TP53 tumor suppressor gene and colorectal cancer (CRC). However, the results are conflicting. This meta-analysis aimed to shed new light on the precise association between TP53 variants and CRC. We analyzed 32 published case-control studies involving 8,586 cases and 10,275 controls using crude odd ratios (ORs) with 95% confidence intervals (CIs). The meta-analysis was performed using a fixed-effect or random-effects model, as appropriate. We found that the TP53 Arg72Pro polymorphism was not significantly associated with CRC risk in the overall population. However, subgroup analysis based on ethnicity revealed an increased risk of CRC among Asians , and similar results were found for rectal cancer . These results suggest that the TP53 Arg72Pro polymorphism CC genotype may contribute to an increased risk of CRC, especially for rectal cancer and among Asians.Several previous studies evaluated the association between the Arg72Pro (rs1042522) polymorphism in the  Colorectal cancer (CRC) is the third most commonly diagnosed cancer in males and the second most commonly diagnosed cancer in females. CRC is also the leading cause of cancer-related death in the Western world, and has exhibited a striking rise in incidence in Asian countries –3. The eTP53 tumor suppressor gene, which is located on chromosome 17p13, is one of the most frequently mutated in human carcinogenesis [TP53 mutations may result in a loss of the protein's tumor suppressor function and thus contribute to the development of malignant tumors. The common TP53 Arg72Pro polymorphism (rs1042522) at codon 72 of exon 4 is the most studied polymorphism in cancer [The ogenesis . The encn cancer . The guan cancer .TP53 Arg72Pro polymorphism and CRC. However, the results are inconsistent and conflicting. The present meta-analysis was performed to provide a more precise estimation of this association.Several studies have been conducted to investigate the association between the Our search strategy yielded a total of 545 records, which were screened to identify original research articles pertaining to TP53 and CRC. The literature search and detailed selection procedures are summarized in Figure TP53 Arg72Pro polymorphism and CRC susceptibility by calculating an odds ratio (OR) and its 95% confidence interval (CI) under the following four genetic models: the allele model (C vs. G), the homozygote model (CC vs. GG), the dominant model (CC+GC vs. GG), and the recessive model (CC vs. GC+GG). A summary of our meta-analysis of the association between the TP53 Arg72Pro polymorphism and CRC is shown in Table TP53 Arg72Pro polymorphism and CRC risk in subgroup analyses based on the source of the controls or the type of CRC . The influence of each individual study on the pooled OR was assessed by performing the analysis while deleting one study at a time. Because the OR was not significantly influenced by omitting any single study (data not shown), we conclude our data are relatively stable and credible.We used Begg's funnel plot and Egger's test to assess the publication bias of the published articles. The symmetrical funnel plot for the allele model shown in Figure TP53 can disrupt these functions, leading to genetic instability and the progression to cancer.The mechanisms that underlie the development of CRC are complex, and both environmental and genetic factors play important roles in the occurrence and progression of this disease . TP53 isTP53 Arg72Pro polymorphism was not associated with CRC in patients stratified based on type of CRC, genotype method or source of controls. When stratified based on ethnicity, there was a positive association between the TP53 Arg72Pro polymorphism and CRC risk in Asian populations, but not Caucasian or mixed populations. These differences may reflect differences in genetic background and/or environmental factors. The Arg72 variant of the TP53 Arg72Pro polymorphism is more efficient with respect to mitochondrial localization than the Pro72 variant and has a stronger capacity to induce apoptosis [TP53 Arg72Pro polymorphism and CRC risk.In this meta-analysis, we found that the poptosis . Researcpoptosis . The grepoptosis , 55. Thepoptosis , 48 and poptosis , 46. We poptosis –39 that TP53 Arg72Pro CC genotype and rectal cancer, but no association was observed between this genotype and colon cancer. One possible explanation for this finding could be that different bacterial flora and a longer transit time in the rectum might change the contact between intestinal cells and potential carcinogens or promoters in the fecal stream, which may lead to more (exogenous) mutations of p53.Several studies have indicated that there are multiple differences in the epidemiological, pathological and molecular features of CRCs –58. KapiFactors known to affect the risk of CRC include gender, age, environmental factors and chronic inflammation. Joshi et al. found that men with the CC genotype and C allele had significantly higher risk for CRC than women with the same genotype . Aizat eTP53 Arg72Pro polymorphism and CRC risk because not all studies reported adjusted ORs. Second, because heterogeneity was obvious, even in some sub-analyses, other potential confounding factors appeared to be present in the included studies; we did not take these confounding factors into account. Third, due to an absence of information, we were unable to assess other factors such as gender, age, alcohol consumption and smoking status, which may have modified the association. Finally, potential gene-gene and gene-environment interactions were not analyzed due to a lack of relevant data.Our meta-analysis had several limitations. First, we did not calculate an adjusted estimate for the association between the TP53 Arg72Pro polymorphism CC genotype may contribute to an increased risk of CRC, especially for rectal cancer and among Asians. Future well-designed studies with larger samples are needed to confirm our findings.In summary, our updated meta-analysis demonstrated that the Potentially relevant articles published prior to December 2014 were identified in the PubMed, EMBASE, Web of Knowledge, and Chinese National Knowledge Infrastructure databases using the following key words: “TP53 or P53,” “polymorphism or variant,” and “colorectal cancer, colon or CRC.” Additional studies on the topic of interest were identified by hand-searching the reference lists of the retrieved articles. When multiple publications reported on the same or overlapping data, the most recent study with the largest sample size was selected.TP53 Arg72Pro polymorphism and CRC risk; 3) the study provided sufficient information to estimate ORs and 95% CIs; and 4) the study had a control genotype distribution in HWE. Studies were excluded for the following reasons: 1) the study was not a case-control study; 2) the publication contained incomplete data; and 3) the study was a duplicate of a previous publication.The studies included in our meta-analysis were required to meet the following criteria: 1) the study was a case-control or cohort study; 2) the study investigated the association between the P-value for HWE, and genotyping methods.Data were independently extracted by two reviewers (Dai and Sun) using a standardized data extraction form. Disagreements were resolved through discussion. The extracted data included the following items: first author, publication year, country of origin, ethnicity, source of control, sample sizes, genotype distribution in cases and controls, 2 test, and the significance level was set at P<0.05. Between-study heterogeneity was assessed by calculating the Q-statistic and quantified using the 2I value. A fixed effect model that used the Mantel-Haenszel approach was applied to calculate the pooled ORs if the between-study heterogeneity was not significant [P>0.05 and 2I<50%, the fixed-effects model was used; otherwise, the random-effects model was used. Subgroup analyses were performed based on ethnicity, source of controls, tumor location and genotype method. Sensitivity analysis was performed to determine the influence of single datasets on the combined estimates. Begg's funnel plot and Egger's test were used to assess publication bias [P values were two-sided.Pooled ORs with corresponding 95% CIs were used to evaluate the strength of the observed associations. Four genetic contrast models, including allelic contrast (C vs. G), homozygote comparisons (CC vs. GG), dominant models (CC+GC vs. GG), and recessive models (CC vs. GC+GG), were applied. HWE was evaluated in the control group for each study using the χnificant . A randonificant . When thion bias , 62. All


Publication bias was tested by funnel plot and Egger’s test. Odds ratio and 95% CI were used to assess the association strength. The statistical analyses in this study were accomplished by STATA software package. A total of 40,609 cases of epithelial ovarian cancer and 368,452 controls in 38 publications were included. The result suggested that endometriosis was associated with an increased risk of epithelial ovarian cancer , tubal ligation was associated with a decreased risk of epithelial ovarian cancer , while hysterectomy show no relationship with epithelial ovarian cancer . A stratified analysis showed there were associations between endometriosis and the increased risk of epithelial ovarian cancer for studies conducted in USA and Europe. Meanwhile, there were associations between tubal ligation and the decreased risk of epithelial ovarian cancer for studies conducted in USA, Asia, Europe and Australia. The result indicated that endometriosis was a risk factor of epithelial ovarian cancer whereas tubal ligation was a protective risk factor of epithelial ovarian cancer, hysterectomy may have no relationship with epithelial ovarian cancer.To investigate the association between endometriosis, tubal ligation, hysterectomy and epithelial ovarian cancer. Relevant published literatures were searched in PubMed, ProQuest, Web of Science and Medline databases during 1995–2016. Heterogeneity was evaluated by I Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer death and the eighth most common cancer in women ,2. ApproRecently, certain modifiable risk factors have been reported to be related to EOC. Ness et al. demonstrated that endometriosis was a risk factor of EOC . HoweverAlthough many researches about the associations of endometriosis, hysterectomy, tubal ligation and EOC based on individual-patients or pooled analyses based on published studies have already been conducted, such as Pearce et al. 2012 on endometriosis, Jordan et al. 2013 on hysterectomy, and Cibula et al. 2011 on tubal ligation ,10,11, sThe medical literature electronic databases of PubMed, ProQuest, Web of Science (SCI) and Medline were searched for case-control studies which were related to risk factors of EOC and published prior to September 2016. The terms ; ;  and  of search strategy were used. In addition, references of each included studies were manually searched to identify any additional studies that were not indexed by the electronic database.The following inclusion criteria were used in selecting case-control studies: (1) studies in which a case-control study design were used and investigated the association between endometriosis or hysterectomy or tubal ligation and EOC; (2) cases consisted of women who were histological diagnosed EOC; (3) the data of case and control numbers in different risk factors were presented in the publication or the data given were necessary to calculate these; (4) Odds ratio (OR) or OR with 95% confidence intervals (CIs) of each risk factor were presented in the publication or the data given were necessary to calculate these; (5) when the publications were from the same or overlapping data, we selected the most recent or largest population; (6) English was stipulated as the publication language; (7) reviews, letters or case reports were excluded.According to the predefined selection criteria, the data in whole process was independently extracted from each study by two reviewers. When disagreements appeared, the reviewers reanalyzed the study and resolved disagreements by discussion. For each study, we recorded number of case and control, the first author’s name, year of diagnosis, year of publication, study geographic region, confounders and study type as the basic contents of the data extraction. If the number of case and control in different risk factors were available, we abstracted directly, or we calculated via raw data given in the articles.We evaluated the quality of individual studies using the Newcastle-Ottawa Scale (NOS) . The NOS2 statistic. If p < 0.10, statistically significant heterogeneity was indicated, then random-effect models were conducted for the heterogeneous data. Otherwise, fixed effects model were used. Publication bias was evaluated via funnel plot and Egger’s test, with p < 0.05 indicating statistical significance. Subgroup analyses were conducted based on area. A cumulative meta-analysis was conducted to reflect a framework for the dynamic change trend for the results of the study and measure the effect of each research as evidence accumulates and find the trend in estimated risk effect [All statistical analyses in this study were performed with STATA software package . OR and OR with 95% CI were used as measures of the association strength. We evaluated the degree of heterogeneity in eligible studies by using Ik effect . In thisAs shown in p of heterogeneity was ˂0.001; for hysterectomy, p of heterogeneity was ˂0.001; for tubal ligation, p of heterogeneity was ˂0.001). High heterogeneity were found among the included studies of each risk factor. Considered that the 38 publications we included were mainly done in North America, Europe, Oceania and Asia, and we wanted to compare the different association among these areas, so we conducted a subgroup analysis based on area. All analyses of each risk factor were based on the random-effects model . For area, there were associations between endometriosis and the increased risk of ovarian cancer for North America , Europe  and Oceania  . For area, there were no associations between hysterectomy and EOC for North America , Europe  and Oceania .There was a significant association between tubal ligation and a decreased risk of EOC . For area, tubal ligation was associated with a decreased risk of EOC for North America , Oceania  and Europe . But there was no association between tubal ligation and EOC for Asia .p = 0.242; for hysterectomy: p = 0.314; for tubal ligation: p = 0.757). Neither funnel plots nor Egger’s test suggested any obvious evidence of publication bias  and endometrioid invasive ovarian cancers  . The comAs for the other risk factor, hysterectomy, Jordan et al. found that hysterectomy decreased the risk of EOC  .Cibula et al.  found thIn our study, we used Stata. 12.0 to analyze the data extracted from 38 articles. The results showed that there was high heterogeneity among the included studies. To explore the source of the heterogeneity, we wanted to conduct subgroup analysis based on histological type, as studies showed that showed that the association between endometriosis and EOC risk varied significantly by histologic type ,41, howeHowever, this meta-analysis still has several limitations. Firstly, only those papers written in English were included, relevant articles using other languages had not been enrolled in, leading information loss. Secondly, all studies we searched were published articles, as a result, unpublished data were not available, some useful information may be lost with much possible, what’s more, Deeks’ funnel plot asymmetry test showed that no significant publication bias among the studies, but the bias caused by those unpublished data should not be completely ignored. Thirdly, despite of the strict inclusive criteria, significant heterogeneity was still detected among different studies, we are clear that the association between endometriosis, hysterectomy, tubal ligation and EOC varied significantly, but we couldn’t conduct a subgroup analysis because histological data were limited. Only several studies among the included articles did histology analysis, so we could not extract enough data to conduct an effective meta-analysis.The results showed that endometriosis was a risk factor of epithelial ovarian cancer whereas tubal ligation was associated with a reduced risk of epithelial ovarian cancer, hysterectomy may had no relationship with epithelial ovarian cancer.


Isoflavones, a class of phytoestrogenic compounds, are abundant in soybeans. A number of epidemiological studies have investigated the association between dietary isoflavones intake and the risk of gastric cancer. However, the results are inconclusive. Therefore, the meta-analysis was conducted to evaluate the effect of dietary isoflavones intake on the risk of gastric cancer.Relevant studies from May 1992 to May 2017 were identified through searching PubMed and Web of Science. Additional articles were identified from the reference lists of relevant review articles. Pooled risk ratios (RRs) or odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a fixed-effects model. Funnel plot and Egger’s test were used to evaluate publication bias.I2 = 27.5%). Subgroup analyses generally yield similar results.Seven articles reporting 12 studies were included in the current meta-analysis. We found no significant association between dietary isoflavones intake and gastric cancer risk with the highest versus the lowest categories of dietary isoflavones intake  contains supplementary material, which is available to authorized users. Gastric cancer, including gastric adeno-carcinoma and gastric cardia adeno-carcinoma, was the third leading cause of death in the world which accounting for 8.8% of the total cancer death, according to GLOBOCAN 2012 [Epidemiological studies have suggested that high fruits and vegetables intake are inversely associated with the risk of gastric cancer , 3. IsofWe searched all relevant literature from May 1992 to May 2017 using electronic databases PubMed and Web of Science, with the search terms: (“isoflavones” or “soy isoflavones” or “phytoestrogen” or “genistein” or “daidzein”) and (“gastric cancer” or “gastric tumor” or “stomach cancer” or “stomach tumor”). Additional articles were identified from the reference lists of relevant review articles.Studies were selected for analysis according to the following inclusion criteria: (1) investigated the relationship of dietary isoflavones intake and gastric cancer risk; (2) the studies were either cohort or case-control studies; (3) articles reported the estimated RR/OR with their 95% CI or the indexes could be calculated. (4) articles were published in English literature. If two or more studies shared same data sets, the one with the largest sample size or the longest follow-up period was selected in the meta-analysis.Studies were excluded if they are: (1) cell studies and animal studies; (2) reviews articles, letters to the editor and case reports; (3) isoflavones were measured with the levels in blood/urinary; (4) the RR/OR with 95% CI could not be estimated from the data in the articles.Two reviewers (Jie You and Yafei Sun) extracted the following information independently: 1) the last name of first author; (2) year publication; (3) country; (4) study design; 5) geographic area; (6) source of control; (7) participants’ characteristics ; (8) isoflavones assessment method; (9) the RRs/ORs and their 95% CIs indicating the highest versus the lowest categories of dietary isoflavones intake; (10) adjustment for covariates. Any discrepancies were definitely resolved by a third senior professor (Quanjun Lu). The quality of the selected papers was assessed by use of the Newcastle–Ottawa scale before pooled into the analysis [ geograph the lastP < 0.05 and/or I2 > 50%, the random-effects model was conducted. Otherwise, a fixed-effects model was used. Chi-square test and the I2 test were used to quantify the heterogeneity of the studies. Subgroup analyses by study design (the type of case-control or cohort study), gender, geographic area, source of control , sample size, dietary assessment, adjustments (family history and dietary energy intake) were also performed to find potential confounder/modifier.The association between the dietary isoflavones intake and the risk of gastric cancer was calculated with the pooled ORs together with their 95% CIs. If P < 0.05 was considered as a significant difference. All statistical analyses were conducted with the software STATA version 12.0 .Egger’s test and Funnel plots were conducted to assess the potential publication bias, and a value of The process of our articles selecting is presented in Fig. I2 = 27.5%)  were calculated to assess the association between dietary isoflavones intake and the risk of gastric cancer. Compared to the lowest dietary isoflavones intake, the highest level was not significantly associated with the risk of gastric cancer . Meta-regression suggested that study design (case-control or cohort design), gender, geographical area, source of control , sample size, dietary assessment, family history and dietary energy intake for adjustments showed no significant impact on between-study heterogeneity (data not shown).The heterogeneity in the meta-analysis was relatively low .Publication bias was evaluated with both Funnel plots and Egger’s tests. As shown in Fig. In this meta-analysis, no significant association between dietary isoflavones intake and the risk of gastric cancer was detected. The subgroup analysis was also performed to further explore the relationship, which yield the similar result.The incidence of gastric cancer has been shown to be associated with many dietary factors –19. PrevSome epidemiological studies reported an inverse association between soy products and gastric risk , 24. SarHelicobacter pylori, may influence isoflavones absorption and metabolism and production of specific intestinal microbial catabolites which may in turn mediate their biological activities. Third, potential small existing effect may be affect by uncontrolled variability that is difficult to quantify between human beings [In the 12 studies we selected, an inverse association between dietary isoflavones and the risk of gastric cancer was only shown in a female cohort study. This may attribute to the insufficient possible confounders adjustment. Moreover, numerous animal studies and cytology experiments have widely demonstrated the anticancer property of isoflavones –30 for in beings .The meta-analysis study has several advantages. First, the potential confounding factors were adjusted in all individual studies . In addition, the subgroup analysis was conducted to further explore the association and strengthened the results. Moreover, the pooled results might be unbiased because no publication bias was observed.Helicobacter pylori infection which is a risk factor for gastric cancer is only reported in one case-control study. Second, the dose levels of dietary isoflavones are not well defined, so the effect of dietary isoflavones intake may be masked.The potential limitations of our meta-analysis should be acknowledged. First, No significant association between dietary isoflavones intake and risk of gastric cancer was found in this meta-analysis, suggesting that dietary isoflavones intake is not associated with a decline in the risk of gastric cancer.Additional file 1: Data extraction from included studies. (XLSX 15 kb)


The analyses of all the genetic models in overall pooled populations did not identify any significant association between GC and hOGG1 rs1052133 , even though stratified analyses were conducted in different ethnicities under each genetic model.A total of 15 articles from published papers were included in our analysis. The meta-analyses for hOGG1 and GC reported up to December 15, 2016 in PubMed, Embase, Web of Science, and the Chinese Biomedical Database were retrieved. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for single-nucleotide polymorphism (SNP) using fixed- and random- effects models according to between-study heterogeneity. Publication bias analyses were conducted using Begg test.All case-control association studies on hOGG1 rs1052133 and GC. Given the limited sample size, further investigations including more ethnic groups are required to validate the association.This meta-analysis showed there was no association between  Gastric cancer (GC) is one of the most common cancers and the leading causes of cancer death in the world , howeverhuman 8-oxoguanine glycosylase 1 (hOGG1) gene, specifically involved in the repair of DNA oxidative damage in the base excision response pathway, has been shown to be associated with a variety of cancers [hOGG1 encodes a DNA glycosylase enzyme that actively removes 8-hydroy-2-deoxyguanine, which is highly mutagenic and a major form of oxidative DNA damage [To date, many genetic polymorphisms in the carcinogen detoxification, antioxidant protection, DNA repair and cell proliferation processes have been reported to play a crucial role in the development of GC . The hum cancers –13. As aA damage , 15. TheA damage .hOGG1 gene has been regarded as a candidate for involvement in the underlying cause of GC and the hOGG1 polymorphism rs1052133 has been widely evaluated in association with GC across different ethnicities [hOGG1 polymorphism rs1052133 has been reported to be associated with an altered risk for GC in Chinese, Japanese and Caucasian populations [hOGG1 rs1052133 and GC risk are inconclusive and conflicting [hOGG1 rs1052133 with GC and provide some new clues for the research on GC. Therefore, in this study we conduct a systematic review and meta-analysis of all association studies on hOGG1 rs1052133 with GC, to summarize and evaluate the association between hOGG1 rs1052133 and GC.The nicities , 17–31. ulations , 19, 32.flicting –31. SuchA flow diagram Figure  shows thhOGG1 rs1052133 with GC and a total of 10046 subjects (4024GC patients and 6022 controls) were tested for hOGG1 rs1052133 in this meta analysis. Stratified analyses were conducted based on three groups, including Asian [hOGG1 rs1052133 in Asian, Caucasian, other and pooled populations were evaluated firstly. The results showed low heterogeneity for the included populations under all the genetic models by fixed-effect analysis, except for the Caucasian population under allelic genetic model , the Asian population under recessive model  and Caucasian population under dominant model , the random-effect analysis was thus adopted for them under each genetic model  to evaluate the association between hOGG1 rs1052133 and GC. Our results did not show any significant association of hOGG1 rs1052133 with GC, even across different ethnic populations. Therefore, our analyses failed to conclude whether hOGG1 rs1052133 is really a GC-associated SNP and more replication data is needed to validate this association. Of course, other factors, such as environment and different lifestyle, might play roles in these differences as well. Further analysis should be performed in more large-scale cohorts or case-control studies to explore the association of hOGG1 rs1052133 with GC. Future studies on gene-environment interaction should also be considered.The association between  with GC , 19, 32. studies , 28, meaulations , 26, 27.controls  and in Hcontrols , respecthOGG1 rs1052133, however, some potential limitations of our study on the understanding of hOGG1 in GC genetics should be considered. (1) This meta-analysis was mainly based on the studies with 2950 GC patients and 3817 controls in Japanese and Chinese populations [hOGG1 rs1052133 with GC.This systematic review and meta-analysis has sufficient power to evaluate and review all the published genetics studies in ulations , 29–31. hOGG1 rs1052133 is not associated with GC under all the genetic models, suggesting that it may not affect individual susceptibility to GC. Further investigations with larger sample sizes and more ethnic groups are required to validate the association and confirm the roles of hOGG1 in GC.In conclusion, this meta-analysis showed that hOGG1 polymorphisms with GC from their starting date to December 15, 2016. Following keywords were used: ‘‘cancer,’’ ‘‘gastric cancer,’’ ‘‘human 8-oxoguanine glycosylase,’’ ‘‘hOGG1,’’ ‘‘rs1052133,’’ ‘‘polymorphism(s),’’ ‘‘variant(s),’’ and ‘‘mutation(s).’’ The internet was searched using the Google search engine. Reference lists of the retrieved articles and reviews were manually checked for additional articles, to identify studies not yet included in the electronic searches.A systematic literature search using the databases PubMed, Embase, Web of Science, and the Chinese Biomedical Database was conducted, to identify all published studies on the association of hOGG1 rs1052133 and GC; (2) used a case–control design to compare GC cases and normal controls in defined populations; (3) gave an OR with 95% CI or other available data from which they could be estimated; and (4) were original research articles, not reviews or comments. Excluded were abstracts from conferences, full texts without raw data available for retrieval, republished data, duplicate studies and reviews.The eligible articles were considered if they (1) evaluated associations between hOGG1genotypes, respectively.Two observers (DDZ and XNG) independently abstracted data from all eligible publications onto paper data collection forms. Two reviewers (JLH and GQZ) were blinded to the details  of these studies during assessment. Disagreements were resolved by discussion until a consensus was achieved. Otherwise, a third investigator was consulted to resolve the dispute. The following items were collected from each study: first author's surname, year of publication, statistical data, ethnicity of subjects, whether Hardy-Weinberg equilibrium (HWE) was examined in controls, genotyping method, total numbers of cases and controls, as well as total numbers of cases and controls for each The Newcastle-Ottawa Scale (NOS) was used to assess the quality of the included studies by two investigators independently. Through the rating system, the NOS was conducted to judge the study quality based on three aspects, which were selection, comparability, and exposure situation in case-control studies. Rating scores range from 0 (worst) to 9 (best). Studies with a score of 7 or greater were thought to have an adequate or good quality.hOGG1 rs1052133 with GC. For genotypic comparison, allelic, addictive, dominant and recessive models were applied in the investigation of the disease association. We conducted stratified analyses by ethnicity, including Asian populations , Caucasian populations , other populations  and pooled populations. Sensitivity analysis was carried out by excluding one study at a time to explore whether the results were influenced by a specific study. Heterogeneity (between-study inconsistency) was investigated and measured using 2I statistic. A p value of 2I < 50% indicated an absence of heterogeneity among studies, the fixed-effect model (Mantel-Haenszel method) was thus used to calculate the pooled ORs. In contrast, if the p value for heterogeneity was 2I ≥ 50%, indicating a high degree of heterogeneity between studies, then the random-effect model (DerSimonian-Laird method) was used to evaluate the summary ORs. Begg liner regression test was used to assess the potential publication bias, where a value of p < 0.05 was considered statistically significant. The Hardy-Weinberg equilibrium (HWE) for each SNP was tested by the χ2 test. All statistical analyses were performed by the Review Manager software , and the STATA software , as well as the Hardy Weinberg package (version 1.3) in R language . Two-sided P values < 0.05 were considered statistically significant.A pooled OR with its corresponding 95% CI was used as a measure of the association of


CPB2), is an inhibitor of fibrinolysis and plays a role in the pathogenesis of venous thrombosis. Experimental findings support a functional role of genetic variants in CPB2, while epidemiological studies have been unable to confirm associations with risk of venous thrombosis. Sex-specific effects could underlie the observed inconsistent associations between CPB2 genetic variants and venous thrombosis.Thrombin activatable fibrinolysis inhibitor (TAFI), encoded by the Carboxypeptidase B2 gene , but not in males . The Thr325Ile did not show a sex-specific effect but showed variation in allele frequencies by geographic region. A subgroup analysis of studies in European countries showed decreased risk, with a recessive model  for venous thrombosis.A comprehensive literature review, including unpublished data, provided greater statistical power for the analyses and decreased the likelihood of publication bias influencing the results. Sex-specific analyses explained apparent discrepancies across genetic studies of Ala147Thr and venous thrombosis. While, careful selection of genetic models based on population genetics, evolutionary and biological knowledge can increase power by decreasing the need to adjust for testing multiple models. CPB2 gene encoding TAFI [Cardiovascular diseases incidence, complications, response to treatment and burden vary between men and women , 2. Thesing TAFI , but sexTAFI is a plasma protein, synthesized primarily by the liver, which circulates in plasma as an inactive precursor. TAFI activation occurs by trypsin-like enzymes such as thrombin, plasmin, and most efficiently by the thrombin-thrombomodulin complex on the vascular endothelial surface –20. ActiCPB2 gene encodes TAFI. This gene is located on chromosome 13q14.11, spans approximately 48kb of genomic DNA that comprises 11 exons and 10 introns [CPB2 gene have the potential to affect TAFI plasma levels, function, and stability and therefore may be functionally relevant to thrombotic disease risk. The two most studied CPB2 variants are Ala147Thr and Thr325Ile, both resulting in amino acid substitutions. The anti-fibrinolytic effect of Ala147Thr variant in exon 6 does not appear to involve TAFI protein stability [The  introns . Varianttability . Interestability , which mtability . The Iletability  and its tability , 31. As tability . A possiDespite the critical hemostatic role of TAFI, epidemiological studies on the effect of the above common TAFI-associated variants on the risk venous thrombosis are inconclusive , 34–55 wCPB2 and thrombotic events, EMBASE, MEDLINE, HuGE Navigator literature, and the HuGE Navigator GWAS Integrator databases were searched from their inception through to September 2015 using a combination of keywords and MeSH terms, including “thrombosis”, “thromboembolism”, “pulmonary embolism”, “cerebral infarction”, “cerebral thrombosis” with “TAFI”, and “CPB2”. Titles and abstracts were screened by two independent reviewers, with records that reported the investigation of the CPB2 variants and thrombotic events carried forward to full-text screening. Here, a thrombotic event was defined as a thrombus occurring in a vein, which may or not embolize and become a pulmonary embolism. Additional records were searched in the reference lists of records included in the full-text screening to achieve a comprehensive search.To identify studies that examined the association between variants of During the full-text screening, two independent reviewers determined eligible studies using the following criteria:Inclusion criteria: Studies that investigated the association between thrombotic events and rs1926447 C/T (Thr325Ile), rs3742264 G/A (Ala147Thr), and/or CPB2 variants in high (>0.8) linkage disequilibrium (LD) calculated for each ethnicity, including GWAS and other genetic association studies.Exclusion criteria: Review articles, genetic linkage studies, non-peer reviewed studies (e.g. conference proceedings).Data was abstracted onto a standardized form by the two independent reviewers based on the Strengthening of Reporting of Genetic Association Studies (STREGA)  and HumaFinally, the corresponding authors of all included articles were contacted for sex-specific genotype counts for cases and non-cases.a priori based on available population genetics, evolutionary and biological data. The dominant model (AA + GA vs. GG) was selected for the Ala147Thr variant based on both evolutionary and biological information: evidence of balancing selection [2 statistic and Cochran’s Q statistic were used to assess the intensity and significance of between-study heterogeneity, respectively. Between-study heterogeneity was considered low, moderate, and high with corresponding I2 values of 25%, 50%, and 75% and a Cochran’s Q p-value <0.05 suggested statistically significant heterogeneity [Crude odds ratios (OR) and 95% confidence intervals (CI) were calculated from the genotype frequencies for each study using the minor allele as the risk allele under dominant and recessive model for the Ala147Thr and Thr325Ile variants, respectively. These primary models for analysis were strategically selected election , which celection . The recelection –33 and selection , 31. An ogeneity . Funnel ogeneity . Sex-spePotential sources of between-study heterogeneity were investigated by sensitivity analyses. First, since departure from HWE is a potential indicator of poor genotyping or ascertainment bias, studies that deviated from HWE were excluded. Departure from HWE was assessed in the non-cases using a chi-squared statistic with one degree of freedom. Second, studies were stratified by geographic region for a subgroup analysis to investigate the effects of potential population substructure. Third, studies with potential misclassification of case and non-case status were excluded . Fourth, high-risk study populations  were analyzed separately to investigate the association for individuals who may already be genetically predisposed for a thrombotic event. Lastly, examination of whether the use of proxy SNPs in LD influenced the results.While the primary analyses were performed using a genetic model that was pre-selected based on biological data of the variants, secondary analyses of the variants examined the association using alternative genetic models. The heterozygote effect, homozygote effect, dominant, recessive, and allelic models were tested for comparison with our hypothesized primary models, as if we would assume the wrong genetic model, statistical power would be decreased.The cumulative evidence for association of the Ala147Thr and Thr325Ile variants was assessed according to the Venice guidelines  that useOverall 17 studies met the inclusion criteria and all met the quality assessment score to be included in this meta-analysis. For the Thr325Ile variant 15 studies had information and 14 studies had information for the Ala147Thr variant, with 12 studies containing information on both variants. A flow chart describing the selection process is presented in CPB2 Ala147Thr variant and venous thrombosis included a total of 8076 cases and 12 772 non-cases. The genotype distribution of Ala147Thr variant in case and non-case groups are shown in In total, the meta-analysis for the 2 = 16.8%, p = 0.270) across all studies, indicating consistent results across studies with a dominant model. There was an indication of small-study effects (p = 0.02) with the GWAS studies [Under a dominant model, the odds of a venous thrombotic event is 0.94  . Overall studies , 64, 65 2 = 66.2%, p = 0.004) in females and no indication of between-study heterogeneity in males . A potential source of heterogeneity is the combination of common forms of venous thrombosis (i.e. venous thromboembolism which is composed of deep vein thrombosis and pulmonary embolism) and less common forms of venous thrombosis ; however, this explanation is unlikely as stratified analysis showed the effect estimates in both groups to be consistent (results not shown). In the eight studies with sex-specific data, there was no indication of publication bias or small study effects (Egger’s test p = 0.392).The genotype distribution of Ala147Thr variant by sex in case and non-case groups is shown in Sensitivity analyses—which included the exclusion of one study that did not show consistency with HWE in our analysis, subgrouping by geographical region, high-risk group and proxy SNPs—did not modify the observed between-study heterogeneity (data not shown). We used geographic region for subgroup analyses as a proxy approach to assess putative effects due to ethnic heterogeneity. Secondary analyses of alternative genetic models showed that results from the allelic (A vs. G) and heterozygote (GA vs. GG) models were fairly consistent with those of the dominant model, where significant associations with thrombotic events were observed in females but not in males . The strIn total, the meta-analysis included 15 studies that examined the association between the Thr325Ile variant and venous thrombosis (5347 cases and 8458 non-cases). The genotype distribution of Thr325Ile variant in case and non-case groups are shown in 2 = 23.4%, p = 0.194). There was no indication of publication bias (Egger’s test p = 0.330 and Under the primary recessive model (TT vs. CT + CC), the odds of a venous thrombosis is 0.91  . OverallAn examination of allele frequencies showed large variation across studies. As ethnicity was not clearly defined for each study, we used the study geographic region as a proxy. The subgroup analysis by geographic region showed odds of 0.83  for venous thrombosis among the ten studies conducted in European countries . The rema priori hypotheses and thus, avoid unnecessary multiple testing. Prior suggestions of sex differences in risk profiles for variants in the CPB2 gene for cardiovascular disease [Our strategy of implementing a systematic and comprehensive literature search, paired with persistent efforts to include unpublished studies and to collect sex-specific genotype counts on these variants by directly contacting authors permitted a thorough meta-analysis to be conducted. Applying biological, population genetics and evolutionary knowledge to select primary genetic models for candidate gene analysis allowed us to approach the data with  disease  led to sCPB2 [The dominant model was selected as the primary model for association as per evidence for a potential heterozygote advantage based on balancing selection in the exons 6–7 region of CPB2  and diffCPB2 , 60. We CPB2  but incoCPB2 , which rThere are key differences between the two venous thrombosis meta-analysis methodologies that may explain the discordant results. First, Qian et al. 2015 included much fewer studies than the current meta-analysis (e.g. 15 versus 8 studies for the Thr325Ile variant). Second, of the studies that were included by Qian et al., two studies appear to have overlapping study samples and included oncologic patients; differences in the etiologies of provoked (e.g. cancer) and idiopathic venous thrombosis are well documented , Third, The analysis of males and females combined show higher heterogeneity between studies compared to males analyzed alone; however, significant heterogeneity still exists when the females were analyzed separately. The Ala147Thr variant showed a significantly higher minor allele frequency in females compared to males and was previously suggested to be associated with coronary heart disease in a sex-specific manner; together these justified the investigation of a sex-specific association. The results of our meta-analysis support a sex-specific association between Ala147Thr and all thrombotic events in females, where we observed 19% decreased risk with those having at least one copy of the minor allele, while no association is observed in males. This observation is consistent with the results of the single study by Silander et al. who showed that the Ala147Thr variant, under a dominant model, had a suggestive protective effect for coronary heart disease (hazard ratio (HR) = 0.31, 95% CI: 0.16, 0.60) in females but no effect in males  . The sizThe recessive model was selected for the primary model based on evidence for homozygotes having changes in protein levels –33 and sCPB2 Ala147Thr and Thr325Ile variants are the most widely studied variants in CPB2 gene and have been previously associated with TAFI levels and activity. Both variants result in amino acid substitutions and offer biologically plausible mechanisms to alter the risk of thrombotic events. However, as for any genetic association studies, there is the potential that the associated variants are in fact in LD with other variants that are causally associated with disease risk. For instance the Ala147Thr is in LD with rs9526136 variant, which has been associated with intact TAFI and TAFI activation peptide [CPB2 gene, rs17844078, that showed a similar association in females to the Ala147Thr variant; these two variants were in high LD [ peptide . Further high LD , making CPB2 variants and risk of a venous thrombotic event, and followed rigorous systematic review methodologies [This systematic review included a comprehensive search of all articles assessing any dologies , 63, 70.CPB2 variants and the risk of thrombotic events, this meta-analysis supports the role of CPB2 variants in the risk of venous thrombosis.This meta-analysis provides evidence that the Thr325Ile variant under the recessive model is significantly associated with decreased risk of venous thrombosis in Europeans. Additionally, there is evidence to support a sex-specific association between the Ala147Thr variant and risk venous thrombosis in females under a dominant model. It is estimated that 15% of SNPs may act in a sex-dependent manner  and may S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S1 FigThe solid squares represent the ORs from individual studies; horizontal lines represent corresponding CIs; the diamonds show the combined ORs.(TIF)Click here for additional data file.S2 Fig(TIF)Click here for additional data file.S3 Fig(TIF)Click here for additional data file.S4 FigThe solid squares represent the ORs from individual studies; horizontal lines represent corresponding CIs; the diamonds show the combined ORs.(TIF)Click here for additional data file.S1 File(DOCX)Click here for additional data file.


No increased risk of skin SCC, skin BCC or melanoma was observed . Rs361525 was not associated with overall SCC risk in the allele, heterozygote, dominant, recessive, or carrier model . Begg's and Egger's tests  demonstrated there was no significant publication bias. These data indicate that the AA genotype of TNF-α rs1800629, but not rs361525, is associated with an increased risk of SCC, suggesting it could potentially serve as a prognostic marker for predicting SCC risk.Tumor necrosis factor-alpha (TNF-α) is a multifunctional pro-inflammatory cytokine that plays an important role in cancer development. We performed a meta-analysis to assess the relationship between single nucleotide polymorphisms in the TNF-α promoter region (rs1800629 and rs361525) and susceptibility to squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and melanoma. After database retrieval, article selection, data extraction, and quality assessment, 20 articles comprising 4865 cases and 6329 controls were included in this study. rs1800629 was associated with an increased overall risk of SCC, lung SCC, and oral SCC in the AA vs G and AA vs GG+GA genetic models (all OR>1,  TNF-α) gene, located on chromosome 6p21.231, consists of four exons [TNF-α gene, is associated with cellular differentiation, proliferation, apoptosis, inflammatory responses, insulin resistance, and tumorigenesis [TNF-α gene [Tumor necrosis factor-alpha  remains inconclusive. For instance, the rs1800629 polymorphism of TNF-α gene has been linked to the risk of esophageal SCC in northern Indian patients [TNF-α rs1800629 polymorphism has been associated with the risks of oral SCC in Taiwan [The role of patients , but notn Taiwan , but notTNF-α gene have been reported to contribute to the risk of skin cancer in certain populations. For example, the study by Rizzato et al. has indicated that TNF-α rs1800629 might affect the SBCC risk in Caucasian population [TNF-α gene rs1800629 polymorphism was also reported to influence the course of BCC in Polish population [TNF-α polymorphisms in skin cancer is still inconclusive. For example, Skov et al. reported that TNF-α release, but not rs1800629 polymorphism, was linked to the SBCC risk in Caucasian population [TNF-α polymorphisms and the risk of skin cancer.Skin cancer comprises cutaneous melanoma, skin SCC (SSCC), and skin basal cell carcinoma (SBCC) . Allelicpulation . The A apulation . Howeverpulation . To our TNF-α polymorphisms and the risk of skin cancer and different SCC diseases.Therefore, in this study, we carried out a comprehensive systematic review and meta-analysis to determine the association of th, 2017 to identify the eligible studies. The search details are shown in Six databases, including PUBMED, Web of Science (WOS), EMBASE, WANFANG, CNKI, and SCOPUS, were electronically searched on January 17TNF-α rs1800629 polymorphism and the risk of SCC under allele model (A vs G), homozygote model (AA vs GG), heterozygote model (GA vs GG), dominant model (GA+AA vs GG), recessive model (AA vs GG+GA), and carrier model (carrier A vs G). Pooled analysis data are shown in Table associationP=0.192), GA vs GG model , GA+AA vs GG , or carrier A vs G model . However, an increased overall SCC risk was observed in AA vs GG model  and AA vs GG+GA model .Meta-analysis of 16 studies , 16–24 cassociationP<0.001). The increased risk of LSCC  and OSCC  was also observed (Table associationP>0.05). These data indicate that the AA genotype of TNF-α rs1800629 polymorphism correlates with the higher susceptibility towards SCC.There are several types of SCC, including skin SCC (SSCC), esophageal SCC (ESCC), oral SCC (OSCC), and lung SCC (LSCC). We performed subgroup analyses of the above SCC types and different ethnicities under all models. As shown in Table ed Table . SimilarTNF-α rs361525 polymorphism and susceptibility to SCC was also performed. Six studies comprising 962 cases and 1116 controls were analyzed [associationP>0.05). Subgroup analysis (Table associationP=0.023), GA vs GG model ; GA+AA vs GG , and carrier A vs G . However, only two case-control studies comprising 196 cases and 435 controls were included in the LSCC subgroup [associationP>0.05). These data indicate that TNF-α rs361525 polymorphism does not contribute to the risk of SCC.Meta-analysis of the relationship between analyzed , 21, 24.subgroup , 20. No TNF-α rs1800629 and the risk of skin cancer, including SSCC, SBCC, and melanoma. Seven studies comprising 2710 cases and 2786 controls were included [associationP>0.05, Table TNF-α rs1800629 polymorphism does not have a significant correlation with the risk of skin cancer.We then performed meta-analysis of the relationship between included , 15–17. 2 value of 77.5 % and Pheterogeneity <0.001), GA vs GG (I2=66.3 % and Pheterogeneity <0.001), GA+AA vs GG (I2=71.4 % and Pheterogeneity <0.001) and carrier A vs G (I2 =64.0 % and Pheterogeneity <0.001) data indicated a high degree of heterogeneity among the studies (Table 2=30.0 % and Pheterogeneity=0.137) and AA vs GG+GA contrast . For the rs1800629 polymorphism and the risk of skin cancer, fixed-effect model was used for all models .For the rs361525 polymorphism and SCC risk, random-effect model was used for the overall SCC, due to the presence of overall significant heterogeneity . Moreover, we conducted a sensitivity analysis and confirmed the stability of our results  from 2045 cases and 6013 controls of European population [In the present study, 16 case-control studies of morphism , 16–24 amorphism , 21, 24 neck SCC , 26. Howneck SCC . Differeneck SCC , 29. Regneck SCC . The rs3neck SCC . Here, nneck SCC . In addineck SCC , 15–17. pulation .TNF-α, including rs1800629 and rs361525, were chosen. In addition, small sample size and/or limited genotype data in eligible articles affected our analysis. For example, there are two case-control studies of the association between TNF-α rs1800629 and melanoma risk [Although our results were validated by Begg's and Egger's tests, and by sensitivity analysis, the limitations in our meta-analysis should also be addressed. (1) Due to the limited number of studies published to date, only the common genetic polymorphisms of oma risk . Howeveroma risk . The freoma risk . (2) A coma risk  and OPSComa risk . The suboma risk , 20, andTNF-α gene expression or TNF-α cytokine release lead to a variety of cancers [TNF-α gene, can lead to the substitution from G common allele to A rare allele [In vitro experiments showed that the “A” rare allele of rs1800629 could increase TNF-α transcription [TNF-α rs1800629 was found to be positively associated with distant metastases of triple negative breast cancer patients [TNF-α gene expression in gastric cancer patients [TNF-α and other genes, including TNF-beta and interleukin-6, on the carcinogenesis and SCC cancer therapy, since this may lead to the discovery of potential novel biomarkers for SCC.TNF-α is an important multifunctional pro-inflammatory cytokine, which is closely linked to the occurrence, progression, metastasis, prevention and therapy of many types of human cancer –37. Alte cancers , 38. Gen cancers . The rs1e allele . In vitrcription , 40. Thecription . TNF-α rpatients . Howeverpatients , 42. Herpatients . The carTNF-α rs1800629 polymorphism may serve as a prognostic biomarker for SCC, especially for LSCC and OSCC in the Asian population. The rs361525 polymorphism does not seem to be a genetic risk factor for SCC. In conjunction with other studies, these results provide a scientific support for the prognostic value of TNF-α rs1800629 polymorphisms in predicting the SCC risk.In conclusion, our meta-analysis indicates that the AA genotype of th, 2017 were searched in the electronic databases, including PUBMED, WOS, EMBASE, WANFANG, CNKI and SCOPUS, without any language restrictions. The present meta-analysis followed “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” (PRISMA) [The related articles published before January 17(PRISMA) , as showP value for HWE (PHWE) was less than 0.05; 11) Studies with unselected mutation sites. The selected articles provide sufficient information regarding the genotypes for TNF-α polymorphisms in case and control groups. PHWE values were obtained by the chi-squared test.Duplicated articles were removed by EndNote X7 software (Thomson Reuters). The following articles were excluded: 1) Reviews, theses, cases and trials; 2) Meeting abstracts and posters; 3) Cell or animal studies; 4) Other genes or diseases; 5) Meta-analyses; 6) Non-mutation data; 7) Data without detailed genotype; 8) Lack of control data; 9) Studies without specific oral cancer type information; 10) 2 and PHWE values in control group. Newcastle-Ottawa Scale (NOS) system  was used to assess the quality of the included studies; NOS score ≥7 indicates a high quality study.The authors extracted independently the following information: First author, publication year, country, ethnicity, number of cases/controls, source of controls, age , genotyping assay, gender , SNP, genotype frequencies, disease type, χPassociation value less than 0.05 was considered statistically significant. Six genetic models, including allele, homozygote, heterozygote, dominant recessive, or carrier models were used. Cochran Q statistic and I2 test were carried out to assess the potential heterogeneities between studies. When Pheterogeneity value of Cochran Q statistic > 0.05 or I2 value <50 %, the fixed-effect model was used. Otherwise, random-effect model was applied. To investigate the potential sources of heterogeneity, sensitivity analyses and subgroup analyses based on SCC disease type, ethnicity or source of controls were performed. Begg's test with pseudo 95 % confidence limits and Egger's test were also conducted to evaluate the potential publication bias. Stata/SE 12.0  software was used for all statistical analyses.Mantel-Haenszel statistics was used to estimate the values of pooled odd radios (ORs) and 95 % confidence intervals (CIs);


TNF-α gene from all eligible case–control studies to assess the associations amongst reported TNF-α gene with GD. A total of ten case–control studies involving 2790 GD patients and 3472 healthy controls were included. The results showed that a significant association was characterized between the rs1800629 polymorphism and GD in the homozygous model (AA compared with GG: odds ratio (OR) = 1.97, 95% confidence interval (CI) = 1.27–3.06, P=0.002) and recessive model . GD susceptibility was significantly detected in European population in all genetic models after ethnicity stratification. In sharp contrast, no significant association could be detected in Asian population. Next, we conducted a meta-analysis for another promoter SNP rs361525. However, SNP rs361525 did not show a significant association with GD in any genetic model before and after ethnicity stratification. Together, our data support that only the promoter single-nucleotide polymorphism (SNP) rs1800629 within the TNF-α gene is associated with increased risk for developing GD, especially in European population. Future large-scale studies are required to validate the associations between TNF-α gene and GD.Graves’ disease (GD) is a common autoimmune disorder with a genetic predisposition. Owing to the biological effect of tumor necrosis factor-α (TNF-α) on the thyroid gland and its gene location, TNF-α should be able to influence an individual’s susceptibility to GD. In the present study, we conduct a meta-analysis of rs1800629 and rs361525 in  TNF-α gene is a functional candidate for studying GD.Graves’ disease (GD) is an autoimmune thyroid disease with a 0.5% rate of prevalence in general population . It is cTNF-α gene spans 2.76-kb DNA, with four exons and three introns. Single-nucleotide polymorphisms (SNPs) within TNF-α have a potential to cause structural changes within regulatory sites that could affect the function or regulation of TNF-α production. These factors could contribute to the autoimmune process making it an ideal candidate for the development of GD . Alt. AltTNF-s (GWAS) ,9. Partii et al.  ~10 yearPubMed, Embase, and ISI Web of Science were searched  using the following search terms: ‘TNF-α OR Tumor necrosis factor-alpha’, ‘polymorphism OR variant OR mutation’, and ‘Graves’ disease’. References, which were listed in each identified article, were also searched manually to identify additional eligible studies.To be eligible, the following inclusion criteria were established: (i) a human case–control study of a polymorphism associated with GD; (ii) studies that included sufficient genotype data for extraction. Main exclusion criteria for studies were as follows: (i) case reports, letters, reviews, and editorial articles; (ii) literature not containing information regarding diabetes research; (iii) study involving only a case population; and (iv) study not written in English. In the case of multiple studies by the same researchers involving the same or overlapping datasets, we selected the most recent study with the largest number of participants.Two curators (Y.T. and G.F.) independently extracted information from included studies. Disagreement was resolved by discussion between the two authors. The following data were extracted: first author’s name, year of publication, ethnicities of the individuals involved, the genotyping method, number of cases and controls for each genotype, and the Hardy–Weinberg equilibrium (HWE) amongst the controls. Ethnicity was categorized as Asian and European. A double-check procedure was performed to ensure accuracy of data entry. To evaluate the study quality, we adopted the Newcastle–Ottawa Scale (NOS) with a nine-star system; this scale assesses the quality of cohort and case–control studies. NOS focusses on three separate sections of stars representing the assessment score. The maximal score of NOS is 9 stars: 4 stars for the selection process, 2 stars for comparability, and 3 stars for exposure/outcome. A score of 7 and above was considered to be high-quality study.TNF-α gene and the risks for GD was assessed by odds ratios (ORs) with 95% confidence intervals (CIs). We explored the association between rs1800629 and GD in homozygote model (AA compared with GG), heterozygote model (GA compared with GG), dominant model (AA + GA compared with GG), recessive model (AA compared with GA + GG), and additive model (A compared with G), respectively. The same genetic models were applied for SNP rs361525 as well. Chi-squared-based Q-statistic test was employed to assess the between-study heterogeneity, and in any case P<0.10 was considered with significant heterogeneity between datasets. Once the effects were assumed to be homogeneous, fixed-effects model was then applied (the Mantel–Haenszel method); otherwise, the random-effects model (DerSimonian and Laird method) was employed appropriately. Sensitivity analysis was performed to assess the influence of each individual study by omitting one study at a time and calculating a pooled estimate for the remainder of the studies. The inverted funnel plots and Egger’s regression test were used to investigate publication bias. Potential publication bias was assessed with funnel plots of the effect sizes compared with the S.E.M.; Begg’s test was used to identify significant asymmetry. If there is evidence of publication bias, funnel plot is noticeably asymmetric. Concerning the significance level of the Begg’s and Egger’s tests was set at 0.05. All statistical tests carried out in the present report were two-tailed. All analyses were conducted using the STATA 11.0 software .The strength of associations between SNPs rs1800629 and rs361525 within the A total of 67 publications were characterized based on our keyword search. After screening the titles and abstracts, 35 studies were identified as irrelevant, and 3 articles were characterized as reviews. Additionally, 16 studies were excluded because 13 of the articles focussed on different genes. Another three articles were excluded because they were not on GD research (two studies) or were not case–control studies (one study). Amongst the remaining thirteen publications, three studies were also rejected as they either failed to provide detailed genotyping information (two articles) or were published in non-English journals (one study) .P>0.05) except for the four datasets highlighted in bold  and recessive model   . For ana P=0.03) . Next, w P=0.03)  and 4. OBegg’s funnel plot and Egger’s test were next conducted to assess publication bias. The shape of the funnel plots appeared to be symmetrical  and the Egger’s test did not show any evidence of publication bias . AnalysiTNF-α has thus been considered to be a candidate gene for GD. Nevertheless, no consistent results have been reached so far in terms of its genetic predisposition in GD pathoetiology. To address this question, we conducted a meta-analysis with the aim of concentration on the two SNPs, G-238A (rs361525) and G-308A (rs1800629) in the promoter region. Our studies demonstrated by clear and convincing evidence that only the promoter SNP rs1800629 within the TNF-α gene is associated with an increased risk for developing GD. The results of our overall meta-analysis supported that only G- > A mutation at −308 in TNF-α was a risk factor for GD, while the other SNP did not show a significant association with GD in any genetic model. To exclude the influence of population stratification, we then divided all datasets into two subgroups, Asian population and European population. Much stronger association was noted in the European populations, while the association was undetectable in the Asian population, representing the existence of genetic heterogeneity between different ethnic groups, which could be caused by the differences of gene–environmental interactions. These results were consistent with the findings of Duraes et al. [TNF-α −308 A allele is associated with a higher level of TNF-α transcript, due to the great potency of the promoter region to activate the transcription [TNF-α gene polymorphisms at position −238 is another SNP which is commonly studied. Although our meta-analysis did not detect an association between −238 and GD, it was reported that the region between −254 and −230 contains a regulatory sequence that acts as a TNF-α repressor site, and thus a mutation at −238 might be disrupting regulation [TNF-α is an inflammatory cytokine that is produced by intrathyroidal inflammatory cells and thyroid follicular cells and plays a pivotal role in regulating immunological reactions and the development of autoimmune diseases . Upon th rs180062 in the ps et al.  in a Polcription ,20. Thergulation ,21.Our meta-analysis has some key advantages compared with individual studies. First, to guarantee the quality of the present study, we included the most updated literature and used explicit criteria for study inclusion and a strict procedure for data extraction. Additionally, a substantial number of subjects were pooled from individual studies, which significantly increased the statistical power. However, there are several limitations in our study. First, the controls were hospital-based study in our included literatures. Compared with hospital-based study, a population-based case–control study can reduce more selection bias and have higher confidence. Second, our search was limited to published English language studies. Some potential studies which were published in other languages or unpublished have been systematically excluded. This may explain some publication bias in our meta-analysis, which may have affected the results of this meta-analysis in as far as those studies that had produced negative results might not have been published. Third, the study population is limited for meta-analysis. Considering this would lead to low statistical power, future studies with a large dataset would be necessary for fully establishing the impact on susceptibility to GD.TNF-α gene is associated with increased risk for developing GD, especially in European population. However, future studies with a large dataset focussing on addressing their functional relevance would be necessary for fully establishing their effect on GD susceptibility.In summary, the results of our meta-analysis identified that only the promoter SNP rs1800629 within the


People who had ever smoked and those who were exposed to environmental tobacco smoke had significantly increased UC odds ratios (ORs) of 1.65 and 1.68, respectively. Participants who had smoked more than 18 pack-years had a significantly increased UC OR of 2.64. People who had ever smoked and who carried the A/A genotype of the TNF-α -308 G/A polymorphism had a significantly higher UC OR (10.25) compared to people who had never smoked and who carried the G/G or G/A genotype. In addition, people who had ever smoked and who carried the IL-8 -251 T/T genotype had a significantly increased UC OR (3.08) compared to people who had never smoked and who carried the T/A or A/A genotype. In a combined analysis of three major risk factors , subjects with any one, any two, and all three risk factors experienced significantly increased UC ORs of 1.55, 2.89, and 3.77, respectively, compared to individuals with none of the risk factors. Conclusions. Our results indicate that the combined effects of cumulative cigarette exposure and the TNF-α -308 A/A genotype and/or the IL-8 -251 T/T genotype on UC OR showed a significant dose-response relationship.Cigarette smoking and exposure to environmental tobacco smoke are well-known risk factors for urothelial carcinoma (UC). We conducted a hospital-based case-control study involving 287 UC cases and 574 cancer-free controls to investigate the joint effects of cigarette smoking and polymorphisms of inflammatory genes on UC risk. Tumor necrosis factor alpha (TNF- The bladder is the most common site of urothelial carcinoma (UC), a multifactorial malignancy influenced by exogenous exposure to environmental risk factors and molecular variations in metabolism-related genes . Cigaretα) and interleukin-8 (IL-8), which are involved in the development of various malignancies [α expression through upregulating the activator protein, AP-1 [α is involved in the immune response during the intravesical instillation of bacillus Calmette-Guerin [α and IL-8 [α initiates signaling pathways that activate proinflammatory gene expression via the transcription factor; nuclear factor-kappa B (NF-κB) is also produced by tumors and acts as an endogenous tumor promoter. Cytokines, like IL-6 and IL-8, are also involved in transformation and angiogenesis, respectively [Oxidative stress can induce proinflammatory cytokines such as tumor necrosis factor alpha  is located in promoter and has functional impact on the TNF-α expression [α, -308 G/A polymorphism was investigated and found to be related to several cancers, including breast, gastric, and bladder cancers [ IL-8 gene is located on chromosome 4q13-q21, and several polymorphisms were identified in this gene [ IL-8, and it was identified to be associated with various cancer risks in Asian group [ TNF-α and IL-8 genes may modify the risk of UC.The polymorphism ofpression –15. Comp cancers , 16–18. his gene . A commo TNF-α -308 G/A and IL-8 -251 T/A polymorphisms on the UC risk, we conducted a hospital-based case-control study. We also examined the combined effects of cumulative cigarette exposure, the TNF-α -308 A/A genotype, and the IL-8 -251 T/T genotype on UC risk.To investigate the effects of Declaration of Helsinki.This study involved 861 participants enrolled from the Departments of Urology and those undergoing a general health examination at National Taiwan University Hospital, Taipei Medical University Hospital, and Taipei Municipal Wan Fang Hospital between September 2002 and May 2009. In total, 287 UC cases were included (with a mean age of 62.95 ± 13.62 years). Each case was diagnosed with histopathological confirmation, which was performed using routine urological practices and verified by board-certified pathologists. In total, 574 age- and gender-matched cancer-free controls (with a mean age of 62.56 ± 13.50 years) were recruited from a hospital-based pool. All participants provided informed consent before the questionnaire interview and biospecimen collection. The Research Ethics Committee of National Taiwan University Hospital  approved this study, and this study complied with the World Medical AssociationWell-trained investigators interviewed each patient using a structured questionnaire. Information collected by the questionnaire included demographic characteristics and lifestyle habits such as cigarette smoking, secondhand smoke exposure, betel nut chewing, alcohol, tea, and coffee consumption, exposure to occupational and environmental carcinogens such as pesticides, and a family history of disease. Study subjects who had smoked more than 100 cigarettes during their lifetime were regarded as people who had ever smoked, while those who had smoked fewer than 100 cigarettes were defined as people who had never smoked. Environmental tobacco smoke (secondhand smoke exposure) was assessed through a questionnaire asking participants whether anyone had ever smoked around them. A 6~8-ml sample of venous blood was drawn from each participant for genotype determination. TNF-α -308 G/A polymorphism: 5′-TCCTCCCTGCTCCGATTCCG-3′ (sense) and 5′-AGG CAATAGGTTTTGAGGGCCAT-3′ (antisense). The thermal PCR conditions were as follows: one cycle at 95°C for 5 min; 35 cycles of 95°C for 30 s, 58°C for 30 s, and 72°C for 45 s; and a final extension at 72°C for 10 min. After complete digestion with the NcoI restriction enzyme, the resulting DNA fragments, which represented the TNF-α -308 G/A polymorphism, were determined . PCR-RFLP genotyping and sequencing of TNF-α -308 G/A are shown in  IL-8 -251 T/A polymorphism, the following primers were used: 5′-ATCTTGTTCTAACACCTGCCACTC-3′ (sense) and 5′-TAAAATACTGAAGCTCCACAATTTGG-3′ (antisense) [ IL-8 -251 T/A polymorphism . PCR-RFLP genotyping and sequencing of IL-8 -251 T/A are shown in Genomic DNA was extracted from the buffy coat of peripheral blood using standard methods and stored at −80°C. Genotyping was completed using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method modified from a study by Duarte et al. . Brieflytisense) . The PCR TNF-α -308 A/A genotype, and the IL-8 -251 T/T genotype on the UC risk were estimated by odds ratios (ORs) and associated 95% confidence intervals (CIs) using a multivariate-adjusted logistic regression. All data were analyzed using the Statistical Analysis Software for Windows, ver. 9.2 . p values of < 0.05 were considered statistically significant.A goodness-of-fit Chi-squared test was used to test for Hardy-Weinberg equilibrium (HWE) among the cancer-free controls. Study subjects who had smoked more than 100 cigarettes during their lifetime were regarded as people who had ever smoked, while those who had smoked fewer than 100 cigarettes were defined as people who had never smoked. The pack-years of cigarette smoking were calculated using the formula: pack-years = (cigarettes per day ÷ 20) × (number of years smoked). Because of dependent variable (UC) is binary, logistic regression is used to assess the association between UC and related risk factors. The combined effects of cumulative cigarette exposure, the TNF-α -308 A/A genotype and the IL-8 -251 T/T genotype among controls fit HWE . The genotype distribution of the control did not show significant difference from the Hardy-Weinberg equilibrium values. Subjects who carried the TNF-α-308 A/A genotype had a significantly increased OR for UC  compared to those with the G/G or G/A genotype. Subjects who carried the A/A genotype of the IL-8 -251 T/A polymorphism had a significantly lower OR for UC  than those carrying the T/T genotype (data not shown).No significant differences were found in age or gender between the UC cases and cancer-free controls. Occasional alcohol drinkers had a significantly lower OR for UC than people who had never consumed alcohol. After adjusting for age, gender, educational level, alcohol consumption, and other risk factors, people who had ever smoked had a significantly higher UC OR of 1.65 (95% CI: 1.19~2.27) compared to people who had never smoked. Individuals who were exposed to environmental tobacco smoke had a significantly higher UC OR  than those with no exposure. Frequencies of the TNF-α -308 G/A and IL-8 -251 T/A genotypes, individual characteristics, including age, gender, educational level, cigarette smoking, environmental tobacco smoke exposure, and alcohol consumption, displayed no significantly different distributions in either of the polymorphism strata  in a combined analysis (p for trend < 0.0001).Furthermore, we included three major risk factors  and found dose-response relationships for UC risk in study subjects with any one risk factor, any two risk factors, and all three risk factors.In this study, the risk of UC in smokers was 2~2.5-fold compared to nonsmokers. This result was consistent with a previous study . In our  TNF-α -308 G/A polymorphism contributes to carcinogenesis and that the variant A allele was associated with increased TNF-α expression [ TNF-α -308 G/A polymorphism was significantly associated with the tumor stage and grade of bladder cancer [ TNF-α -308 G/A polymorphism had a significantly higher OR for UC than those with the G/G or G/A genotype. These results suggest that the TNF-α -308 G/A polymorphism might regulate angiogenesis, which plays a role in the invasion and metastasis of various tumors. However, another study did not report the same findings in urinary stone diseases or bladder cancer in Taiwan [Functional polymorphisms of inflammatory genes can affect cytokine production. A previous study reported that thepression . A Korear cancer . In thisn Taiwan .α in the case and control groups of this study was 2.23% and 0.67%, respectively, and the TNF-αA/A genotype carried a 3.56-fold risk of UC. A meta-analysis study showed that the A/A genotype frequency of TNF-α in cervical cancer cases and controls was 0.97%~7.33% and 0%~6.78%, respectively. The TNF-α A/A genotype significantly elevating risks of cervical cancer was found in a Caucasian population  [α A/A genotype frequency was very low in Japanese (141 bladder cancer patients and 173 control subjects), the allelic frequency of patients (3.5%) was higher than that in controls (0.6%) [α expression in an animal model [α level was higher in people who had ever smoked compared to people who had never smoked [α -308 genotypes was associated with HCC risk in Taiwan males who were exposed to cigarette and alcohol [ TNF-α -308 polymorphism on the OR (10.25) for UC. This finding suggests that the TNF-α -308 G/A polymorphism can modify the OR for UC, especially in people who had ever smoked.Compared to previous studies, differences in genotype frequencies may have been due to ethnic variations. The A/A genotype frequency of TNF-34~3.25) . Althougs (0.6%) . A previ alcohol . In the  IL-8 promoter region can influence its expression and may increase one's susceptibility to bladder cancer [ IL-8 -251 T/A polymorphism and various cancer risks, but the findings were inconsistent [ IL-8 -251A allele has significantly higher promoter activity than the -251T allele [ IL-8 -251T allele had significantly higher transcriptional activity than the -251A allele of the IL-8 gene [IL-8 plays a critical role in inflammation. A common single-nucleotide polymorphism at the -251 position of ther cancer . In the nsistent , 30. SomT allele . HoweverL-8 gene . In addiL-8 gene , 11. IL-L-8 gene . A meta-L-8 gene . It is pα protein stability was impacted by amino acid residue substitutions of P84L (rs4645843) and A94T (rs1800620) [Single-nucleotide polymorphisms of genes can increase disease susceptibilities via affect gene expression. Silico analysis is a novel computational approach to identify potential SNPs causing transcription factor binding affinities to change and influence regulatory functions of genes . Since p1800620) . The eff1800620) . Althoug1800620) . TNF-α and IL-8 genes. More functional polymorphisms of the TNF-α and IL-8 genes should be included in future analyses with larger samples to validate our findings. Other proinflammatory cytokines such as NF-κB also need to be further investigated. In addition, interactions of cigarette smoking and other cytokines on the UC risk should be explored in the future.Our study has some limitations. We only investigated one polymorphism located in the promoter region, which might not entirely account for the functions of the TNF-α-308 A/A genotype and the IL-8 -251 T/T genotype, and who experience cumulative cigarette smoking have a significantly increased OR for UC in a dose-response manner.We found a dose-response relationship between the number of risk factors and the OR for UC. These findings suggest that individuals who carry high-risk genotypes, including the