysis as the plausible effect size** P-value of the excess statistical significance test.¥ Expected number of statistically significant studies using the summary random effects estimate of each meta-analysis as the plausible effect size ȣ Expected number of statistically significant studies using the effect of the largest study of each meta-analysis as the plausible effect size.(DOCX)Click here for additional data file.


Background and Purpose: Conclusions of previous cohort studies on the relationship between 25-hydroxyvitamin D level and the risk of dementia and Alzheimer's disease were not consistent. Thus, we performed a dose–response meta-analysis to evaluate this relationship by summarizing cohort studies.Methods: Pubmed, Embase, Cochrane, and Web of Science databases were searched for relevant studies. Cohort studies concerning the association between 25-hydroxyvitamin D level and dementia or Alzheimer's disease were included. Results of studies were pooled and the dose–response relationship was determined using a random-effect model.Results: Ten cohort studies, with 28,640 participants were included. A significant inverse relationship was found between 25-hydroxyvitamin D level and the risk of dementia and Alzheimer's disease. In addition, we found a linear dose–response relationship in that a 10 nmol/L increase in 25-hydroxyvitamin D level may lead to a 5% decrease in the risk of dementia  and 7% in the risk of Alzheimer's disease .Conclusion: Plasma or serum 25-hydroxyvitamin D concentration was inversely related to the risk of dementia and Alzheimer's disease, consistent with a linear dose–response relationship. Despite being a common disease, dementia can neither be effectively prevented nor cured at present. With the prolongation of people's lives, the incidence of dementia is also increasing Abbott, . NowadayVitamin D is a fat-soluble secosteroid which is generated mainly in our skin by ultraviolet B (UVB) sunlight, and can also be provided by diet Webb, . VitaminI2 statistic to describe and quantify the heterogeneity; however, Borenstein et al.  AND (humans OR persons OR inpatients OR outpatients OR patients OR volunteers OR subjects OR participants) AND  AND (cohort OR cohort studies [Mesh] OR risk [Mesh]). We also carried out manual retrieval using references from literature. No time or language restriction existed during the whole searching process.We sought cohort studies about the association between the level of vitamin D and the risk of dementia or Alzheimer's disease by searching Pubmed, Embase, Cochrane, and Web of Science databases. Pubmed search terms were: (AlzheimerStudies included had to meet the following criteria: (1) subjects were humans; (2) exposure was the level of 25(OH)D in plasma or serum; (3) outcome of the study was dementia or Alzheimer's disease and the diagnostic standards were provided; (4) dementia or Alzheimer's disease risk of different 25(OH)D levels was compared; (5) relative risk (RR), hazard ratio (HR) or odds ratio (OR) with 95% confidence intervals (95% CI) was provided; and (6) they were cohort studies. We excluded articles that met the following standards: (1) case–control or cross-sectional study; (2) letter, review, editorial or supplement; and (3) non-human study. If the same study was published repeatedly, we included the one with longer follow-up time.Two investigators were independently responsible for data extraction and study quality assessment. Disagreement was solved by asking a third investigator. The following information was extracted from included studies: authors, year of publication, location, study design, follow-up time, categories of 25(OH)D levels, number of participants, number of cases, age, and sex of the participants, adjusted factors, and RRs, HRs or ORs with 95% CI. The quality of studies was assessed based on the Newcastle–Ottawa scale D concentration was ng/ml, we multiplied the value to 2.5, converting the units into nmol/L Holick, . The 25D level in different studies using a random-effect model  with a random-effect model. Significant level in this meta-analysis was set as 0.05.Our search identified 1,120 studies, of which 1,110 were excluded from, and ten were included in our meta-analysis  and Begg's test (p = 0.115) showed no significant publication bias. Sensitivity analysis conducted by removing one study at a time and analyzing the rest showed that no single study influenced the pooled RRs (range 0.68–0.77).All 12 studies were included in highest vs. lowest meta-analysis of the relationship between 25(OH)D level and risk of dementia. In one study . The linear trend showed that the risk of dementia decreased by 5%  for every 10 nmol/L increment in 25(OH)D level, without significant heterogeneity D level into only two categories  when we removed one study . The linear trend showed that the risk of Alzheimer's disease decreased by 7%  for every 10 nmol/L increment in 25(OH)D level without significant heterogeneity D level was inversely associated with the risk of dementia and Alzheimer's disease, and the subgroup analysis indicated a similar result. In addition, we found a linear dose–response relationship showing that a 10 nmol/L increase in 25(OH)D level may lead to a 5% decrease in dementia and 7% in Alzheimer's disease.A previous meta-analysis D level and dementia or Alzheimer's disease with a dose–response model which enabled a better use of information. Moreover, we used PI to evaluate the heterogeneity in this random-effects meta-analysis. The PI ranged within 0.45–1.14 for risk of dementia and 0.39–1.54 for risk of Alzheimer's disease. Thus, it is possible that future studies will show an increased dementia and Alzheimer's disease risk in people with higher compared with lower 25(OH)D level.However, our meta-analysis has several limitations. Firstly, we focused on the relationship between baseline 25(OH)D levels and the risk of dementia and Alzheimer's disease. It was unclear whether the 25(OH)D level had changed during the follow-up. However, this effect is likely to be small because studies have shown that 25(OH)D concentration can be relatively stable for a long period D could help to prevent dementia and Alzheimer's disease, ways to increase 25(OH)D level should be given attention. Approximately 80–100% of the vitamin D required by humans is produced by the UVB radiation in sunshine Kimlin, . HoweverIn summary, this dose–response meta-analysis showed that plasma or serum 25(OH)D level was inversely associated with the risk of dementia and Alzheimer's disease, consistent with a linear dose–response relationship. Maintaining adequate 25(OH)D status may lower risk of dementia and Alzheimer's disease.HC and WT designed the study. HC and LT searched the databases. WT and WX selected studies. JL and KF evaluated the quality of studies. HC and WT performed all analyses. HS and BZ wrote the manuscript. All authors revised the 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.


Background: Studies on serum one-carbon metabolism factors  with lung cancer (LC) risk have produced inconsistent results. We aimed to systematically evaluate the association between them.Methods: This study was reported in accordance with the PRISMA Statement and was registered with PROSPERO (no. CRD42018086654). Relevant studies were searched in PubMed, Embase, MEDLINE, and CNKI up to February 2018. Random-effects models were used to estimate the pooled standardized mean differences (SMD) or odds ratios (OR), as well as their 95% confidence interval (CI). Sensitivity and subgroup analysis were performed to identify the source of heterogeneity. Publication bias was also assessed.Results: A total of 14 articles  were included. The concentration of serum folate and vitamin B6 of LC patients were lower than the controls . While the concentration of homocysteine of the cases was higher than the controls . However, there were no significant differences between LC patients and the controls in terms of vitamin B12 and methionine . Subgroup analysis showed that these results were more significant in Europe, Asia, former and current smokers, and the male population .Conclusions: Serum folate and vitamin B6 might be protective factors against lung carcinogenesis and homocysteine could contribute to LC risk. Despite advancement in treatment, lung cancer remains the most common and fatal cancer in the world . At presA growing body of evidence shows that DNA methylation plays an important role in the progression of cancers . DNA metHowever, researchers are still debating on the role of these factors in the development of LC. Some studies found no association between some OCM related factors and LC risk –12. HoweTo the best of our knowledge, previous meta-analyses have not analyzed the relationship between all OCM factors in serum and LC risk. Thus, this study aims to systematically and comprehensively estimate the association of B vitamins , homocysteine and methionine with LC risk in order to evaluate their important roles in LC.This systematic review and meta-analysis was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) Statement  and was registered with PROSPERO (no. CRD42018086654).We systematically searched the PubMed, Embase, MEDLINE and CNKI  databases to identify relevant studies up to February 1, 2018. The search, which placed no restrictions on language or publication status, used the following search terms: (Lung Neoplasms [MeSH]) AND ((Vitamin B9 [MeSH] OR Folate [MeSH]) OR  OR  OR Homocysteine [MeSH] OR Methionine [MeSH]). We also reviewed the relevant references cited in the retrieved articles. The search strategy used for PubMed is listed in Appendix A .Studies were included in the meta-analysis if they met the following criteria: (1) the study focused on the association between serum B vitamins  or homocysteine or methionine involved in one-carbon metabolism and lung cancer risk; (2) the outcome was lung cancer incidence; (3) case-control study, cohort study, or randomized controlled trial (RCT); and (4) the variables were reported as means (M) and standard deviations (SD), or as odds ratio (OR) and 95% confidence intervals (95% CI).The exclusion criteria were (1) studies on dietary intake or supplementation of these B vitamins, homocysteine and methionine; (2) overlapping articles or studies that involved overlapping data; (3) conference abstract or meta-analyses; and (4) studies lacking healthy controls. If the same data were presented in more than one study, we included the study with the largest number of cases or provided more detailed information.Two investigators independently extracted the following data: first author, publication year, region/country, methods, study design, sample size, age, gender, source of controls and smoking status. We also extracted means (M) and standard deviations (SD) for the serum levels of B vitamins , homocysteine and methionine as well as odds ratio (OR) and 95% confidence interval (CI). To ensure the accuracy of the data, inconsistencies were discussed with another reviewer until a consensus was reached.The Newcastle-Ottawa Scale (NOS)  was usedP-values were 2-sided; P-values < 0.05 were considered statistically significant. Standardized mean difference (SMD) and 95% confidence interval (95% CI) were used to estimate the serum folate, B6, B12, homocysteine and methionine in the overall and subgroup  population; Odds ratio (OR) and 95% CI were used to evaluate these factors in subgroup population . If the pooled effect size SMD < 0 or OR < 1, the factor was protective; otherwise it was a risk factor.All reported Phet) and I-squared (I2) statistics test. If Phet < 0.1 or I2 > 30%, then there was significant heterogeneity. The fixed-effect model was used if there was no heterogeneity; otherwise, a random-effect model was applied. If significant heterogeneity existed, sensitivity and subgroup analysis was used to explore heterogeneity sources and studies with 95%CI markedly deviated from the others or factors leading to I2 largely decreased were primary originators.Heterogeneity was calculated by Q test  was summarized in Table p = 0.001]. Further subgroup analyses were carried out according to clinical features. By region, serum folate level of LC patients was lower in Europe  and Asia , but not in the US . By method, serum folate level was lower in using CLIA/RIA  and HPLC method , but not by microbiological method . By gender, serum folate level was lower in male patients , but not in females . By smoking status, the difference was especially significant in former smokers  and current smokers , but was not significant in never smokers  , p = 0.001] and Asia , but not in the US . By gender, serum B6 level was lower in male patients than controls , but not in females . By smoking status, the difference was especially significant in former smokers  and current smokers , but was not significant in never smokers  , p = 0.055]. We did not observe association by method or smoking status , p = 0.001] , p = 0.001]. By method, serum Hcy was higher in patients than controls by using CLIA/RIA  and HPLC  method. No significant association was observed by smoking status , 4, 0.58, 95% CI 0.2, 0.59, p = 0.001] , p = 0.853] nor the US . No association was observed by subgroup analysis according to gender or smoking status , ] Figure . FurtherI2 89.4%, Phet 0.061), B6 , B12 , Hcy  and methionine . Then the trim-and-fill analysis was used to estimate the effect of publication bias. It was found that the results from random and fixed effects models were consistent with the original results    with insIn addition to folate, we comprehensively analyzed the association between other important factors involved in the OCM and LC risk , 7. For In terms of Hcy, which acts as an essential intermediate in methionine metabolic cycle. Our findings suggest that serum Hcy could contribute to lung cancer and similar results were reported in all types of cancer in a previous meta-analysis . HoweverRegarding vitamin B12 and methionine, we did not find an associated with LC risk. For vitamin B12, some studies argued it was associated with higher mortality of LC cases , 48. It Particularly, subgroup analysis results showed that the significant association between folate, vitamin B6, Hcy and LC risk was detected in Asia and Europe, but not in the US. The null result may due to only a small number of studies from the US were included , 26. ThuThis is the first comprehensive and systematic evaluation of the relationship between serum folate, vitamin B6, vitamin B12, homocysteine, and methionine (OCM-related factors) and the LC risk. Previous meta-analyses focused only on the association of one or two OCM factors with LC or all types of cancer risk. Moreover, we investigated blood values instead of intake level, which can better reflect the association after the factors absorbed and metabolized in the body. In addition, this study included more than 8,000 lung cancer patients who participated in very recent studies and analyzed by different subgroups, which reduced selection bias and corrected some errors in previous meta-analysis .There were some limitations as well. First, although most of the original studies adjusted for variables, such as BMI, education, alcohol intake, tobacco exposure, and sex and we assessed potential sources of heterogeneity  through sensitivity analysis and subgroup analyses, we cannot completely rule out possible effects of unknown factors, such as pathology and clinical stages. Second, some epidemiological studies have shown that OCM related factors are potentially interrelated , 37, so This study showed that among OCM-related factors, serum folate and vitamin B6 could function as protective factors against lung carcinogenesis but that serum homocysteine could contribute to lung cancer risk. No significant association was observed between vitamin B12 or methionine and LC risk. Our findings were significant in Europe and Asia, former and current smokers, and males. Further research is needed to validate these results in other populations.JY and HL conceived and designed the study. JY, HL, and HD took full responsibility for data collecting and accuracy. JY and HL performed the meta-analysis, systematic review and drafted the manuscript. ZW helped revise the 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.


Many researches were conducted to assess the association of vitamin E intake on the risk of ovarian cancer, with conflict results. The current meta-analysis of published observational studies aimed to investigate the effect of vitamin E intake on ovarian cancer risk. The summary relative risks (RRs) with corresponding 95% confidence intervals (CIs) were calculated to measure the effectiveness of vitamin E intake on ovarian cancer risk using a random-effects model. As a result, 14 studies including 4597 patients were identified. Eleven studies reported about total vitamin E intake, eight studies about vitamin E intake from food only and five studies about vitamin E intake from supplement only on the risk of ovarian cancer. Overall, the summary RRs on ovarian cancer risk was 0.95 (95%CIs = 0.78–1.16) in total vitamin E intake, 0.99 (95%CIs = 0.77–1.27) in vitamin E intake from food only and 0.82 (95%CIs = 0.54–1.25) in vitamin E intake from supplement only. Results in subgroup analyses by study design and geographic location were consistent with overall result. In conclusions, the findings of this meta-analysis suggested that high intake of vitamin E from food or vitamin E supplement had no significant effect on the risk of ovarian cancer. Ovarian cancer is one of the most common malignant tumors in women, accounting for 2.5% of female cancers . About 1To collect studies that met the criteria for this meta-analysis, we reviewed all literature on the relationship between vitamin E and ovarian cancer risk. Literature searches were performed using Web of Science, EMBASE and PubMed databases . The following key words and subject terms were used in the search: “vitamin E” OR “vitamin*” OR “tocopherol” combined with “ovarian cancer” OR “ovarian tumor”. We also manually screened the bibliography of original research and review articles. The initial qualification is determined independently by the two reviewers. Disagreements between the reviewers are resolved by a third-party reviewer at a consensus meeting.To be included in the meta-analysis, these studies must be: (1) case–control, cross-sectional or cohort studies; (2) patients were diagnosed as ovarian cancer; (3) report relative risks (RRs) and 95% confidence intervals (CIs) about vitamin E and ovarian cancer. When two or more articles report the same data, the most recently updated data will be considered. The two reviewers screened the titles and abstracts of the records retrieved from the literature. The full text of the potential related articles is independently searched and evaluated by two reviewers, and the differences in research qualifications are resolved by a third author.The exclusion criteria were as follows: (1) case reports, conference abstracts, letters, editorials, reviews; (2) overlapping or duplicate studies; (3) irrelevant studies; (4) no available data of RRs and 95%CIs and (5) animal studies.Two investigators independently extracted these information from all eligible studies selected according to predefined criteria. Data were extracted about the last name of first author, age, study design, country, cases and participants, RR and 95%CI, sources of vitamin E  and category of vitamin E on ovarian cancer risk.Q statistic and I² to assess variation and heterogeneity within and between studies [Q test P < 0.05 or I² > 50%, it is suggested that the study may be heterogeneous [P < 0.05, the difference was statistically significant.All statistical analyses were conducted using the STATA software V.12.0 . We conducted a meta-analysis of the relationship about vitamin E on ovarian cancer risk. Pooled results were expressed as RRs and 95%CIs with a random-effect model [ studies . The hetogeneous . Sensitiogeneous  were useWe identified 731 studies using electronic and manual retrieval methods, 394 of which were excluded because they were copies of other reports. Of the remaining 337 articles, 292 articles were excluded after review based on the title and abstract, and 45 were reviewed in full-text. Meanwhile, 31 articles were excluded due to reasons present in I2 = 53.2%, Pfor heterogeneity = 0.019)  in cohort studies and 0.84  in case–control studies. Meanwhile, we further explore the association between ovarian cancer and geographic location. The results suggested that total vitamin E intake is not associated with the risk of ovarian cancer in North America .Eleven studies ,22–27 wi= 0.019) . Four stI2 = 52.8%, Pfor heterogeneity = 0.038) in vitamin E intake from food only  or in case–control studies .Eight studies ,23–25 wiood only . Four stI2 = 82.3%, Pfor heterogeneity < 0.001).Five studies ,21,24,25P = 0.620), in vitamin E intake from food only (P = 0.876) and in vitamin E intake from supplement only (P = 0.365). To assess publication bias, Begg’s test was conducted. After the analysis is complete, we did not detect any significant publication bias in total vitamin E intake . Second, the sample size of some studies is relatively small. Third, almost all the included studies come from North America, and the results in our study are suitable for North America only. Therefore, to explore the relationship about vitamin E on the risk of ovarian cancer, more studies with other countries are warranted to further confirm this result. There is no doubt that the limitations mentioned above may affect our final conclusions. However, this meta-analysis also has its advantages. To the best of our knowledge, our meta-analysis is the comprehensive evidence to provide vitamin E intake on ovarian cancer risk. Similarly, compared with individual studies, our data on the relationship between vitamin E intake and ovarian cancer risk, due to the results of multiple independent analysis, improved statistical power and resolution, resulting in higher accuracy. However, given the limitations described above, further research is needed to address bias, confusion and opportunity.In conclusions, the findings of this meta-analysis indicated that high intake of vitamin E from food or vitamin E supplement had no significant effect on the risk of ovarian cancer. More studies are required to further explore these associations due to some limitations existed in our study.