Previous studies reported the associations between the ATP-binding cassette sub-family B member 1  polymorphisms and their haplotypes with risk of response to antiepileptic drugs in epilepsy, however, the results were inconclusive.The Pubmed, Embase, Web of Science, CNKI and Chinese Biomedicine databases were searched up to July 15, 2014. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a fixed-effects or random-effects model based on heterogeneity tests. Meta-regression and Galbraith plot analysis were carried out to explore the possible heterogeneity.A total of 57 studies involving 12407 patients (6083 drug-resistant and 6324 drug-responsive patients with epilepsy) were included in the pooled-analysis. For all three polymorphisms , we observed a wide spectrum of minor allele frequencies across different ethnicities. A significantly decreased risk of AEDs resistance was observed in Caucasian patients with T allele of C3435T variant, which was still significant after adjusted by multiple testing corrections . However, no significant association was observed between the other two variants and AEDs resistance. Of their haplotypes in ABCB1 gene , no significant association was observed with AEDs resistance. Moreover, sensitivity and Cumulative analysis showed that the results of this meta-analysis were stable.In summary, this meta-analysis demonstrated that effect of C3435T variant on risk of AEDs resistance was ethnicity-dependent, which was significant in Caucasians. Additionally, further studies in different ethnic groups are warranted to clarify possible roles of haplotypes in ABCB1 gene in AEDs resistance, especially in Caucasians. Epilepsy, one of the most common, chronic and disabling neurologic disorder, affects approximately 1% of the population worldwide, especially in developing countries. AlthoughThe ATP-binding cassette sub-family B member 1  gene, which encodes human P-glycoprotein, can transport several AEDs. In additTo date, six meta-analyses focused on the association of ABCB1 variants with AEDs resistance. –18 HowevA comprehensive electronic search involving Pubmed, Embase, and Web of science, CNKI  and Chinese Biomedicine Databases was carried out to identify the association of ABCB1 gene polymorphisms with antiepileptic drug response in patients with epilepsy, using the following search terms: ‘‘multidrug resistance 1 gene” or “ABCB1” or “MDR1” or “C1236T” or “C3435T” or “G2677T/A” or “rs1045642” or “rs1128503” or “rs2032582”, “polymorphism” or “variant” or “SNP”, AND “epilepsy” or “seizure” (the last search update was 15 July 2014). In addition, the bibliographies of all retrieved articles were hand-searched for additional potential studies.The studies were eligible for the meta-analysis if they meet the following criteria: 1) case-control or cohort design 2) reported the association between MRD1 polymorphisms and drug response in epilepsy patients 3) phenotypes of drug response were clearly defined. Studies were excluded for the following exclusion criteria: 1) compared drug-resistant patients with healthy individuals 2) did not describe the definition of drug response 3) comments, review articles, or articles only with an abstract.Two independent investigators extracted the following data from each included study: first author, publication year, ethnicity , age and sample size of patients with drug-resistance and drug responsiveness, definition of drug-resistance and drug responsiveness, allele and genotype distribution in drug-resistant and drug-responsive patients. Disagreements were resolved by consulting with a third author. In addition, articles that reported results from more than one subpopulation or adults and children separately were considered as separate studies.2 test were carried out to assess the heterogeneity between studies, which was considered significant when P<0.10.[The overall association between three polymorphisms in ABCB1 gene  and antiepileptic drug-resistance was assessed by odds ratios (ORs) with 95% confidence intervals (CIs). The significance of the pooled OR was determined by the Z-test, and the P values were adjusted using Bonferroni correction by the number of compared SNPs. (P = 0.05/3 = 0.017). For simplification of the analysis of the G2677T/A variant, the A allele was included with the T allele as previously described.[n P<0.10., 28 A ran P<0.10., 30 Moren P<0.10. Finally,n P<0.10., 33To assess the stability of the results, sensitivity analysis by sequential removal of each study was carried out. Moreover, sensitive analysis limited to English language studies or studies in HWE was also performed to assess the stable of results. Cumulative meta-analyses for each polymorphism were also performed to investigate the trend and the stability of risk effect as evidence accumulated over time, through assortment of studies with publication time.Begg’s Funnel plots and Egger regression asymmetry test were performed to assess the potential publication bias, and a p-value from the Egger’s test less than 0.05 was considered statistically significant., 35 If tThe literature review identified 811studies, of which 741 articles were excluded by review of titles and abstracts and 20 studies were excluded after assessing of full-text articles . FinallyIn the drug-resistant patients, we observed that T allele frequency of C3435T variant was significant higher in Caucasians (49.75%±8.24%) than those in Asians (40.47%±8.09%), which was also observed in drug-response and overall patients with epilepsy.  For G267The fifty six studies that investigated the correlation between C3435T variant and drug response included 12407 patients with epilepsy (6083 drug-resistance and 6324 drug-response). Although a significant association of C3435T polymorphism with antiepileptic drug-resistance was observed in the allelic and genetic models , p = 0.02; TT vs CC: T OR = 0.79, p = 0.03) , the sigIn the pooled analysis of 25 studies for G2667T polymorphism, no significant association was recorded , p = 0.52).  SimilarlThe associations of ABCB1 C1236T variant with responses to AEDs were investigated in 20 studies, and the results presented in We further investigated the association of the haplotypic combinations of C1236T, G2677T, and C3435T variants with AEDs response, which included 10 studies involving 1113 drug-resistant and 1454 drug-responsive patients.  Haplotyph<0.01, and T vs G for G2677T: Ph<0.01) The heterogeneity was removed in the subgroup of Caucasians, Indian, children, small sample size, publications before 2010 for C3435T variant, but only in children subgroup for G2677T variant. Then, meta-regression was performed to assess the source of heterogeneity for allelic model by ethnicity, age of patients, sample size and year of publications. However, the results showed that no source contributed to the substantial heterogeneity. In addition, Galbraith plot for observing heterogeneity identified 1 study in G2677T polymorphism and 10 studies in C3435T polymorphism as outliners, which were the potential origin of heterogeneity. .There was significant heterogeneity in most comparisons of C3435T and G2677T variants in overall populations.  by sequential removal of each study, the results of which showed that no single study qualitatively changed the pooled ORs, suggesting that the results of this meta-analysis are highly stable. . MoreoveBegg’s funnel plot and Egger’s test were performed to assess potential publication bias of literatures. The shapes of the Begg’s funnel plots did not reveal any signs of obvious asymmetry.  In additABCB1, a kind of multidrug transporters, belongs to the adenosine triphosphate (ATP)-binding cassette super family. Protein encoded by ABCB1 gene is a 170-kDa transmembrane glycoprotein expressed in blood–brain barrier , which aIn this comprehensive meta-analysis involving 57 studies, we found that patients with a T allele in C3435T polymorphism had a significantly decreased risk of drug-resistance in Caucasians, but not among Asians and Indians. No statistical associations were observed of the other two variants in ABCB1 gene (G2677T and C1236T) with risk of drug-resistance in overall populations or subgroup analysis by ethnicity, sample size, date of publication, and age of patients. Additionally, the pooled analysis did not reveal evidence of the association between haplotypes of these three loci and AEDs responsive.Genetic polymorphism often varies between ethnic groups, which was one of the factors that might affect the results. Distribution of allelic frequencies in ABCB1 C3435T variant also displays an ethnic difference. ,37,47 InAge might be another factor that influences the AEDs response. ,81 TypesPrevious study demonstrated that C3435T in exon 26 is a silent variant (no amino acid change), it may influence the AEDs drug response by linkage disequilibrium with another variant, including G2677T and C1236T variants in ABCB1 gene. Linkage Heterogeneity was significant for the most comparisons of C3435T and G2677T variants in overall population. To identify the potential source of heterogeneity, we performed subgroup analysis, meta-regression and Galbraith plot analysis. The results showed that heterogeneity was removed or significantly decreased in Indian and children subgroup group for C3435T variant, and in Caucasian, Indian, and children for G2677T variants. These might be attributed to different genetic backgrounds, different environments, different lifestyles or different AEDs among different ethnicities and ages. However, meta-regression analysis did not found any potential source contributing to the heterogeneity.In addition, variability in the definitions of drug-response and drug-resistance might also contribute to the significant heterogeneity. Of all included studies, the follow-up time ranged from 3 months to 2 years (most studies followed 1 year), whereas the new definition of treatment outcome from International League Against Epilepsy (ILAE) reported that the shortest follow-up period was 12 months. MoreoverSeveral limitations need to be considered for interpretation of our results. First, most AED responses are influenced by an interaction of multiple factors: environmental or patient-related factors and characteristics of the epilepsy itself, and genetic factors, statistical adjustment for individual level factors were not carried out for the insufficient data. Second, types of seizures might also cause variety in AEDs types, dosage, and drug response, a subgroup analysis by types of seizures was necessary in further meta-analysis. Finally,In conclusion, the present systematic review and meta-analysis involving 57 studies with 12407 PWE suggested that C3435T variant, but not G2667T or C1236T variant, might play a role in altered AEDs response ethnicity-dependently. In addition, the association between haplotypes of ABCB1 variants and AEDs response were reported only in Indians and Asians, thus, further studies in different ethnic groups are warranted to clarify possible roles of haplotypes in ABCB1 gene in AEDs resistance, especially in Caucasians. As the new definition of the ILAE has been published, variability in the definitions of AEDs resistance in further studies should be avoided. Finally, these findings might provide predictive genetic markers for antiepileptic drug effectiveness or resistance in individual patients or a possibility for future pharmacogenetically-adjusted dosing of AED, which could be translated into clinical practice.S1 PRISMA Checklist(DOC)Click here for additional data file.S1 Table(DOC)Click here for additional data file.S2 Table(DOC)Click here for additional data file.S3 Table(DOC)Click here for additional data file.S4 Table(DOC)Click here for additional data file.S5 Table(DOC)Click here for additional data file.S6 Table(DOC)Click here for additional data file.S1 FigThe 95% confidence interval is between the two outer parallel lines at two units above and below the regression line.(TIF)Click here for additional data file.S2 FigResults were computed by omitting each study (left column) in turn, Bars: 95% confidence interval.(TIF)Click here for additional data file.S3 FigThe circles and horizontal lines show the accumulation of estimates as results from each study at the end of each year were added.(TIF)Click here for additional data file.


Objective:: Several previous studies have reported the role variant of ERCC1 rs3212986 and ERCC2 rs13181 polymorphisms in the risk of glioma, but the results of these studies are inconsistent. Therefore, we aimed to conduct a meta-analysis to investigate the role of ERCC1 rs3212986 and ERCC2 rs13181 on the risk of glioma.Methods: A comprehensive research was conducted through the databases of Pubmed, EMBASE and the China National Knowledge Infrastructure (CNKI) platforms until June 1, 2014, including 14 eligible case-control studies.Results: Our meta-analysis found that ERCC1 rs3212986 AA genotype was significantly associated with increased risk of glioma compared with CC genotype, and the pooled OR (95%CI) was 1.29(1.07-1.55). By subgroup analysis, ERCC1 rs3212986 AA genotype was found to be significantly correlated with increased glioma risk in Chinese population , Similarly, we found that ERCC2 rs13181 GT and TT genotypes were significantly associated with increased risk of glioma in Chinese population, with ORs(95%CI) of 1.47(1.17-1.85) and 1.50(1.02-2.22). But ERCC1 rs3212986 and ERCC2 rs13181 polymorphisms had no significant association with glioma risk in Caucasian populations. By begg’s funnel plot, we found that no publication bias was existed in this meta-analysis.Conclusion: Our meta-analysis suggested that ERCC1 rs3212986 and ERCC2 rs13181 polymorphism play an important risk factor for brain tumor development in Chinese population, but no association in Caucasian populations. Previous studies reported that mutations of many genes can affect the risk of glioma.7-9Gliomas are the most common occurring type of brain tumors worldwide, accounting for approximately 80% of all malignant brain tumors.10It is well known that changes in DNA induced by exposure to environmental and endogenous agents may result in genetic instability and mutagenesis. DNA repair mechanisms play an important role in maintaining genomic integrity and preventing carcinogenesis. Therefore, if genetic variations in DNA repair genes change the amount or activity of the proteins that they encode, they might also increase the risk of disease and the risk of cancer in particular. Excision repair cross complementation group 1 (ERCC1) and ERCC2 lie on chromosome 19q13.3, and they play an important role in NER pathway.Several previous studies have reported the role variant of ERCC1 rs3212986 and ERCC2 rs13181 polymorphisms in the risk of glioma, but the results of these studies are inconsistent. Therefore, we aimed to conduct a meta-analysis to investigate the role of ERCC1 rs3212986 and ERCC2 rs13181 on the risk of glioma.Search strategy: A comprehensive research was conducted through the databases of Pubmed, EMBASE and the China National Knowledge Infrastructure (CNKI) platforms until June 1, 2014. The literature search was conducted using the following terms: “glioma” or “brain tumor”, “polymorphism” or “variant”, and “ERCC1 C8092A”, “ERCC2 Lys751Gln”, “rs3212986” or “rs13181”. The reference lists of articles included for review and past meta-analyses were examined for any further relevant publications. No publication date or language restrictions were applied.Study selection: The inclusion criteria for studies were as follows: studies are case-control design; studies evaluated the association between ERCC1 rs3212986 and ERCC2 rs13181 polymorphisms and glioma risk; studies reported the results of available genotype frequencies.The exclusion criteria for studies were as follows: articles only have an abstract, review articles and comments; studies are overlapped with other studies; studies have no comparison or control group; studies have no data of genotype frequencies.Corresponding authors were contacted in an attempt to obtain unreported genotype counts if studies were otherwise eligible.Data extractionTwo authors independently screened the electric search with all terms. Duplications and obviously irrelevant studies were excluded according to the exclusion criteria. We extracted the full texts of all eligible studies according to the inclusion criteria. The study ID, study design, participation number, case-control number and genotype information were extracted for each eligible study.Statistical analysis2) was taken to evaluate the Hardy–Weinberg equilibriums in control groups. The pooled odds ratios (OR) and 95% confidence interval (CI) were taken to calculate the role of ERCC1 rs3212986 and ERCC2 rs13181 polymorphisms on the risk of glioma. The heterogeneity between studies was estimated by I2 test and heterogeneity Q statistic test. When I2 were at the range of 0-25%, there was no degree of heterogeneity. When I2 were at the range of 25-50%, there was moderate heterogeneity. When I2 were at the range of 75-100%, there was great heterogeneity. A random-effects model or fixed-effect model was taken to calculate the pooled OR (95%CI) according to the degree of heterogeneity between studies. The publication bias in studies was calculated using Begg’s funnel plot and Egger’s test.All meta-analysis analysis was conducted by STATA 9.0 software. A chi-square . Only one study about ERCC2 rs13181 deviated from Hardy-Weinberg equilibrium in the control groups. There was no significant heterogeneity between pooled studies, and thus we performed a fixed-effect model to assess the association between ERCC1 rs3212986 and ERCC2 rs13181 and risk of glioma. Our meta-analysis found that ERCC1 8092 AA genotype was significantly associated with increased risk of glioma compared with CC genotype, and the pooled OR (95%CI) was 1.29(1.07-1.55). However, we did not find significant association between ERCC2 rs13181 polymorphisms and risk of glioma.By subgroup analysis, ERCC1 rs3212986 AA genotype was found to be significantly correlated with increased glioma risk in Chinese population  . SimilarBy begg’s funnel plot, we found that the shapes of the funnel plots for ERCC1 rs3212986 and ERCC2 rs13181 were symmetry, which suggests no publication bias in this meta-analysis . MoreoveTo the best of our knowledge, the current meta-analysis comprehensively analyze the association between ERCC1 rs3212986 and ERCC2 rs13181 polymorphism and glioma risk. The results of this meta-analysis suggest that the ERCC1 rs3212986 and ERCC2 rs13181 polymorphism polymorphisms was significantly associated with increased risk of glioma in Chinese population, but no association in Caucasian Chinese.26,27 Deficient of ERCC1 expression usually shows a high mutation frequency, an increased level of genomic instability and decreased S-phase-dependent illegitimate chromosome exchange, and it can cause a response adopted by rodent cells to prevent the accumulation of DNA double strand breaks.28 ERCC2 is located at chromosome 19q13.3, and this gene possesses both single strand DNA-dependent ATPase and 5’-3’ DNA helicase activities and participates in DNA unwinding during the process of NER pathway.29,30 Variants of ERCC2 gene is reported to have a role in decreasing the helicase activity, causing a lower DNA repair capacity of NER pathway and affecting the risk of cancer.31,32 Therefore, variants of ERCC1 and ERCC2 genes can influence the cellular DNA repair capacity and affect the susceptibility to glioma risk.11,19 Our meta-analysis demonstrated that ERCC1 rs3212986 polymorphism was significantly associated with glioma risk, but ERCC2 rs13181 polymorphism was not correlated with glioma risk. When conducting stratified analysis by ethnicity, ERCC1 rs3212986AA, ERCC2 rs13181 GT and TT genotypes was associated with increased risk of glioma in Chinese population. But there was no significant increased risk in Caucasian population. Our study suggests that ERCC1 rs3212986 and ERCC2 rs13181 showed different effect on the risk of glioma across different populations. ERCC1 and ERCC2 genes are two important rate-limiting enzymes, and they play a role in the NER process. ERCC1 is a subunit of the NER complex, and ERCC1 usually interacts with XPA, XPF and RPA and can guides 5’ cleavage activity during the process of NER.In our study, we did not detect significant difference between-study heterogeneity of all included case-control studies, and the pooled OR did not alter using the sensitivity analysis. Our study indicates that the results of our study are robust and high stable.Several limitations in our study should be considered. First, the sample size of cases and controls in the stratified analysis was relatively small, which could reduce the statistical power to find the difference between groups. Second, the studies involving Asian patients were too limited to identify precise gene associations. Third, we could not perform a stratified analysis according to ethnicity because of insufficient data. Future studies may address the effect of the ERCC1 rs3212986 and ERCC2 rs13181 polymorphism on different histological brain tumor subtypes to provide a better understanding of tumor pathogenesis.In summary, our meta-analysis suggested that ERCC1 rs3212986 and ERCC2 rs13181polymorphism play an important risk factor for brain tumor development in Chinese population, but has no association in Caucasian populations. Since potential biases and confounders could not be completely excluded from this meta-analysis, further studies with larger sample sizes and standardized, unbiased genotyping methods are warranted to confirm our findings.


CYP1A1 and glutathione-S-transferase M1 (GSTM1) polymorphisms with oral cancer susceptibility.Our meta-analysis was aimed to evaluate the association of CYP1A1 (rs4646903 and rs1048943) and GSTM1 polymorphisms with oral cancer risk. A random-effects model or fixed-effects model was employed depending on the heterogeneity.The related articles were searched in PubMed, Embase, and CNKI databases. Fifty eligible studies were included in our meta-analysis. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the relationship of CYP1A1 rs4646903 polymorphism was associated with the risk of oral cancer , whereas rs1048943 showed no obvious association with oral cancer susceptibility. Moreover, subgroup analysis by ethnicity demonstrated that rs4646903 and rs1048943 both related with increased risk of oral cancer in Asians. Moreover, the analysis based on source of control suggested that rs4646903 could increase the risk for oral cancer in both population- and hospital-based populations, whereas no remarkable relationship of rs1048943 with oral cancer susceptibility was observed. For GSTM1 gene, null genotype appeared to be a risk factor for oral cancer , which was also proved in the subgroup analysis.In overall analysis, CYP1A1 rs4646903 and null genotype of GSTM1 polymorphisms might serve as risk factors for oral cancer.The results demonstrated that  Recently, the relationship of genetic polymorphisms and the risk of cancers have been researched widely. Among the genes, cytochrome CYP1A1 and GSTM1 polymorphisms with oral cancer susceptibility.69 However, the results remained conflicting. Therefore, the meta-analysis was carried out to gain more comprehensive evidences for the association.Up to now, several epidemiological studies have focused on the association of CYP1A1” or “cytochrome P450 1A1,” “GSTM1” or “glutathione-S-transferase M1,” “polymorphism,” and “oral cancer.” The reference lists in retrieved papers were also screened manually for potential articles. All the selected studies should comply with the following inclusion criteria: case–control studies, studies about the association of CYP1A1 and GSTM1 polymorphisms with oral cancer susceptibility, and adequate data for estimating an odds ratio (OR) with 95% confidence interval (CI). When the same data existed in >1 publication, the largest or most recent publication was included. This study is a meta-analysis and does not involve populations; ethical approval was not required.The relevant articles were searched in PubMed, Embase, and CNKI databases using the keywords “The following data were extracted from each study by 2 independent investigators: name of first author, publication date, country of origin, ethnicity, source of controls, genotyping methods, total number of cases and controls, genotype frequencies in case and control groups and Hardy–Weinberg equilibrium (HWE). Disagreements were solved by a discussion between the 2 investigators. The characteristics of the included articles were shown in Tables CYP1A1 and GSTM1 polymorphisms with oral cancer susceptibility. Heterogeneity assumption was estimated by the χ2-based Q test. When P < 0.05, which indicated significant heterogeneity among studies, the pooled OR was calculated using the random-effects model; otherwise, the fixed-effects model was used. The pooled results of CYP1A1 were analyzed under the following genetic models: 22 versus 11, 22 + 12 versus 11, 22 versus 11 + 12, 2 versus 1, and 12 versus 11. For GSTM1, null versus present and present versus null models were used. Sensitivity analysis was conducted to measure the stability of pooled results. Publication bias was assessed by Begg funnel plot and Egger test. HWE was checked by χ2 test. Statistical data were performed using the STATA software .We applied crude ORs with corresponding 95% CIs to evaluate the association of 69As displayed in Figure CYP1A1 rs4646903 polymorphism was closely associated with the increased risk of oral cancer according to the pooled ORs . Using the CC+TC versus TT model and the TC versus TT model, we did not find any significant association  but not in whites and other ethnic groups , especially in Asians , compared with present genotype. Moreover, it was demonstrated that null genotype could affect individual susceptibility to oral cancer in both hospital- and population-based populations , as displayed in Figure With respect to Sensitivity analysis was performed to evaluate the influence of each individual study on the pooled ORs. The recalculated ORs were not substantially influenced, which suggested our results were stable.P = 0.656). Thus, there was no obvious publication bias in our meta-analysis, and the results were credible.Egger test and Begg funnel plot were conducted to estimate publication bias. The shape of the funnel plot was relatively symmetrical Figure . Additio70 Moreover, it has been demonstrated that genetic and environmental factors could affect individual susceptibility to oral cancer. Therefore, it is significant to investigate the association of CYP1A1 and GSTM1 polymorphisms with oral cancer risk.Oral cancer has become a major health problem characterized by high incidence, poor survival rate, and severe functional and cosmetic defects accompanying the treatment.CYP1A1 rs4646903 and rs1048943 polymorphisms contribute to increased enzyme activity of CYP1A1 and are crucial to the activation of PAHs.39 The null genotype of GSTM1 polymorphism could result in the inactivation of GSTM1 enzyme and thus decrease the capacity of detoxifying carcinogens.71 So far, several epidemiological studies have evaluated the association of CYP1A1 and GSTM1 polymorphisms with oral cancer susceptibility. In our study, CYP1A1 rs4646903 was verified to increase the risk of oral cancer, particularly in Asians, whereas CYP1A1 rs1048943 polymorphism did not show significant relationship with oral cancer susceptibility, when we pooled all data together, but demonstrated a statistically significant association when data were limited to Asians, which was consistent with the results of most previous studies.72 However, there were some studies with opposite results to ours. Among them, Losi-Guembarovski et al51 and Amtha et al58 found that there was no significant association between CYP1A1 rs4646903 polymorphism and oral cancer risk. In the studies of Katoh et al38 and Sreelekha et al,39CYP1A1 rs1048943 showed no association with the susceptibility of oral cancer. Compared with the above studies, our study showed advantages in population composed of Asians, whites, and other ethnic groups and relatively lager sample size, which make our result much more credible.GSTM1 polymorphisms and oral cancer risk, the results were also not conclusive.74 Our meta-analysis demonstrated that null genotype of GSTM1 polymorphisms was significantly associated with overall risk of oral cancer. However, the significance was lost in further analysis among whites.For the association between null genotype of CYP1A1 and GSTM1 polymorphisms modify oral cancer risk in an ethnic-specific fashion due to different genetic backgrounds. These possibilities clearly require to be investigated in future research.The 3 polymorphisms analyzed in the present work have 1 thing in common. None of them demonstrated a significant association with genetic risk of oral cancer in whites. The null results may be biased because the current sample is insufficient to determine whether there is an association in this population. Another possibility is that both 54 Second, subgroup analysis of CYP1A1 polymorphisms involved relatively fewer data in whites and other ethnic groups, which may produce some bias in the results. Finally, lack of original data about present genotype of GSTM1 polymorphisms might influence the combined results.Certain limitations in our study should be noted. First, our study was not stratified by smoking status, which was identified as a key factor in oral cancer risk.CYP1A1 rs4646903, rs1048943, and null genotype of GSTM1 polymorphisms are possible risk factors for oral cancer, especially in Asians. In the future, in-depth studies are required to further explore the association.In conclusion, our meta-analysis indicates that


Abnormal expression of serum TGF-β1 was found in patients with diabetic nephropathy. However, the association of TGF-β1 with the risk of diabetic nephropathy remains unknown. The present study was undertaken to investigate whether such an association exists.We searched the Chinese VIP, Wangfang, China National Knowledge Infrastructure, PubMed, Embase, and Google Scholar databases for relevant studies and extracted all eligible data. Stata12 software was used for statistical analysis.Nine reports met our criteria and were used for data extraction. There were 264 patients and 227 healthy controls from qualified reports in this meta-analysis. The results suggested that serum TGF-β1 levels were significantly up-regulated in patients with diabetic nephropathy; the instrumental variable was 3.94 .Meta-analysis suggested that elevated serum TGF-β level in patients with diabetes is associated with a high risk of nephropathy. Further studies are required to validate these observations. Diabetic nephropathy, one of leading causes of death in patients with diabetes, is a progressive kidney disease caused by damage to the capillaries in the kidneys’ glomeruli . The preThe glomerular capillary wall consists of podocytes , glomerular endothelial cells, glomerular basement membranes, and mesangial cells . One of Currently, evidence from various studies have implicated TGF-β1, as well as its associated signaling pathways, were associated with diabetic nephropathy –16. MoreA literature search was conducted using the Chinese VIP, Wangfang, China National Knowledge Infrastructure, PubMed, Google Scholar, and Embase databases for randomized controlled trials by using the keywords “Transforming Growth Factor” and “Diabetic Nephropathy” through June 2015. There were no language preferences.Eligible studies included in this meta-analysis met the following criteria: (1) patients with diabetic nephropathy were enrolled; (2) the study included at least two case control groups: healthy control subjects and patients with type 2 diabetes but without nephropathy; and (3) serum TGF-β1 levels (mean ± SEM) were reported in the study. Exclusion criteria included: (1) reviews, editorials, conference reports, and dissertations; 2) studies conducted in animal models ; 3) cell line-based or in-vitro studies; and 4) duplicate publications .Two reviewers independently extracted the data using a special data extraction form. The following information was recorded: (1) first author’s family name and publication year; 2) average age and ethnicity of patients; (3) sample size of each group; (4) diagnosis markers and discrete value of serum TGF-β1 levels. Disagreements were resolved by the intervention of a third reviewer.2 was assessed for heterogeneity; if the I2 value was greater than 50%, efforts were made to determine the source of heterogeneity by sensitivity or subgroup analysis to identify outliers. The The main outcome was the comparison of serum TGF-β1 levels in diabetic nephropathy patients to those in healthy controls and type 2 diabetes patients without nephropathy. Random modeling was performed by using Stata software version 12.0  for meta-analysis. Weighed mean differences, standardized mean differences, and 95% confidence intervals (CI) for the outcome of continuous variables were determined. The value of IAs shown in the flow diagram in Data from the included articles were extracted and are shown in 2 value was 83.6% (P<0.01), suggesting a significant heterogeneity in all the included studies. Moreover, the instrumental variable (IV) was -0.76,  indicates that that serum TGF-β1 levels were not changed in patients with only Type II diabetic.A total of 264 patients with diabetic nephropathy and 227 healthy controls were included in this meta-analysis. As shown in 2 = 37% in group 1; the SMD was 3.43  and the I2 = 4.6% in group 2; and the SMD was 5.49  and I2 = 0% in group 3. These results indicated that the criteria used for diagnosing diabetic nephropathy may be responsible for the high heterogeneity in these studies.We next strove to identify the source of heterogeneity. In the studies by Wu et al., Fu et al., and Xie et al., no detailed information was provided regarding the criteria for diagnosing diabetic nephropathy. In the studies by Ju et al., Wang et al., and Zhang et al. (2004), the average urinary protein in diabetic nephropathy patients was above 300 mg per 24 h. However, for the other studies, the urinary protein in the experimental groups ranged between 30 and 300 mg per 24 h. Therefore, we divided diabetic nephropathy patients from these studies into three subgroups depending on the urinary protein quantity. As shown in As positive results are more readily to be accepted and negative results may be omitted, accounting for the possible publication bias in our included study, therefore, publication bias was tested by Begg’s funnel plots and Egger’s test. No obvious publication bias was observed for the overall population (Begg’s p = 0.048 and Egger p = 0.019) which indicate that the conclusion we draw from our results believable.The activation of the TGF-β1 signaling pathway in the renal system was found to be an intermediary step in diabetic kidney injury. TGF-β1 not only stimulates the synthesis of some key components of the ECM, such as type I and type IV collagen, but also decreases matrix degradation by inhibiting the protease activity , 27. ManBy applying meta-analysis, a powerful tool which can combine the results of different randomized controlled studies, nine reports with 264 cases and 227 healthy controls were analyzed to investigate whether elevated serum TGF-β1 is a risk factor for the development of diabetic nephropathy. Our results showed that serum TGF-β1 was significantly up-regulated in patients with diabetic nephropathy (p<0.01), and that serum TGF-β1 does represent a risk factor for the occurrence of diabetic nephropathy. As the population sample of this meta-analysis was sufficiently large (>200), the results of our meta-analysis are persuasive. Moreover, no significant publication bias was observed when tested using Begg’s funnel plots and Egger’s test.2 value was 83.6%. By analyzing the data in detail, we concluded that the heterogeneity was due to the different criteria used to diagnose diabetic nephropathy, as well as the fact that data was extracted from patients with different stages of nephropathy. Some studies had not adequately described how diabetic nephropathy was diagnosed and lacked discrete urinary protein values, while patients in other studies were divided into different stages of nephropathy depending on their urinary microalbuminuria gradient. The I2 values in the three subgroups (the third being studies not included in the two aforementioned groups) did not exceed 50%.High heterogeneity was found when analyzing all the included studies; the ITGF-β1 T869C gene polymorphism with diabetic nephropathy risk. A survey of eligible studies from PubMed, the Cochrane Library, and the Chinese Biological Medicine Database found the TT genotype of TGF-β1 T869C was associated with diabetic nephropathy risk in the overall population. This suggested a potential role for TGF-β1 gene expression in the progression of diabetic nephropathy [Previous meta-analyses had reported the association of the hropathy . Anotherhropathy . ConcordIn conclusion, our study is the first meta-analysis to have assessed the association between serum TGF-β1 levels and diabetic nephropathy risk. The results suggest that up-regulation of serum TGF-β1 is associated with an increased risk of diabetic nephropathy. Larger-scale case controlled studies are required to confirm these findings.S1 PRISMA Checklist(DOC)Click here for additional data file.


K121Q and G/T polymorphism of the ENPP1 and TCF7L2 genes respectively plays a significant role and found to be associated with increased risk of T2DM in many worldwide populations. However, a very few studies have been done for this association in North Indian Punjabi populations. In the present cross section study K121Q polymorphism of ENPP1 gene and G/T polymorphism of TCF7L2 gene were analysed to determine the association of these genes with type 2 diabetic North Indian Punjabi subjects.The A total of 450 participants consisting of 239 T2DM and 211 healthy subjects were recruited for this study. Genomic DNA was amplified by PCR-RFLP method. Anthropometric and physiometric variables such as height, weight, Body Mass Index (BMI), Waist hip ratio (WHR), Waist circumference (WC), Hip circumference (HC), biceps skinfold, triceps skinfold, SBP, DBP, MBP, Pulse rate and pulse pressure were measured using standard protocol. The Chi-square analyses were used to test the significance difference in genotype, allele frequencies and Hardy-Weinberg equilibrium deviation. Associations of genotypes with T2DM and its corresponding Pvalues were calculated using Web-Assotest program.ENPP1 K121Q polymorphism.The results revealed that anthropometric and clinical characteristics such as WHR, fasting and random glucose levels, SBP, DBP, pulse rate and pulse pressure have significant (p<0.001) differences between T2DM and control subjects. However, none of the anthropometric and clinical characteristics have found significant difference with respect to their genotypic distributions for both of genes except DBP for ENPP1 gene G/T variant of TCF7L2 gene have significant association with type 2 diabetes with dominant and recessive model of action respectively in North Indian Punjabi populations.The association analysis of the present results showed K121Q variant of


Subgroup analysis revealed that time lag, study location, number of patients, proportion of females, study design, number of adjusted variables might be potential source of heterogeneity. Sensitivity analysis showed robustness of the results. No publication bias was observed in studies on AHD or LP. The current meta-analysis indicated that males are at higher risk of AHD or LP compared with females. More attention should be paid to males to make sure early testing, diagnosis, and treatment, and ultimately improve individual and population health.Effectiveness of highly active antiretroviral therapy is limited for a large proportion of individuals living with HIV presenting for medical care at an advanced stage. Controversial results of gender differences in risk of late HIV diagnosis were reported among existing literatures. Therefore, we conducted this meta-analysis to synthesize a summary of gender differences in risk of advanced HIV disease (AHD) and late presentation (LP) according to European consensus definitions. Totally, 32 studies were included based on predetermined selection criteria. The pooled adjusted  Highly active antiretroviral therapy (HAART) has dramatically reduced HIV-related morbidity and mortality since it has been available in the mid 1990s. Many HIV infected individuals are living with HIV/AIDS as a chronic manageable disease rather than an inevitably progressive and fatal illness13Late presenters are associated with higher rates of opportunistic infections578610111415171820However, different criteria have been used to define late presentation among HIV infected individuals, which generally include CD4 cell count and/or AIDS-defining diseases12Previous studies showed that males were more likely to present late in HIV diagnosis252795% confidence interval (CI), 33 articles with inconsistent definition of outcomes, 3 articles only recruited patients infected via heterosexual contact, 2 articles contained unspecified the exact duration between initial HIV diagnosis and AIDS diagnosis, were excluded. After this selection, only one study used Poisson regression adjusted by age as a quadratic to calculate adjusted relative risk (aRR), while the others used logistic regression to calculate adjusted odds ratios (aOR). This study was finally excluded owing to small number and inconsistency in method, leaving 32 studies for final inclusion in the meta-analysis.The search strategy retrieved 1095 unique citations. Of these, 935 citations were excluded after the first screening based on abstracts or titles, leaving 160 articles for full-text review . On thisCharacteristics of the 43 arms in 32 selected studies are shown in aORs were reported in all studies. All risk measures were adjusted for confounding factors with number of adjusted variables ranging from 2 to 16.The selected studies were published between 2002 and 2014. The number of participants per study/arm on advanced HIV diseases ranged from 113 to 28382, for a total of 1.55 million participants across 29 arms (63734 incident cases of AHD). The number of participants per study/arm on late presentation ranged from 352 to 5545, for a total of 48923 participants across 12 arms (29754 incident cases of LP).Nine studies were conducted in the United States, 8 in Italy, 3 in Spain, 2 in France, 2 in Mexico, and the other 10 studies were conducted in the following countries or region: Hong Kong, Thailand, India, Vietnam, Germany, Nigeria, Republic of Korea, Belgium. The percentage of females ranged from 9.00% to 70.88%. The et al., 2010a and Yang et al., 2010b were excluded to calculate the pooled aOR due to shorter time lag), all but two found higher risk of presenting with AHD for males compared with females, although not all were statistically significant. Males had an increased risk of presenting with advanced HIV disease compared with females, with a pooled aOR of 1.73    to 1.76  for studies on AHD  to 1.43  for studies on LP (Among the 29 arms in 26 selected studies on AHD (Yang 59–1.89) . Among t18–1.62) . A sensis on AHD , and 1.3es on LP .aOR of 1.85  with 0 month, aOR of 1.53  with 1 month, aOR of 1.72  with 3 month, aOR of 1.67  with 6 month, and aOR of 1.70  with 12 month, respectively. The pooled risk of LP in males compared with females of different time lags were aOR of 1.36  with 0 month, aOR of 1.41  with 3 month, and aOR of 1.54  with 12 month, respectively. The selected study characteristics did not seem to significantly influence the results (P > 0.05), and only partly explained the source of heterogeneity.To explore the between-study heterogeneity, we performed subgroup analyses and meta-regression across a number of key study characteristics . The finz = −0.49, P = 0.626; Egger’s test: bias = 0.87, t = 1.47, P = 0.153) or LP . Visual inspection of the Begg funnel plot revealed mostly symmetrically distribution confirming the absence of publication bias  and misclassification attributable to other health care processes with a longer window I2 = 68.70%, P < 0.001) for AHD and no heterogeneity  for LP, possibly because more complex confounding factors were introduced into larger number of patients. Difference in data source and method of collecting data among cross-sectional study, retrospective study, and prospective study, might contribute to heterogeneity as well. More studies included higher proportion of males, and the different sex ratio of patients might cause heterogeneity of the pooled risk of advanced HIV disease or late presentation for males compared with females. Taken together, the result of subgroup analysis revealed that time lag, study location, number of patients, proportion of females, study design, number of adjusted variables might constitute source of heterogeneity, but only partly explained the heterogeneity.However, the proposed definitions did not specify the time lag between initial diagnosis of HIV infection and AIDS. Then Michael Kozak aOR may be a source of publication bias, despite the fact that no evidence of publication bias was exhibited by Begg’s or Egger’s tests.To the best of our knowledge, this is the first meta-analysis to quantify the risk of AHD and LP for males compared with females. Advantages of the current study are applying European consensus definitions of AHD and LP and stratifying the results by varied time lags between initial diagnosis of HIV infection and AIDS. However, several limitations should be noted. To begin with, significant heterogeneity was observed in overall and subgroup analyses. Otherwise, the observation of heterogeneity should not reduce the confidence in the finding but just add some uncertainty about the magnitude of that54In conclusion, the current meta-analysis indicates that males are at higher risk of AHD or LP compared with females. Considering the consistent findings of a number of studies, and the reliability and robustness of our meta-analysis, we strongly recommend that more attention should be paid to males, more effort should be made to encourage individuals with high-risk behavior to participate counseling and testing, in order to make sure early testing, early diagnosis, and early treatment, ultimately to improve individual and population health.This meta-analysis was conducted in accordance with the Meta-Analysis of Observational Studies in Epidemiology guidelines. Pubmed, Embase, and Web of Science databases were searched for English-language publications dated until April 30th, 2015. Keywords used in the databases search included: Search Search (((((((gender) OR sex) OR males) OR females) OR men) OR women)) AND ((((((((((“HIV testing”) AND late)) OR ((“delayed diagnosis”) AND HIV)) OR “late HIV diagnosis”) OR ((“late presenters”) AND HIV)) OR “advanced HIV disease”) OR ((“late diagnosis”) AND HIV)) OR ((“late presentation”) AND HIV)) OR ((“late testers”) AND HIV)). Chinese Scientific Journals Fulltext Database (CQVIP), China National Knowledge Infrastructure (CNKI) and Wanfang Data were searched for Chinese-language publications dated until April 30th, 2015. Keywords used in the databases search included: (“Ai Zi Bing (AIDS)” OR “HIV”) and (“Jian Ce (Testing)” OR “Zhen Duan (Diagnosis)”). References lists of the retrieved articles and previous systematic reviews were also reviewed by researchers.aOR, or aRR or adjusted Hazard Ratio (aHR) with the corresponding 95% CI of gender difference in “LP” or “AHD”. Studies were excluded if they did not specified the exact duration between initial HIV diagnosis and AIDS diagnosis. If multiple publications reported results based on the same research, the more recent or complete article was included.Two authors examined the titles and abstracts of all studies containing keywords independently for eligibility. Studies were included based on the following criteria: (1) reported original data; (2) described “LP” as presence of an AIDS condition or CD4 cell count <350 cells/μL at presentation for care, or “AHD” to as the presence of either an AIDS condition or a CD4 cell count <200 cells/μL at presentation12aOR or aRR or aHR with the corresponding 95% CI, and adjusted variables. Number of patients and cases was the number of subjects included in the model of multivariate analysis.Data extraction was carried on by two authors independently using a pre-designed data extraction form. The following information was extracted from the included publications: last name of the first author, publication year, study period, study population, study location, outcome definition, time lag , data source, study design, number of patients, number of cases (patients with late presentation or advanced HIV disease), 95% CI of gender difference in risk of AHD or LP were used to calculate the pooled estimates based on weighted pooled measures. If multiple arms using varies time lags in one study, arm with the longest time lag was included to calculate the overall pooled estimates. Forest plots were used to visually assess the individual and pooled estimates with the corresponding 95% CI, and heterogeneity among studies was assessed using the Cochrane Q statistic significant when P < 0.10 and the I2 statisticP < 0.10 and I2 < 50%58P < 0.05 was considered significant, except where otherwise specified.The adjusted estimates with the corresponding How to cite this article: Jiang, H. et al. Gender difference in advanced HIV disease and late presentation according to European consensus definitions. Sci. Rep.5, 14543; doi: 10.1038/srep14543 (2015).


C. pneumoniae-mediated inflammatory state with atherosclerotic cardiovascular diseases, providing inconsistent results. Therefore, we performed a meta-analysis to clarify whether C. pneumoniae may contribute to the pathogenesis of atherosclerosis by enhancing inflammation. 12 case-control, 6 cross-sectional, and 7 prospective studies with a total of 10,176 patients have been included in this meta-analysis. Odds Ratio (OR) with a 95% confidence interval was used to assess the seroprevalence of C. pneumoniae and differences between levels of inflammatory markers were assessed by standard mean differences. Publication bias was performed to ensure the statistical power. hsCRP, fibrinogen, interleukin- (IL-) 6, TNF-α, and IFN-γ showed a significant increase in patients with atherosclerosis compared to healthy controls (P < 0.05), along with a higher seroprevalence of C. pneumoniae . More interestingly, hsCRP, IL-6, and fibrinogen levels were significantly higher in C. pneumoniae IgA seropositive compared to seronegative atherosclerotic patients (P < 0.0001). In conclusion, the present meta-analysis suggests that C. pneumoniae infection may contribute to atherosclerotic cardiovascular diseases by enhancing the inflammatory state, and, in particular, seropositivity to C. pneumoniae IgA, together with hsCRP, fibrinogen, and IL-6, may be predictive of atherosclerotic cardiovascular risk.Several studies have attempted to relate the  In response to proinflammatory cytokines, endothelial cells express high levels of leukocyte adhesion molecules on their surface, leading to further mononuclear cell recruitment and, hence, to a chronic inflammatory state [Atherosclerosis, a chronic inflammatory disease of multifactorial aetiology, typically begins with endothelial dysfunction followed by low density lipoprotein (LDL) infiltration of the arterial intima, mononuclear cell recruitment into vascular wall, and the differentiation of macrophages in foam cells , 2. Macrry state , 4. As ary state . Chlamydia pneumoniae, an obligate intracellular microorganism, known as being responsible for respiratory tract infections [In the last decades, several infectious agents have been related to the pathogenesis of atherosclerotic cardiovascular diseases, and current opinion is that the most implicated pathogen isfections , 7. C. pneumoniae and atherosclerotic cardiovascular diseases has been well documented by seroepidemiological studies [ C. pneumoniae inoculation of hyperlipidemic animal models [The association between studies –12, dire studies –17, and l models –23.C. pneumoniae is presumed to play a role in atherosclerotic cardiovascular diseases for its ability to systematically disseminate from the lung through peripheral blood mononuclear cells and to localise in extrapulmonary tissues, such as the vascular wall [ C. pneumoniae has been shown to act directly on the cells involved in atherosclerotic process, contributing to endothelial dysfunction, foam cell formation, vascular smooth muscle cell (VSMC) proliferation and migration, and platelet aggregation [ C. pneumoniae is able to multiply within macrophages, platelets, endothelial cells, and VSMCs and to induce the elicitation of proinflammatory cytokines, such as IL-6, IFN-γ, and TNF-α, and adhesion molecules, such as ICAM-1 and VCAM-1, as well as reactive oxygen species, thus contributing to the chronic inflammatory state responsible for the initiation, progression, and destabilisation of atherosclerotic plaque [lar wall –28. Onceregation –33. Indec plaque –40. C. pneumoniae persistent form seems to be responsible for chronic infection and, hence, for the inflammatory process underlying atherosclerosis, since it is able to endure for a long time inside host cells [Specifically,st cells , 42. C. pneumoniae has also shown to contribute to the systemic inflammation involved in the pathogenesis of atherosclerotic cardiovascular diseases, as evidenced by high levels of IL-6 and high sensitivity c-reactive protein (hsCRP) [In addition to the direct effect on vascular cells, previously described, (hsCRP) , 43. C. pneumoniae, several studies have attempted to relate the C. pneumoniae-mediated inflammatory state with atherosclerotic cardiovascular diseases, providing inconsistent results.Given the central role of inflammation in the atherosclerotic process and the inflammatory effects of C. pneumoniae may contribute to the pathogenesis of atherosclerotic cardiovascular diseases by the means of enhanced inflammatory state.We performed, therefore, a meta-analysis to clarify whetherWe performed a systematic search of all articles in journals indexed on the electronic databases PubMed and Scopus up to December 2014. The search terms used were “chlamydia pneumoniae” or “chlamydophila pneumoniae,” “inflammatory markers” or “inflammation,” “atherosclerosis,” and “cardiovascular disease.” The reference lists of reviews and retrieved articles were hand-searched simultaneously. When more than one of the same patient population was included in several publications, only the most recent or complete study was included in this meta-analysis. C. pneumoniae IgG or IgA, (ii) studies comparing atherosclerotic patients in relation to the seropositivity to C. pneumoniae IgG or IgA, and (iii) studies analysing the levels of inflammatory markers.The inclusion criteria in this meta-analysis were as follows: (i) studies comparing atherosclerotic patients with healthy subjects (control group) in relation to the seropositivity toCase reports, reviews, letters, and studies which did not present their results in a correct and/or explicit manner, animal studies, and studies where the control groups were made up of patients with other chronic inflammatory disorders were excluded from our meta-analysis. We did not define any minimum number of patients to include a study in our meta-analysis. C. pneumoniae antibodies (IgA or IgG), determined by microimmunofluorescence or ELISA, and the levels of inflammatory markers .Information was carefully extracted from all eligible publications independently by two authors according to the inclusion and exclusion criteria listed above. Disagreement was resolved by discussion between the two authors. The following data were collected from each study: first author's surname, year of publication, study design, type of cases, type of controls, total numbers of cases and controls, prevalence of traditional risk factors for CVD , the prevalence ofOnly inflammatory markers analysed by at least two studies were included in our meta-analysis.P). P of less than 0.05 was considered as statistically significant. Potential publication bias was estimated using Egger's linear regression test and funnel plots. Sensitivity analyses were assessed by deleting each study; in all cases, pooled estimates were very stable.Differences between groups were assessed by means of differences in averages and standard deviations of the difference, as markers assessed were all continuous. Standard errors were computed after a normal approximation. Pooled effects were computed by means of a meta-analysis. The meta-analysis conducted was strictly under heterogeneity among studies, by means of a hierarchical Bayesian model. Effect sizes were assumed to be normally distributed. Each study effect was assumed to arise from a Gaussian centered on a study-specific effect and the extracted standard error, inflated by 25% to obtain a conservative statement. The study-specific effect was assumed to be Gaussian, centered on an unknown pooled effect, which is the main object of interest. An informative prior was used for the variance of the pooled effect, as an inverse Gamma centered on an estimator obtained with a moment-based approach (inflated by 25% to obtain a conservative statement). We also estimated posterior probabilities of no difference  [ C. pneumoniae seroprevalence was 59.2% (95% CI: 57.8–60.7) in cases and 31.2% (95% CI: 30.0–32.5) in controls, with an OR of 3.11 . Concerning the inflammatory markers, hsCRP, IL-6, fibrinogen, TNF-α, and IFN-γ showed a significant increase in patients with atherosclerosis compared to health controls (P < 0.05), whereas the adhesion molecules ICAM-1 and VCAM-1 did not show any significant difference (P > 0.05)  , 67, 68. > 0.05) . C. pneumoniae IgG or IgA with seronegative patients. Specifically, 7 studies comparing atherosclerotic patients seropositive to C. pneumoniae IgG with seronegative patients , were evaluated.In addition, the meta-analysis was also performed on studies comparing atherosclerotic patients seropositive to C. pneumoniae IgG analysis, hsCRP, IL-6, and fibrinogen levels were significantly higher in seropositive compared to seronegative patients (P < 0.0001) (For the 0.0001) . C. pneumoniae IgA analysis, hsCRP, IL-6, and fibrinogen were markedly increased in seropositive patients (P < 0.01), whereas IFN-γ did not show any significant difference between seropositive and seronegative patients (P > 0.05) (For the > 0.05) .Results are independent of the main confounding factors as the meta-analysis was computed under heterogeneity. We also have verified that they could not form a relationship with mean age and study proportions of males, patients with diabetes, hypertension, obesity, smoking, dyslipidemia, and risk factors for CVDs.P = 0.012). In particular no publication bias was detected for hsCRP for IgA (P = 0.200), IgG (P = 0.890), and case-control data (P = 0.122).Funnel plots and Egger's test were performed to assess publication bias. Publication bias was detected only for meta-analysis of fibrinogen with IgA , suggest that C. pneumoniae infection may contribute to the chronic inflammation underlying the development and progression of atherosclerosis, even though it is not possible to establish a causal relationship.The first result of our meta-analysis showed a significant increase in hsCRP, fibrinogen, IL-6, TNF- C. pneumoniae on the inflammation underlying atherosclerosis, we performed a further analysis on studies comparing the levels of inflammatory markers in atherosclerotic patients seropositive to C. pneumoniae IgG or IgA with seronegative patients.Consequently, in order to better define the contribution of C. pneumoniae IgA seropositivity was overall more strongly related to the inflammatory state than IgG seropositivity. Indeed, our results showed an increase of inflammatory marker levels, such as hsCRP, fibrinogen, and IL-6, in IgA seropositive patients. Specifically, the standard mean differences of hsCRP, fibrinogen, and IL-6 were, respectively, 7.17, 7.79, and 1.37 times higher in the IgA compared to the IgG analysis, thus showing that seropositivity to C. pneumoniae IgA might better correlate to a chronic inflammatory state in patients with atherosclerosis. This is not particularly surprising since C. pneumoniae IgA is considered a marker of chronic infection, known to be involved in chronic disorders.The more relevant data is thatThe main strength of our meta-analysis is the statistical robustness of our data, since the results were not affected by exclusion of any specific study from the pooled analysis. C. pneumoniae might be overestimated. Of note, in all the studies included in our meta-analysis, data regarding other infectious agents were missing or incomplete and, hence, we were not able to quantify their influence on chronic inflammation. Second, potential bias might be introduced in that not all the included studies reported data concerning the confounding factors. Lastly, two different diagnostic tests, along with different cutoffs, were used for detecting C. pneumoniae seropositivity in the included studies and, hence, may partly account for further bias.However, our meta-analysis has potential limitations. First, since multiple infectious agents, labeled as infectious burden, rather than any single pathogen, have been shown to contribute to the pathogenesis of atherosclerosis, the inflammatory effect of C. pneumoniae infection may contribute to atherosclerotic cardiovascular diseases by enhancing the inflammatory state, as demonstrated by increased levels of systemic inflammatory markers. Furthermore, seropositivity to C. pneumoniae IgA, together with hsCRP, fibrinogen, and IL-6, may be predictive of atherosclerotic cardiovascular risk.In conclusion, despite some limitations, our study suggests that C. pneumoniae in inflammation in atherosclerotic cardiovascular diseases.In the future, large scale, prospective, and well-designed studies should be needed to deepen our knowledge concerning the causative role ofC. pneumoniae IgG (Table S1) or IgA (Table S2) was observed (P < 0.0001).The standard mean differences with 95% confidence interval of inflammatory marker levels, between patients seropositive and seronegative to anti-chlamydial antibodies were assessed. The association of hsCRP, IL-6 and fibrinogen with


P < 0.001). Meta-analysis of the rs11209026, rs1343151, rs10489629 and rs11465804 polymorphisms indicated the same pattern as for rs7517847. Meta-analysis showed an association between the rs10889677A allele and CD . Similarly, meta-analysis of the rs2201840, rs1004819, rs1495965 and rs11209032 polymorphisms revealed the same pattern as that shown by meta-analysis of rs10889677. Stratification by ethnicity revealed that IL-23R gene polymorphisms were associated with CD in the Caucasian group, but not in Asians. In summary, the meta-analysis suggests a significant association between IL-23R polymorphisms and CD, especially in Caucasians.Studies investigating the association between Interleukin-23 receptor (IL-23R) gene polymorphisms and Crohn’s disease (CD) report conflicting results. Thus, a meta-analysis was carried out to assess the association between the IL-23R polymorphisms and CD. A systematic literature search was conducted to identify all relevant studies. Pooled odds ratio (ORs) with 95% confidence interval (CIs) was used to estimate the strength of association. Finally, a total of 60 case-control studies in 56 articles, involving 22,820 CD patients and 27,401 healthy controls, were included in the meta-analysis. Overall, a significant association was found between all CD and the rs7517847 polymorphism (OR = 0.699, 95% CI = 0.659 ~ 0.741,  Crohn’s disease (CD) is a chronic, inflammatory, autoimmune disease characterized by transmural inflammatory lesions that affect the entire gastrointestinal tract247910Interleukin-23 (IL-23), an important immuno-regulatory cytokine secreted by activated macrophages and dendritic cells, regulates the differentiation of T helper 17 cells from native CD4+ T cells131821222324252627282930313233343536373839404142434445464748495051525354555657585960616263646566676869707172737475Meta-analysis is a statistical method for augmenting the effective sample size through combining the results of several studies to produce a single estimate of the major effect with enhanced precision. It is considered to be a powerful tool for pooling inconsistent results from different studies525354555657585960616263646566676869A literature search was conducted for studies that examined association between the IL-23R gene polymorphisms and CD risk in October 13, 2015. We used PubMed database, Elsevier Science Direct, China National Knowledge Infrastructure database (CNKI) and Chinese Biomedical database (CBM) to identify articles with the following terms: “Interleukin-23 receptor, IL-23R, Crohn’s disease, Crohn disease, inflammatory bowel disease, CD and IBD”. References in the studies were also reviewed to find additional studies. The languages were limited to English and Chinese.A study was included in the analysis if a) it was a case-control or cohort study; b) it included original data (independence among studies); and c) it provided sufficient data to calculate the odds ratio (OR). We excluded the followings: a) studies contained overlapping data; b) studies in which family members had been studied because of the analysis based on linkage considerations.Data were collected by two independent investigators (Qi-Bing Xie and Yi Zhao). The characteristics of the selected articles were in Allele frequencies at the IL-23R gene polymorphisms from the respective study were determined by the allele counting method. The contrast of the allelic effect of minor allele versus common allele of the IL-23R gene polymorphisms was tested. The strength of association between the IL-23R gene polymorphisms and CD susceptibility was assessed by odds ratios (OR) and 95% confidence intervals (95% CI).2-statistic also measures the degree of inconsistency in the studies by computing what percentage of the total variation across studies was due to heterogeneity rather than by chance. A high value of I2 indicated a higher probability of the existence of heterogeneity . If a P-value of the heterogeneity Q-statistic was more than 0.10, the pooled OR was calculated by the fixed effects model. Otherwise, a random effects model was adopted. Potential publication bias was analyzed by Egger’s linear regression test and the Funnel plot. If P-value was less than 0.05, statistically significant publication bias might existThe heterogeneity of between-studies was evaluated by the Chi-square test based Q-statisticAll the statistical analysis of meta-analysis was performed by STATA statistical software .The process for selecting the studies was shown in 21222324252627282930313233343536373839404142434445464748495051525354555657585960616263646566676869707172737475212122232425262728293031323334353637383940414243444546474849505152535455565758596061626364666768345161707172737465Between-study heterogeneity was found in some meta-analysis of the IL-23R gene polymorphisms in CD . TherefoP < 0.05. It was shown that there was no significant publication bias between all of the comparisons .The funnel plot asymmetry and Egger’s test were performed to assess potential publication bias. If there was asymmetry, the index to determine Egger’s test will show A summary of the meta-analysis of the association between the IL-23R gene polymorphisms and CD was listed in P < 0.001; P < 0.001), but not in the other subgroups. Meta-analysis of the rs1343151 and rs10489629 polymorphisms showed the same pattern as for rs7517847. Minor alleles of all polymorphisms might be protective alleles for CD susceptibility in Caucasians, but not in the other populations . Ethnicity-specific analysis showed that the rs2201841C allele was significantly associated with CD in the Caucasian and African subjects . The forest plot was shown in P < 0.001)  . Howeveret al.et al.et al.et al.et al.A genome-wide association study by Duerr P value < 0.001). Ethnicity-specific analysis showed that the polymorphisms in the IL-23R gene might confer susceptibility to CD in Caucasians, but not in Asians.Therefore, to better comprehend the association between polymorphisms in the IL-23R gene and CD susceptibility, a pooled analysis with a larger sample size, subgroup analysis performed and heterogeneity explored is needed. Overall, results of this meta-analysis suggested that IL-23R gene polymorphisms were associated with CD susceptibility . Furthermore, Doecke et al.P < 0.001). However, haplotype AT (rs1004819 (G) + rs7517847 (G)) was positively related to CD risk .With respect to the IL-23R haplotypes and CD, Taylor Compared with the previous meta-analysis52Some limitations of the present study should be considered. First, we could not analyze the potential gene-environment interactions and gene susceptibility haplotypes owing to lack of data, such as the data of environmental risk factors and genotypes. Second, our literature search was only dependent on English and Chinese, language bias might be considered. Third, potential publication bias was not found by statistical method, but it might exist because of only published articles included. Fourth, only one published studies in the African origin was included in the meta-analysis, the stratified analysis for Africans might not be reliable. Thus, the results were applicable only to the Asian and Caucasian groups. Finally, different genotyping methods and disease status might affect the data interpretation of the included studies.In summary, the current study provides a comprehensive examination of the available evidence for the association between polymorphisms in the IL-23R gene and CD. This updated meta-analysis suggests that IL-23R gene polymorphisms are associated with CD susceptibility. However, larger sample size studies taking environmental risk factors into account and including more ethnic groups should be considered in future to confirm the results from our meta-analysis.How to cite this article: Xu, W.-D. et al. Association of Interleukin-23 receptor gene polymorphisms with susceptibility to Crohn,s disease: A meta-analysis. Sci. Rep.5, 18584; doi: 10.1038/srep18584 (2015).


P < 0.001) for over survival (OS), 2.55  for disease-specific survival (DFS) and 2.02  for disease-specific survival (DSS)/metastasis-free survival (MFS) by the random, fixed and random effect model respectively. Similar results were also observed in the stratified analyses by tumor types, ethnicity background and sample source. This meta-analysis suggests that Ezrin may be a potential prognostic marker in cancer patients. High Ezrin is associated with a poor prognosis in a variety of solid tumors.More and more studies have investigated the effects of Ezrin expression level on the prognostic role in various tumors. However, the results remain controversial rather than conclusive. Here, we performed a systematic review and meta-analysis to evaluate the correlation of Ezrin expression with the prognosis in various tumors. the pooled hazard ratios (HR) with the corresponding 95% confidence intervals (95% CI) were calculated to evaluate the degree of the association. The overall results of fifty-five studies with 6675 patients showed that elevated Ezrin expression was associated with a worse prognosis in patients with cancers, with the pooled HRs of 1.86 (95% CI: 1.51–2.31,  Ezrin is an important member of the ERM (Ezrin-radixin-moesin) cytoskeleton-associated proteins family, which started to look like a transit protein between membrane proteins and actin filaments134578910111213Ever since the first report about the prognosis effect of Ezrin on uveal malignant melanoma in 2001161718192021222324252627281516171819202122232425262728293031323334353637383940414243444547484950515253In the present meta-analysis, the aim is to assess the correlation between Ezrin expression and the survival outcomes in cancer patients via collecting global related literatures to carry out a systematic analysis.As shown in The main characteristics of the eligible studies are summarized in P < 0.001) for OS and 2.02  for DSS/MFS with a random model because of the significant heterogeneity . Additionally, high Ezrin expression was also correlated with DFS, with the pooled HR of 2.55  calculated by a fixed model because of the absence of heterogeneity .The association between Ezrin expression and various cancers prognosis is illustrated in P < 0.001) and DSS/MFS  in Asian cancer patients, but not in Caucasian ones .To explore the sources of heterogeneity, sub-group analysis for OS and DSS/MFS were conducted by the ethnicity, sample source and cancer types. The main results of this subgroup analysis for prognostic role of Ezrin in various tumors are shown in P < 0.001) and DSS/MFS  from FFPE samples, but not those from TMA ones . However, we founded that there were a significant heterogeneity between the two kinds of samples whether they were for OS or for DSS/MFS.In the sub-group analyses based on sample source, the results demonstrated that high Ezrin expression had a worse prognosis for OS , HNSCC , gynecologic cancer , osteosarcoma , hepatobiliary cancer , NSCLC  and a worse DSS/MFS in digestive cancers . However, positive Ezrin expression was a predictor of good prognosis in bladder cancer for OS . Furthermore, we also performed sub-group analysis restricted to cancer type in different ethnicities for OS (P < 0.001) and gynecologic cancer  among Asians (P = 0.108). However, individuals elevating Ezrin expression had a significantly improved survival of bladder cancer  among Caucasians  family, is mainly expressed in a variety of malignant tissues which originate from epithelial or non-epithelial cells5759et al.et al.et al.et al.et al.et al.et al.et al.et al.As the first qualitative analysis of Ezrin expression related to survival outcome of various tumors, Han This meta-analysis was performed according to the guidelines and recommendations for improving the quality of reporting of medical research such as REMARKThe evidence included in the present meta-analysis indicated Ezrin expression as a poor prognostic marker in a variety of tumors. However, it should be noted that there are some limitations to the analyses presented here. First, because the number of prognostic studies dealing with each type of cancers was ≤5, the results of the particular carcinomas might be less powerful. Second, English articles were only recruited, and language bias might exist. Third, some HRs were calculated indirectly by the data extracted from the literature, however, these data were less reliable than direct data from the original literature. Fourth, different cutoffs used to assess high Ezrin level in the studies might also have contributed to the heterogeneity, because there is not a standard cutoff value of Ezrin level for increased survival risk. Fifth, significant heterogeneity existed in between studies, even though we calculated the pooled subgroup data with random-effects models. The heterogeneity in these studies could be attributed to the differences by different population characteristics or study designs. In addition, different sample types could also explained the heterogeneity, because tissue microarray (TMA) probably obtained more false-negative cases than the whole section. Finally, some inevitable publication bias might exist in the literature-based analysis, because more positive results tended to be published, thus potentially exaggerating the association between Ezrin expression and poor outcomes. Moreover, because all of the included studies were retrospective, which may have also introduced reporting bias. Therefore, our findings should be interpreted with caution.In summary, our meta-analysis has demonstrated that the high Ezrin expression is significantly associated with poor survival in cancer patients. However, our results should be also considered cautiously for the above reasons. Further multicenter prospective studies and large clinical investigations should be conducted to validate the prognostic value of Ezrin in various tumors.Guided by the guidelines of the Meta-analysis of Observational Studies in Epidemiology group (MOOSE), we carried out the meta-analysisiii) absence of key information, such as HR, 95% CI, and P value, or useful data for calculation established by Parmar, Williamson, and Tierney7374In this meta-analysis, the candidate studies were recruited according to the following criteria: (i) studied the patients who suffering from any type of cancers; (ii) evaluated Ezrin expression using Immunohistochemical method; (iii) assesed the correlation between Ezrin expression level and clinical outcome; and (iv) English articles. Articles were excluded based on any of the following criteria: (i) reviews, letters, comments, conference abstracts, or laboratory articles; (ii) articles not in English; (vi) a definite cut-off of Ezrin. Otherwise, We would exclude the studies in order to ensure the quality of the meta-analysis.According to a critical review checklist of the Dutch Cochrane Centre proposed by MOOSE, we strictly assessed the quality of all the studies includedP values. Multivariate Cox proportional hazards regression analysis was used in the present analysis. If the HR and its 95% CI were not available directly, they were calculated from the corresponding data or Kaplan-Meier curves provided in the articles using the method reported previouslyTwo reviewers extracted the required information from all eligible studies independently. The extracted data included the following elements: the first author’s name, publication year, country of origin, sample size, tumor type, Ezrin measurement method, cut-off value, follow-up duration, the HRs of Ezrin for OS, DFS or DSS/MFS, as well as their 95% CIs and Tierney’s methodIP value < 0.05 and/or I2 > 50% indicated significant heterogeneity, a random-effect model was used to calculate the pooled HR; otherwise, the fixed-effect model was used. Generally, pooled HR of >1 was assumed to indicate a significant association with worse prognosis and was interpreted as statistically significant if the 95% CI for the pooled HR did not overlap one. Sensitivity analysis was carried out by removing each study at a time to evaluate the stability of the results. Publication bias was analyzed by performing funnel plots qualitatively, and estimated by Begg’s and Egger’s test quantitatively. Two sided P < 0.05 was considered statistically significantAll these HRs and the corresponding 95% CIs were calculated to combine the pooled data following How to cite this article: Li, J. et al. Prognostic Value of Ezrin in Various Cancers: A Systematic Review and Updated Meta-analysis. Sci. Rep.5, 17903; doi: 10.1038/srep17903 (2015).


APOA5) is associated with plasma triglyceride (TG) levels, a risk factor for coronary heart disease (CHD). This study explored the association between CHD and the APOA5 rs662799 polymorphism.Apolipoprotein A5  for this case-control study. Meta-analysis was performed using Review Manager Software and Stata Software.2 = 8.964, df = 2, P = 0.011) and allele . A breakdown analysis by gender showed a significant association of APOA5 rs662799 with CHD in males . An additional meta-analysis using 21378 cases and 28428 controls established that rs662799 is significantly associated with CHD (P < 0.00001).Significant differences were observed between CHD cases and controls at the level of both genotype (χAPOA5 rs662799 and CHD. In addition, our results suggest a male-specific association between the APOA5 rs662799 polymorphism and CHD.Both our case-control study and meta-analysis confirm a significant association between  Coronary heart disease (CHD) is a type of cardiovascular disease that is caused by ischemia and hypoxia in the coronary artery  and is tAPOA5 is located in the apolipoprotein APOA1/C3/A4 gene cluster [APOA5 is predominantly expressed in hepatocytes and secreted into the blood [ cluster  on chrom cluster ,9. APOA5he blood ,11. The APOA5 is associated with TG levels [APOA5 plays an important role in determining TG levels in serum [Apoa5 leads to decreased concentrations of TG in plasma, whereas a shortage of apoA5 causes hypertriglyceridemia, a risk factor for atherosclerosis and CHD [APOA5 is associated with CHD [Atherogenic dyslipidemia is a major risk factor for CHD –14, as aG levels . APOA5 pin serum . In mice and CHD . These f and CHD . Taken twith CHD –20.APOA5 rs662799 (-1131T>C) is a promoter polymorphism that was shown to be associated with increased levels of TG in young adult Indians [APOA5 is associated with TG leaves and acute myocardial infarction (MI) [APOA5 rs662799 (A>G). The minor allele frequency in European populations (HapMap-CEU) is 1.7%, much lower than the 13.3% observed in individuals of African descent (HapMap-YRI), 26.7% in Chinese (HapMap-CHB) and 28.9% in Japanese (HapMap-JPT). In our previous study, we could not detect a significant association between APOA5 rs662799 and CHD [APOA5 rs662799 plays a role in the risk of CHD in Han Chinese. Indians . In Ital662799 -11T>C is aion (MI) . Accordi and CHD , possiblSamples from 1,521 unrelated individual inpatients were randomly collected from the Ningbo Lihuili Hospital and the Ningbo Yinzhou People's Hospital, Zhejiang, China. The samples included 783 cases of CHD  and 738 controls . All individuals were free from congenital heart disease, cardiomyopathy and severe liver or kidney disease. Details of the classified criteria have been described in our previous studies . The stuGenomic DNA was isolated from peripheral blood lymphocytes using a nucleic acid extraction automatic analyzer . PCR was performed on the ABI GeneAmp PCR System 9700 Dual 384-Well Sample Block Module . PCR conditions included an initial denaturation of 95°C for 2 min, followed by 45 cycles of 95°C for 30 sec, 56°C for 30 s, 72°C for 1 min and then a final extension at 72°C for 5 min. After purification by SAP Reaction, we proceeded with primer extension. The primer extension protocol included an initial denaturation at 94°C for 30 s, followed by 40 cycles of amplification , 5 cycles of amplification , a final extension at 72°C for 3 min after which samples were held at 4°C. Single nucleotide polymorphism genotyping was performed using the Sequenom Mass-ARRAY iPLEX platform per the manufacturer's instructions . The priAPOA5 (rs662799) and CHD were considered to be eligible for the current meta-analysis. We only included studies that presented data on allele or genotype frequencies for both cases and controls and displayed a genotype distribution meeting Hardy-Weinberg equilibrium (HWE) [APOA5” and “rs662799” or “-1131T>C”. After a series of selection procedures, we excluded 15 duplicate studies, 5 meta-analysis studies, 120 irrelevant studies, 28 studies on other diseases, and 7 studies without genotyping data  . Informaing data . In addiing data  [11,13,1http://faculty.vassar.edu/lowry/odds2x2.html) [2 tests. An I2 > 50% indicated the existence of heterogeneity among the studies in the meta-analysis. Publication bias was shown by Begg’s funnel plot analysis, which was generated with Stata software . P values < 0.05 were significant.The HWE test was performed using the Arlequin program (version 3.5), and P > 0.05 was considered to be in HWE . Genotypx2.html) . Meta-anx2.html) . HeterogAPOA5 rs662799 polymorphism in cases (P = 0.220) or controls (P = 0.544). Genotypic and allelic comparisons between cases and controls are shown in 2 = 8.964, df = 2, P = 0.011; allele: P = 0.002; OR = 1.275, 95% CI = 1.089–1.492). A further gender-stratified association shows that rs662799 is significantly associated with CHD in males  but not in females. In addition, frequency of the rs662799-G allele is significantly higher in male cases (31.5%) than in male controls , we selected a fixed-effect model for the meta-analysis, otherwise, the random-effect model was used for the meta-analysis with great heterogeneity (I2 > = 50%). The current meta-analysis has great heterogeneity (I2 = 70%), therefore random-effect model was used. As shown in APOA5 rs662799 and CHD in Asians , Chinese  and Caucasians . The meta-analyses show no publication bias by Begg’s funnel plot analysis . The minor G allele of APOA5 rs662799 may increase the risk of CHD by 27.5% . Consistent with previous reports, the rs662799-G allele is associated with higher leaves of TG in both CHD patients and controls [APOA5 rs662799 indicates that our study has 85.9% power to detect significance in the association test.Our results show that the rs662799 polymorphism in the controls ,67. A poEnvironmental factors, such as gender and age, are important factors of CHD. The prevalence of CHD in females was different from males ,68,69. EAPOA5 rs662799 and CHD in the male group, providing a novel molecular explanation for the gender disparity observed in CHD. In addition, we showed a statistically significant difference between rs662799 and CHD in the subgroup aged from 55–65, although the underlying mechanism will require additional studies.Gender and age are independence risk of CHD ,72–74. EAPOA5 rs662799 polymorphism varies greatly among different populations. The rs662799-G allele frequency is 26.7% in Chinese populations, similar to that in Japanese populations (29.1%). However, the Chinese frequency is much higher than that in European populations (1.7%). Nevertheless, accumulating evidence indicates a strong association between APOA5 rs662799 and CHD among different populations. In addition to APOA5 rs662799, there are associations between other APOA5/A4/C3/A1 polymorphisms and CHD, which include APOA5 rs3135506 and APOA/A4/C3/A1 cluster haplotypes [The frequency of the plotypes . FurtherAPOA5 polymorphisms involved in the genetic studies Click here for additional data file.S1 File(DOCX)Click here for additional data file.S1 Table* p values were determined by the Wilcoxon-Mann-Whitney test.(DOCX)Click here for additional data file.S2 Table(DOC)Click here for additional data file.