Objective: The association between phthalates and endometriosis risk is inconclusive. This meta-analysis aims to evaluate the association between five different phthalate metabolites and endometriosis, based on current evidence. Methods: The literature included PubMed, WOS (web of science), and EMBASE, published until 3 March 2019. We selected the related literature and evaluated the relationship between phthalates exposure and endometriosis risk. All statistical analyses were conducted with STATA version 12.0. Results: Data from eight studies were used in this review. The results of this analysis showed that mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) exposure was potentially associated with endometriosis . We have not found positive results in mono(2-ethylhexyl) phthalate (MEHP), monoethyl phthalate (MEP), monobenzyl phthalate (MBzP) and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) analyses . In subgroup analyses for regions, the associations were significant between MEHHP and endometriosis in Asia , but not in USA . Conclusions: Our findings suggested a potential statistical association between MEHHP exposure and endometriosis, particularly, the exposure of MEHHP might be a potential risk for women with endometriosis in Asia. However, positive associations between the other four Phthalate acid esters (PAEs) and endometriosis was not found. Given the weak strength of the results, well-designed cohort studies, with large sample sizes, should be performed in future. Phthalate acid esters (PAEs) are mainly composed of dialkyl esters, or alkyl and aryl esters of orthophthalic acid  ,4. In reOver the past decade, a number of studies have been conducted to explore the relationship between reproductive problems in humans and PAEs ,10. StudTherefore, the purpose of the present study is to assess the potential effects of five phthalate metabolites exposure on endometriosis by a quality appraisal and a meta-analysis, based on human epidemiological studies.Searches were carried out using PubMed, EMBASE, and WOS (web of science) from 1 January 1995 to 3 March 2019. The literature search was conducted by two independent authors. We searched the keywords of phthalates  phthalate” or “diisodecyl phthalate” or “diisononyl phthalate ” or “benzyl butyl phthalate” ) AND endometriosis (“endometriosis” or “endometrioses” or “endometrioma” or “endometriomas”).We included studies according to the following criteria: (1) Papers investigated phthalates and their metabolites; (2) one outcome was endometriosis; (3) cohort, case-control or cross-sectional studies; (4) odds ratio (OR) or relative risk (RR) were offered for the associations between phthalate exposure and endometriosis; (5) published in English.Two authors (Cai and Yang) independently examined all studies. Disagreements were resolved through discussions.The following data were collected: Authors, country, year; number of cases; study design; types of sample; exposure assessed, OR with 95% CIs. The data are available to all readers as required.We evaluates the studies in our meta-analysis based on the Newcastle–Ottawa Scale (NOS) ,27. Asse2) with corresponding p-values. We used the random-effect model in our meta-analysis and conducted a subgroup analysis with the study population , the study design , and the study region (USA or Asia).Data in this meta-analysis were analyzed using STATA, version 12.0 , OR with 95% corresponding CI were used to assess the relationship between phthalate exposure and endometriosis. To estimate the heterogeneity among studies, we used chi-squared test and Cochran Q score . The publication bias was not evaluated because the number of included studies was not more than ten .Based on the NOS, 5 of 8 studies scored 7, and the other 3 studies scored 6. Pooled results suggested that MEHHP was significantly associated with the risk of endometriosis , but not in USA . No specific relationships were identified between MEHHP exposure and endometriosis risk in the subgroups of the study design or population. The detailed results are summarized in In subgroup analyses for regions, MEHP was associated with endometriosis risk in Asia . However, the result was weak and additional future studies need to be included in the analysis. No specific relationships were identified between MEHP exposure and endometriosis risk in other subgroups. The detailed results are summarized in Subgroup analyses for MEP, MBzP, MEOHP exposure were performed in We conducted sensitivity analyses in order to exclude the influence of single study on the overall results. As Phthalates have been shown to increase the rate of premature menopause in animals. Phthalates are estrogen and anti-androgen endocrine disruptors ,35,36,37As far as we are aware, the current study is the first meta-analysis on the association of exposure to phthalates and endometriosis. In our meta-analysis, we investigated five types of phthalate metabolites, including MEHHP, MBzP, MEP, MEHP, and MEOHP. The findings of this meta-analysis indicated that only MEHHP was potentially associated with endometriosis. This result was consistent with a previous study that assessed the relationship between phthalates and endometriosis ,32. BesiSubgroup analysis found that MEHHP exposure in Asia was associated with endometriosis. For the other metabolites, the results of subgroup analysis were not significant. For MEHHP group, after subgroup analysis was conducted by region, we found positive results in Asia but not in USA, suggesting that different countries have different levels of PAEs exposure, which plays a significant role, and different races also affect the outcome. Heterogeneity, that comes from regional diversity, race diversity, weight difference, sample size difference, age variation, health status, the concentration and duration of exposure of the study subjects or different detection methods, is relatively high for some meta-analysis and might have a potential effect when interpreting the synthesized results. After subgroup analysis was conducted by region, heterogeneity in the Asian group decreased, suggesting that regional factors may be related to heterogeneity, and that differences in PAEs exposure levels, in different countries, may be more important factors in this case.Our meta-analysis has some advantages. Firstly, there has not been any meta-analysis on the relationship between phthalate metabolites and endometriosis risk before. Second, our meta-analysis identified the potential risk associated with five different phthalate metabolites and endometriosis. Third, this meta-analysis study was the ability to do a complete analysis on subgroups, such as types of studies , region, subgroup of laparoscopic/laparotomy population, and general population, as well as the samples used (urine and plasma).However, our meta-analysis also has some limitations: First, since there were only eight studies, the sample size is relatively limited. Second, there are potential confounding factors, such as age variation, weight difference, health status, BMI, and sample size differences. Although, some research data is based on the adjusted model, our results could be biased by the inherent limitations in the original studies. Third, different PAEs may coexist in some cases. And it has been found that MBzP, MEP, MEHP, and MBP may have some correlation, which indicates that they have a possible common sources of exposure . AlthougOur findings suggested a potential statistical association between MEHHP exposure and endometriosis, particularly, the exposure of MEHHP might be a potential risk for women with endometriosis in Asia. No associations were identified between endometriosis with MEHP, MEP, MBzP, and MEOHP. Since the quality of the studies was moderate, it would be not appropriate to claim that these metabolites have no role in the progression of endometriosis. Our meta-analysis included only eight studies, involving fouor countries, and five common phthalate metabolites. Therefore, the available evidence is very limited, which may cause some bias in some aspects. Future studies should be conducted with larger sample size and higher number of phthalate metabolites.


To investigate the potential prognostic role of pre-treatment prognostic nutritional index (PNI) in urinary cancers.Relevant articles were searched comprehensively from PubMed, Embase and Web of Science, up to November 2018. The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were extracted to evaluate their associations.A total of 12 related articles including 6561 patients were ultimately enrolled. Our results indicated that a relatively lower level of pre-treatment PNI was associated with decreased OS, CSS/DSS and DFS/RFS/PFS . Subsequent stratified analysis by cancer type for OS showed that PNI could also be a predictor no matter in renal cell cancer (RCC) or bladder cancer (BC) . Similar results could be found in DFS/RFS/PFS  and in CSS/DSS . As for the treatment subgroup, a relatively lower level of PNI could also be a positive predictor for OS  and DFS/RFS/PFS .The outcomes of us shed light on that elevated pre-treatment PNI was positively associated with OS, CSS/DSS and DFS/RFS/PFS, indicating that it could be an independent prognostic factor in urinary cancers. Urinary cancers, as a term mainly consisting of prostate cancer (PC), bladder cancer (BC), renal cell cancer (RCC), are much more common in men than in women and the incidence of these tumors ranks the second, fifth and seventh most commonly diagnosed cancer in the United States, 2017 , survivaPrognostic nutritional index (PNI), as a predictor of cancer prognosis, was firstly introduced by Onodera et al.  to invesTo investigate the potential role of PNI in urinary cancers, relevant articles were searched comprehensively from online databases PubMed, Embase and Web of Science, up to November 2018. The search strategy was consisted of the following keywords in combination with Medical Subject Headings (MeSH) terms and text words:  and  and . This meta-analysis was performed according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement  and no lArticles eventually enrolled in this meta-analysis should meet the following criteria: (1) cohort studies or case–control studies; (2) patients were diagnosed with urinary cancers histopathologically; (3) the association of pre-treatment PNI with specific endpoint , PFS, disease-free survival (DFS), disease-specific survival (DSS) or CSS; (4) available data by means of hazard ratios (HRs) with 95% confidence interval (CIs) should be provided. Exclusion criteria were as follows: (1) lack of accurate data; (2) letter, review and case report; (3) simple description without comparison. Additionally, only the largest sample size study was included if the same series of research were used in various articles.http://www.ohri.ca/programs/clinical_epidemiology/oxford.htm), which was one of the most useful scale to evaluate the quality of non-randomized studies [The whole selection process was performed independently by two blind investigators (F.Q and X.Z). Disagreements were addressed by consultation with a third reviewer (Y.W). Following data were extracted from articles based on standard form: first author’s name, year of publication, country, cancer type, study design, treatment methods, sample size , PNI cut-off values, endpoints, HRs with 95% CIs and follow-up. Data were extracted from Kaplan–Meier curves to extrapolate HRs with 95% CIs using previously described methods, if it could not be directly obtained from each article , 13. Met studies . Total q2 statistic were used to evaluate the heterogeneity. If significant heterogeneity (P < 0.10 or I2 > 50%) existed, the random effect model (a DerSimonian-Laird method) would be applied. Otherwise, the fixed effect model (a Mantel–Haenszel method) was adopted [P < 0.05 was considered to be statistically significant [To investigate the potential role of PNI in urinary cancers, this meta-analysis was conducted based on available data and the pooled HRs with 95% CIs were utilized to evaluate their efficacy. Cochran’s Q test and Higgins I adopted . The stanificant . In addiA total of 12 –28 articP = 0.968, I2 = 0.0%). Our results indicated that a relatively lower level of pre-treatment PNI was associated with decreased OS    . Our results indicated that a relatively lower level of pre-treatment PNI was associated with decreased DFS/RFS/PFS    . Our results indicated that a relatively lower level of pre-treatment PNI was associated with decreased CSS/DSS    ratio and pre-treatment lymphocyte-monocyte ratio (LMR) had been proved to be an independent prognostic factor in various urinary cancers –42. Gene2), was first applied by Onodera et al. [In this meta-analysis, conclusion could be drawn that a relatively lower pre-treatment PNI was tightly associated with a poorer OS, DFS/PFS/RFS and CSS/DSS. Subgroup analysis by cancer type or treatment type showed the similar results. PNI, calculated by serum albumin levels and lymphocyte count and its accurate value equals to 10 * serum albumin concentration (g/dL) + 0.005 * lymphocyte counts . Due to the relatively small sample size, unavoidable bias might also exist. Thirdly, most of the included articles were from Asia which may make the subgroup analysis hard to be performed. Last but not least, upcoming prospective RCTs were required to provide more available data and subsequent researches should resolve the aforementioned difficulties before pretreatment PNI was widely used in clinical practice.In summary, the outcomes of this meta-analysis shed light on that a higher level of pre-treatment PNI was positively associated with OS, CSS/DSS and DFS/RFS/PFS, indicating that it could be an independent prognostic factor in urinary tumors. Due to the limited researches, it restricted our in-depth investigation of the role of PNI. Hence, larger-samples with higher-quality randomized controlled trials were required to verify our findings.


SLC2A1) and the risk of type 2 diabetes (T2DM) leading to nephropathy. We also performed a meta-analysis of 11 studies investigating association between diabetic nephropathy (DN) and SLC2A1 variants. The cohort included 197 cases (T2DM with nephropathy), 155 diseased controls (T2DM without nephropathy) and 246 healthy controls. The association of variants with disease progression was tested using generalized odds ratio (ORG). The risk of type 2 diabetes leading to nephropathy was estimated by the OR of additive and co-dominant models. The mode of inheritance was assessed using the degree of dominance index (h-index). We synthesized results of 11 studies examining association between 5 SLC2A1 variants and DN. ORG was used to assess the association between variants and DN using random effects models. Significant results were derived for co-dominant model of rs12407920 [OR = 2.01 (1.17–3.45)], rs841847 [OR = 1.73 (1.17–2.56)] and rs841853 [OR = 1.74 (1.18–2.55)] and for additive model of rs3729548 [OR = 0.52 (0.29–0.90)]. The mode of inheritance for rs12407920, rs841847 and rs841853 was ‘dominance of each minor allele’ and for rs3729548 ‘non-dominance’. Frequency of one haplotype (C-G-G-A-T-C-C-T-G-T-C-C-A-G) differed significantly between cases and healthy controls [p = .014]. Regarding meta-analysis, rs841853 contributed to an increased risk of DN  between diseased controls versus cases and healthy controls versus cases, respectively. Further studies confirm the association of rs12407920, rs841847, rs841853, as well as rs3729548 and the risk of T2DM leading to nephropathy.An association study was conducted to investigate the relation between 14 variants of glucose transporter 1 gene ( Diabetic nephropathy is a major microvascular complication of diabetes mellitus . It is tSLC2A1, i.e., the member 1 of the solute carriers family 2, is a most important representative of the facilitative glucose transporters. Its expression in the glomerular mesangial cell membrane is rate-limiting for intracellular glucose flux and utilization . The normality of continuous variables was tested by the Kolmogorov–Smirnov test. Pair-wise comparisons of continuous variables were performed with the t-test or the Mann–Whitney U test for unpaired data, as appropriate. The frequencies of categorical variables were compared by means of the χ2 test or the Fisher’s exact test.The data for continuous variables were expressed as mean value and standard deviation [mean ± SD] and data for categorical variables as count (or ratio) and percentage  indicating a protective role of allele T of rs3729548 for disease progression to nephropathy , rs841847 C/T (h = 0.93) and rs841853 C/A (h = 0.94), the mode of inheritance is ‘dominance of each minor allele’, indicating that the homozygous for the minor allele has a greater risk of being diabetic with nephropathy than the homozygous for the frequent allele, and that the heterozygote has a risk of diabetes leading to nephropathy closer to the homozygote for the minor allele than to the midpoint between the two homozygotes. The mode of inheritance attributed to the variant rs3729548 C/T is ’non-dominance’ (h = 0.10), indicating that the heterozygote CT has a risk of being diseased that lies in the middle of the risk-protected CC and risk-exposed TT homozygous genotypes  between pairs of SCL2A1 variants for patients with diabetes leading to nephropathy (cases) and healthy controls. In cases 107 out of 182 (59%) and in healthy controls 120 out of 182 (66%) pairs of variants tested were in LD (p < .05). In 11 of the 14 SLC2A1 variants above 50% of variant pairs were in LD in both populations . Especially, variant rs12071418 C/G was not in LD with any other variant in cases, whereas it was in LD with only 3 other variants  in controls. Moreover, omitting the rs12071418 C/G variant pairs, lead to 63% of pairs being in LD in cases and 69% in healthy controls, respectively.SLC2A1 variants  for cases and healthy controls is presented in p = .132). In the analysis of the individual haplotypes, however, C-G-G-A-T-C-C-T-G-T-C-C-A-G derived significant results . This haplotype may confer protection for type 2 diabetes leading to nephropathy, as alleles, which were shown to increase the risk of diabetes leading to nephropathy , are all missing in the haplotype, whereas allele T of rs3729548 C/T, which seems to act protectively, is included.The distribution of the estimated haplotype frequencies of the 14 SLC2A1 variants, 8 genetic variants were studied . Out of the aforementioned variants, only five variants examined in two studies or more and so meta-analyzed . Only XbaI SNP produced significant results in analysis using diseased controls versus cases and healthy controls versus cases giving a summary ORG of 1.428  and 1.581 , respectively  are involved in disease progression. In addition, these variants are associated with the risk of diabetes leading to nephropathy: significant results were derived for the co-dominant model of the variants rs12407920 C/T [OR = 2.01 (1.17–3.45)], rs841847 C/T [OR = 1.73 (1.17–2.56)] and rs841853 C/A [OR = 1.74 (1.18–2.55)] as well as for the additive model of the variant rs3729548 C/T [OR = 0.52 (0.29–0.90)]. The mode of inheritance for the variants rs12407920 C/T, rs841847 C/T and rs841853 C/A was ‘dominance of each minor allele’ and for the variant rs3729548 C/T was ‘non-dominance’. The frequency of one haplotype (C-G-G-A-T-C-C-T-G-T-C-C-A-G) was significantly different on a comparison between cases and healthy controls . This haplotype may confer protection for type 2 diabetes leading to nephropathy, as all the alleles contributing to the risk of diabetes leading to nephropathy  are missing in the haplotype, whereas allele T of rs3729548 C/T, which seems to act protectively, is included.The analysis showed that certain variants of SLC2A1  enhance susceptibility to diabetic nephropathy [In agreement to our findings, a previous systematic review and meta-analysis of nine genetic association studies in patients with either type 1 or type 2 diabetes found that certain genetic variants in hropathy . The simSLC2A1 variants [SLC2A1 variants. A more recent genetic association study in Brazilian patients with type 1 diabetes mellitus and inadequate blood glucose control showed that another variant of SLC2A1 (rs3820589) is associated with progression of nephropathy [In our study the genetic association was performed in patients with type 2 diabetes of Greek (Caucasian) origin. Subgroup analyses for Caucasians, in the above systematic review, revealed association between diabetic nephropathy due to both type 1 and type 2 diabetes and variants . All fouhropathy . Along wSLC2A1 may not be involved in the pathogenesis of type 1 diabetes but its involvement in type 2 diabetes is plausible according to functional criteria. Nevertheless, according to a study of two populations in the Pacific, the variant rs841853 of SLC2A1 was not predisposing to diabetes type 2. Concretely, the rs841853 alleles frequency was the same (high) in both populations, one Polynesian population with high prevalence for type 2 diabetes and one highland New Guinean population with a notable absence of type 2 diabetes [SLC2A1 may confer increased susceptibility to type 2 diabetes mellitus [However, any genetic association study on the risk for development of diabetic nephropathy in either type of diabetes mellitus might be readily confounded if the genetic factors under investigation are also predisposing to diabetes. This is especially true when healthy controls, i.e., controls without diabetes, are included. diabetes . In contmellitus . In our SLC2A1, involved in disease progression in our study, are all intron variants . As intronic variants, they cannot possibly cause changes in the protein sequence and they are not associated to alterations of the SLC2A1 expression. For these reasons, although significant associations were detected in this study, their functional significance seems questionable and their relevance would need further experimental proof. These polymorphisms may not be causative, but linkage disequilibrium with other loci with an etiologic role in diabetic nephropathy cannot be excluded.Single nucleotide polymorphisms of SLC2A1 in complications in diabetes [In addition, in our study, the sample size was relatively small. The association of diabetic nephropathy and 4 genetic variants in the GLUT1 gene is remarkable. However, the number of patients and controls is low for the inference of genetic association. This is a common phenomenon in candidate-gene association studies . In genediabetes . Howeverdiabetes ,46,50,51SLC2A1 as a marker in diabetes leading to complication. This can be achieved by examining the genomic convergence of these different types of studies [Diabetic nephropathy is a complex disease with multifactorial etiology and it involves epistatic and gene-environment interactions, and therefore, single type of genetic studies, such as gene-candidate association studies, have a reduced likelihood to provide conclusive inferences. In addition to hypothesis-driven studies , hypothesis-free studies such as GWAS ,52,53, m studies ,56,57.SLC2A1 variants and diabetic nephropathy. In total, eight SLC2A1 variants were investigated, out of which only five variants were examined in two studies or more and so considered in meta-analysis. Among these five variants, two were also genotyped in our case-control study . We recorded a significant association between XbaI polymorphism and diabetic nephropathy in analysis of diseased controls versus cases and healthy controls versus cases, after accounting between study heterogeneity using the random effects model. It is noteworthy to mention that meta-analysis when included, our case-control study changed the pattern of results in comparison with healthy controls versus cases, as a significant association was detected for XbaI polymorphism suggesting that this genetic variant maybe associated with diabetic nephropathy.However, since the sample size of the present association study was relatively small, we performed a meta-analysis considering all published studies, which investigated the association between SLC2A1 variants, since it includes all polymorphisms with available data for meta-analysis and all available comparisons between cases, diseased controls and healthy controls. These three comparisons made the trait discrimination more feasible. An important issue in all genetic studies regarding diabetic nephropathy is the demarcation of genetic loci associated with diabetic nephropathy per se and not with the type of diabetes which caused the renal disease. One additional strength of our meta-analysis is the strict definition of cases, as only subjects with persistent moderately increased albuminuria were considered as cases.To the best of our knowledge, it is the most comprehensive meta-analysis regarding However, our meta-analysis has also some limitations. A common issue in meta-analysis is the publication bias, as only published studies were included in meta-analysis. Furthermore, the search was restricted in studies published in English. We should also interpret with caution the results of the meta-analysis because the number of studies is small and the sample size of each study also small.SLC2A1 and the risk of type 2 diabetes leading to nephropathy and it also reviews the current epidemiology findings regarding the contribution of SLC2A1 variants in diabetic nephropathy. The results suggest that SLC2A1 variants and haplotypes may be involved in the pathogenesis of diabetic nephropathy. However, additional studies and a genetic convergence analysis of different data sources are needed in order to merit prioritization in future studies producing more conclusive claims of the association between SLC2A1 and genetic susceptibility to diabetic nephropathy.In conclusion, the present study presents the results of an association study, which investigated the relation between 14 tag variants across


Klebsiella pneumoniae (CRKP) infection have provided inconsistent results, partly due to the choice of the control group. We conducted a systematic review and meta-analysis to assess the risk factors for CRKP infection by comparing CRKP-infected patients with two types of controls: patients infected with carbapenem-susceptible Klebsiella pneumoniae (comparison 1) or patients not infected with CRKP (comparison 2).Studies on risk factors for carbapenem-resistant Data on potentially relevant risk factors for CRKP infection were extracted from studies indexed in PubMed, EMBASE, Web of Science or EBSCO databases from January 1996 to April 2019, and meta-analyzed based on the outcomes for each type of comparison.comparison 1 = 3.20, ORcomparison 2 = 4.44), central venous catheter use , mechanical ventilation , tracheostomy , urinary catheter use , prior use of antibiotic , exposure to carbapenems  and exposure to aminoglycosides . Another 10 risk factors were unique to comparison 1: longer length of hospital stay (OR = 15.28); prior hospitalization (within the previous 6 months) (OR = 1.91); renal dysfunction (OR = 2.17); neurological disorders (OR = 1.52); nasogastric tube use (OR = 2.62); dialysis (OR = 3.56); and exposure to quinolones (OR = 2.11), fluoroquinolones (OR = 2.03), glycopeptides (OR = 3.70) and vancomycin (OR = 2.82).The meta-analysis included 18 studies for comparison 1 and 14 studies for comparison 2. The following eight risk factors were common to both comparisons: admission to intensive care unit (ICU; odds ratio, ORK. pneumoniae infection; eight factors may be associated with both K. pneumoniae infections in general and CRKP in particular. The eight shared factors are likely to be ‘true’ risk factors for CRKP infection. Evaluation of risk factors in different situations may be helpful for empirical treatment and prevention of CRKP infections.Eighteen factors may increase the risk of carbapenem resistance in  Klebsiella pneumoniae, are an emerging cause of healthcare-associated infections that pose a significant threat to public health [K. pneumoniae infections resistant to carbapenems continues to rise [K. pneumoniae carbapenemase originated in the northeastern USA in the early 2000s, but rapidly disseminated to other regions worldwide [Carbapenem-resistant Gram-negative bacteria, mainly c health . The per to rise , 3, with to rise , 2. K. porldwide .K. pneumoniae (CRKP) infection is difficult to treat since carbapenems are often considered last-resort antibiotics for severe K. pneumoniae infections. The most important genes that can confer carbapenem resistance (via carbapenemases) are present in K. pneumoniae, rendering almost all available treatment options ineffective [K. pneumoniae (CSKP) [Carbapenem-resistant ffective . Mortaliffective , signifie (CSKP) . Prevente (CSKP) , 7.K. pneumoniae infections in general and CRKP in particular. Risk factors that are significant in both comparisons can be considered ‘true’ risk factors for CRKP infection [Numerous studies have assessed risk factors for CRKP infection with different and sometimes even contradictory conclusions. A previous meta-analysis attempted to address this inconsistency  but did nfection , 12.Thus, we performed a systematic review and meta-analysis to clarify risk factors for CRKP infection relative to infection with CSKP (comparison 1) or to the absence of CRKP infection (comparison 2). This design, similar to a case-control-control study, aimed to compare the results of the two analyses and their different implications for the clinical practice, allowing the identification of the likely true risk factors for CRKP infection.This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines .Klebsiella pneumoniae” AND (“carbapenem-resistant” OR “imipenem-resistant” OR “meropenem-resistant” OR “ertapenem-resistant” OR “carbapenemase-producing” OR “Klebsiella pneumoniae carbapenemase”) AND (“risk factors” OR “risk” OR “factors”). Only studies published in English were considered. Reference lists in selected articles and relevant review articles were manually searched to identify additional studies.Two authors (H.Y.Z. and Z.Y.) searched for relevant studies in PubMed, EMBASE, Web of Science and EBSCO databases that were published from January 1996 to April 2019. The search terms included “K. pneumoniae isolate identification and tests for resistance to carbapenem  involving well-defined microbiological methods; and (5) infection was explicitly defined. The inclusion criterion (3) led us to exclude studies comparing patients infected with carbapenemase-producing K. pneumoniae (CPKP) with controls without such infection, since such controls may have been infected with carbapenem-resistant, non-carbapenemase-producing K. pneumoniae. Studies were also excluded if they had the format of a report, review, comment, meeting abstract or letter to the editor; or if they reported insufficient data to assess outcomes.Studies were included if they met the following criteria: (1) case-control or cohort study design, whether prospective or retrospective; (2) the risk factors for CRKP infection were reported; (3) either comparison 1 or comparison 2 was made; (4) CRKP and CSKP were classified based on Two authors (H.Y.Z. and W.M.Z.) independently evaluated and extracted data from the included studies using a predefined, standardized protocol. The extracted data on general characteristics of studies included the first author’s name, year of publication, journal of publication, country, study period, study design and setting, type of inter-group comparison, sample size, average age, and sex distribution. Potential risk factors were included in the meta-analysis only if at least three studies examined them and those studies reported the numbers of individuals in each comparison group. Disagreements about extracted data were resolved through discussion.Two authors (W.M.Z. and Z.Y.) independently evaluated the quality of each study using the Newcastle-Ottawa Scale (NOS), a scale for assessing the quality of published non-randomized studies in meta-analyses . The scaZ-test was used to determine the significance of the pooled OR, and the results were considered statistically significant when P < 0.05. Statistical heterogeneity among studies was assessed using a chi-squared test in which P < 0.10 was taken as the threshold for significant heterogeneity, or by calculating I2 value, with I2 > 50% considered evidence of heterogeneity [The meta-analysis was performed using RevMan 5.2 software provided by The Cochrane Collaboration . Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for all outcomes. The ogeneity . DependiP < 0.05. Sensitivity analyses were conducted by omitting studies one by one, and the P values of pooled ORs were compared. The results were considered robust when the P values were not substantially different.Publication bias was quantitatively analyzed using Egger’s test in STATA software version 12.0  , and theA total of 428 unique records were retrieved from electronic databases, and 203 duplicate records were removed. After screening of titles and abstracts, 171 records were excluded. The remaining 54 studies were read in full to determine the eligibility. In the end, 18 studies performing comparison 1  and 14 fThe main characteristics of the 18 studies included in comparison 1 are presented in Table The main characteristics of the 14 studies included in comparison 2 are presented in Table All studies in the review were judged to be of high quality based on NOS assessment. The 18 studies in comparison 1 scored an average of 7 (range 5–8) Table .Table Table Egger’s test showed no obvious asymmetry in the risk factors, suggesting low risk of publication bias Tables  and 4.The sensitivity analysis was performed by repeating the meta-analysis after omitting each study one by one and examining whether the results changed substantially. For most risk factors, no single study seemed to substantially alter the results. We noted two exceptions: in comparison 1, omitting the study by Mouloudi et al. from 2010  made theK. pneumoniae infections involving meropenem resistance in China increased from 14.1% in 2013 to 28.6% in 2018, with four provinces showing CRKP proportions > 10% in 2013 (the highest was Zhejiang province with 37.40%) and 13 in 2017 (the highest was Henan province with 53.01%) [K. pneumoniae infections involving meropenem resistance has grown steeply in the USA from 0.6% in 2004 to 10.8% in 2007 [K. pneumoniae infections in 2017 showed carbapenem resistance [CRKP is one of the most serious life-threating nosocomial pathogens worldwide, and CRKP infections are highly prevalent in most of the countries where the studies included in our review were performed . The proportion  53.01%) . The pro in 2007 . The mossistance . Israel sistance . The ideUnfortunately, although many studies have investigated risk factors for CRKP infection, they have come to diverging, often conflicting, conclusions. For example, some studies have reported that exposure to carbapenems increased the risk of CRKP infection , 31, 33,K. pneumoniae but tests of antibiotic susceptibility are pending. In this case, the clinician estimates the probability of resistance to carbapenem based on risk factors, adopting an empirical approach that prioritizes interventions to prevent transmission of carbapenem resistance at this early stage. In this type of comparison, our analysis identified the following risk factors: prior hospitalization (within the previous 6 months), longer length of stay, admission to the ICU, concomitant diseases , certain invasive procedures , prior use of any antibiotic, and specific exposure to vancomycin or other five classes of antimicrobial agents . These risk factors are more likely to be present in patients with more severe illness and greater susceptibility to infection, and who are therefore exposed to greater antibiotic selection pressure, which may ultimately increase the likelihood of infection with multidrug-resistant pathogens [We based our review on the idea that the choice of the control group for risk assessment can provide different results, as suggested in several previous studies –12. We mathogens .K. pneumoniae infection in general and CRKP in particular. The impact of risk factors on CRKP infection reflects an integrated effect of K. pneumoniae characteristics and carbapenem resistance. This may allow clinicians and hospital epidemiologists to take timely action to prevent CRKP transmission, even when no pathogen is detected in patient specimens, which may be due to their use of medications. In this type of comparison, our analysis identified the following risk factors: admission to ICU, certain invasive procedures , prior use of any antibiotic, and exposure to carbapenems or aminoglycosides. Importantly, these risk factors were also statistically significant in comparison 1, which means that they are probably true risk factors for acquiring CRKP infection among hospitalized patients.Comparison 2 is more relevant for the situation when hospitals need to identify patients at increased risk of suffering K. pneumoniae. Indeed, fluoroquinolone exposure can generate resistance not only to fluoroquinolones but also to carbapenems, as fluoroquinolones lead to upregulation of the multidrug efflux pump MexEF-OprN and downregulation of the porin OprD, which is involved in carbapenem resistance [K. pneumoniae plasmids carrying carbapenemase genes [In contrast, dialysis and exposure to fluoroquinolones or glycopeptides were risk factors only for the first comparison. These factors may therefore increase primarily the risk of carbapenem resistance in sistance , 52. In se genes . These cOur sensitivity analysis confirmed that meta-analysis results were robust, with the possible exceptions of exposure to β-lactam + β-lactamase inhibitor (comparison 1) and diabetes (comparision 2). The status of these variables as risk factors changed depending on the inclusion of two small studies , 37. TheCompared to a previous meta-analysis with a similar goal , the preLike the previously published meta-analysis on risk factors of CRKP infection , our excThe findings of our meta-analysis should be interpreted with caution given that some potential risk factors were analyzed based on data from a small number of studies. Indeed, data for some factors showed significant heterogeneity across studies, especially in comparison 2, probably because control patients included those without any infection as well as those infected with nosocomial pathogens other than CRKP. Most studies in our review were retrospective and all were observational, increasing the risk of patient selection bias, outcome reporting bias and confounding. Nevertheless, all studies received NOS scores indicating high quality, and no obvious publication bias was observed for any of the factors. Factors affecting risk of CRKP infection should be further examined in large, well-controlled prospective studies.K. pneumoniae infection and eight factors which were associated with both K. pneumoniae infections in general and CRKP in particular. The eight shared factors are probably ‘true’ risk factors for CRKP infection. These findings may help clinicians and hospital epidemiologists estimate the likelihood of CRKP infection in different situations, and thereby initiate timely, targeted treatment and prevention measures.This meta-analysis identified 18 factors that increase the risk of carbapenem resistance in


Some studies have looked at the age at menarche and risk of Multiple Sclerosis (MS).We aimed to conduct a systematic review and meta-analysis to estimate a pooled odds ratio of developing MS by increasing age at menarche.We searched PubMed, Scopus, EMBASE, CINAHL, Web of Science, Ovid, google scholar and gray literature  up to 10th April 2019.2 = 49%, p = 0.1). Mean age at menarche was significantly different between case and control groups .The literature search found 312 articles. After eliminating duplicates, reviews, case reports and trials, 18 articles remained. Three articles were ultimately included in the final analysis. Two studies were from Iran, and one from Canada. The pooled odds ratio (OR) for increasing 1 year of age at menarche was 0.88 (95% CI:0.82-0.94), with no significant heterogeneity (IThe result of this systematic review showed that the risk of MS decreases by increasing age at menarche. Multiple sclerosis (MS) is an autoimmune disease affecting women more than men and is the most frequent leading cause of neurological disability in young adults along with trauma –3. DiffeAlthough MS appears mostly in young adults, pediatric MS is now prevalent and there are challenging issues regarding its occurrence .Previous studies have shown that earlier menarche is associated with an increased risk of various diseases such as breast cancer and type 2 diabetes , 8.In women, sex hormones have crucial roles in the immune system development which leads to higher levels of immunoglobulins, strong activation of T-cell and more antibody response reactions to antigens . PreviouIn a recent case-control study conducted in Iran, Salehi et reported 8% reduction of MS risk for each one-year increase of menarche age .As the age of menarche differs in different countries and published articles reporting odds of MS by increasing age at menarche, we aimed to conduct this systematic review and meta-analysis to estimate a pooled odds ratio of developing MS by increasing age at menarche.We searched PubMed, Scopus, EMBASE, CINAHL, Web of Science, Ovid, Google scholar and Gray literature  up to 10th April 2019.Case-control studiesStudies providing crude odds ratio (OR) for the age of menarche and risk of MSArticles published in the English languageInclusion criteria were:The search syntax for identifying studies was:(Puberty OR menarche) AND  OR Sclerosis, Disseminated) OR Disseminated Sclerosis) OR MS (Multiple Sclerosis)) OR Multiple Sclerosis, Acute Fulminating).Data extraction and evaluation of studies were performed by two independent researchers. Name of the first authors, publication year, country, number of cases in each group of the study, crude OR, lower limit and upper limit of 95% CI of crude ORs were extracted.The risk of bias was assessed by the modified NEWCASTLE - OTTAWA QUALITY ASSESSMENT SCALE (for case-control studies)  Additio.2) calculation. Accordingly, and as discussed by Deeks et al. [2 of more than 40% was considered high for heterogeneity. Mean difference was calculated for the age at menarche comparison.STATA Version 13.0  and RevMan 5.3  were used for data analysis. Random effects models were used and heterogeneity was determined by the inconsistency   (The CI do not include one)  (The CI do not include zero) Fig. .Fig. 3MAll included studies had good quality (≥5) using NEWCASTLE - OTTAWA QUALITY ASSESSMENT SCALE (for case-control studies) Table .Table 2To our knowledge, this is the first systematic review and meta-analysis evaluating age at menarche and risk of MS.The pooled OR for increasing 1 year of age at menarche was 0.88 (95% CI:0.82-0.94) (The CI do not include one) which shows that each year increase of age will result in 12% reduction of MS odds. The OR for age at menarche and risk of MS differed between studies ranging from 0.78 to 0.92. The difference in reported odds could be due to different sample sizes and patient characteristics.Mean age at menarche was significantly different between case and control groups  (The CI do not include zero). There are controversies regarding the findings of previous studies about age at menarche in MS cases and controls. For the first time, Antonovsky et al. examined the age at menarche in MS female cases and controls and found no significant difference .p = 0.01) [Operskalski et al. compared 108 MS women with 108 healthy controls and reported mean age at menarche in cases as 12.1 years vs 12.7 years in controls ( = 0.01) .Gustavsen et al. compared 391 MS patients and 535 female controls and reported no significant difference (13.07 vs. 12.97) .MS is a complex neurological disease and the exact causative factors are not yet conclusively determined. Female domination is prominent and the relationship between menarche age and risk of MS may demonstrate the role of sex hormones in MS development . EstrogeAlthough puberty affects brain development, brain development affects puberty conversely by activating GnRH neurons . Sloka eIt has been suggested that elevated levels of estrogen during pregnancy results in relapse rate reduction and estradiol protects oligodendrocytes from death .There are controversies regarding the use of contraceptives and the risk of MS. Salehi et al. found that use of oral contraceptive pill (OCPs) will increase risk of MS development by 40%  which isTo our knowledge this is the first meta-analysis to assess age at menarche and risk of (MS) which has limitations. First the included studies do not cover female cases of all ethnicities.Second, the number of cases and controls are not the same in all included studies. The difference between the case-control-ratio may cause bias.Third, the number of included studies are limited.2 parameter was 49 and 65% in two meta-analyses of the current study, which was indicative for high heterogeneity level as defined by Deeks et al. [On the other hand, Is et al. .Altogether, more studies including findings from patients of all five continents with larger sample sizes are recommended. Also, more precise results could be achieved in case the included studies are more homogenous, both clinically and statistically.The result of this systematic review showed that the risk of MS decreases by increasing age at menarche.Additional file 1: MODIFIED NEWCASTLE - OTTAWA QUALITY ASSESSMENT SCALE for quality assessment for cohort and case-control studies.


Provide an updated and comprehensive evaluation of the prognostic value of the albumin-fibrinogen ratio (AFR) and the fibrinogen-prealbumin ratio (FPR) for patients with cancer.Four databases  were searched. The primary endpoints were overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS). Pooled data were synthesized using StataMP 14 and expressed as hazard ratios (HRs) and 95% confidence intervals (CIs).This update examined 19 studies (7282 cases) that assessed the correlation of AFR with cancer prognosis. Pooled univariate and multivariate analyses indicated significant correlations of low AFR with poor OS , poor DFS , and poor PFS . Pooled univariate and multivariate analyses of 6 studies (2232 cases) indicated high FPR significantly correlated with poor OS . One study reported that high FPR correlated with poor DFS  and one study reported a correlation of high FPR with poor PFS in univariate analysis alone .A low AFR and a high FPR correlated with increased risk of cancer mortality and recurrence. AFR and FPR may be promising prognostic markers for cancers. Cancer incidence and mortality are rapidly increasing worldwide. There were an estimated 18.1 million newly diagnosed cancer cases and 9.6 million cancer deaths throughout the world during 2018 . TherefoMalnutrition is common in cancer patients and is associated with increased morbidity and mortality . Serum lPrealbumin, also known as transthyretin, has a much shorter half-life and smaller serum pool than albumin. Its main functions are to bind and transport endogenous proteins and small molecules. Prealbumin is more sensitive to changes in protein-energy status than albumin, and its concentration closely reflects recent dietary intake rather than overall nutritional status . PrealbuClinicians have long recognized specific associations of hemostatic system disorders with diverse cancers. The polypeptide fibrinogen is the central protein in the hemostasis pathway and occurs as a deposit in most tumors that occur in humans and experimental animals . FibrinoPrevious meta-analyses of cancer patients indicated that several ratios of pretreatment systemic inflammatory markers or/and nutritional markers, such as the neutrophil-lymphocyte ratio (NLR) , the albPotential studies were identified by searching four online databases  using PRISMA guidelines . All stuEligibility criteria were defined according to the Population, Intervention, Comparison, Outcome and Study Design (PICOS) strategy. Thus, “Population” refers to cases diagnosed with cancers; “Intervention” refers to low AFR or high FPR; “Comparison” refers to the control group (without low AFR or high FPR); “Outcome” refers to OS, DFS, or PFS; and “Study design” refers to a prospective or retrospective study. A study was deemed ineligible if it was a duplicate, a review article, a comment or letter, or a case series. When there were duplicate records, the most recently published record was used.Data were collected independently by two authors using a predefined form. These forms were further checked by the third author, and disagreement was reconciled by consensus among all authors. The data extracted from each article included author names, publication year, country, cancer category, cancer stage, study design (prospective or retrospective), primary treatment option, optimal cut-off value and method used to select the optimal cut-off value, number of cases , prognostic outcome, hazard ratios (HRs) with 95% confidence intervals (CIs), method of data analysis, data source (crude data or fitted curve), and follow-up interval. HR data were extracted from univariate and multivariate analyses if available.Q and I2 statistics were utilized to assess the heterogeneity among included studies [P < 0.1 and/or I2 > 50%), pooled data were analyzed using a random-effects model; otherwise, a fixed-effects model was used. All statistical tests were two-sided, and a P value less than 0.05 was deemed statistically significant. The statistical analyses, stratification analyses, and sensitivity analyses were the same as those used in our previous publications [When prognostic outcomes were provided as Kaplan-Meier curves, Engauge Digitizer 4.1 software was used to read the curves and identify the times of deaths. These data, defined as time-event outcomes, were used to calculate HRs and 95% CIs using the method of Tierney et al. . These d studies . When thications , 21.We initially identified 1805 records, and 995 of these records remained after removal of duplicates  showed a significant association between low AFR and poor OS   also showed a significant association between low AFR and poor OS   using univariate analysis and in 17 studies (6704 cases) using multivariate analysis. Based on the univariate analyses, the pooled results of a random-effects model  demonstrated a significant association between low AFR and poor DFS   also showed a correlation of low AFR with poor DFS   using univariate analysis and in 4 studies (1505 cases) using multivariate analysis. Based on the univariate analyses, the pooled results of a random-effects model    using univariate analysis and in 2 studies (583 cases) using multivariate analysis. According to a fixed-effects model, meta-analysis showed that low AFR was associated with poor PFS in the univariate analyses  indicated a significant association between high FPR and poor OS in the univariate analysis   also showed a significant relationship between high FPR and poor OS in the multivariate analysis   and multivariate analysis . The other study examined 71 cases of metastatic colorectal cancer and found a significant association between high FPR and poor PFS  based on univariate analysis alone.The correlation of FPR with OS was evaluated in 6 studies (2232 cases) using both univariate and multivariate analyses. The pooled data of a fixed-effects model  and biological processes that determine the AFR and FPR are responsible for this relationship. Serum albumin and prealbumin are two of the most commonly used indicators for assessing malnutrition, and malnutrition adversely affects the outcomes of cancer patients, in that it increases the incidence of infections, the length of hospital stay, and the risk of death . HoweverAlthough albumin/prealbumin, and fibrinogen abnormalities are well-documented prognostic markers in cancer patients, not all cancer patients suffer from deficiencies of albumin/prealbumin and an overabundance of fibrinogen; some patients only have an albumin/prealbumin deficiency or only a fibrinogen overabundance. The ratio indexes that we used—AFR and FPR—better reflect the levels of both albumin/prealbumin and fibrinogen. That is to say, the AFR and FPR are better markers of alterations of albumin/prealbumin (representing nutrition) and fibrinogen (representing hemostasis or inflammation).Additionally, serum albumin, prealbumin, and fibrinogen are available in the medical records of most cancer patients, and measurements are inexpensive and reproducible. Thus, use of the AFR and FPR as prognostic markers in cancers has great potential. In summary, both AFR and FPR could be promising markers of cancer prognosis. These results may help to guide future cancer treatments by identifying sub-populations with different prognoses.There were some weaknesses in this updated meta-analysis. The main weakness is that the relationship of FPR on DFS and PFS was based on only one included study, rather than a meta-analysis. Second, there was heterogeneity among the studies included, and our pooled results were nearly all based on random-effects models. Differences in the baseline values and characteristics of patients, treatment options, and cut-off values, and other factors among studies may account for this heterogeneity. Third, there was publication bias regarding the relationship between AFR with OS (more than 10 studies), though we did not present these results or funnel plots.A low AFR and a high FPR correlated with an increased risk of cancer mortality and recurrence. Thus, AFR and FPR may be promising prognostic markers for cancers.Additional file 1. Forest plots of the relationship between AFR and OS via multivariate analyses, before deleting the subgroup with paradoxical results .Additional file 2. Sensitivity analysis of the correlation of AFR with OS via univariate analyses (A) and multivariate analyses (B); with DFS from univariate analyses (C) and multivariate analyses (D); and with PFS from univariate analyses results (E) and multivariate analyses (F).Additional file 3. Sensitivity analysis of the correlation of FPR with OS via univariate analyses (A) and multivariate analyses (B).


Background: The glutathione S-transferase (GST) genes encode enzymes that metabolize carcinogenic compounds, and their variants, GSTP1 , GSTT1 (null/present), and GSTM1 (null/present), reduce enzyme activity that may affect the risk of developing cerebral glioma. This study undertook a case-control study and a meta-analysis to evaluate associations between these GST gene variants and the risk of glioma.Methods: The study enrolled 384 glioma patients  and 340 healthy controls . The amplification refractory mutation system assay was performed to identify GST gene variants of all 724 subjects. A meta-analysis enrolled 15 studies (including our case-control results) was performed.Results: Our case-control study found that the frequency of GSTP1 Ile105Val Val/Val genotype was significantly higher in the glioma group than that in the healthy controls (11.7% vs. 6.4%) ; the frequency of the Val/Ile + Ile/Ile genotypes was different from glioma patients and controls (88.3% vs. 93.6%) (OR=1.47(1.04-2.10); P=0.015); there were no associations between GSTP1 Ala114Val, GSTT1 (null/present) and GSTM1 (null/present) variants and glioma risk. Our meta-analysis confirmed that the GSTP1 Ile105Val variant was associated with an overall increased glioma risk. Moreover, our meta-analysis also confirmed the GSTP1 Ala114Val and GSTT1 null/present variants were associated with an increased glioma risk in the Caucasian population, rather than the Asian population.Conclusions: This study showed that GST gene variants were associated with an increased risk of glioma with ethnic differences. Future large-scale, multi center, controlled, prospective studies are required to support these findings and to determine how these GST gene variants may affect the pathogenesis of glioma. GSTM1), u (GSTT1) and k (GSTP1) variants, which have been reported to be associated with the etiology of cerebral tumors Glioma accounts for approximately 80% of all brain tumors and are associated with poor patient survival GSTP1 gene , variants of the GSTT1 gene (null/present), and variants of the GSTM1 gene (null/present) might result in significant changes in the function of the GST enzymes GST gene variants and cancer risk has been investigated in previous studies GST gene variants and the risk of glioma in the Han Chinese population GSTP1 , GSTT1 (null/present) and GSTM1 (null/present) variants and the risk of glioma in the Han Chinese population compared with the Caucasian population.Previously published studies have shown that variants of the GST gene variants and the risk of glioma, it was deemed necessary to perform a meta-analysis. At this time, there have been several previously published and formally analyzed systematic reviews and meta-analysis of published studies on the GSTP1, GSTM1 and GSTT1 variants and the risk of primary brain tumors, including glioma GSTP1 , GSTT1 (null/present) and GSTM1 (null/present) variants and the risk of glioma that included data from this case-control study of 724 patients combined with other recently published and relevant studies.Due to the inconsistent findings in previously published studies regarding the association with The study subjects, including glioma patients and healthy controls, were enrolled from the Xiangya Hospital of Central South University  between 2006 and 2013. All cases included in this study were histologically confirmed as glioma. The healthy controls were Han Chinese people, with no tumor and normal on physical examination and who were randomly selected from the Medical Examination Center of Xiangya Hospital.The Chinese Clinical Trial Register approved the clinical study admission (Registration No. ChiCTR-COC-15006186), and the Ethics Committees of the Xiangya School of Medicine and the Institute of Clinical Pharmacology of Central South University approved the study protocol. A standardized questionnaire was used to collect demographic details and clinical data, including patient age, sex, smoking status, and glioma types. All the patients provided written informed consent in compliance with the Code of Ethics of the World Medical Association (Declaration of Helsinki) prior to participating in the study.et al, was performed to identify four alleles of GSTP1 using two different sets of primers amplifying exon 5 and exon 6 DNA was isolated from 3ml of whole blood samples, using the phenol-chloroform extraction method, and then stored at 4°C. An amplification refractory mutation system assay, described by Hemmingsen The primers included a forward primer upstream of the codon 105 substitution (5′-ACCCCAGGGCTCTATGGGAA-3′) and two reverse primers, primer 'A'  and primer 'B' .BsmA1 restriction enzyme  and resolved using a 3.5% agarose gel to identify the Ile105Val variant. GSTT1 and GSTM1 null/present variants were detected by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method, as previously described The polymerase chain reaction products were digested with the GSTP1, GSTM1, GSTT1 variants and risk of brain cancer, including glioma; and available genotypic frequencies. The exclusion criteria included: the lack of a control group; duplicate publications; and no available data on genotypic frequencies. Literature search updated on January 23, 2019. The information collected from each study included author name, year of publication, patient ethnicity, and frequency of variants in both groups. The Newcastle-Ottawa scale was used for quality assessment of literature reviewed Two investigators (MQZ and YJW) searched PubMed, PMC, EMBASE, Web of Science, and WanFang databases using the following search terms: 'glutathione S-transferase P1', 'glutathione S-transferase M1', 'glutathione S-transferase T1', 'GSTP1', 'GSTM1', 'GSTT1' combined with 'glioma' or 'brain tumor'. Studies that met the following inclusion criteria were included in the analysis: studies on 2 test. Data on age, sex and other characteristics were compared to glioma patients and healthy controls with the Student's t-test or χ2 analysis. The different distributions of the GSTP1 variants of the two groups were examined by the χ2 test. P<0.05 was considered to indicate statistically significant differences. The meta-analysis was performed using STATA version 12 .The significances of the pooled odds ratio (OR) were tested by the Z-test, and P<0.05 was considered to be statistically significant. Heterogeneity was calculated with the χ2 analysis based on the Q-test and I2. If P<0.05 and I2>50% were present, the Mantel-Haenszel random effect model was used, otherwise a fixed effect model was used The SPSS software for Windows, version 13.0  was used for statistical analysis. The Hardy-Weinberg equilibrium was analyzed with the χOf the 384 patients with glioma (194 men and 190 women) , and the 340 healthy controls (174 men and 166 women)  were enrolled in the case-controlled study. The demographic and clinical characteristics of the patients and controls are summarized in Table GSTP1 , GSTM1 (null/present) and GSTT1 (null/present) variants were genotyped in 384 glioma patients and 340 healthy controls. The investigated SNPs were all in Hardy-Weinberg equilibrium. As shown in Table vs. 6.4%) (OR=1.50(1.05-2.04); P=0.01). The frequencies of the GA + AA genotypes were significantly different from the two groups (88.3 vs. 93.6%) (OR=1.47(1.04-2.10); P=0.015). There was no difference in the allele or genotype frequencies of Ala114Val (rs1138272) between glioma patients and healthy controls. As shown in Table GSTM1 (null/present) and GSTT1 (null/present) variants between Han Chinese glioma patients and healthy controls: GSTM1 ; P=0.31); GSTT1 ; P=0.052).1.501.05-.04; P=0.GSTP1 variants, 13 publications that included GSTM1 variants and 12 publications that included GSTT1 variants. The characteristics of the included publications are summarized in Table Figure GSTP1 variants. According to the GSTP1 Ile105Val recessive model , the pooling ORs of eight publications including 4,128 glioma patients and 2,134 healthy controls showed a significant association. Because there was heterogeneity , a Mantel-Haenszel random-pooling model was used to analyze the published data. The results showed that there was significant difference risk of glioma between the GSTP1 Ile105Val Val/Val genotype and Ile carriers among the Han Chinese population (OR=2.035(1.216-3.406); P=0.007) compared with that expected in the overall population (OR=0.902(0.650-1.251); P=0.535), the Caucasian population (OR=0.799(0.504-1.268); P=0.342) and a mixed population (OR=0.756(0.541-1.057); P=0.102) . Because there was heterogeneity , a Mantel-Haenszel random-pooling model was used to analyze the published data. The results showed that the distribution of GSTP1 Ile105Val Val variant carriers in glioma and healthy controls showed no difference (OR=0.797(0.495-1.285); P=0.352) . Because there was no study heterogeneity , a Mantel-Haenszel fixed pooling model was used for analysis. The GSTP1 Ala114Val carriers were associated with an increased risk of glioma in the overall population (OR=1.163(1.002- 1.350); P=0.047) and in the Caucasian population (OR=1.215(1.001-1.476); P=0.049) , a Mantel-Haenszel random-pooling model was used in the analysis. No significant association was found between the GSTM1 null/present variant and glioma risk of the overall population (OR=1.121(0.924-1.360); P=0.247), the Caucasian population (OR=1.260(0.966-1.643); P=0.088) and the overall mixed population (OR=0.935(0.698-1.252); P=0.651)  variant and glioma risk. Because there was heterogeneity , a Mantel-Haenszel random-pooling model was used in the analysis. There was no significant association with GSTT1 (null/present) variant and glioma risk in the Caucasian population (OR=1.296(1.023-1.641); P=0.031)  had no significant effects on the pooled ORs and the final strength of the association  had no significant effect on the pooled OR and the final strength of the association.Publication bias was examined by Egger's test and Begg's test. For all pooled OR analysis, Egger's test and Begg's test showed no publication bias Figure . For theGSTP1, GSTT1, and GSTM1, encode enzymes that metabolize carcinogenic compounds and reduced enzyme activity that may affect the risk of developing cerebral glioma. This case-control study investigated the associations with GSTP1 , GSTT1 (null/present) and GSTM1 (null/present) variants and the risk of cerebral glioma. The study was supported by meta-analysis on GST gene variants and cerebral glioma in the Han Chinese population, which showed that GSTP1 Ile105Val and GSTT1 null/present variants were associated with the risk of glioma.The GST gene variants, XRCC1 gene may affect the risk of developing glioma in the Chinese population GSTP1 I105V and A114V and deletions in the GSTM1 and GSTT1 genes could substantially reduce the activity of these protective GST enzymes Susceptibility genes for the development of glioma have been identified with this study, and the findings are supported by previous studies. It has been previously reported that the rs25489 (Arg280His) and Arg399Gln (rs25487) polymorphisms of the GSTP1 is associated with susceptibility to other types of malignancy, including prostate cancerGSTP1gene may affect the response to chemotherapy and treatment outcome in breast cancer GSTP1 gene is an important gene associated with the development and treatment of cancer.It has been previously reported that GSTP1 polymorphisms and the risk of developing glioma, but the reported findings have been inconsistent. Gao et al. analyzed the association with GSTP1 polymorphisms and the risk of developing glioma in 301 patients with glioma and 302 healthy controls and reported a positive result for GSTP1 Ile105Val (rs1695) et al. also found the GSTP1 Ile105Val polymorphism to be involved in the susceptibility to astrocytoma and the development of glioblastoma multiforme (GBM) . Some studies combined subtypes of glioma to analyze the distribution of GSTP1 gene polymorphisms. Therefore, more patients are required to classify the subtypes of glioma and analyze the polymorphisms by subtype.Previous case-control studies assessed the association with et al. and Gao et al. both involving the Han Chinese population et al. study, the distribution of rs1695 in GSTP1 allelic frequencies was significantly different from 72 cases of GBM and 302 control cases in the Han Chinese population. Furthermore, rs1695 in GSTP1 decreased the risk of GBM in the log-additive model  et al. investigated 301 glioma patients and 302 controls in a case-controlled study and found a positive association between GSTP1 rs1695 and glioma risk. In the present study, Ile105Val GG genotype patients had a 1.5 times increase in risk compared with wild-type patients, and GG genotype patients had a 1.47 times increase in risk compared with AA+AG patients. Furthermore, both the literature review and the analysis undertaken in this study confirmed the positive associations.The results of this study were consistent with those of Qin  GSTP1 gene Ala114Val (rs1138272) polymorphism might be used as a predictive factor for cisplatin-based chemotherapy in osteosarcoma patients GSTP1 rs1138272 minor alleles might represent a susceptible population with increased risk of asthma associated with air pollution GSTP1 Ala114Val (rs1138272) was associated with the risk of glioma in the overall population and Caucasian population studied.Among the published genome-wide association studies (GWAS) relevant to the literature review and the analysis undertaken in this study, there was no direct information or data that could be applied to this analysis GST gene variants and glioma risk. In the meta-analysis in this study, a significant association was found between GSTP1 Ile105Val  and glioma risk in the Han Chinese population, but not in the Caucasian or mixed population. The GSTT1 null/present variant was only significantly associated with increased risk of glioma in the Caucasian population. These results implied that the effects of GST gene variants affecting glioma was associated with ethnic differences. Further studies are required in future that includes populations of different ethnicities.Ethnicity is an important factor associated with GSTP1 variants and the risk of glioma GSTP1 Ile105Val (rs1695) were positive GSTP1 Ala114Val variant was significantly associated with the risk of glioma GSTP1 Ile105Val (rs1695). To draw more precise conclusions, meta-analysis was done to investigate GST gene variants and the risk of glioma.In the literature review and analysis undertaken in this study, there were several publications on that showed an association with GSTP1 Ile105Val and Ala114Val variants. The funnel plots of the results of the three comparisons demonstrated that there was publication bias in the GSTP1 Ile105Val analysis; this may have been due to the limited research samples and unpublished negative results. There were no robust results from the exact effects of the GSTP1 variants. A widely expanded large-sample case-control study or GWAS may be necessary to identify the key pathogenic gene or genes associated with glioma.Meta-analysis undertaken in this study included nine publications that showed no significant association with the GSTP1 Ile105Val . To find the source of heterogeneity, an ethnicity subgroup analysis was performed and found significance only in the Han Chinese group of heterogeneity, which implied that ethnicity was part of the source of heterogeneity. Also, a random model and a fixed model were used to confirm the positive results. The Egger's test and Begg's test also showed no publication bias for all pooled OR analysis  gene status. While there were some studies that found the different genetic susceptibility to glioma subgroups, such as GBM and non-GBM tumors, IDH-mutant and IDH wild-type tumors This study had several limitations. The study was performed in a single center and had a limited patient sample size. Because of the limited number of patients, the cases of glioma were combined, without distinguishing between the histological type of glioma, grade, stage, or isocitrate dehydrogenase  polymorphism was associated with an increased risk of glioma in the Han Chinese population, and the meta-analysis results confirmed this association and also showed that the GSTP1 Ala114Val variant was associated with overall increased risk of glioma and an increased risk in the Caucasian population, and the GSTT1 null/present variant was associated with an increased risk of glioma in the Caucasian population. Future large-scale, multi center, controlled, prospective studies are required to support these findings and to determine how these GST gene variants may affect the pathogenesis of cerebral glioma.In conclusion, a case-controlled study, including a total of 724 subjects was performed, and showed that the Supplementary figures.Click here for additional data file.


MTHFR) taggingpolymorphisms in 584 HCC cases and 923 controls. Polymerase chain reaction washarnessed to detect MTHFR genotype. Overall, our results showedthat genotype distribution of MTHFR rs4846048 and rs4845882polymorphisms was not different between HCC patients and controls.MTHFR rs9651118 and rs1801133 loci were protective factorsfor HCC (rs9651118: CT vs. TT: adjusted odds ratio (OR) = 0.67,95% confidence interval (CI): 0.49–0.90,P=0.008 and TC/CC vs. TT: adjusted OR = 0.70,95% CI: 0.53–0.93, P=0.015; rs1801133: GAvs. GG: adjusted OR = 0.72, 95% CI: 0.54–0.97,P=0.031, AA/GA vs. GG: adjusted OR = 0.76,95% CI: 0.57–0.99, P=0.045). However,MTHFR rs3753584 locus was a candidate for susceptibility toHCC . Results ofhaplotype analysis suggested that MTHFRGrs1801133Trs3753584Grs4845882Ars4846048Trs9651118was associated with the risk of HCC . The power ofour study also confirmed these associations .In summary, our findings suggested that MTHFR rs3753584,rs9651118 and rs1801133 polymorphisms may affect the risk of HCC in Chinese Hanpopulation. In future, our findings should be further validated in additionalcase–control studies.Polymorphisms in one-carbon metabolism genes may influence the susceptibility tohepatocellular carcinoma (HCC). In the present study, we studiedmethylenetetrahydrofolate reductase ( In 2015, liver cancer (LC) ranked the third most frequent type of malignancy in malesand the sixth most frequent type in females, approximately 343700 and 122300 casesoccuring in China, respectively 7. AccumuMTHFR gene may influence the development of cancer.Folic acid is important for DNA synthesis and methylation, mitosis and controllingrelated gene expression. Recently, epidemiological investigations showed thatsufficient fruits and vegetables intake may be a protective factor forcarcinogenesis . It istMTHFR gene which is locatedon chromosome 1p36.3. MTHFR single nucleotide polymorphisms (SNPs)may be a potential biomarker of cancer. In addition, Jiao et al. [MTHFR rs1801133 AAgenotype and A allele may have a better prognosis than those who carriedMTHFR rs1801133 GG genotype and G allele. Recently, somestudies investigated a potential association of MTHFR loci with HCCsusceptibility [MTHFR tagging SNPs and the risk of HCC.In humans, MTHFR protein is coded by the o et al.  reportedtibility 15; howevOur study recruited 584 consecutive HCC cases from two Clinical Medical Collegeof Fujian Medical University  during 2002–2016. Twodoctors confirmed HCC diagnosis by pathology. The criterion of Barcelona ClinicLiver Cancer (BCLC) was used to determine the stage of HCC . In addiMTHFR tagging SNPs were selected through Haploview software,which are described in our previous case–control studies [ studies ,19.MTHFR SNPs as describedin our case–control studies [EDTA-anticoagulated blood was donated and collected. According to the standardexperimental protocol, genomic DNA was obtained by using a DNA Kit . A SNPscan Kit was used to determine the variants of  studies .At this2χ test orFisher’s exact test was harnessed to analyze the differences in sex,chronic HBV infection, age, smoking, drinking and the genotype frequencies ofHCC patients compared with controls. In addition, age was expressed as means± standard deviation (SD). The difference in age between two groups wasdetermined by Student’s t test. With an internetHardy–Weinberg equilibrium (HWE) test (http://ihg.gsf.de/cgi-bin/hw/hwa1.pl), genotype frequenciesamong controls was used to assess the HWE status [MTHFR SNPs and HCCrisk was evaluated by odds ratios (ORs) and 95% confidence intervals(CIs). Logistic regression analysis was used to determine the associationsbetween MTHFR polymorphisms and the risk of HCC by adjustingsex, chronic HBV infection, age, smoking and drinking. A two-tailedP<0.05 was considered as significant. We used SHESISonline program  to constructMTHFR haplotypes [http://biostat.mc.vanderbilt.edu/twiki/bin/view/Main/PowerSampleSize)(α = 0.05) [In the present study, E status ,22,23,24plotypes . SAS 9.4 = 0.05) .P=0.327). There were 210(35.96%) smokers among HCC group and 327 (35.43%) among non-cancercontrols, while non-smokers were 374 (64.04%) in HCC cases and 596(64.57%) in the controls. Drinking and chronic HBV infection ratio in HCCpatients was higher than that of controls . The BCLC stage of HCC was summarized in MTHFR gene were listed in As described in MTHFR genotype frequencies in HCC patients and controlgroups. Overall, we found that MTHFR rs4846048 and rs4845882genotype distribution were not statistically significant between two groups.MTHFR rs1801133 GA genotype significantly decreased therisk of HCC (P<0.001). When rs1801133 GG frequency wasused as reference, there was a difference in MTHFR rs1801133 AAand AA/GA genotype frequency between two groups . Adjustment for sex, chronicHBV infection, age, smoking and drinking, the significant decreased risk alsore-appeared in two genetic models .Compared with rs1801133 GG genotype frequency, we found thatMTHFR rs3753584 had an increased susceptibility toHCC (CT vs. TT: P=0.037). Adjustments for sex, chronicHBV infection, age, smoking and drinking, the findings were more significant (CTvs. TT: adjusted P=0.003 and TC/CC vs. TT: adjustedP=0.005).We also found MTHFR rs9651118 and HCC susceptibility. However, whenadjusted for sex, chronic HBV infection, age, smoking and drinking, astatistically decreased risk of HCC was identified in two genetic model (CT vs.TT: adjusted P=0.008 and TC/CC vs. TT: adjustedP=0.015).In crude comparison, we did not find any relationship betweenMTHFRgenotype frequencies in the subgroup analyses by the status of chronic HBVinfection. We found that MTHFR rs1801133 and rs9651118polymorphisms were associated with the decreased risk of HCC in no chronic HBVinfection subgroup . However, we identified thatMTHFR rs1801133 polymorphism was associated with HCC riskin chronic HBV infection subgroup (rs1801133: AA vs. GG: adjustedP=0.035 and GA/AA vs. GG: adjustedP=0.035). Additionally, the association ofMTHFR rs3753584 and rs4845882 polymorphism with the risk ofHCC was also found .MTHFR gene (MTHFRArs1801133Trs3753584Grs4845882Ars4846048Trs9651118haplotype was a protective factor for HCC(P=0.008). However,MTHFRGrs1801133Trs3753584Grs4845882Ars4846048Trs9651118was associated the risk of HCC(P=0.003).We constructed six haplotypes of HFR gene . HaplotyMTHFR rs1801133 polymorphism, the power value was 0.835 inthe GA vs. GG genetic model and 0.726 in GA/AA vs. GG genetic model. ForMTHFR rs3753584 locus, the power of the present study was0.984 in the CT vs. TT genetic model and 0.965 in CT/CC vs. TT genetic model.When we focused on the MTHFR rs965118 polymorphism, the powervalue was 0.935 in the CT vs. TT genetic model and 0.910 in CT/CC vs. TT geneticmodel. In addition, the power of MTHFRArs1801133Trs3753584Grs4845882Ars4846048Trs9651118and MTHFRGrs1801133Trs3753584Grs4845882Ars4846048Trs9651118haplotypes were 0.771 and 0.844, respectively.The present study’s power was determined (α = 0.05). ForMTHFR rs1801133 polymorphism and 0.852 in the CT vs. TTgenetic model and 0.803 in CT/CC vs. TT genetic model for MTHFRrs3753584 locus. The power value of other subgroups was less than 0.8 (data werenot shown).In the subgroup without chronic HBV infection, we found that the power value was0.946 in GA vs. GG genetic model and 0.944 in GA/AA vs. GG genetic model forMTHFR could influence the risk of cancer. Severalcase–control studies were designed to identify the association ofMTHFR variants with HCC risk. However, the includedparticipants in these studies were relatively small. In addition, the observationsof pooled analyses were conflicting [MTHFR SNPs andsusceptibility of HCC. Our results suggested the associations ofMTHFR rs3753584, rs9651118 and rs1801133 polymorphisms with HCCdevelopment. In addition, haplotype analysis of MTHFR genesuggested that MTHFRGrs1801133Trs3753584Grs4845882Ars4846048Trs9651118increased the susceptibility of HCC. The power value of the present study alsoconferred these associations .The HCC susceptibility to individuals may be affected by certain environmental riskfactors ,28. The flicting . Here, wMTHFRgene. This SNP is a missense variant . MTHFR isvital enzyme in the process of remethylation, and catalyzes Hcy to Met. Rs1801133locus codes the NH2-terminal catalytic domain of MTHFR. MTHFR rs1801133 Aallele decreases the activity of protein enzyme [MTHFR rs1801133 may confer a protective effect on HCC inHBV-infected individuals. Some pooled analysis investigated a potential correlationof MTHFR rs1801133 with HCC risk. Several meta-analyses reportedthat MTHFR rs1801133 A allele might increase the risk of HCC [MTHFR rs1801133 locusand HCC risk. The observations were controversial. Thus, we conducted a relatedlarge sample size study to investigate the correlation of rs1801133 locus with HCCrisk. We concluded that rs1801133 A allele was a protective factor for HCC.Recently, some pooled-analyses demonstrated that this locus is protective for thedevelopment of colorectal cancer in Asians [MTHFR rs1801133 locus is a protective factor for HCCdevelopment.Rs1801133 polymorphism is the most extensively studied SNP in n enzyme . A few cn enzyme ,35,36.An enzyme . Howeverk of HCC 33,38. Hok of HCC  suggesten Asians ,40. An An Asians ,42, whicMTHFR rs3753584T>C polymorphism with hepatocarcinogenesis. MTHFR rs3753584is located in nearGene-5, which may regulate the stability, transcription andtranslation of RNA. Liu et al. [MTHFR rs3753584 locus affected the development of lung cancer.Another study found that MTHFR rs3753584 variants increased thesusceptibility of colon cancer [MTHFR rs3753584 may confer a risk to HCC. Ourobservation was similar to those findings mentioned above.To our knowledge, we first clarified the impact of u et al.  suggesten cancer . Here, wMTHFR rs9651118 with susceptibility to breast cancer(BC), and the results suggested that rs9651118 CC genotype decreased the risk of BC.Additionally, in Caucasians, Swartz et al. [MTHFR rs9651118 T>Cpolymorphism has a tendency to decrease risk of esophagogastric junctionadenocarcinoma. In the present study, we first explored the association betweenMTHFR rs9651118 T>C polymorphism and risk of HCC. Ourfindings clarified that MTHFR rs9651118 C allele was relevant to aprotective role for hepatocarcinogenesis. MTHFR rs9651118 was anintron SNP, which may influence the alternative splicing pattern. A functional studyindicated that rs9651118 CC genotype of MTHFR, compared with TTgenotype, reduced the Hcy level [MTHFRrs9651118 C allele may reduce the Hcy level, and then decrease the susceptibility ofHCC.Lu et al.  conductez et al.  reportedz et al.  reportedcy level .Recentlcy level . Thus, MMTHFRGrs1801133Trs3753584Grs4845882Ars4846048Trs9651118increased the susceptibility of HCC. We first investigated the potential correlationof these MTHFR tagging SNPs haplotypes with HCC susceptibility. Itcould be used as a potential biomarker for HCC diagnosis. Previous investigationshave focused on the relationship between MTHFR haplotypes of thesetagging SNPs and cancer susceptibility; however, MTHFRGrs1801133Trs3753584Grs4845882Ars4846048Trs9651118was not found to be associated with the risk of non-small cell lung cancer [Our findings suggested g cancer  and esopg cancer . In the MTHFRtagging SNPs and the risk of HCC here, the sample size might be insufficient toidentify weak associations of HCC. Second, in the present study, we only includedseveral risk factors ,other environmental factors were not considered. Third, the present study washospital-based, which could not fully represent the Chinese population and the biasmight have happened. In the future, population-based investigations are needed tofurther explore the role of MTHFR SNPs to risk of HCC. Fourth, theintake of folate and diet habits were not collected in our study. Thus, we did notfocus on the association of MTHFR variants and folate level withthe susceptibility of HCC. Finally, we only evaluated the MTHFRSNPs with HCC, polymorphisms in other one-carbon metabolism genes were notincluded.This hospital-based study might have some potential limitations. First, though werecruited 1507 subjects to investigate a relationship of MTHFR rs9651118 andrs1801133 polymorphisms may be protective for HCC. However, MTHFRrs3753584 polymorphism is a candidate for susceptibility to HCC. In the future,these findings should be further validated in additional studies.Taken together, in Chinese Han population,


Background and Objectives: Previous studies have investigated the impact of the ATG16L1 rs2241880 (Thr300Ala) polymorphism on individual susceptibility to cancer, but the conclusions are still controversial. To get a more precise evaluation of the correlation between ATG16L1 rs2241880 polymorphism and cancer susceptibility, we performed a meta-analysis of the association of all eligible studies. Materials and Methods: Searches were performed in the Web of Science, PubMed, Scopus and Google Scholar databases up to November 2018. A total of 12 case-control studies from 9 articles comprising 2254 cases and 4974 controls were included. Statistical analysis was achieved by STATA 14.1 and Review Manager 5.3 software. The odds ratios (ORs) with 95% confidence intervals (95% CIs) under five genetic models were used to determine the strength of association among rs2241880 polymorphism and cancer susceptibility. Results: The findings did not support an association between the rs2241880 variant in either the overall study population or the subgroups, based on cancer types and ethnicity in any of the genetic models. As far as we know, our study is the first meta-analysis of the association between rs2241880 polymorphism and cancer risk. Conclusions: In conclusion, the findings of this meta-analysis proposes that the ATG16L1 rs2241880 polymorphism may not play a role in cancer development. Further well-designed studies are necessary to clarify the precise role of the ATG16L1 rs2241880 polymorphism on cancer risk. Cancer is one of the main public health problem worldwide with about 18.1 million new cancer cases and 9.6 million cancer deaths in 2018 ,4.Autophagy, an evolutionarily conserved process, is important for survival, differentiation, development, and homeostasis through degrading damaged organelles and long-lived proteins ,6,7,8. AATG16L1) is located on the long arm of chromosome 2 (2q37.1) [ATG16L1 gene is situated on coding exon 9.The autophagy-related 16-like 1 gene ((2q37.1) . It enco(2q37.1) . ATG16L1(2q37.1) . ATG16L1(2q37.1) . The nonATG16L1 and several cancers among different ethnic populations have had conflicting outcomes [ATG16L1 rs2241880 polymorphism on cancer susceptibility.Several studies that have investigated the relationship between the rs2241880 (Thr300Ala) polymorphism in outcomes ,37,38,39ATG16L1 rs2241880 polymorphism and susceptibility to cancer. The search terms used were “ATG16L1 or autophagy related 16 like 1” and “cancer or malignant or tumor” and “polymorphism or variant or rs2241880 or T300A or +898A > G” or Thr300Ala. The selection process of eligible studies is shown in ATG16L1 polymorphism and risk of cancer, with sufficient information for estimation of the odds ratios (ORs) and their 95% confidence intervals. Studies were excluded from consideration if not correlated to ATG16L1 polymorphism and cancer risk; conference papers, reviews, meta-analyses; and studies without detailed genotyping data.In order to identify eligible articles, we comprehensively searched the Web of Science, PubMed, and Scopus databases, up to April 2019, for the relationship between the Two authors screened and extracted the data from eligible studies independently. Any disagreements were discussed with the third author. The following data were extracted from each study including the first author’s name, year of publication, country, ethnicity, type of cancer, source of control, genotyping methods, sample size, as well as genotype and allelic frequencies of the cases and controls. ATG16L1 polymorphism with cancer risk in five genetic models. The significance of the pooled OR was determined by the z-test, and a p < 0.05 was considered statistically significant. The Hardy–Weinberg equilibrium (HWE) of control genotypes was inspected using a χ2 test. We used pooled odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association of the 2 statistic. p < 0.10 was considered statistically significant. The random effects model was applied if heterogeneity was observed among studies; otherwise, the fixed effects model was used.Heterogeneity among the studies was assessed by using the Q statistic and the Ip value < 0.05 was considered significant publication bias.Publication bias was inspected visually by a funnel plot and an asymmetric plot suggested a possible publication bias. Funnel plot asymmetry was measured further using the Egger and Begg tests. A Sensitivity analysis was conducted to evaluate whether the findings were affected significantly by a single study by neglecting each study in turn to determine the effect on the pooled analysis. Statistical analyses were achieved using the STATA 14.1 software and Review Manager 5.3.ATG16L1 rs2241880 polymorphism in all subjects are shown in Through the literature search and selection in accordance with the inclusion criteria, nine articles, including 12 case-control studies, comprising 2254 cases and 4974 controls, were ultimately included in the quantitative analysis . The genATG16L1 rs2241880 polymorphism and cancer risk. Overall, no significant associations were found for AG vs. AA  polymorphism of the  process  and alsoi et al.  reportedi et al.  showed ti et al.  found thi et al.  found noi et al.  reportedi et al.  showed ti et al.  revealedi et al.  showed ti et al.  observedi et al.  proposedATG16L1 rs2241880 gene polymorphism and overall cancer susceptibility. Our findings showed no significant association between the rs2241880 polymorphism of the ATG16L1 gene and cancer susceptibility in any genetic models. The results of this meta-analysis are not consistent with some previous studies [To the best of our knowledge, this is the first meta-analysis that aimed to investigate the possible association between the  studies ,34,36,37ATG16L1 rs2241880 polymorphism was significantly associated with survival in lung adenocarcinoma patients.How the rs2241880 (Thr300Ala) polymorphism alters the biology of ATG16L1 is not yet known. Yuan et al.  showed tIn spite of the heterogeneity across studies, no evidence of publication bias was detected by either Begg’s or Egger’s tests. In addition, the sensitivity analysis did not significantly alter the overall results for all genetic models, which implies stability and reliability for our findings. This meta-analysis has some limitations that should be taken into account. First, only published articles in English were included in the pooled analysis because data in other languages and data from other ongoing studies were not available. Second, heterogeneity was observed among the studies, which have distorted the conclusion. The heterogeneity among studies may be due to differences in cancer types and ethnicities. Third, we calculated crude ORs, which were unadjusted estimations. Fourth, due to the lack of raw data, we were unable to perform gene–environment interactions. Finally, the number of individual studies for each cancer type was inadequate for stratified analysis. Our findings should therefore be interpreted with caution.ATG16L1 rs2241880 polymorphism and the risk of cancer. Our results did not support an association between the ATG16L1 rs2241880 polymorphism and cancer risk. Larger well-designed studies are needed to elucidate the exact role of the ATG16L1 rs2241880 polymorphism on cancer risk.In conclusion, the current study is the first meta-analysis to evaluate the association between the