To evaluate the influence of polymorphisms in nucleotide excision repair (NER) and homologous recombination repair (HRR) pathways on the development of osteosarcoma patients.Genotypes of ERCC1 rs11615 and rs3212986, ERCC2 rs1799793 and rs13181, NBN rs709816 and rs1805794, RAD51 rs1801320, rs1801321 and rs12593359, and XRCC3 rs861539 were conducted by Polymerase Chain Reaction Restriction Fragment Length Polymorphism (PCR-RFLP) assay.Total 148 osteosarcoma patients and 296 control subjects were collected from Taizhou First People’s Hospital. Conditional logistic regression analyses found that individuals carrying with GA+AA genotype of ERCC2 rs1799793 and GC+CC genotype of NBN rs1805794 were significantly associated with increased risk of osteosarcoma, and the ORs(95%CI) were 1.58(1.03-2.41) and 2.66(1.73-4.08), respectively. We found that GA+AA genotype of ERCC2 rs1799793 or GC+CC genotype of NBN rs1805794 were associated with an increased risk of osteosarcoma in females, with ORs(95%CI) of 2.42(1.20-4.87) and 2.01(1.07-4.23), respectively.Our results suggest that ERCC2 rs1799793 and NBN rs1805794 polymorphisms were associated with an increased risk for osteosarcoma, which suggests that NER and HRR pathways modulate the risk of developing osteosarcoma. Osteosarcoma is a rare bone cancer that has a first peak of incidence in adolescents around 16 years, and a second peak in patients older than 60 years.4Genetic polymorphisms in DNA repair genes may lead to amino acid substitution and cause differential capacity to repair DNA damage. The genetic polymorphisms in DNA repair genes have been found to be associated with increased genetic instability and carcinogenesis.Excision repair cross-complementation group 2 (ERCC2) gene and excision repair cross complementation group 1 (ERCC1) are parts of an endonuclease complex. More complex DNA damage requires different mechanisms such as HRR for successful repair. In HRR, nibrin (NBN) is part of the complex involved in recognition of DNA damage, while RAD51 recombinase (RAD51) catalyses homologous search and strand invasion with the help of other proteins, including X-ray complementing defective repair in Chinese hamster cells 3 (XRCC3).9Single nucleotide polymorphisms (SNPs) of NER genes have already been associated with development of different cancer types,Between January 2012 and January 2014, 148 osteosarcoma patients were diagnosed from Taizhou First People’s Hospital. Osteosarcoma patients were newly diagnosed and histopathologically confirmed independently by two gynecologic pathologists. 296 control subjects were collected from health check center of Taizhou First People’s Hospital, who came to our hospital for medical check up. All the control subjects were confirmed not suffering from osteosarcoma, and had no medical history of any tumor or cancer and no family history of osteosarcoma or other cancers in first-degree relatives. The control subjects were matched to cases by sex and age, and two cases were matched to one case. The study was approved by the Taizhou First People’s Hospital.Controls were investigated to obtain demographic parameters. For the cases, clinical and pathological information were extracted from the medical records, including tumor stage and location, histological type, and family history of cancer.5ml peripheral blood was collected from each patient and was kept in -70ºC until use. Genomic DNA was isolated from peripheral blood using the TIANamp Blood DNA Kit  according to the manufacturer’s instructions. Genotypes of ERCC1 rs11615 and rs3212986, ERCC2 rs1799793 and rs13181, NBN rs709816 and rs1805794, RAD51 rs1801320, rs1801321 and rs12593359, and XRCC3 rs861539 were conducted by Polymerase Chain Reaction Restriction Fragment Length Polymorphism (PCR-RFLP) assay. Probes and primers for ERCC1 rs11615 and rs3212986, ERCC2 rs1799793 and rs13181, NBN rs709816 and rs1063054, RAD51 rs1801320, rs1801321 and rs12593359, and XRCC3 rs861539 were designed using Primer 5.0 software . The cycling programme of PCR reaction condition was performed as follows: one initial denaturation step at 5 minutes at 94ºC, followed by 35 denaturation cycles of 45s at 94ºC, 60s of annealing at 62ºC, and 60s of extension at 72ºC, and followed by a final extension at 72ºC for 10 minutes. In order to perform quality control, genotyping was repeated in 20% samples to check for genotyping accuracy.2-test. The χ2-test was performed to verify whether the genotype distributions were in Hardy–Weinberg equilibriums of ERCC1 rs11615 and rs3212986, ERCC2 rs1799793 and rs13181, NBN rs709816 and rs1805794, RAD51 rs1801320, rs1801321 and rs12593359, and XRCC3 rs861539. The association between osteosarcoma group and control group were assessed using unconditional logistic regression, and the results were expressed using odds ratio (OR) and their confidence intervals (CI). All P-values were two sided, and a P-value was regarded as statistically significant when it less than 0.05.Continuous variables were expressed as the mean ± SD and analyzed by student t test. Categorical variables were shown as N(%) and analyzed by χThe characteristics of patients with osteosarcoma and controls are shown in 2-test, genotype distributions of ERCC1 rs11615 and rs3212986, ERCC2 rs1799793 and rs13181, NBN rs709816 and rs1805794, RAD51 rs1801320, rs1801321 and rs12593359, and XRCC3 rs861539 in the control subjects were found to be in line with Hardy–Weinberg equilibrium. Conditional logistic regression analyses found that individuals carrying with GA+AA genotype of ERCC2 rs1799793 were significantly associated with increased risk of osteosarcoma when compared with GG genotype . Moreover, individuals carrying GC+CC genotype of NBN rs1805794 were correlated with a heavy enhanced risk of osteosarcoma when compared with GG genotype, and the OR(95%CI) was 2.66(1.73-4.08). However, we did not find significant association between ERCC1 rs11615 and rs3212986, ERCC2 rs13181, NBN rs709816, RAD51 rs1801320, rs1801321 and rs12593359, and XRCC3 rs861539 and risk of osteosarcoma.By χMoreover, we conducted stratification analysis on the association between ERCC2 rs1799793 and NBN rs1805794 and demographic characteristics in osteosarcoma patients. We found that GA+AA genotype of ERCC2 rs1799793 or GC+CC genotype of NBN rs1805794 were associated with an increased risk of osteosarcoma in females, and the ORs(95%CI) were 2.42(1.20-4.87) and 2.01(1.07-4.23), respectively.In this hospital-based case-control study, we investigated the role of ten SNPs in NER and HRR pathways about the risk of osteosarcoma. Since there is increasing evidence that genetic variation leads to different DNA repair capacities in the human population, such common polymorphisms can play a role in an individual’s genetic susceptibility to cancer.21We also found that ERCC2 rs1799793 and NBN rs1805794 may be associated with carcinogenesis of osteosarcoma. GA+AA genotype of ERCC2 rs1799793 and GC+CC genotype of NBN rs1805794 were associated with increased risk of osteosarcoma, but that gene polymorphisms of ERCC1 rs11615 and rs3212986, ERCC2 rs13181, NBN rs709816, RAD51 rs1801320, rs1801321 and rs12593359, and XRCC3 rs861539 were not correlated with risk of this cancer. Previous studies have showed that the non-synonymous ERCC2 rs1799793 SNP is associated with lower DNA repair capacity.Development of osteosarcoma was caused by different multiple factors, including genetic and environmental factors.There are some limitations to the present study that should be mentioned. First of all, although this study suggested that ERCC2 rs1799793 and NBN rs1805794 polymorphisms were associated with osteosarcoma risk, more biological background data are needed to explain our results. The current finding might involve gene-to-environment interactions, which were not explored in the present study. Second, the sample size of this study is relatively small, which may not have enough statistical power to explore the real association. Third, this is a hospital based case control study, so the selection bias cannot be ignored and the subjects may not be representative of the general population. Finally, these results should be interpreted with caution because the population was only from China, which reduces the possibility of confounding from ethnicity, so it does not permit extrapolation of the results to other ethnic groups.In conclusion, our study is, to our knowledge, the first to examine prospectively an increased risk role of ten SNPs in DNA repair pathway in osteosarcoma susceptibility, and we found that ERCC2 rs1799793 and NBN rs1805794 polymorphisms modulate the risk of developing osteosarcoma. Additional studies are greatly needed to confirm this finding.


Association between Cyclin D1 (CCND1) polymorphism and cervical cancer risk are conflicting with published articles. We performed a meta-analysis to investigate the association between CCND1 G870A polymorphism and cervical cancer risk.PubMed, Embase and CNKI data were researched to conduct a meta-analysis on the associations between CCND1 G870A polymorphism and cervical cancer risk. Ten published case–control studies including 2,864 patients with cervical cancer and 3,898 controls were collected in this meta-analysis. Odds ratio (OR) with 95% confidence interval (CI) were applied to assess the relationship; meta-regression, sensitivity analysis and cumulative analysis were also conducted to guarantee the strength of results.P = 0.76 I2 = 74.5%), codominant model , dominant model  and recessive model . Similarly, in the stratified analysis by ethnicity, study design and genotyping type, no significant association detected in all genetic models either.Overall, no significant association between CCND1 G870A polymorphism and cervical cancer risk were found in allele contrast  for this article can be found here:  Cervical cancer is one of the most common malignant diseases; it is the third most commonly diagnosed cancer and the fourth leading cause of cancer death in females with approximately 529,800 new cases and 275,100 deaths among females in 2008 worldwide [Cervical cancer is a multifactorial and multistep disease. Innate immune deficiency, environmental aggravation, and genetic mutation have been considered as important pathopoiesis factors. New molecular epidemical studies revealed that human papillomavirus (HPV), particularly HPV 16 and 18 infections may be the common and important factor contributing to the development of cervical cancer, which is known to cause approximately 70% of cervical cancers ,3.Abnormal cell proliferation is an important step in cancer development. Cyclins are a family of proteins that control cell progression through the cell cycle by activating cyclin-dependent kinase (CDK) enzymes . Cyclin Recently, molecular epidemiologic studies have directed considerable attention toward the association between genetic mutation and cancer susceptibility. Single-nucleotide polymorphisms (SNPs) are the most common type of genetic variation among people. The change in a nucleotide may alter gene functions and may influence protein expression, which could inhibit or promote cell proliferation and increase susceptibility to cancer development. In 1995, Betticher et al. [Catarino et al. published the first research about the association between CCND1 G870A polymorphism and cervical cancer risk in 2005 . Since tThree electronic databases, including Pubmed, Embase, and China National Knowledge Infrastructure (CNKI), were searched with the terms “CCND1”, “Cyclin D1”, “cervical cancer”, and “polymorphism” for studies published from 1995 to June 2014. Additional studies were identified through manual searches of the references of original studies or review articles on the topic of interest. Only studies published in English or Chinese were included. All studies selected for our meta-analysis met the following criteria: (a) observational (case–control or prospective) studies on the association between CCND1 G870A polymorphism and cervical cancer risk, (b) sufficient published data for estimating an odds ratio (OR) and 95% confidence interval (CI), and (c) the largest or most recent samples were selected when they overlapped with other studies.Data from all included studies were extracted independently by two investigators (Niu and Zheng). The extracted data included the name of the first author, publication date, country of origin, sources of controls, racial descent of the study population , number of different genotypes, and Hardy-Weinberg equilibrium (HWE) in controls.P value of less than 0.05 was considered significant disequilibrium. Stratified analyses were used to evaluate ethnicity, study design, and genotyping type technique. Heterogeneity was explored with the use of a chi-squared test, and the quantity of heterogeneity was measured by the I2 statistic. I2 values of 25%, 50%, and 75% represent low, moderate, and high heterogeneity, respectively. The OR of each model was estimated by using the fixed-effects model (Mantel–Haenszel method) when I2 ≤ 50%; otherwise, the random-effects model (DerSimonian and Laird method) was used. Meta-regression analyses were performed to assess potential covariates that can predict intertribal heterogeneity. Publication bias was assessed on the basis of modified Egger’s bias test and Begg’s funnel plot. Statistical analysis was performed by using STATA versions 11.0 . Two-sided P value (P < 0.05) was considered statistically significant.The strength of the association between CCND1 G870A polymorphism and cervical cancer was evaluated by ORs with 95% CI, comprised with allele contrast (A vs. G), codominant model , dominant model (GA + AA vs. GG), and recessive model (AA vs. GG + GA). The HWE of the control group was assessed, and a n = 12), Embase (n = 9), and CNKI (n = 4) ; codominant model ; dominant model . In the succeeding analysis of HWE studies, similar associations were found. In the stratified analyses of ethnicity, study design, and genotype, no significant association was found between CCND1 G870A polymorphism and cervical risk in almost all models. Heterogeneity was observed in all five genotype models. Meta-regression and stratified analyses were conducted, but no critical factors were found to explain heterogeneity in the subgroup of ethnicity, design, and genotype either .Overall, no significant association was found between CCND1 G870A polymorphism and cervical cancer risk in this meta-analysis Table . Values Studies included in the meta-analysis were deleted one by one to reflect the influence of an individual dataset on the pooled ORs. The results were consistent Figure .Figure 3P = 0.643 for A vs. G; GA vs. GG: P = 0.427; AA vs. GG: P = 0.558; (GA + AA) vs. GG: P = 0.423; AA vs. (GG + GA): P = 0.884).Funnel plot and Egger’s test were used to estimate publication bias. The shapes of the funnel plots for all genetic models did not reveal any asymmetrical evidence. Figure Cervical cancer is one of the most dangerous causes of health deficiency and death worldwide. Epidemiological studies have revealed that HPV infection is an important factor contributing to cervical cancer. Furthermore, gene mutation and abnormal tumor cell proliferation may serve critical functions in cancer development.The CCND1 gene is located at chromosome 11q13 and encodes a key cell cycle regulatory protein with 295 amino acids. CCND1 is an activator of CDK, which can regulate cell division by accelerating/decelerating the transition from G1 to S phase. Over-expression of CCND1 could result in the aberrant proliferation of DNA damage and the accumulation of genetic errors. Some SNPs of CCND1 have been reported. The G-to-A mutation is found in a well-known locus in the boundary of exon 4 and intron 4. This mutation does not alter any amino acid in the protein sequence. CCND1 G870A mutation results in an alternatively spliced transcript with a longer half-life than the CCND1 G allele and thus enables abnormal cells to pass through the G1-S checkpoint easily. Previous studies have demonstrated that CCND1 G870A polymorphism is significantly associated with the development of various cancers, such as breast cancer, prostate cancer, colorectal cancer, and other cancer types -25.In 2005, Catarino et al. firstly find that CCND1 GG polymorphism is associated with a 3.45-fold higher risk for the development of cervical cancer in a Portuguese population  . The samIn 2011, Ni et al. reported the first meta-analysis on the association between CCND1 G870A polymorphism and cervical cancer risk . Only fiOur analysis has some limitations. First, some heterogeneity still exists despite stratified analysis, and the meta-regression could not be explained successfully. Second, some environmental factors, such as smoking, drinking, and HPV infection, were not included in our meta-analysis because of data deficiency. Third, the sample size was relatively small, which might have yielded false results and inaccurate conclusions.In conclusion, this meta-analysis indicated that CCND1 G870A polymorphism may not be a risk factor of cervical cancer development. Large and well-designed case–control studies are needed to validate our findings further.Written informed consent was obtained from the patient for the publication of this report and any accompanying images.


In the subgroup analysis, significant increased risk was detected in the U.S. studies  and in the studies with <10 years of follow-up , and the greatest increase in risk was observed in those studies without adjustment for smoking . There was some evidence of publication bias (P for Egger’s test = 0.03). Cumulative evidence from prospective studies suggests that coffee consumption is not associated with risk of gastric cancer. The observed positive results may be confounded by smoking and need further investigation.The potential role of coffee consumption in the development of various types of cancer has been extensively investigated in epidemiologic studies. How coffee consumption may modulate risk of gastric cancer, however, remains a subject open for investigation. To better quantify this relation, we quantitatively summarized evidence from prospective studies. Eligible studies were identified on PubMed databases. The summary risk estimates were obtained using the random-effects model. Subgroup, sensitivity and dose-response analyses were conducted. The present meta-analysis included 12 prospective cohort studies. A pooled analysis of these studies suggested that coffee consumption (highest  Gastric cancer is the fourth most common type of cancer and the second leading cause of cancer death . The incCoffee is one of the most widely consumed beverages globally, and its potential role in the development of many chronic diseases, including various types of cancer has received considerable attention over the past several decades ,4. How cetc. [The association of coffee consumption with risk of gastric cancer has been investigated in a number of epidemiologic studies, with ambiguous findings ,15,16,17etc. ,12, all etc. ,19,20,21Since the 2006 meta-analysis , 5 largeWe searched for potentially relevant publications published before June 2014 on PubMed and Embase databases using the search terms “coffee” or “caffeine” in combination with “gastric cancer” or “stomach cancer” or “cardia cancer”, with no language restrictions. We also carefully reviewed the reference lists of retrieved publications in order to identify any further studies. The title and abstract of the relevant studies were screened and then the full papers of potentially eligible studies were carefully accessed. To be included, the study had to meet the following criteria: (1) study design was prospective; (2) exposure of interest was coffee consumption; (3) outcome was gastric cancer; and (4) relative risks (RRs) with corresponding 95% confidence intervals (CIs) were available (either reported or could be estimated according to reported data).Two authors independently extracted data using a standardized data-collection form, and discussion would be performed if there were any disagreements. The following data were extracted from each included eligible study: the first author’s last name, year of publication, country of origin, years of follow-up, sex of subjects, number of cases and subjects, levels of consumption, range of consumption, RRs of gastric cancer with corresponding 95% CIs, and statistical adjustment in the analysis.I2 statistics [P-value of less than 0.1 was considered statistically significant heterogeneity. Potential publication bias was evaluated by use of Begg’s funnel plots and Egger’s regression asymmetry test [The RRs reflecting the greatest degree of control for confounders were used in the meta-analysis. The summary risk estimates were obtained with the method of DerSimonian and Laird using the assumptions of the random-effects model that takes into account both within-study and between-study variations . Statistatistics . For thetry test .Stratified analyses were performed for the following subgroups: geographic areas, length of follow-up, number of cases, sex, range of consumption, and adjustment for potential confounders. A sensitivity analysis was also conducted by omitting one study at each turn and pooling results from the remaining studies. Because the levels of consumption among individual studies differed substantially, A dose-response analysis using the method by Greenland and Longnecker was conducted . AccordiThe flow chart of literature search is shown in P = 0.07, I2 = 37.0%) , with moderate heterogeneity (= 37.0%) .et al. [The results of subgroup analysis stratified by geographic areas, length of follow-up, number of cases, sex, range of consumption, and adjustment for potential confounders are presented in et al.  was not et al. [The results of subgroup analysis stratified by geographic areas, length of follow-up, number of cases, sex, range of consumption, and adjustment for potential confounders are presented in et al.  was not P = 0.07, I2 = 41.4%)  . The RR P = 0.03), and the Begg’s funnel plots also showed some asymmetry , and a null association with gastric non-cardia cancer  was observed in the NIH-AARP study; but in the Singapore Chinese Health Study , the posPotential mechanisms whereby coffee may modulate cancer risk have been extensively studied, with both protective and adverse effects proposed. Coffee is a complex mixture of hundreds of chemicals, among which caffeine and polyphenols are suspected to affect cancer risk. Coffee is rich in phenolic compounds that have been found to inhibit several carcinogens . ExperimThe strengths of this meta-analysis, in addition to the inclusion of large number of cases that enhanced the statistical power of the study, the prospective design of all included studies also minimized the risk of selection bias and information bias, both of which are a common concern in case-control studies in which exposure was determined after the diagnosis of diseases. One may question the validity of information about coffee consumption in case-control studies because cases may have differentially recalled their diet intakes, or have reduced their coffee consumption due to the precursor conditions of gastric cancer .There are also several limitations that should be pointed out. As is mentioned above, the first one is the concern of insufficient adjustment. The second concern is non-differential misclassification of exposure resulting from measurement error, which may have attenuated any true relation. Third, none of the individual studies considered differences in preparation methods, which may affect the concentration of different compounds in coffee . FinallyIn conclusion, findings from this meta-analysis of prospective studies suggest that coffee consumption is not associated with risk of gastric cancer. Future prospective studies carefully accounting for potential confounders for gastric cancer are warranted.


PSCA gene plays an important role in cell adhesion, proliferation and survival. Increasing studies have focused on the association of PSCA gene rs2294008 C>T and rs2976392 G>A with cancer risk. However, the conclusions were inconsistent. Therefore, we performed a meta-analysis to elucidate whether there is a true association, or artifact. We systematically searched eligible studies from MEDLINE, EMBASE and CBM database. Odds ratios and 95% confidence intervals were used to evaluate the strength of the association. The final analysis included 32 studies consisting of 30028 cases and 38765 controls for the rs2294008 C>T polymorphism, and 14 studies with 8190 cases and 7176 controls for the rs2976392 G>A polymorphism. Consequently, the PSCA rs2294008 C>T polymorphism was significantly associated with increased overall cancer risk. Further stratifications indicated the increased risk was more pronounced for gastric (diffused type and non-gastric cardia adenocarcinoma) and bladder cancer. A similar association was observed for the rs2976392 G>A polymorphism. This meta-analysis demonstrated that both of the PSCA rs2294008 C>T and rs2976392 G>A polymorphisms are associated with increased cancer risk, especially for gastric cancer and bladder cancer. Further large-scale studies with different ethnicities and subtypes of gastric cancer are required to confirm the results from this meta-analysis. Despite the significant improvements in the early detection and treatment, cancer still remains a major public health burden worldwide, with approximately 12.7 million new cases and 7.6 million new deaths in 2008 -5. Screeprostate stem cell antigen (PSCA) gene were found to be significantly associated with increased stomach cancer risk , genotyping methods, total numbers of cases and controls, and the genotype counts for the PSCA rs2294008 C>T and rs2976392 G>A polymorphism with cancer risk were measured by crude ORs and their corresponding 95% CIs for each study. The crude ORs and 95% CIs under the homozygous (TT vs. CC), heterozygous (CT vs. CC), recessive (TT vs. CT/CC), and dominant models (CT/TT vs. CC), as well as allele comparison model (T vs. C) were calculated for the rs2294008 C>T polymorphism, while homozygous model (AA vs. GG), heterozygous model (AG vs. GG), recessive model (AA vs. AG/GG), dominant model (AG/AA vs. GG), and allele comparison model (A vs. G) for the rs2976392 G>A polymorphism.Based on the genotype frequency distribution in cases and controls, the associations of P < 0.10, the random-effects model (DerSimonian–Laird method) [Goodness-of-fit chi-square test was conducted to check deviation from HWE among controls, and the deviation was significant at the 0.05 level. Between-study heterogeneity was assessed using chi-square-based Q statistical test. Generally, the fixed-effects model (Mantel–Haenszel method)  was adop method) , was cho method) . In sensP values were two-sided, and P < 0.05 was considered as statistically significant.The statistical analysis was performed by using STATA version 11.0 . All


BRCA2 gene plays an important role in homologous recombination. Polymorphic variants in this gene has been suggested to confer cancer susceptibility. Numerous studies have investigated association between BRCA2 N372H polymorphism and risk of several cancers, especially breast cancer. However, the results were inconsistent. We performed a comprehensive meta-analysis to provide a more precise assessment of the association between N372H and cancer risk, following the latest meta-analysis guidelines (PRISMA). Forty six studies involving 36299 cases and 48483 controls were included in our meta-analysis. The crude ORs and the 95% CIs were used to evaluate the strength of the association. The results indicated that the BRCA2 N372H variant was significantly associated with an increased risk of overall cancer . Moreover, stratified analyses by the cancer type and source of control observed significantly increased risk associated with BRCA2 N372H in subgroups with ovarian cancer, non-Hodgkin lymphoma and population-based controls, but not breast cancer or hospital-based controls. We also found such association among Africans. Overall, the meta-analysis suggested that BRCA2 N372H may be a cancer susceptibility polymorphism. Well-designed and large-scale studies are needed to substantiate the association between BRCA2 N372H polymorphism and cancer risk. Cancer remains one of the leading causes of death worldwide, with approximately 8.2 million cancer-related deaths in 2012 (GLOBOCAN 2012). It has long been recognized that the imbalance between DNA damage and repair plays pivotal role in carcinogenesis. As an example, environmental agents such as mutagenic chemicals and certain types of radiation may induce various DNA alterations, which, if not repaired properly, would cause genetic instability, gene mutations, and chromosomal alterationsBRCA2 gene is a well-known cancer susceptibility gene. Its protein product, comprised of 3418 amino acid residuals, has multiple cellular functions in repairing of DSBs by HR56BRCA2 is related to not only increased breast cancer risk, but also increased risk of the ovary, prostate, pancreas, and male breast, partially due to impaired capacity of repairing DNA DSBs as mentioned above. Accumulating studies have indicated that the polymorphic variants in BRCA2 gene may also confer genetic susceptibility to cancer because of the alteration in DNA repair capacity.There are a variety of DNA repair pathways in humans, with each responsible for repairing a certain type of DNA damage13BRCA2 gene, resulting in the single amino acid substitution of histidine  for asparagine BRCA2 N372H polymorphism may influence transcriptional activation function of BRCA2 protein.The N372H is the only common non-synonymous polymorphism in the BRCA2 N372H polymorphism and the risk of cancer, mainly breast cancer. Several studies reported that homozygous carriers of the H allele of BRCA2 N372H have an increased risk of breast cancer1213Over the past decade, many studies were conducted to evaluate the association between As shown in 121314151718192021222324252627293032333435363940BRCA2 N372H variant and overall cancer risk. The overall ORs and 95% CIs among all cancer types were as follows: [homozygous model: OR (95% CI) = 1.13 (1.03–1.23) (As indicated in 03–1.23) , dominan03–1.23) , but not03–1.23) .Q test and 2I statistic were used to assess the heterogeneity among the studies. There was no heterogeneity under the heterozygous model  in the overall analysis. In contrast, significant heterogeneity was observed under the homozygous , dominant  and recessive model . Then, we use meta-regression to determine the source of heterogeneity by cancer type, ethnicity and source of controls. As is shown in P = 0.017; recessive model: P = 0.001), but not cancer type , source of controls  and quality score .We performed leave-one-out sensitivity analysis by excluding a study at a time and recalculating ORs and 95% CIs. There was no substantial change found in the pooled ORs and 95% CIs during the overall analysis, suggesting the stability of our analysis.BRCA2 N372H and overall cancer risk under the heterozygous, dominant, or recessive model by using Egger's weighted regression test  (P = 0.032).Begg's funnel plot was used to check the existence of publication bias. There was no evidence of publication bias for the association between polymorphism of = 0.341) , whereasBRCA2 N372H polymorphism and cancer risk, 46 studies with a total of 36299 cases and 48483 controls were included. This great sample size provided adequate statistical power to detect potential association with cancer risk. Pooled analysis suggested a major role of the polymorphism in shaping over cancer risk. Specifically, BRCA2 N372H polymorphism was shown to confer 13%, 7%, and 13% increases in cancer risk under the homozygous, dominant and recessive models, respectively. Moreover, while stratified analyses were performed by cancer type, significant associations were observed for ovarian cancer, non-Hodgkin lymphoma and other cancers , but not for breast cancer. Moreover, stratified analyses by ethnic group and the source of control identified the association among Africans and mixed groups, as well as subgroup with PB controls. To the best of our knowledge, this is the first meta-analysis to evaluate the association between BRCA2 N372H polymorphism and overall cancer risk.In this comprehensive meta-analysis for the association between BRCA2 gene is located at chromsome13q13.1 and composed of 27 exons. The BRCA2 protein directly interacts with the RAD51 recombinase to regulate homologous recombinationBRCA2 gene, which may confer genetic cancer predisposition. It has been shown that BRCA2 modulates transcriptional activation of other genes by bonding to histone acetyltransferase P/CAFBRCA2 N372H, the non-conservative amino acid substitution-causing polymorphism may influence transcriptional activation function of BRCA2 protein. And a review of epidemiological literatures suggests that this polymorphism may be involved in carcinogenesisBRCA2 N372H and risk of breast cancer. A meta-analysis conducted in 2006 including 15627 cases and 15968 controls revealed no significant association under all the modelsBRCA2 N372H and breast cancer risk. However, this polymorphism was shown to significantly increase the risk of ovarian cancer and NHL in stratification analyses by cancer type. Four29303233343637The BRCA2 N372H polymorphism may be in close linkage with another nearby causal variant in one ethnic population but not in another. Moreover, clinical features  or lifestyle habits  may also explain the heterogeneity of ethnicity. More studies are needed to explore the heterogeneity in the future.Moreover, although subgroup analysis by ethnicity found association among Africans, the results should be considered with caution. Since there were only two studies included in the African group, the result may be unstable and false positive, although it was confirmed by meta-regression analysis. Stratification analyses also revealed the between-study heterogeneity observed in the overall analysis might be attributed to the differences among ethnic groups. Many factors may contribute to the strong heterogeneity among overall analysis. The ethnicity-dependent association may be attributed to the discrepancies in genotype distributions among controls of different ethnic groups. Cancer is complicated disease as a result of gene-environment interaction. Therefore different genetic backgrounds among different ethnicities help to explain the ethnicity-dependent results. For example, different populations usually have different linkage disequilibrium types. It is possible that Finally, several limitations in this meta-analysis should be taken into consideration. First, individual studies included in some subgroup analysis, like ovarian cancer and among Africans (<5 studies), may be insufficient. And this could diminish statistical power to detect the potential association. Second, because of lacking the original data from individual studies, our analysis was based on the risk estimates (ORs) without adjustment for other confounding factors. As a result, our findings might suffer from potential confounding bias. Therefore, if possible, future studies should take into account other potential confounding factors to improve the precision of risk estimates for this polymorphism and cancer risk. Third, publication bias also may be one of the concerns because studies with positive results were more prone to be published than those with negative results. The funnel plot and Egger's test suggested that potential publication bias may exist under the homozygous model. Trim-and-fill methods were employed to infer the existence of unpublished hidden studies and yield unbiased pooled estimates. The OR did not significantly change after the publication bias was adjusted (1.13 vs. 1.08). Overall, due to these limitations, the results of this meta-analysis should be interpreted with caution.BRCA2 N372H polymorphism and cancer risk revealed that this polymorphism was significantly associated with an increased risk of overall cancer, and the association was also observed for ovarian cancer. In addition, the significant association was observed in population-based studies while not in hospital-based studies. Finally, well-designed, large-scale studies will be needed to investigate these findings.In conclusion, this systematical meta-analysis regarding the association between The meta-analysis was conducted according to the latest meta-analysis guidelines (PRISMA), including literature search, data collection, inclusion, etc.BRCA2 or N372H”, “polymorphism or variation or variant” and “cancer or carcinoma or tumor” through the PubMed and EMBASE up to May 2014 for all relevant studies with no language restriction, according to the latest meta-analysis guidelines (PRISMA)A comprehensive literature retrieval was performed using the search terms as “BRCA2 and risk of cancer; (iii) provided sufficient detail of the genotype frequency or data for estimating odd ratios (ORs) and corresponding 95% confidence intervals (CIs); In addition, studies were excluded if significant departures from Hardy–Weinberg equilibrium (HWE) (HWEP < 0.05) in controls were observed, unless there were further evidence from other polymorphism of BRCA2 gene satisfy HWE. When studies had overlapping subjects with others, only the latest or the most complete study was included.The studies included in our meta-analysis should meet the following criteria: (i) only case-control study or cohort studies were taken into account; (ii) assessed the association between BRCA2 N372H genotypes or the OR and 95% CI under different genetic models, source of controls, genotype method and the P-value of HWE in controls. The subgroup analysis was performed by cancer type , ethnicity , the source of controls  and quality score The detailed information was extracted from all the eligible publications independently by two authors as the criteria described above. Conflicts were fully discussed by the two authors until consensuses were reached. The following information from the individual study was collected: name of the first author, year of publication, country of origin, ethnicity, numbers of cases and controls for the BRCA2 and cancer risk. For BRCA2 N372H, the pooled ORs were performed for the homozygous model (CC vs. AA), heterozygous model (CA vs. AA), dominant model (CA + CC vs. AA) and recessive model (CC vs. AA + CA), respectively. Z test was used to determine whether an association was statistically significant. Cochran Q-test and I2 statistic were used to assess and quantify the between-study heterogeneity . Fixed-effect model was used if there was no heterogeneity observed when P > 0.1 for Q-test; otherwise, a random-effect model was used. Leave-one-out sensitivity analysis was performed by sequentially excluding one single study at a time. Chi-square test was conducted to test if the study is departed from HWE. Additionally, the symmetry of the funnel plot was assessed by Egger's liner regression test to detect the potential publication bias, when at least 4 available dataset were included in subgroup analysis. A meta-regression analysis was performed to investigate the major sources of the heterogeneity across the studies in our meta-analysis.The crude ORs and the corresponding 95% CIs were used to evaluate the association between polymorphism of P values were two-side test and P < 0.05 was considered statistically significant.All statistical tests were performed by STATA version 11.0 , all the All authors contributed significantly to this work. W.X., Y.H., J.Z. and J.M. performed the research study and collected the data; W.X., Y.H. and J.Z. analyzed the data; W.J. and J.H. designed the research study; W.X., Y.H., J.Z., J.H. and W.J. wrote the paper, and W.X. and Y.H. prepared Figures 1–4, Tables 1–3 and Supplemental Table 1. All authors reviewed the manuscript. In addition, all authors approved the final draft.Dataset 1


No previous meta-analysis was to report the association between the apolipoprotein B (APOB) XbaI and EcoRI polymorphisms and serum lipids in Chinese. We performed the study to investigate their potentially association. Studies in English and Chinese were found via a systematic search of Pubmed, Embase, CNKI and Wanfang databases. The dominant genetic model and random-effects model were used to pool data from individual studies. As a result, a total of 30 articles with 5611 subjects for XbaI and 2653 subjects for EcoRI were included in the current study. For the XbaI polymorphism, overall, subjects carrying X+ allele were significantly associated with higher TC,TG and LDL compared with X-X- genotype  = -0.55 ; Pvalue = 0.0004, OR (95 %) = -0.30 ;  = -0.23, respectively). Similar results were observed in the subgroups of Han, healthy individuals (HT), coronary heart disease (CHD), cerebral infarction (CI), and cholelithiasis. For HDL, positive association between X+ allele with Lower lipid value was found in CHD and CI subgroups. For EcoRI polymorphism, overall, the E- allele carriers were found to be obviously linked with elevated LDL and lower HDL compared with E + E+ genotype  = -0.27 ; Pvalue = 0.01, OR (95 %) = 0.17 , respectively). TC was significantly high in subjects carrying E- allele in the subgroup of hyperlipidemia. No evidence of publication bias was observed.The two genetic variants of APOB may be associated with serum lipids in Chinese. Many epidemiological studies have reported that metabolic disorders in serum lipids are considerable risk factors for premature coronary artery disease and atherosclerosis . Serum lApolipoprotein B (APOB) is an important protein component in contribution to intermediate density lipoprotein, the formation of very low density lipoprotein, low density lipoprotein particle, and is related to the clearance of LDL in serum. Beside these, it mediates cellular uptake of cholesterol and is the ligand that binds to the LDL receptor . The genA meta-analysis by Boekholdt et al.  ten yearTo identify the studies evaluating the relationship between the APOB XbaI and EcoRI polymorphisms and lipid profile in Chinese, a computerized literature search of PubMed, EMBASE, Wanfang and CNKI databases was carried out, applying the following keywords: ‘apolipoprotein B or APOB’, ‘polymorphism’, ‘lipid’, ‘Chinese or China or Taiwanese or Taiwan’ . The articles in English and Chinese would be included. References of the relevant articles were also examined. If multiple articles used the same data, only the more detailed one was selected. The included studies should be accordance with the later criteria: (i) studies evaluating the association of the APOB XbaI and EcoRI polymorphisms with lipids in Chinese, (ii) At least one of the lipid phenotypes was measured: total cholesterol (TC), triglyceride (TG), low density lipoprotein(LDL), and high density lipoprotein(HDL), (iii) Sufficient data involving genotype frequency as well as mean and standard deviation (SD) of lipids, (iv) If the article was a retrospective case-control study, each population (case/control groups) was treated as a single study and genotype frequency among control populations must be tested for Hardy-Weinberg equilibrium (HWE). If the genotype frequency was not supplied or calculated, the writers of these papers would be contacted by emails.Two of the authors extracted the information from each study independently. Inconsistencies were discussed between the authors to reach an agreement. For each study, the following information would be collected: first author, year, ethnicity, resident region, detection method, sample size, character of participants, and lipid phenotypes of each study.2-based Q-statistic test and considered significant for P < 0.10 [http://ihg.gsf.de/cgi-bin/hw/hwal.pl). All data were analyzed with Review Manager 5.0  and STATA 12.0 . All P values reported were two-sided, and a significance level of less than 0.05 was considered statistically significant.In our study, standardized mean difference (SMD) with their 95 % CIs were used to measure the strength of the association of the APOB XbaI and EcoRI polymorphisms with lipids. For the two polymorphisms, we tested the dominant genetic model , because the low frequency of homozygosity for the mutant alleles would yield a large number of studies with zero cell counts, leading to the unreliable estimates, and the X + X-/X + X+ and E + E-/E-E- genotypes in most studies were combined into one group. The random-effects model was used to assess the pooled estimates and the significance of the pooled estimates was determined using a Z-test. Heterogeneity among studies was assessed by the XP < 0.10 . SubsequP < 0.10 , 8 we reAs a beginning analysis, 77 relevant articles were found after literature search and selection. Among these selected studies, 43 articles were removed because their data were overlapping or duplicated. One paper  was deleIn our study, based on the available genotype and allele frequency, we observed that, the X+ allele frequency of XbaI was 7.0 % in the whole population, and the E- allele frequency of EcoRI was 8.0 %, which both obviously had a lower frequency of the mutant allele than the Caucasian population.Pvalue = 0.0006, OR (95 %) = −0.55 ). Similar findings were seen in the subgroups of Han  = −0.59 ), CI  = −0.85 ) and cholelithiasis  = −0.54 ). However, no positive association was obtained in the subgroups of non-Han minorities, HT, CHD, and hyperlipidemia. For the TG analysis, 5425 subjects (37 studies) were collected. In the whole population, X+ allele carriers were found to be obviously associated with higher TG value compared with X-X- genotype  = −0.30 ). Similar results were observed in the subgroups of Han  = -0.32 ), HT  = −0.31 ) and CHD  = −0.53 ). There was no evidence of correlation in the subgroup of non-Han minorities, CI, cholelithiasis and hyperlipidemia.The results of the relationship between the APOB XbaI ploymorphism and lipids in Chinese were shown in Table Pvalue = 0.05, OR (95 %) = −0.23 , Fig. Pvalue = 0.02, OR (95 %) = −0.26 ) and cholelithiasis  =−0.4 ). No statistically significant differences were found in the subgroups of Han, HT, CHD, CI and hyperlipidemia. Finally for HDL, 5337 subjects (36 studies) were analyzed. No significant association was observed in the overall and in the subgroups of Han, HT, hyperlipidemia and cholelithiasis. In the non-Han minorities, CHD and CI subgroups, subjects carrying X+ allele were associated with lower HDL value than X-X-  = 0.24 ; Pvalue = 0.01, OR (95 %) = 0.50  = 0.43 , respectively ).For LDL, 5611 subjects (38 studies) were collected. Overall, a marginally positive association between X+ allele with higher lipid value was found  = −0.56 ). There was no difference in the whole population and in the subgroups of Han, HT and CHD. For TG, 2653 subjects (21studies) were assessed. We found no significant association between the EcoRI ploymorphism and TG in overall and even in the subgroup analysis. For LDL, 2653 subjects (21 studies) were found. Overall, subjects carrying the E- allele were found to be obviously linked with higher LDL compared with E + E+ genotype  = −0.27 , Fig. Pvalue = 0.04, OR (95 %) = −0.28 ). In the subgroups of HT, CHD and hyperlipidemia, no significant association was found. For the HDL analysis, 2653 subjects (21studies) were included. Overall, HDL was significantly low in subjects carrying the E- allele compared with E + E+ genotype  = 0.17 ). However, in all the subgroups, there was no significant association.The results of the relationship between the APOB EcoRI ploymorphism and lipids in Chinese were shown in Table In the sensitivity analysis, we deleted one study at a time and found whether there was a individual study affecting the pooled SMD and the between-study heterogeneity. For the XbaI polymorphism, the removal of any single study did not obviously affect the heterogeneity and it still exist. However, the overall pooled SMD of LDL was apparently changed with the elimination in turn of eight studies  can not be well done. Thirdly, the analysis did not focus on the detailed functional research of the studied two polymorphisms. Finally, beside genetic influence, the relationship between APOB single nucleotide polymorphisms and lipid profile was also affected by many environmental factors that didn’t be fully conducted in this study, which possibly confounded the results.In conclusion, our meta-analysis showed significant association between the APOB XbaI polymorphism and lipids  in Chinese. Similar conclusions were observed in the subgroups of Han, HT, CHD, CI and cholelithiasis. For the AOPB EcoRI polymorphism, the E- allele carriers may be a genetic factor for higher LDL and lower HDL levels in Chinese. Additional studies with larger sample size should be conducted in Chinese to make clear the association of APOB SNPs with lipids. Studies investigating their detailed function were equally needed.


TP53 Arg72Pro polymorphism (rs1042522) and the risk of leukemia remains controversial. Consequently, we performed a meta-analysis to accurately evaluate the association between TP53 Arg72Pro polymorphism and leukemia risk. A comprehensive search was conducted to find all eligible studies of TP53 Arg72Pro polymorphism and leukemia risk. Fourteen case-control studies, with 2,506 cases and 4,386 controls, were selected for analysis. The overall data failed to indicate a significant association between TP53 Arg72Pro polymorphism and the risk of leukemia . In a subgroup analysis of clinical types, an increased risk was observed in the acute lymphocytic leukemia (ALL) subgroup  but not in the acute myeloid leukemia (AML) subgroup. In the subgroup analysis, no significant associations with ethnicity and the source of the controls were observed. In conclusion, the results suggest that there is no association between TP53 Arg72Pro polymorphism and the risk of leukemia, but the CC genotype may increase the risk of ALL TP53 Arg72Pro polymorphism CC genotype may increase the risk of ALL but is not associated with AML. Further large-scale, well-designed studies are needed to confirm our results.The relationship between the  Leukemia is a malignant tumor of the hematopoietic systems. It has a poor prognosis due to a range of complicated features3The TP53 tumor suppressor gene, which is located on chromosome 17p13, plays a pivotal role in the maintenance of genomic stability through encoding of the TP53 protein. The TP53 protein functions by regulating cell cycle arrest, DNA repair, apoptosis, and gene transcription to mediate cellular responses to DNA damage6TP53 Arg72Pro polymorphism and predisposition to leukemia, but the impact of TP53 Arg72Pro polymorphism on leukemia was still conflicting due to inconsistent findings in individual studies. It was necessary to quantitatively summarize the evidence using the gradually accumulated data. Therefore, the current meta-analysis of the 14 most recent and relevant case-control studies involving 2,506 cases and 4,386 controls was performed to provide a more precise estimate of the associations.To date, numerous studies have investigated the relationship between the TP53 Arg72Pro polymorphism with leukemia were included in the meta-analysis101112131415161718192021TP53 Arg72Pro polymorphism are summarized in A total of 14 case-control studies that examined the association of TP53 Arg72Pro polymorphism and the risk of leukemia   (.57) see . Likewis= 0.025) . When stTP53 Arg72Pro polymorphism, and the corresponding pooled ORs were not materially changed , and the risk of other types of leukemia (n = 4), and the results were consistent with ours. Thus, our study confirms the association between TP53 Arg72Pro polymorphism and the risk of leukemia found in previous analysis. However, further studies with larger patient cohorts are needed to clarify this association.However, previous a meta-analysis has reported that TP53 Arg72Pro polymorphism has been implicated in implantation failureet al. reported no association was observed between TP53 Arg72Pro polymorphism and pregnancy loss risk, but the interaction of the TP53 Arg/Arg (rs1042522) and MDM2 TT (rs2279744) genotypes was shown to increase the risk to pregnancy lossTP53 Arg72Pro polymorphism may be a modifier of risk for childhood ALL susceptibility and might interact with MDM2. The Arg72 variant is more efficient than the Pro72 variant at inducing apoptosis. The greater apoptotic potential of the Arg72 protein is caused by greater interaction of this protein with MDM2, which facilitates the nuclear export, and probably also the subsequent mitochondrial localization31TP53 Arg72Pro polymorphism is associated with an increased risk of developing ALL. To the best of our knowledge, this meta-analysis is the first to investigate the effect of TP53 Arg72Pro polymorphism on ALL. Furthermore, due to a limited number of available published studies, further studies with larger sample sizes are needed to reach a more convincing conclusion.ALL is more common in children, who comprise over 80% of all acute leukemia cases. Childhood ALL shows a consistent association with miscarriagesTP53 Arg72Pro polymorphism might influence susceptibility to leukemia with other factors, but we did not conduct relative research, such as the gene-gene and gene-environment interactions, because the data were insufficient. Third, we could not perform further subgroup stratification analysis by ages because of the limited number of published studies. Finally, publication bias is possible because no attempts were made to identify unpublished studies, although the results of our Begg’s funnel plot and Egger’s test revealed no evidence of publication bias in the allele model.In interpreting our results of this meta-analysis, some limitations must be addressed. First, our meta-analysis was based on unadjusted estimates. However, a more precise analysis might be conducted if individual data were available, such an analysis would have allowed us to adjust for other covariates, such as age, family history and environmental factors. Second, the TP53 Arg72Pro polymorphism and the risk of leukemia in the overall studies, without the influence of ethnic diversity. However, a statistically significant association was found there was a stronger power trend towards a risk between the TP53 Arg72Pro polymorphism and ALL. Further studies with larger sample sizes and well-designed studies are required to investigate the associations between TP53 Arg72Pro polymorphism and leukemia.In conclusion, this meta-analysis did not find any evidence of an association between A comprehensive literature search of studies published through December 2014 was performed using the PubMed, EMBASE, Web of Knowledge and the Chinese National Knowledge Infrastructure (CNKI) databases. Various combinations of the terms “TP53 or P53”, “polymorphism or variant”, and “leukemia or leucocythemia” were used to screen for potentially relevant studies. The search was conducted without language restrictions. Additional articles were located manually through the references of the related reports.TP53 Arg72Pro polymorphism and the risk of leukemia, b) case-control or cohort studies, c) studies with a control genotype distribution in HWE, and d) studies with sufficient genotype data for calculating the odds ratio (OR) with 95% confidence intervals (95% CIs). If studies included overlapping subjects, only the study with a larger sample size was selected. Studies were excluded if one of the following existed: a) not a case-control study, b) no sufficient data were reported, and c) case reports or reviews.The following inclusion criteria were applied: a) studies evaluating the association between P-value for Hardy-Weinberg equilibrium (HWE), and genotyping methods. The study design was categorized as a hospital-based study  or a population-based study .Two investigators (Dai and Sun) independently collected the data from each article using a standardized protocol. Disagreement was resolved by discussion with the other co-authors. The following information from the eligible studies was extracted: the first author’s surname, publication year, country of origin, ethnicity, source of control, sample sizes of cases and controls, number of genotypes, The quality of the studies was independently assessed by the two reviewers  according to the scale for quality assessment see . These sP values were two-sided. The Hardy-Weinberg equilibrium of controls for each study was tested using the χ2 test (significant at the 0.05 level). An OR with the corresponding 95% CI was used to assess the strength of the association between the TP53 Arg72Pro polymorphism and leukemia susceptibility according to allelic contrast (C vs. G), homozygote comparisons (CC vs. GG), dominant models (CC + GC vs. GG) and recessive models (CC vs. GC + GG). The significance of the summary OR was determined with a Z-test, and a p value of less than 0.05 was considered to be statistically significant. Between-study heterogeneity was assessed by calculating the Q-statistic and then quantified using the I2 value. When the effects were assumed to be heterogeneous , the random-effects model was used; otherwise, the fixed-effects model was more appropriate3335All statistical analyses were performed using Stata software version 12.0 , and all How to cite this article: Tian, X. et al. Association between TP53 Arg72Pro polymorphism and leukemia risk: a meta-analysis of 14 case-control studies. Sci. Rep.6, 24097; doi: 10.1038/srep24097 (2016).


Controversial results of the association between coffee consumption and bladder cancer (BC) risk were reported among epidemiological studies. Therefore, we conducted this meta-analysis to clarify the association. Relevant studies were identified according to the inclusion criteria. Totally, 34 case-control studies and 6 cohort studies were included in our meta-analysis. The overall odds ratio (OR) with 95% confidence interval (CI) between coffee consumption and BC risk was 1.33 (95% CI 1.19 to 1.48). The summary ORs of BC for an increase of 1 cup of coffee per day were 1.05 (95% CI 1.03 to 1.06) for case-control studies and 1.03 (95% CI 0.99 to 1.06) for cohort studies. The overall ORs for male coffee drinkers, female coffee drinkers and coffee drinkers of both gender were 1.31 (95% CI: 1.08 to 1.59), 1.30 (95% CI: 0.87 to 1.96) and 1.35 (95% CI: 1.20 to 1.51). Compared with smokers , non-smokers had a higher risk  for BC. Results of this meta-analysis suggested that there was an increased risk between coffee consumption and BC. Male coffee drinkers and non-smoking coffee drinkers were more likely to develop BC. Bladder cancer is the most common cancer of the urinary tract and the ninth most common cancer among men, accounting for approximately 330,000 new cases and 130,000 deaths per year worldwideCoffee is a popular drink worldwide, especially among western countries, which also possess high incidence of BC157811121314In order to clarify the association between coffee consumption and the risk of BC and provide theoretical basis for the prevention of BC, we conducted a meta-analysis of all published case-control and cohort studies.The study identification and selection progression was summarized in 10111213141517181920212223242526272829303132333436373839P = 0.008 for heterogeneity, I2 = 38.4%). For case-control studies, the combined OR was 1.37 (95% CI 1.22 to 1.53), with a moderate heterogeneity of P = 0.017 and I2 = 37.1%. For cohort studies, the combined OR was 1.10 (95% CI 0.78 to 1.54), with a moderate heterogeneity of P = 0.112 and I2 = 44.0%.The results from the random-effect model combining the ORs for the risk of BC in relation to coffee consumption had been shown in P = 0.073 for nonlinearity). Thus, linear model had been applied among case-control studies. The summary relative risk of bladder cancer for an increase of one cup of coffee per day was 1.05 . As for cohort studies, a linear association was confirmed (P = 0.433 for nonlinearity). The summary relative risk of bladder cancer for an increase of one cup of coffee per day was 1.03 .Studies101112P value for test of 0.603. When stratified by gender, the studies on male and both gender had shown a significantly increased association . However, the association among female group was lack of statistical significance , with the P value of 0.204. According to geographical region, positive relations were detected in Europe  and America , but non-association was noted in Asia . Moreover, in order to avoid residual confounding variables by smoking, we also conducted the subgroup analyses of whether the pooled ORs were adjusted for smoking or not and extracted 18 independent reports from the included 40 studies to evaluate the difference of the studied association between non-smokers and smokers. The results had shown that there was a greater increased risk among the smoking non-adjusted group  than the smoking adjusted group . Interestingly, we found a moderate increased risk in the non-smokers group , but no significance in the smokers group . Besides, high coffee consumption was found to be associated with BC risk among the subgroups of publication year (≤2000 or >2000) and adjustments (≥3 or <3). In order to further explore the potential association between different aspects of coffee consumption and the risk of BC, subgroup analyses of type of coffee and coffee drinking status had been conducted. The pooled OR for regular coffee group was 1.39 (95% CI 0.85 to 2.27), while the combined OR for decaffeinated group was 1.29 (95% CI 0.88 to 1.89). When stratified by coffee drinking status, significantly increased associations were found in both groups of ex-coffee drinker  and current coffee drinker .Results of subgroup analyses had been shown in Sensitivity analyses were performed to evaluate the sensitivity of our conclusions about the overall effect of coffee consumption on the risk of BC. Firstly, the results of fixed-effect model, random-effect model and quality-effect model  were comP = 0.051; Begg, P = 0.139). Thus, no publication bias was observed in this study.Visual inspection of the funnel plot showed little asymmetry . The EggDrinking coffee can both facilitate and inhibit the occurrence and the development of BC in several mechanisms2122789Potential bias is the major challenge for the meta-analysis of observational studiesIn most cases, coffee drinkers tended to smoke, lack enough exercises and possess high body mass index (BMI), which had been reported to be the potential risk factors of the BC4546In particular, the interaction between coffee and smoking had been studied with more details within the present meta-analysis. Study between smokers and non-smokers had revealed that the risk of the BC among non-smokers  was higher than smokers . The observed outcome could be partly explained by coffee-induced BC mechanisms researches. It was reported that caffeine was the substrate of cytochrome P450 (CYP) enzymes in the liver, such as CYP1A2 or NAT2, and these enzymes might increase the metabolic activation of carcinogens like polycyclic aromatic hydrocarbons in cigarette smokingBladder cancer is a complex disease resulting from interactions between genetic factors and environment37There were several limitations in the present meta-analysis. First, we did not search for unpublished studies or original data, thus publication bias might be inevitable, even though no significant evidence of publication bias was observed. Second, categories of coffee consumption varied from studies, which might be responsible for the heterogeneity among studies in this analysis. Third, owing to the small number of Asian studies, the selection bias was unavoidable and the association among different countries remained unclear. Besides, due to the lack of relevant studies, important aspects of coffee drinking, including duration of coffee consumption, type of coffee and the status of coffee drinking, had not been studied enough. Furthermore, major risk factors including high risk occupations, disinfection byproducts, arsenic in the drinking water and genotype for the major metabolic enzymes were hard to be avoided.In summary, the present meta-analysis, consisting of 34 case-control studies and 6 cohort studies, had suggested a significantly increased risk between coffee consumption and the risk of BC. Subgroup analyses indicated that male drinkers and non-smokers with high coffee consumption were more likely to develop BC. However, caution is needed in interpreting the findings from our meta-analysis because of the inevitable heterogeneity. Further well-designed large-scaled studies are warranted to provide more definitive conclusions.In this paper, we conducted a literature search of PubMed (Medline), Embase, Web of Science and Cochrane Library from January 1966 through August 2014 for observational studies examining the association between coffee consumption and risk of BC. Search terms including “coffee”, “caffeine”, “drink”, “beverage” or “fluid” combined with “bladder cancer”, “bladder tumor”, “bladder neoplasm” or “bladder carcinoma” had been applied in the database search. Besides, reference lists from retrieved articles were also reviewed. Only articles published in English were considered. We followed the standard criteria for conducting meta-analyses of observational studies and reporting the resultsStudies meeting the following criteria were included in the meta-analysis: (1) the study design was observational, (2) the exposure of interest was coffee consumption, (3) the outcome of interest was bladder cancer, (4) the study reported adjusted risk estimates (relative risks or hazard risks or odds risks) with their 95% CI for the association between coffee consumption and BC or provided sufficient information to allow their calculations, (5) the study provided the frequency of every category of coffee consumption. Additionally, we excluded reviews, editorials, non-human studies, and letters without sufficient data. When multiple reports based on the same study were published, only the most recent or complete report would be used.Eligibility evaluation and data extraction were carried out independently by two reviewers (W.W. and Y.T.) according to the guidelines for meta-analysisTwo reviewers (W.W. and Y.T.) independently performed the quality assessment using the Newcastle-Ottawa ScaleThe statistical analyses for the overall association between coffee consumption and BC risk were based on comparisons of the highest intake category of coffee consumption with the reference. In most cases, the reference refer to the lowest consumption of coffee, including the non-drinkers. Among the 30 identified studies, 10 studies101113152226282931The median or mean coffee consumption in each category was used as the corresponding dose of consumption. Different measurements of coffee consumption in the original studies were converted into approximate cups/day. We defined 240 ml or 8 oz of coffee equal to one cup. When the median or mean consumption per category was not reported in the article, we assigned the midpoint of the upper and lower boundaries in each category as the average consumption. If the highest category was open-ended, we set the midpoint of the category at 1.5 times the lower boundary. When the lowest category was open-ended, the lower boundary was set to zero.P value for nonlinearity would be calculated by testing the null hypothesis that the coefficient of the second spline was equal to zeroIn the dose-response analysis, the number of cases and the total number of objects were used as covariates among case-control studies, while the number of cases and person-years were applied among cohort studies. Thus, analyses had been conducted for case-control studies and cohort studies, respectively. We performed the dose–response analysis to examine a potential nonlinear relationship. This was done by modeling coffee consumption using restricted cubic splines with 3 knots at fixed percentiles 10%, 50%, and 95% of the distribution. A 2 statisticP ≤ 0.10. For the I2 metric, low, moderate, and high I2 values were considered to be 25%, 50%, and 75%, respectivelyThe heterogeneity among studies was estimated by the Cochran Q test and IP < 0.05 was considered to be representative of a significant statistical publication bias. Forest plots were applied to assess the overall association between coffee consumption and BC.To explore the potential heterogeneity among studies, subgroup analyses were conducted according to study design, gender, geographical region, publication year, adjustments. Besides, subgroup analyses of type of coffee and coffee drinking status had been conducted to further explore the potential association between different aspects of coffee consumption and the risk of BC. Sensitivity analyses were employed to find potential origins of heterogeneity and to examine the influence of various exclusions on the combined OR. Publication bias was assessed through the visual inspection of funnel plots and with tests of Begg rank correlationP values) were two-sided, with P < 0.05 considered statistically significant.In addition to quality-effect modeling (conducted with MetaXL version 2.2 software), all statistical analyses were performed with STATA version 12.0 software . All reported probabilities (All authors contributed significantly to this work. W.W., Y.T. and Q.L. designed the research study; W.W., Y.T., Q.Z., G.Y. and X.W. performed the research study and collected the data; W.W., Y.T. and Q.Z. analyzed the data; W.W., Y.T., Q.L. wrote the paper; Q.Z., G.Y. and X.W. prepared Figures 1–6, Figure S1–S2 and Supplemental Table S1–S4. All authors reviewed the manuscript. In addition, all authors approved the final draft.Supplementary Information


XPC Lys939Gln polymorphism and colorectal cancer (CRC) risk reported inconclusive results. We performed a meta-analysis to derive a precise estimation of the relationship.Published studies investigating the association between XPC Lys939Gln polymorphism and CRC risk was assessed by odds ratios (ORs) together with their 95% confidence intervals (CIs).A comprehensive literature search was done in databases PubMed, EMBASE, and Cochrane library up to December 2013. The association between XPC Lys939Gln polymorphism was correlated with an increased CRC risk when all studies were pooled into the meta-analysis . In stratified analyses by ethnicity, smoking, and study quality, significant increased CRC risk was found in Asians , nonsmokers , and high quality studies. In subgroup analysis by source of control, significant increased CRC risk was found in both hospital-based studies and population-based studies. However, in subgroup analysis according to cancer location, no any significant association was detected.Eight studies with 3,301 cases and 4,177 controls were included in the meta-analysis. We observed that the XPC is a candidate gene for CRC susceptibility. The XPC Lys939Gln polymorphism may play an important role in CRC development among Asians and nonsmokers. Further large and well-designed studies are needed to confirm this association.This meta-analysis suggests that the http://www.diagnosticpathology.diagnomx.eu/vs/1665902729125948The virtual slide(s) for this article can be found here:  Colorectal cancer (CRC) is one of the most common cancers and is the third leading cause of cancer-related death worldwide ,2. In EuXPC gene is located at chromosome 3p25 and contains 16 exons and 15 introns. There are at least 687 reported single nucleotide polymorphisms (SNPs) in the XPC gene region (http://www.ncbi.nlm.nih.gov/snp/). Among all the identified SNPs, Lys939Gln polymorphism has received much attention in recent years. It is a substitution of lysine for glutamine in exon 15 of the XPC gene [The xeroderma pigmentosum complementation group C (XPC) is one of the key members in the nucleotide excision repair (NER) pathway . The NERXPC gene , and theXPC gene -16.XPC Lys939Gln polymorphism and CRC risk, but the results remain controversial and inconclusive. For genetic association studies that check candidate polymorphisms, sample size is an important influencing factor for study accuracy. Small sample size might have insufficient power to explore a true association of modest effect [Over the last two decades, several molecular epidemiological studies have evaluated the association between t effect , especiat effect . CombiniXPC Lys939Gln polymorphism and CRC risk using the following combined keywords: ‘xeroderma pigmentosum group C’, ‘XPC’, ‘colon cancer’, ‘rectal cancer’ and ‘colorectal cancer’. The latest search was done in December 2013, without any language restriction. Additional articles were identified through the references cited in the first series of articles selected. Articles included in the meta-analysis were in any language, with human subjects, published in the primary literature and had no obvious overlap of subjects with other studies. Among overlapping reports, only the studies with more information on origin of cases/controls were retained. The study was performed according to the proposal of Meta-analysis of Observational Studies in Epidemiology group (MOOSE) [We searched Pubmed, Embase and Cochrane library databases for all articles on the association between  (MOOSE) .XPC Lys939Gln polymorphism and CRC risk; (ii) sufficient genotype data were presented to calculate the odds ratios (ORs) and 95% confidence intervals (95% CIs); (iii) control population did not contain malignant tumor patients. Major reasons for exclusion of studies were (i) review, or meta-analysis, or letter, or comment; (ii) duplicated studies, or studies without raw data we need; and (iii) studies that focused on HNPCC or FAP. Family–based studies of pedigrees with several affected cases per family were also excluded, because their analysis is based on linkage considerations.The following inclusion criteria were used for literature selection: (i) Case–control or cohort studies which evaluated the association between Two authors (Qiliu Peng and Xianjun Lao) independently reviewed and extracted data from all eligible studies. Data extracted included the first author, year of publication, country of origin, ethnicity, genotyping method, matching criteria, source of control, CRC ascertainment, total numbers of cases and controls and genotype frequencies of cases and controls. Ethnic backgrounds were categorized as Caucasian, and Asian. Smoking status (smoker or nonsmoker) was additionally recorded for stratified analysis. Smokers included current smokers and former smokers. Nonsmokers had never smoked. Cancer location was divided into colon cancer and rectum cancer and was also additionally recorded for the stratified analysis. To ensure the accuracy of the extracted information, the two authors checked the data extraction results and reached consensus on all of the data extracted. If different results were generated, they would check the data again and have a discussion to come to an agreement. A third reviewer (Weizhong Tang) was invited to the discussion if disagreement still existed.The quality of eligible studies was evaluated independently by two authors (Qiliu Peng and Xue Qin) according to a set of predefined criteria Table  based onXPC Lys939Gln polymorphism and CRC risk. We evaluated the XPC Lys939Gln polymorphism and CRC risk using co-dominants (Gln/Gln vs. Lys/Lys and Gln/lys vs. Lys/Lys), recessive model (Gln/Gln vs. Gln/lys + Lys/Lys), and dominant model (Gln/Gln + Gln/lys vs. Lys/Lys). The Chi-square-based Q statistic test [PQ < 0.10, the pooled ORs were analyzed using the random-effects model [P values were two-sided. To ensure the reliability and the accuracy of the results, two authors entered the data into the statistical software programs independently with the same results.Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association between the tic test ,22 was uts model . Otherwits model  was selets model . If publts model . The disXPC Lys939Gln polymorphism and CRC susceptibility were identified. Two of these articles were excluded because they did not present sufficient data for calculating OR and 95% CI [XPC Lys939Gln polymorphism genotype distributions according to smoking status (smokers and nonsmokers). The cases were histologically or pathologically confirmed as CRC in five studies [Based on the search criteria, ten studies investigating the d 95% CI ,28. Manud 95% CI -36 . In subgroup analysis by ethnicity, significant increased CRC risk was found in Asian populations , but not in low quality studies. In subgroup analysis by smoking status, significant increased CRC risk was observed in nonsmokers , but not in smokers. In subgroup analysis according to source of control, significant increased CRC risk was found in both hospital-based studies  and population-based studies . However, in subgroup analysis according to cancer location, statistical significant association was not detected in both colon cancer patients and rectum cancer subjects.As shown in Table PQ < 0.10. There was no statistical significant heterogeneity among studies when all eligible studies were pooled into the meta-analysis. In subgroup analyses according to ethnicity, source of control, cancer location, smoking, and study quality, statistical significant heterogeneity was not observed in all subgroups (Table Heterogeneity between studies was estimated using the Chi-square-based Q test and the significance of which was set at ps Table .Sensitivity analysis was performed by sequential omission of individual studies. For analyses of pooling more than three individual studies, the significance of the pooled ORs was not influenced excessively by omitting any single study Figure , indicatBegg’s funnel plot and Egger’s test were performed to assess the publication bias of literatures in all comparison models. The shape of the funnel plot did not reveal any evidence of obvious asymmetry Figure . Then, tXPC gene may alter DNA repair capacity of the NER pathway, which further play a critical role in carcinogenesis [XPC Lys939Gln polymorphism and CRC risk, but the results remain inconclusive. Meta-analysis has been recognized as an important tool to more precisely define the effect of selected genetic polymorphisms on the risk for disease and to identify potential important sources of between-study heterogeneity [XPC Lys939Gln polymorphism contributes to increased CRC susceptibility.Maintenance of genomic integrity by DNA repair genes is an essential component of normal cell homeostasis necessary to cell growth, differentiation, and apoptosis ,38. Incrogenesis . To dateogeneity . To deriXPC Lys939Gln polymorphism and CRC risk is likely to be caused by chance because study with small sample sizes may have insufficient statistical power to detect a slight effect or may have generated a fluctuated risk estimate. Currently there were only four studies on XPC Lys939Gln polymorphism and CRC risk for Asian populations, and Caucasian populations, respectively. Therefore, the observed results of our study should be interpreted with caution.In subgroup analysis by ethnicity, statistical significant increased CRC risk was detected in Asians. However, no significant association was found in Caucasians. Actually, it might not be uncommon for the same polymorphism playing different roles in cancer susceptibility among different ethnic populations, because cancer is a complicated multi-genetic disease, and different genetic backgrounds may contribute to the discrepancy. Nevertheless, owing to the limited number of relevant studies included in the meta-analysis, the observed association between When stratified according to the quality score of the articles, statistical significant increased CRC risk was observed in high quality studies but not in low quality studies. The possible reason for the discrepancy may be that the existence of selection bias and recall bias in the low quality studies. In addition, genotyping methods without quality control in studies of low quality should be also considered when deciphering these inconsistent results. In subgroup analysis according to the source of control, statistical significant increased CRC risk was found in both population-based studies and hospital-based studies. However, the ORs and 95% CIs differ largely in these two subgroups. The reason may be that the hospital-based studies have a high risk of producing unreliable results because hospital-based controls may not always be truly representative of the general population. Therefore, a methodologically preferable design, such as using a proper and representative population-based high quality study, is of great value in case–control studies.XPC variant genotype may possess deficient DNA repair capability. Accordingly, the XPC protein product may be less efficient in repairing the DNA lesions induced by tobacco smoke, and thereby could enhance the susceptibility, favoring the development of CRC. Therefore, we carried out subgroup analysis according to smoking status. Our results showed an increased CRC risk in nonsmokers but not in smokers, which was inconsistent with the hypothesis above. The results should be interpreted with caution because of the limited numbers of the original studies. Therefore, further studies concerning stratification for smoking are needed to increase power for the association estimation.It is well established that the carcinogenesis of CRC is a result of the interaction between environmental factors and genetic background ,44. BesiSome possible limitations in this meta-analysis should be acknowledged. First, in subgroup analysis by ethnicity, the included studies regarded only Asians and Caucasians. Data concerning other ethnicities such as Africans were not found. Thus, additional studies are warranted to evaluate the effect of this functional polymorphism on CRC risk in different ethnicities, especially in Africans. Second, our results were based on unadjusted estimates. We did not perform the analysis adjusted for other covariates such as age, drinking status, environment factors, and so on, because of the unavailable original data of the eligible studies. Third, in subgroup analyses by ethnicity, cancer location, and smoking status, the sample size of the subgroups was relatively small for stratified analyses, which may lead to relatively weak power to detect the real relationship.XPC is a candidate gene for CRC susceptibility. The XPC Lys939Gln polymorphism may play an important role in CRC development especially among Asians and nonsmokers. In order to further verify our findings, large well designed epidemiological studies are warranted.Our meta-analysis provided a more precise estimation based on larger sample size compared with the individual studies. Our study suggested that the CRC: Colorectal cancer; HWE: Hardy–Weinberg equilibrium; NER: Nucleotide excision repair; XPC: Xeroderma pigmentosum complementation group C; SNP: Single nucleotide polymorphism; OR: Odds ratio; CI: Confidence interval.All authors declare that they have no competing interest in relation to this study.QP, XQ performed the literature search, data extraction, statistical analysis and drafted the manuscript. QP, XL, WT, ZC, and RL participated in data extraction. QP, XQ, ZC, SL supervised the literature search, data extraction, statistical analysis and drafted the manuscript. All authors read and approved the final manuscript.Flow diagram of included studies for this meta-analysis.Click here for file


Many epidemiological studies have suggested an association between estrogen receptor-beta (ER-β) polymorphisms with endometriosis risk. However, the results of these studies have been inconsistent. In the present study, we performed a meta-analysis to clarify the associations between the ER-β rs4986938 and rs1256049 polymorphisms and endometriosis risk.Eligible publications were retrieved from the PubMed, ISI Web of Science, and several Chinese language databases. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using a random or fixed effect model.A total of eight studies (1100 cases/1485 controls) for the rs4986938 polymorphism and four studies (353 cases/450 controls) for the rs1256049 polymorphism were included in this meta-analysis. Regarding the rs4986938 polymorphism, no obvious associations were found for all genetic models when all studies were pooled into the meta-analysis. In the subgroup analyses by ethnicity, study sample size, endometriosis-associated infertility, and stage of endometriosis, a significantly increased risk was observed among mixed populations  and among cases with endometriosis-associated infertility . Regarding the rs1256049 polymorphism, no obvious associations were found for all genetic models in the overall population. Subgroup analyses by ethnicity and study sample size revealed that only one study of a mixed population with small sample size showed an increased risk of endometriosis. No publication bias was found in the present study.The results of this meta-analysis suggest that the ER-β rs4986938 and rs1256049 polymorphisms may not be associated with endometriosis risk, while the observed increased risk of endometriosis-associated infertility may be due to bias by the inclusion of small-scale studies.http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_184The virtual slide(s) for this article can be found here:  Endometriosis is a steroid-dependent condition defined by the presence of endometrial tissue outside of the uterine cavity resulting in diverse clinical manifestations, such as infertility, pelvic pain, and dysmenorrhea . EndometAluI, whereas the latter results in a G-A exchange at nucleotide 1082 in exon 5 and creates a recognition site for RsaI. In recent years, many meta-analyses have reported associations of these two SNPs in the ER-β gene with several diseases, including prostate cancer [Estrogen has been shown to play a critical role in the growth of endometriotic tissues . By binde cancer , Parkinse cancer , osteoare cancer , and bree cancer .To date, a great number of case–control studies have been conducted to investigate the associations between the ER-β rs4986938 and rs1256049 polymorphisms and endometriosis risk in humans. However, the results of published studies are inconclusive and even controversial -23, and A systematic literature search of the PubMed, ISI Web of Science, and several Chinese language databases  was carried out to identify studies involving the associations between the ER-β rs4986938 and rs1256049 polymorphisms and endometriosis risk. No language restrictions were applied. To search and include as many related studies as possible, we used different combinations of the following key words: (estrogen receptor beta or estrogen receptor β or ER-β) and (polymorphism or variant or mutation) and endometriosis. All references of the retrieved studies were also reviewed to identify other relevant publications. Review articles were also searched to find additional eligible studies. If more than one article was published using the same study data, only the study with largest sample size was included. The literature search was updated on June 20, 2014.Studies fulfilling the following selection criteria were included in this meta-analysis: (1) case–control design; (2) evaluation of the correlation of the two SNPs (rs4986938 and rs1256049) of the ER-β gene with endometriosis risk; (3) provision of sufficient data to calculate the odds ratio (OR) and its corresponding 95% confidence interval (CI). Studies were excluded if one of the following criteria existed: (1) no relevance to the rs4986938 and rs1256049 polymorphisms, ER-β, and endometriosis; (2) non-clinical; and (3) review articles or commentaries. When several studies with overlapping data were eligible, those with the smaller sample size or less reliability were excluded. Furthermore, studies without detailed information were excluded after efforts to extract data from the original paper or contact the corresponding authors failed.p) value for the test of Hardy–Weinberg equilibrium (HWE) in controls. Discrepancies occurring during the process of study selection and data extraction were resolved by discussion with a third reviewer (Limin Feng) to arrive at a consensus on each item.Two authors (Renyong Guo and Nengneng Zheng) independently assessed the quality of each study. Any disagreement was resolved by consensus. The following information was extracted: name of first author, year of publication, country of origin, ethnicity of the study population, number of cases and controls, mean age of subjects and controls, number of infertility cases, genotype distributions in cases and controls, and probability  allelic model: allele A vs. G, where A = variant allele and G = wild allele, (2) homozygote comparison: AA vs. GG, (3) heterozygote comparison: GA vs. GG, (4) dominant model: AA + GA vs. GG, and (5) recessive model: AA vs. GA + GG. The statistical significance of the pooled OR was assessed with the Z test and a p < 0.10 . When bep < 0.10 ; otherwip < 0.10 . Subgroup < 0.10 . Begg’s nificant ,29. DataThe literature search identified a total of 90 potentially relevant papers. After removing 29 duplications and reading the titles and abstracts, a further 45 articles were excluded. A total of 16 remaining articles were then retrieved for further assessment of eligibility. Among these studies, seven were excluded because they were (1) reviews or meta-analysis -33, (2) A total of seven studies with 1100 cases and 1485 controls were included to examine the association between the ER-β rs4986938 polymorphism and endometriosis risk. The overall results suggested no statistically significant association of this polymorphism with endometriosis susceptibility (dominant model, OR = 1.21, 95% CI = 0.83–1.77; recessive model, OR = 0.86, 95% CI = 0.41–1.77; AA vs. GG, OR = 0.95, 95% CI = 0.46–1.97; GA vs. GG, OR = 1.24, 95% CI = 0.80–1.91; A vs. G, OR = 1.16, 95% CI = 0.82–1.64; Table A total of 353 cases and 450 controls were identified to assess the association between the rs1256049 polymorphism and endometriosis risk. The overall results suggested no statistically significant association of this polymorphism with endometriosis susceptibility (dominant model, OR = 2.11, 95% CI = 0.85–5.26; recessive model, OR = 1.43, 95% CI = 0.66–3.08; AA vs. GG, OR = 1.50, 95% CI = 0.59–3.79; GA vs. GG, OR = 1.95, 95% CI = 0.75–5.09; A vs. G, OR = 1.71, 95% CI = 0.92–3.16; Table During the meta-analysis, significance of between-study heterogeneity was observed Tables  and 3. Tp > 0.05, Table To assess possible publication bias in the currently available literature, Begg’s test and Egger’s test were performed, which showed no publication bias for studies published on the rs4986938 and rs1256049 polymorphisms (all ERs are nuclear receptors that contain an estrogen-binding domain and a DNA-binding domain. Studies on tissue distribution and expression patterns indicate that ER-α has a broad expression pattern, whereas ER-β has a more focused pattern with high levels in the ovary, prostate, epididymis, lung, and hypothalamus . FazleabTo the best of our knowledge, this is the first meta-analysis to assess the relationship between the two ER-β gene polymorphisms and endometriosis risk across different ethnic populations and sample sizes. Even though the association of endometriosis risk and genetic polymorphisms involving biosynthesis of sex steroids and their receptors was assessed in a previous meta-analysis , the resIt should be noted that not all studies addressed the correlation of ER-β gene polymorphisms with the pathogenesis or risk of endometriosis-associated infertility. Regarding the rs4986938 polymorphism, only four studies evaluated the effect of interactions, with three studies ,19,21 prSeveral limitations to this study should be addressed. First, the results of our meta-analysis should be interpreted with caution because the sample size was relatively small for the subgroup analysis according to endometriosis-associated infertility and stage of endometriosis. Second, our meta-analyses were based on unadjusted estimates and therefore potential covariates, which might influence the effect estimates, were not controlled. Third, there were relatively few studies on the association of the rs1256049 polymorphism and endometriosis. Therefore, subgroup analysis according to endometriosis-associated infertility and stage of endometriosis was not performed. Hence, further studies with larger sample sizes to provide more detailed information are neededIn conclusion, the results of this study suggest that the ER-β rs4986938 and rs1256049 polymorphisms may be not associated with endometriosis risk. However, ER-β rs4986938 is likely associated with endometriosis-associated infertility, and it might also act as a modifier of the relationship between risk of endometriosis-associated infertility and some environmental factors. To date, there is insufficient evidence implicating the ER-β rs4986938 polymorphism in the etiology of endometriosis-associated infertility for population testing. The observed increase in risk of endometriosis-associated infertility may be due to bias because of the inclusion of small-scale studies. It is critical that larger and well-designed multicenter studies should be performed to re-evaluate potential associations.