In further subgroup analyses, the increased risk of cancer was observed in a subgroup of Caucasians with regards to endometrial cancer. Our meta-analysis suggests that the PAI-1 4G/5G polymorphism most likely contributes to susceptibility to cancer, particularly in Caucasians. Furthermore, the 4G allele may be associated with an increased risk of endometrial cancer.Plasminogen activator inhibitor-1 (PAI-1), belonging to the urokinase plasminogen activation (uPA) system, is involved in cancer development and progression. The PAI-1 promoter 4G/5G polymorphism was shown to contribute to genetic susceptibility to cancer, although the results were inconsistent. To assess this relationship more precisely, a meta-analysis was performed. The electronic databases PubMed, Scopus, Web of Science and Chinese National Knowledge Infrastructure (CNKI) were searched; data were extracted and analyzed independently by two reviewers. Ultimately, 21 eligible case-control studies with a total of 8,415 cancer cases and 9,208 controls were included. The overall odds ratio (OR) with its 95% confidence interval (CI) showed a statistically significant association between the PAI-1 promoter 4G/5G polymorphism and cancer risk (4G/4G vs. 5G/5G: OR=1.25, 95% CI=1.07–1.47, P Despite many years of primary and clinical research aimed at curbing tumor growth, metastasis remains the main cause of mortality in cancer patients . During The PAI-1 gene is located on chromosome 7 and contains 8 introns and 9 exons ,11 have To date, a number of molecular epidemiological studies have been performed to evaluate the association between PAI-1 promoter 4G/5G polymorphism and risks for different types of tumor, including breast cancer –17, coloWe carried out a search in PubMed, Scopus, Web of Science and Chinese National Knowledge Infrastructure (CNKI) databases with a combination of the following keywords: ‘plasminogen activator inhibitor-1’, ‘PAI-1’, ‘SERPINE1’, ‘polymorphism’, ‘variation’, ‘variant’, ‘carcinoma’, ‘tumor’ and ‘cancer’ (the last search was updated on 10th February 2012). We evaluated potentially relevant publications by examining their titles and abstracts. All studies with full text matching the eligible criteria were retrieved. Additional relevant studies were identified by a manual search of the references of retrieved articles and reviews.Studies included in this meta-analysis met the following criteria: a) evaluation of the link between PAI-1 promoter 4G/5G polymorphism and cancer risk, b) a case-control design, c) contained sufficient published data for estimating odds ratios (ORs) and 95% confidence intervals (CIs).The quality of each study was assessed independently by two reviewers who used the Newcastle-Ottawa Scale (NOS) . The NOSInformation was extracted independently by two reviewers according to the inclusion criteria. Any disagreement was settled by consensus among the two. For each study, the following characteristics were collected: the first author’s last name, year of publication, country of origin, ethnicity, numbers of genotyped cases and controls, source of control groups and genotyping methods. Different ethnic descents were categorized as Caucasian, Asian and mixed, which included more than one ethnic descent. We also contacted study authors for any missing data.When the source of controls was not clearly defined in the paper, it was defined ‘not specified’ to be conservative. The ethnicity of each study population was defined as the ethnic group of ≥90% of the study subjects. When the paper did not specify the ethnicity of the study population, it was hypothesized based on the most frequent ethnic group in the study country.Crude ORs together with their corresponding 95% CIs were used to calculate and assess the strength of association between PAI-1 promoter 4G/5G polymorphism and cancer risk. We first estimated cancer risk associated with PAI-1 promoter 4G/5G polymorphism by 4G/4G and 4G/5G genotypes compared with the 5G/5G (co-dominant model) and then evaluated 4G/4G+4G/5G vs. 5G/5G, and 4G/4G vs. 4G/5G+5G/5G, assuming the dominant and recessive effects of the variant 4G allele, respectively. The departure of frequencies from those expected under Hardy-Weinberg equilibrium (HWE) was assessed by Chi-square goodness-of-fit tests in controls. Stratified analyses were also performed by cancer type  and ethnicity.For the heterogeneity test, a random-effect model (the DerSimonian and Laird method)  was usedWith regard to sensitive analyses, the influence of each study in the pooled OR was examined by repeating meta-analyses while omitting each study one at a time. We performed visual inspection of funnel plots to examine the underlying publication bias, and also used Egger’s weighted regression method to calculate P for bias . All staWe identified 21 articles –28,33–35The NOS results showed that 81.0% of the studies were of high quality (NOS score >6), with an average NOS score of 7.6, which indicated that the methodological quality was generally good. We defined studies that scored ≥7 as having high methodological quality, and we judged 4 ,22,26,35heterogeneity=0.001; 4G/4G vs. 4G/5G+5G/5G: OR=1.10, 95% CI=1.03–1.17, Pheterogeneity=0.194; 4G/4G+4G/5G vs. 5G/5G: OR=1.17, 95% CI=1.01–1.35, Pheterogeneity=0.041; heterogeneity=0.001; 4G/4G vs. 4G/5G+5G/5G: OR=1.12, 95% CI=1.04–1.21, Pheterogeneity=0.136; 4G/4G+4G/5G vs. 5G/5G: OR=1.28, 95% CI=1.04–1.57, Pheterogeneity=0.000; heterogeneity=0.951; 4G/5G vs. 5G/5G: OR=1.56, 95% CI=1.08–2.25, Pheterogeneity=0.830; 4G/4G vs. 4G/5G+5G/5G: OR=1.64, 95% CI=1.19–2.27, Pheterogeneity=0.866; 4G/4G+4G/5G vs. 5G/5G: OR=1.74, 95% CI=1.23–2.47, Pheterogeneity=0.979; The overall OR with its 95% CI revealed a statistical association between the PAI-1 promoter 4G/5G polymorphism and the risk of cancer  of each study was plotted against its log (OR). An asymmetric plot suggests a possible publication bias. Funnel plot asymmetry was assessed by the method of Egger’s linear regression test, a linear regression approach for measuring funnel plot asymmetry on the natural logarithm scale of the OR. The significance of the intercept was determined by the t-test  . As a reThe promoter 4G/5G polymorphism is the most well-characterized PAI-1 polymorphism, but the reported associations with cancer risk among studies are inconsistent. Our present meta-analysis, incorporating 21 case-control studies , suggests that the promoter 4G/5G polymorphism is significantly associated with increased cancer risk, particularly in Caucasians.How a promoter 4G/5G polymorphism increases the risk of developing cancer is yet to be established; however, it is known that the transcription of the PAI-1 gene is affected by the presence of a guanosine insertion (5G)/deletion (4G) polymorphism at the promoter region ,36. BothSince tumor origin may influence the results of the meta-analyses, we performed subgroup analyses by cancer type. The association of the PAI-1 promoter 4G/5G polymorphism with increased risk of cancer in this meta-analysis was significant in the endometrial cancer subgroup. In addition to the above reasons, the presence of the 4G allele results in a higher PAI-1 transcription response to cytokines or growth factors than the 5G allele, so the 4G/5G polymorphism may influence tissue PAI-1 levels in endometrial cancer patients through the action of cytokines released by tumor cells . HoweverDue to differences in the underlying genetic backgrounds and/or environmental and social factors of the different populations studied, the incidence of gene polymorphisms varies substantially between different racial or ethnic populations. In this meta-analysis, when stratifying by ethnicity we found that the association between PAI-1 promoter 4G/5G polymorphism and increased risk of cancer was significant only in Caucasians, not in the Asian population. As a multi-factorial disease, the factors causing cancer vary in different populations. Although the reasons for this difference remain controversial, there are several studies showing that it depends on a combination of differences in polymorphism distributions with nongenetic factors. Therefore, the functional difference of this polymorphism of PAI-1 in Caucasians and Asians may result from interactions with environmental and social factors. In addition, considering the multistage character of cancer, genetic factors may play a role at specific stages only, which may vary between populations. Therefore, larger-scale studies and combined analysis are warranted to further confirm the effect of ethnic difference in this polymorphism on cancer risks. These studies should be stratified by ethnicity, differentiated by the stage of carcinogenesis and include an assessment of interactions with environmental factors.Additionally, heterogeneity may influence the results of meta-analyses. Evident heterogeneity between studies was observed in overall comparisons and also in certain subgroup analyses. Through the subgroup analysis, we found that the source of heterogeneity was from types of cancer and ethnicity, suggesting that tumor site and population play an important role for the same polymorphism.When interpreting the results, the following limitations of the study should be considered. First, only published articles were included in this study. Although we conducted a thorough and comprehensive search and also contacted study authors for missing data , publicaOur results suggest that the PAI-1 promoter 4G/5G polymorphism is a potential clinical genetic marker contributing to cancer susceptibility. Whether it could be applied to genotyping for clinical assessment requires large-scale population studies among different ethnicities and regions.


GSTM1, GSTT1 and GSTP1 polymorphisms might be involved in inactivation of procarcinogens that contribute to the genesis and progression of cancers. However, studies investigating the association between GSTM1, GSTT1 or GSTP1 polymorphisms and prostate cancer (PCa) risk report conflicting results, therefore, we conducted a meta-analysis to re-examine the controversy.The GSTM1, GSTT1 or GSTP1 polymorphisms and PCa risk were included. The principal outcome measure was the odds ratio (OR) with 95% confidence interval (CI) for the risk of PCa associated with GSTM1, GSTT1 and GSTP1 polymorphisms.Published literature from PubMed, Embase, Google Scholar and China National Knowledge Infrastructure (CNKI) were searched . According to our inclusion criteria, studies that observed the association between GSTM1 null genotype, and the similar results were observed when stratified by ethnicity and control source. Further, the more important is that the present study first reported the high risks of PCa for people who with dual null genotype of GSTM1 and GSTT1 , or who with GSTT1 null genotype and GSTP1 A131G polymorphism . But no association was determined between GSTT1 null genotype  or GSTP1 A131G polymorphism  and the PCa risk.Fifty-seven studies involving 11313 cases and 12934 controls were recruited. The overall OR, which was 1.2854 (95% CI = 1.1405–1.4487), revealed a significant risk of PCa and GSTM1 null genotype, with dual null genotype of GSTM1 and GSTT1, or with GSTT1 null genotype and GSTP1 A131G polymorphism are associated with high risks of PCa, but no association was found between GSTT1 null genotype or GSTP1 A131G polymorphism and the risk of PCa. Further rigorous analytical studies are highly expected to confirm our conclusions and assess gene-environment interactions with PCa risk.Our meta-analysis suggested that the people with  Prostate cancer (PCa) has become a major public health problem concern worldwide for its high morbidity and mortality levels. It is the second leading cause of cancer related to death in Europe, North America, Latin America, and some parts of Africa in men. It has been reported that PCa have a prominent variation in incidence among different ethnic groups and geographic regions. For instance, North Americans have the highest incidence, especially the African-Americans in USA, and the lowest is among Asian men GSTA),μ(GSTM),θ(GSTT),π(GSTP),σ(GSTS),κ(GSTK),ο(GSTO),τ(GSTZ), while several of them are polymorphic that contain one or more homodimer or heterodimer forms Glutathione S-transferases (GSTs) constitute a superfamily of ubiquitous, multifunctional phase II metabolic enzymes. These enzymes play a crucial function in the detoxification of both endogenous and exogenous carcinogens GSTM1, GSTT1 and GSTP1 have been studied most. The GSTM1, GSTT1 and GSTP1 gene were located on chromosome 1p13.3, 22q11.23, 11q13 respectively GSTM1 and GSTT1 gene exhibit an inherited homozygous deletion polymorphism (null genotype), which has been associated with the loss of enzyme activity and increased vulnerability to cytogenetic damage GSTP1 polymorphism, a single nucleotide polymorphism in exon 5  received most attention. The A-to-G transition results in an amino acid change from isoleucine to valine so that leading to significantly lower conjugating activity among individuals who carry one or more copies of the G allele  compared with those who have the A/A (Ile/Ile) genotype GSTM1, GSTT1 or GSTP1 polymorphisms, but inconsistent results have been reported. In 2009, Zengnan Mo et al. conducted a meta-analysis GSTM1 null genotype conferred an increasing risk of PCa on a wide population basis, but no relationship was found between GSTT1 and GSTP1 polymorphisms and the PCa risk. During recent three years, many new researches were performed to study the association between PCa risk and GSTM1, GSTT1 or GSTP1 polymorphisms, so an updated meta-analysis is needed.In recent years, GSTM1’, ‘glutathione S-transferase T1’ or ‘GSTT1’, ‘glutathione S-transferase P1’ or ‘GSTP1’, ‘prostate’ or ‘urothelial’, ‘cancer’ or ‘carcinoma’ or ‘neoplasm’, ‘polymorphism’ or ‘polymorphisms’. To minimize potential publication bias, no restrictions were placed on language, time period, sample size, type of study and population. All eligible articles were retrieved and their references were checked for other relevant studies. The inclusion criteria were: (1) studies which evaluated associations between GSTM1, GSTT1, GSTP1 polymorphisms and PCa risk; (2) control population did not contain malignant tumor patients. The exclusion reasons of studies were: (1) insufficient original data for the calculation of odds ratios (ORs) with corresponding 95% confidence intervals (95%CIs); (2) when multiple reports were available for the same study population, we included only the most recent or the largest report. Two investigators independently reviewed the titles, abstracts to determine if an individual study was eligible for the inclusion and exclusion criteria and all disagreements were resolved during a consensus meeting among all reviewers.According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (Checklist S1), we identified all publications  by conducting computer-based searches of PubMed, Embase, Google Scholar and China National Knowledge Infrastructure (CNKI). The combination of key words were as follows: ‘glutathione S-transferase M1’ or ‘P-value for Hardy Weinberg Equilibrium (HWE). To ensure the accuracy of extracted information, two independent researchers (Gong and Dong) extracted raw data according to the inclusion criteria. The conflicting evaluations were settled by a discussion among all investigators. Ethnic groups were mainly defined as Caucasian, Asian, African and African-American. Study designs were stratified into three groups: population-based studies, hospital-based studies and benign prostatic hyperplasia (BPH) based studies.GSTM1, GSTT1 and GSTP1 polymorphisms and risk of PCa. The significance of the pooled OR was determined by the Z test and P value (two-tailed) <0.05 was considered significant. In our study, the 2I test was used to assess the heterogeneity between studies  2I>50% or P<0.10. When there was no heterogeneity (2I≤50% or P≥0.10), the fixed-effects model (the Mantel-Haenszel method) was used, otherwise, the random-effects model (the DerSimonian and Laird method) was used when the heterogeneity existed (2I>50% or P<0.10) P<0.05 We used crude ORs with corresponding 95% CIs as a measure of the association between GSTM1, GSTT1, and GSTP1. Therefore, we obtained 62 relevant articles that examined the association between the polymorphisms of GSTM1, GSTT1 or GSTP1 and PCa risk. Out of them, three studies were excluded because of the insufficient data for OR calculation. Four researches GSTM1 polymorphism and PCa risk, 37 were about GSTT1, and 35 were about GSTP1. In all eligible studies, there were 26 studies on GSTM1 genotype of Caucasians, 13 studies of Asians, 3 studies of Africans, 1 study of African-Americans and 1 of mixed populations. Accordingly, 23 studies on GSTT1 genotype were of Caucasians, 9 studies of Asians, 3 studies of Africans, 1 study of African-Americans and 1 of mixed populations. About GSTP1 genotype, there were 25 studies of Caucasians, 6 studies of Asians, 2 studies of African-Americans and 1 of mixed populations. According to the control source, 26 were population-based researches, 15 were hospital-based researches, 9 studies were used BPH patients as controls, two were used both healthy people and BPH patients as controls, while the other two studies used hospital-based and BPH patients as controls. In addition, there was one study mixed the healthy people and BPH patients as controls, and the other two were not clarified.After searching with our eligibility criteria, initially a total of 94 potentially relevant publications were indentified. When screening the title or abstract, 32 studies were excluded because they are not associated with PCa risk and the polymorphisms of GSTM1 polymorphism. The overall data showed that the individuals who carried the GSTM1 null genotype had a significantly increased PCa risk compared with those who carried the GSTM1 present genotype in all subjects  and Asians . But it seems that there was no association between PCa risk and the GSTM1 null genotype in Africans . When considered the source of the control groups, two studies GSTM1 null genotype in population-based , hospital-based  or in BPH-based controls .Data from 44 case-control studies comprising 7,893 PCa cases and 9,668 controls were pooled together for analysis of the GSTT1 null genotype. Overall, no enhanced risk was found between the null genotype of GSTT1 polymorphism and PCa , Asians  or Africans . In addition, we conducted the subgroup analysis by source of controls with omitting two researches GSTT1 null genotype in population-based , in hospital-based  or in BPH-based controls .Totally, 37 studies met the inclusion criteria and were selected in the meta-analysis with 7,187 cases and 8,761 controls for analysis of the PCa risk and GSTP1 A131G polymorphism. However, the result showed no significant risk between PCa and the GSTP1 A131G polymorphism  was similar with the previous one. We also performed subgroup analysis stratified by ethnicity and control source. By ethnicity, we did not acquire remarkable enhanced risks of PCa with GSTP1 A131G polymorphism either in Caucasians  or in Asians . By control source, two studies P = 0.3817, 2I = 62.58%), hospital-based  or BPH-based  controls with the GSTP1 A131G polymorphism.We obtained 35 articles after searching and data extraction based on our eligibility criteria. In total, 8,560 cases and 9,084 controls were pooled for the association between PCa risk and GSTM1, GSTT1 and GSTP1 genotypes  and people who with GSTT1 null genotype and GSTP1 A131G polymorphism . However, when combined the GSTM1 null genotype and GSTP1 A131G polymorphism , or the three genotypes , no dramatic PCa risks were obtained.Several studies reported the combination of enotypes . For theGSTM1, GSTT1 or GSTP1 genotypes (data not shown). The results of sensitivity analyses indicated the stability of the results of this meta-analysis.Sensitivity analyses were performed by sequential omission of individual studies for all subjects and subgroups. The corresponding pooled ORs were not materially altered in all subjects and subgroups of GSTM1 and GSTP1 polymorphisms were symmetrical (data not shown) and the P values of Egger’s test were 0.0625 and 0.4738 respectively, so the results showed no evidence of publication biases. However, the shape of GSTT1 genotype revealed a little unsymmetrical (data not shown), therefore the Egger’s test was further applied to provide statistical evidence and the result suggested the publication bias might be existed, and the P value was 0.0415. Hence, we conducted the trim-and-fill in order to get further information. The result revealed that the number of imputed studies was zero, and also the corrected OR was 1.102 (95% CI = 0.9596–1.2655) which was the same as the uncorrected one.Funnel plot and Egger’s test were both performed to access the publication bias in this meta-analysis. The funnel plot shapes of GSTM1, GSTT1 and GSTP1 should be pointed out because the polymorphisms of these genes may influence the enzyme activity, and eventually increase vulnerability to genotoxic damage GSTM1, GSTT1 or GSTP1 and PCa has been intensively investigated.PCa is the most commonly diagnosed non-skin malignancy among men and its incidence is expected to increase as the population age elevated GSTM1, GSTT1 or GSTP1 genetic variants and PCa risk were examined and all the results of the present meta-analysis were summarized in GSTM1 null genotype, whereas no elevated PCa risks were observed with the GSTT1 null genotype and GSTP1 polymorphism. It is consistent with the result of former meta-analysis, which was conducted by Zengnan Mo et al. in 2009. However, we included 11313 cases and 12934 controls from 57 studies in the present meta-analysis, which is much more than the previous one including 7,984 cases and 9,143 controls from 39 case-control studies. Hence, a more stringent and comprehensive result has been obtained.In this study, association between GSTM1 null genotype are in all subjects, especially in Caucasians and Asians, but not in Africans. The possible reason of the conflicting results among diverse ethnicities could be that different genetic backgrounds and environment they exposed to may have different effects on the PCa risk. Additionally, as limited sample size may have not enough statistical power to detect a real effect or generate a fluctuated estimation, the small sample size of Africans in this meta-analysis should also be taken into consideration.It is known that the allele frequencies of metabolic genes are not equally distributed throughout the human population but follow diverse ethnic patterns, therefore, the subgroups according to ethnicity were performed. Our results indicated that significant PCa risks of people with GSTM1 null genotype has strikingly increased the risk of PCa susceptibility when stratified by control source. However, we obtained the highest risk of PCa when only considered the hospital-based controls. The possible reason may be that GSTM1 null genotype could influence the susceptibility to non-cancer diseases, such as COPD GSMT1 null genotype Furthermore, we also showed that GSTM1, GSTT1 or GSTP1 genotypes and PCa risk and revealed important results. Eleven articles examined the people with dual null genotype of GSTM1 and GSTT1, and our result proved a remarkable increased PCa risk for these people. Moreover, the result also revealed a very strong risk of PCa for people who with GSTT1 null genotype and GSTP1 A131G polymorphism from five articles. The present meta-analysis is the earliest one to evaluate the potential interaction of the gene-to-gene and PCa risk. However, we should treat the results with caution for the limited sample size.In addition, we first observed the association between the combination of GSTT1 null genotype and GSTP1 A131G polymorphism, we failed to find the association between PCa risk and the polymorphisms, even though we stratified for ethnicity and control source, which is consistent with the previous meta-analysis For the GSTM1 polymorphism among the studies was extreme. It suggested that there were other potential confounding factors in the included studies, such as the genotyping error, selection bias, or population-specific gene-gene or gene-environment interaction, allelic heterogeneity, or chance GSTT1 polymorphism and PCa risk, but did not find it in the studies about the PCa risks with GSTM1 and GSTP1 polymorphisms. It is known that positive results usually have a greater probability of being published, and such bias may occur when studies with null or unexpected results. In addition, we also performed the trim-and-fill and the corrected OR was the same as the uncorrected one. Therefore, our result of GSTT1 null genotype was reliable and stable to some extent. Thirdly, the overall outcomes were based on unadjusted effect estimates. Although the cases and controls were matched on age, sex and residence in all studies, these confounding factors might slightly modify the effective estimates and a more precise evaluation needed to be adjusted by the potentially suspected factors. Finally, as the meta-analysis remains a retrospective research which is subject to the methodological deficiencies of the included studies, we tried to develop a detailed protocol before initiating the study, and then performed an explicit method for study researching, selection, data extraction and data analysis to minimize the likelihood of bias.However, there are some limitations in this meta-analysis. First of all, even though we performed subgroup analyses stratified by ethnicity and control source, the heterogeneity for GSTM1 null genotype is associated with a high increased risk of PCa and no significant PCa risks were obtained for GSTT1 and GSTP1 polymorphisms. To our knowledge, the present study is the first meta-analysis to date to report the interaction between the combination of GSTM1, GSTT1 or GSTP1 genotypes and PCa risk. In the meta-analysis, we proved remarkable elevated PCa risks for people who with dual null genotype of GSTM1 and GSTT1, and also for people who with GSTT1 null genotype and GSTP1 A131G polymorphism. Larger and more rigorous analytical studies will be required to confirm our findings and evaluate gene-environment interactions with PCa risk.In conclusion, our meta-analysis suggested that Checklist S1(DOC)Click here for additional data file.


Emerging evidence showed that VEGF gene polymorphisms are involved in the regulation of VEGF protein expression, thus increasing an individual's susceptibility to preeclampsia (PE); but individually published results are inconclusive. The aim of this meta-analysis was to investigate the associations between VEGF gene polymorphisms and PE risk.A systematic literature search of MEDLINE, Embase, Web of Science, and CNKI  databases was conducted. Statistical analyses were performed using STATA 12.0 software and Review manager 5.1. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations.According to the inclusion criteria, 11 case-control studies were finally included in this meta-analysis. A total of 1,069 PE cases and 1,315 controls were included in this study. Our meta-analysis indicated that VEGF +936C/T  or −634G/C polymorphism  was associated with the risk of PE, whereas there was no association between −2578C/A  or −1154G/A  polymorphism and PE risk in our study.Our meta-analysis suggested that VEGF −2578C/A or −1154G/A polymorphism had no association with PE risk in all examined patients, whereas there was an association between VEGF +936C/T or −634G/C polymorphism and risk of PE. Preeclampsia (PE), a human-pregnancy-specific disease defined as the occurrence of hypertension and significant proteinuria in a previously healthy woman on or after the 20th week of gestation, occurs in about 2–8% of pregnancies Vascular endothelial growth factor (VEGF), a member of VEGF family, is a major angiogenic factor and potential regulator of endothelial cell proliferation There are several common single nucleotide polymorphisms (SNPs) in the VEGF gene, including +936 (rs3025039), −634 (rs2010963), −1154 (rs1570360), and −2578 (rs699947) positions, which could alter gene expression and protein production, and alter the risk of developing diseases characterized by deranged angiogenesis single-nucleotide polymorphism”, “variant”, “genotype”, “mutation”, “pregnancy induced hypertension”, and “gestational hypertension”.A systematic literature search of MEDLINE , Embase , Web of Science , and CNKI  databases was conducted by two study investigators (D.C. and Y. H.) independently for all relevant articles. Key words used in the research included “vascular endothelial growth factor”, “VEGF”, “preeclampsia”, “polymorphism”, “Studies eligible for inclusion in this meta-analysis should meet the following criteria: (a) case-control studies or cohort studies focused on associations between VEGF polymorphism and risk of PE; (b) patients have clinically confirmed PE; (c) The studies provided the number of cases and controls for various genotypes. PE was defined as elevated blood pressure (≥140/90 mm Hg on two measurements ≥6 hours apart) with ≥1+ proteinuria or 300 mg/24 hours after the 20th week of pregnancy Information was carefully extracted from all the eligible publications. The following data were collected from each study: first author’s name, publication date, country, ethnicity, source of controls, genotyping method, total numbers of cases and controls, and number of cases and controls for each VEGF polymorphism. An attempt was made to contact authors if data presentation was incomplete or if it was necessary to resolve an apparent conflict or inconsistency in the article. Any disagreements were resolved by consensus.P value of heterogeneity test was <0.1. The OR and 95% CI were calculated for each study, and the combined OR and 95% CI were calculated for all eligible studies. The significance of the combined OR was determined by the Z-test, in which P<0.05 was considered significant. Heterogeneity assumption was assessed by the Chi-square based Q test and was regarded to be statistically significant if P<0.10. The potential publication bias was assessed by Begg’s funnel plot and Egger’s test Review manager 5.1 program provided by the Cochrane Library and Stata  were used to perform all the statistical analysis. The association was evaluated with the use of the allelic contrast , as well as the dominant model (WM+MM versus WW), the recessive model (MM versus WM+WW), and the homozygous contrast [MM versus WW], respectively. Two models of pooling data for dichotomous outcomes were conducted: the random-effects model and the fixed-effects model. The pooled statistical analysis was calculated using the fixed effects model, but a random-effect model was performed when the The flow chart that displays the study selection process was shown in The characteristics of 11 included studies were summarized in P<0.1), which might be the result of the difference in ethnicity, country, source of controls, and genotype methods, so random effects model was conducted to pool the results. Overall, the significant association was found between VEGF +936C/T polymorphism and risk of PE in allele contrast , recessive model , and homozygous contrast . The results suggested that the T allele carriers might have an increased risk of PE compared with those individuals with the CC homozygote.The evaluation of association between VEGF polymorphisms and PE risk was presented in P = 0.78, P = 0.98; recessive model, OR = 0.93, 95%CI = 0.68–1.26, P = 0.64; and homozygous contrast, OR = 0.93, 95%CI = 0.65–1.32, P = 0.68).A total of 572 cases and 574 controls from 7 case-control studies were included for data synthesis. The meta-analysis results showed that VEGF –2578C/A polymorphism was not linked to the risk of PE under all genetic models , while the differences in recessive model  and homozygous contrast  were not significant.A total of 441 cases and 485 controls from five case-control studies were included for data synthesis. We noted a statistically significant finding in the pooled analysis for the VEGF –634G/C in PE. In the allelic contrast, a significantly increased risk was presented for the comparison of the C allele with the G allele .A total of 217 cases and 209 controls from only three case-control studies were included for data synthesis. The meta-analysis results showed that VEGF –1154G/A polymorphism was not associated with the risk of PE under all genetic models  , which indicated low risk of publication bias in this meta-analysis.Begg’s funnel plot and Egger’s test were performed to assess the publication bias of included studies. The shapes of the funnel plots did not reveal any evidence of obvious asymmetry under the allele contrast  . Egger’sThe cause of PE remains largely unknown but there is growing evidence that an imbalance between VEGF family and possible anti-angiogenic factors is closely related to the pathogenesis of PE. During a normal healthy pregnancy, a highly coordinated program ensures that the placenta and fetus are supplied with an adequate blood supply necessary for proper oxygen and nutrient delivery. In the development of PE, defective angiogenesis and the related fetoplacental vascular dysfunction are therefore considered key steps. Therefore, one area of intensive research in recent years focused on VEGF signaling pathway in PE development, which is necessary for the maintenance of proper endothelial cell function and health.Recently, case-control studies have shown associations between VEGF gene polymorphisms and PE. In the present study, the associations between four genetic polymorphisms in VEGF genes and PE were investigated from eleven eligible case-control studies. We found two SNPs were statistically associated with PE, which suggests that genetic variation in +936C/T and –634 G/C loci might play a role in this disease. To our knowledge, this is the first meta-analysis to evaluate the relationship between SNPs in the VEGF gene and the risk of PE.et al., VEGF +936C/T variant may be an important determinant of VEGF plasma levels. Livingston JC, et al. et al, VEGF is a multifunctional cytokine that plays a pivotal role in angiogenesis in vivo. There are several polymorphisms in the VEGF gene and many polymorphisms are associated with the protein production. Among these, four VEGF SNPs, +936C/T in the 3′-untranslated region, –634G/C in the 5′-untranslated region, and –2578C/A and –1154G/A in the promoter region, were reported to modulate VEGF expression Several limitation of this present study should be acknowledged. Although an adequate search strategy was used to identify eligible studies, it was possible that some eligible studies were not included, which may have biased our results. In addition, we analyzed a relatively small number of studies (11 studies), including 1,069 cases, which may reduce the statistical power for identifying possible associations between the VEGF polymorphisms and PE risk. Moreover, other clinical factors such as age, ethics, and different gestational weeks in each study might lead to bias. Determining whether or not these factors influence the results of this meta-analysis would need further investigation. Therefore, a more well-designed study with larger sample sizes is needed to further assess the precise effect of these VEGF polymorphisms in PE, and further studies are needed to see if other genotype of VEGF confers a risk of PE in the populations.Our meta-analysis suggested that VEGF –2578C/A or –1154G/A polymorphism had no association with PE risk in all examined patients, whereas there was an association between VEGF +936C/T or –634G/C polymorphism and risk of PE. However, further studies are necessary in order to warrant and validate the associations between VEGF gene polymorphisms and PE risk.Figure S1PRISMA 2009 Flow Diagram.(DOC)Click here for additional data file.Checklist S1PRISMA 2009 Checklist.(DOC)Click here for additional data file.


Frequent deletions of the kinesin-like protein gene 1B (KIF1B) have been reported in neural tumors. Recently, a genome-wide association study revealed an association between polymorphisms in the KIF1B gene and the risk of hepatocellular carcinoma (HCC), and several case-control studies have further investigated this relationship. However, these studies have yielded controversial results. We therefore performed a meta-analysis to derive a more precise estimation of the association between the KIF1B gene polymorphisms and HCC risk.PubMed, EMBASE, the ISI Web of Science and the CNKI databases were systematically searched to identify relevant studies. A total of 5 studies containing 13 cohorts with 5,773 cases and 6,404 controls were included. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were used to assess the strength of the associations. Subgroup analyses were conducted based on ethnicities, sample sizes and quality scores. Overall, the G allele at rs17401966 of the KIF1B gene was associated with a significantly decreased risk for HCC . Furthermore, subgroup analyses showed that the G allele at rs17401966 of the KIF1B gene significantly reduced the risk for HCC in Chinese cohorts , large-sample-size cohorts  and high-quality cohorts . However, no significant associations were found in small-sample-size cohorts, studies with low-quality scores and when excluding the cohorts from the study reporting the original discovery.These findings demonstrate that the presence of the G allele at rs17401966 of the KIF1B gene may decrease the risk for HCC and suggest that KIF1B may play a critical role in the development of HCC. High-quality studies with larger sample sizes and different ethnic populations will be of great value to further confirm these findings. Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer worldwide and the third most frequent cause of cancer-related death During the last several decades, hypothesis-based research has revealed a number of genetic predispositions associated with HCC Over the past decades, kinesin-like factor 1 B (KIF1B) has been explored extensively as a kinesin superfamily member. The members of this family are responsible for the transport of organelles, vesicles, protein complexes and RNA to specific destinations A systematic review and meta-analysis were performed according to the guidelines of PRISMA  Studies were considered for inclusion in the meta-analysis if they met the following criteria: (i) evaluated the association of KIF1B gene polymorphisms and the risk of HCC, (ii) cohort-based or case-control studies, and (iii) presented sufficient data for calculating the odds ratios (ORs) with corresponding 95% confidence intervals (95%CIs). The major exclusion criteria were as follows: (i) review or comment articles, case-only studies or family-based studies, (ii) lack of availability of sufficient data for estimation of ORs with 95%CIs, and (iii) duplication of previous publications and replicated samples.Two reviewers (Z.C. Wang and Q. Gao) screened the studies and extracted the raw data from all eligible publications independently. The following characteristics were collected using a data extraction form that included the first author's name, the year of publication, the cohort of the study, the ethnicity of the patients, the type and number of patients and controls with various genotypes, age at the time of the study, gender and genotyping method. Genotype distributions reported in percentages were converted to numbers. If allele frequencies were not given, they were calculated from the corresponding genotype distributions. For some studies For the KIF1B gene, we estimated the HCC risk associated with the G allele of the KIF1B gene at rs17401966 in dominant, co-dominant and recessive genotypic models, compared with the A allele. The genotypic models were as follows: allele (G vs. A), co-dominant , dominant (GG+AG vs. AA), and recessive (GG vs. AG+AA). ORs with corresponding 95% confidence intervals (CIs) and P-values were calculated to estimate the strength of the association between the KIF1B polymorphisms and risk of HCC.I2 tests were performed to assess the statistical heterogeneity, and the Q-statistic tests with P≤0.10 were used to define a significant degree of heterogeneity. If there was no heterogeneity (P>0.10), the fixed effects were calculated as the inverse variance-weighted average of the log OR. If there was substantial heterogeneity (P≤0.10), random effects were calculated. The 95% CIs were calculated using Woolf's method A Cochrane chi-square-based Q-test was performed to test the heterogeneity among studies or cohorts The combined search yielded 21 references. Eventually, 16 studies were excluded based on the inclusion/exclusion criteria , resultiWe perform the meta-analysis of the included studies in three stages. In the first stage, we analyzed the pooled data including populations from China, Japan, Korea and Saudi Arabia, irrespective of ethnicity. In the second stage, we stratified thirteen cohorts by their ethnicities. Of the thirteen cohorts, there were nine Chinese cohorts, two Japanese cohorts, one Korean cohort and one Saudi Arabian cohort. We only performed subgroup analysis in the Chinese cohorts because the other three ethnicities did not meet the PRISMA criteria that a meta-analysis usually applies to more than 3 original data sets In the pooled analysis of 13 cohorts, a significant allelic association was recorded under a random-effect model, with OR  = 0.81 , indicating that the G allele was associated with a decreased HCC risk compared to the A allele . The het2I = 45%, P = 0.01) and recessive  genotypic models. Notably, a low heterogeneity and a high effect were also detected in co-dominant models . Compared with the heterogeneity and significance in all the 13 cohorts, the heterogeneity in the Chinese subgroups did not decrease considerably, except in the co-dominant model , while the effects and significance levels all slightly increased within the co-dominant , dominant  and recessive  genotypic models.When stratifying the pooled data, only the Chinese subgroups met the criteria for subgroup analysis. The significant associations were detected under dominant , co-dominant  and recessive  genotypic models . HoweverTo decrease the reporting bias and increase reliability, we conducted the meta-analysis excluding the discovery study. A meta-analysis was performed in the remaining cohorts after excluding the discovery cohorts . No signEach cohort was excluded individually to investigate the influence of the individual data set on the pooled ORs. The exclusion of any single cohort did not alter the overall significance of the final decision, suggesting that the results were robust.Funnel plots were calculated in each stage of the meta-analysis to allow for visual inspection of the results of Egger's test. The shape of the funnel plots for these polymorphisms was symmetrical , indicatUnbiased epidemiological investigations with large sample sizes of gene polymorphisms can provide insights into the relationship between candidate genes and diseases. Through this method, many associations between gene polymorphisms and the risk of several types of cancers have been detected The positive association of the G allele at rs17401966 in KIF1B polymorphisms among all populations and in the subgroup of the Chinese population under co-dominant, dominant and recessive genotype models suggests that this variant could decrease HCC risk in these populations. Even though the heterogeneity among these studies and cohorts was relatively high, the association still existed under a random-effect model. Subgroup analyses revealed that cohorts with small sample sizes and low quality scores were sources of heterogeneity. In addition, the decreased heterogeneity and the increased significance in Chinese subgroups suggested that the high heterogeneity was also partly related to variations in ethnicity.A meta-analysis of the cohorts while excluding those used in the previous discovery study showed no association between KIF1B polymorphisms at rs17401966 and HCC risk. This inconsistency might be attributed to the fact that there were heterogeneous population structures, considering that 4 different ethnicities were represented in the cohorts when the cohorts from the discovery studies were excluded, particularly the frequencies of the G allele varied between the Saudi Arabian cohort (P = 0.39) KIF1B, located on chromosome 1p36.21, encodes a kinesin superfamily member involved in the transport of organelles and vesicles Some limitations of our meta-analysis should be acknowledged when interpreting the results. First, the between-cohort heterogeneity was a major concern because obvious heterogeneity was detected in the overall analyses and Chinese subgroups. We explored several possible sources of heterogeneity, including ethnicity, sample sizes and quality scores. Fortunately, we did find that small sample sizes and low quality scores were sources for this heterogeneity. However, we cannot entirely rule out the possibility that other unknown confounding factors might have biased this finding. Therefore, the conclusion should be adopted conservatively. Second, some potential confounding factors, such as age, tobacco smoking, alcohol drinking and aflatoxin exposure, could not be assessed due to insufficient data. Third, the data on ethnicities other than Chinese were limited. Finally, the sample sizes were relatively small, especially in some subgroup analyses.In conclusion, this study is the first meta-analysis to summarize the relationship between KIF1B gene polymorphisms and the susceptibility to HCC. Our results suggests that the G allele at rs17401966 in the KIF1B gene decreases the risk of HCC, providing additional data supporting the potential functional role of KIF1B in hepatocarcinogenesis, which needs to be authenticated through molecular and cellular approaches. Further studies with large sample sizes, different ethnic populations and the exclusion of other confounding factors are still required.Figure S1Selection of the related studies.(TIF)Click here for additional data file.Figure S2Forest plot of association between KIF1B polymorphisms and HCC risk when excluding the discovery cohorts.(TIF)Click here for additional data file.Figure S3Funnel plot of the association between KIF1B polymorphisms and HCC risk in all cohorts.(TIF)Click here for additional data file.Table S1Characteristics of the studies and cohorts included in the meta-analysis.(DOC)Click here for additional data file.Table S2KIF1B polymorphisms in all cohorts when excluding the discovery study under alternative genetic models.(DOC)Click here for additional data file.Table S3PRISMA 2009 checklist of this systematic review and meta-analysis.(DOC)Click here for additional data file.


Published evidence suggests that the rs2233678 (−842 G>C) polymorphism in the PIN1 (peptidyl-prolyl cis/trans somerase NIMA-interacting 1) promoter region may be associated with cancer risk; however, the conclusion is still inconclusive.We conducted a meta-analysis to determine whether −842 G>C polymorphism was associated with cancer risk. Odds ratio (OR) and 95% confidence intervals (95% CI) were used to assess the strength of association. Genotype distribution data and adjusted ORs were collected to calculate the pooled ORs. Meta-regression was conducted to detect the source of heterogeneity. Publication bias was evaluated by Egger’s test and Begg’s test.heterogeneity = 0.014, estimated by genotype distribution data; CC+GC vs. GG, OR = 0.668, 95% CI: 0.594–0.751, Pheterogeneity = 0.638, estimated by adjusted ORs). No evidence of publication bias was observed. Meta-regression revealed that ethnicities (p = 0.021) and sample size (p = 0.02) but not sources of control (p = 0.069) were the source of heterogeneity.A total of 11 eligible studies, including 9280 participants, were identified and analyzed. Overall, we found that carriers of the −842 C allele were associated with significantly decreased cancer risk  polymorphism significantly reduces cancer risk. Pro-directed phosphorylation is an important signaling mechanism, which regulates various cellular processes, such as cell proliferation, cell cycle progression, transcriptional regulation, RNA processing and cell differentiation Single nucleotide polymorphisms (SNPs) of PIN1 and cancer risk have been investigated by several studies There were 87 articles relevant to searching strategy . The flow chart shown in heterogeneity = 0.014, heterogeneity = 0.885; Begg = 1.000, PEgger = 0.604, Begg = 0.175, PEgger = 0.234, Egger’s test and Begg’s test were performed to assess the publication bias of eligible studies. These tests revealed no evidence of publication bias  family of proteins The two SNPs  occurring in the PIN1 promoter region have been shown to affect the expression level of PIN1. Segat and colleagues found that the −842 CC genotype was significantly associated with lower levels of PIN1 protein compared with the −667 CC genotype in peripheral mononuclear cells of healthy participants In the present meta-analysis, we found that significant heterogeneity was present in heterozygote and allele comparison. By performing subgroup analysis and meta-regression, we found that ethnicities and sample size were responsible for the heterogeneity. This could be explained by that the genetic background, risk factors in life styles, and the environmental factors exposed are different between Asian and Caucasian population. In addition, sensitivity analysis was performed to assess the effect of each individual study, and the results suggested that our meta-analysis was not affected by individual study. Furthermore, no evidence of publication bias was detected, which showed that our results were reliable.However, our results should be interpreted with caution, since this meta-analysis had some limitations. Firstly, limited by the number of genetic association studies, we did not assess the −842 G>C polymorphism and risk of a certain type of cancer. Since the risk factors of one cancer differ from others, our results could not simply applied to all kinds of cancer. Secondly, sample size of each included studies were relatively small, which may possibly lead to bias though sensitivity analysis, Begger’s test and Egger’s test revealed no significant findings. Thirdly, the genotype distribution in controls did not agree with Hardy-Weinberg equilibrium in one study, which may disturb pooled results. However, when this study was excluded, we still observed a significant association.To summary, our meta-analysis suggests that the −842 G>C polymorphism is associated with decreased cancer risk. To conform this association, large sample-sized and well-designed case-control studies are warranted.This study was carried out and reported in agreement with the PRISMA guidelines for systematic reviews and meta-analyses (supplementary information: Studies were selected according to the following inclusion criteria: (1) case-control studies; (2) investigating the association between PIN1 −842 G>C polymorphism and cancer risk; (3) with genotype distribution data to calculate combined ORs and 95% CIs or available adjusted ORs and 95% CIs. Studies without detail genotype distribution data were excluded. Titles and abstracts of searching records were primarily screened and full text papers were further retrieved to confirm eligibility. Two reviewers (Qi Li and Zhao Dong) extracted eligible studies independently according to the inclusion criteria. Disagreement between two reviewers was discussed with another reviewer (Yong Gao) till consensus was achieved.Data of eligible studies was extracted by two reviewers (Qi Li and Zhao Dong) independently with a pre-designed data-collection form. The following data was collected: name of first author, year of publication, country where the study was conducted, ethnicity, cancer types, source of control, Hardy-Winberg equilibrium, number of cases and controls, genotype frequency in cases and controls, adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Different ethnicity descents were categorized as Asian and Caucasian. Eligible studies were defined as hospital-based (HB) and population-based (PB) according to the control source. When Hardy-Winberg equilibrium (HWE) in the controls was tested by chi-square test for goodness of fit. Two reviewers reached consensus on each item.The association strength between PIN1 rs3746444 (−842 G>C) polymorphism and cancer risk was measured by OR with 95% CI. The estimates of pooled ORs were achieved by calculating a genotype distribution datagenotype distribution data or adjusted ORs and 95% CIs from each study. A 95% CI was used for statistical significance test and a 95% CI without 1 for OR indicating a significant increased or reduced cancer risk. The pooled ORs were calculated for allele comparison (C versus G), homozygote comparison (GG versus CC), heterozygote comparison (GC versus GG), dominant (CC+GC versus GG) and recessive (CC versus GC+GG) modes, assuming dominant and recessive effects of the variant C allele, respectively. Subgroup analyses were also conducted to explore the effects of confounding factors: ethnicities, sources of control and sample size. Sensitivity analyses were performed to indentify individual study’ effect on pooled results and test the reliability of results.Chi-square based Q test was used to check the statistical heterogeneity between studies, and the heterogeneity was considered significant when p<0.10 Publication bias was detected with Begg’s funnel plot and the Egger’ linear regression test, and a p<0.05 was considered significant Table S1PRISMA checklist.(DOC)Click here for additional data file.


The C/T-13910 lactase variant (rs4988235) was genotyped in 630 men with prostate cancer and 873 matched control participants. Dairy product consumption was assessed by diet questionnaire. Odds ratios (ORs) for prostate cancer in relation to lactase genotype were estimated by conditional logistic regression. Lactase genotype frequency varied significantly between countries, with frequencies of the T (lactase persistence) allele ranging from 7% in Greece to 79% in Denmark. Intake of milk and total dairy products varied significantly by lactase genotype after adjustment for recruitment center; adjusted mean intakes of milk were 44.4, 69.8 and 82.3 g/day among men with CC, CT and TT genotypes, respectively. The lactase variant was not significantly associated with prostate cancer risk, both in our data  and in a meta-analysis of all the published data . These findings show that while variation in the lactase gene is associated with milk intake in men, the lactase polymorphism does not have a large effect on prostate cancer risk.High dairy protein intake has been found to be associated with increased prostate cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). To further examine this possible relationship, we investigated the hypothesis that a genetic polymorphism in the High dairy protein intake has previously been found to be associated with increased prostate cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). The current study was nested in EPIC, and results from this first Europe-wide study suggest that while the C/T13910 lactase polymorphism is associated with milk intake, the variant has no large effect on prostate cancer risk. The data illustrate the challenges of applying mendelian randomisation to explore the relationship between dairy product consumption and cancer risk. Very large studies with both genetic and dietary data are thus needed for investigations using genetic proxies of nutritional exposures. A high intake of dairy protein has been found to be associated with increased risk for prostate cancer in the European Prospective Investigation into Cancer and Nutrition,lactase gene, is the major variant associated with activity of the lactase enzyme in European populations.lactase genotype is limited.15The main sugar in dairy products is lactose, and the digestion and absorption of lactose is dependent on the activity of the lactase enzyme (lactase-phlorizin hydrolase) in the wall of the intestine. A C/T polymorphism (rs4988235), which resides 13,910 base pairs upstream of the lactase coding sequence in the lactase C/T polymorphism and the limited evidence suggesting a link with dairy product consumption provide an opportunity to explore the Mendelian randomization approach, using lactase genotype as a proxy for dairy intake and exploiting the random allocation of alleles from parents to offspring, to overcome potential confounding of the association between dairy product consumption and cancer risk.The existence of the lactase genotypes in relation to intake of dairy products and risk for prostate cancer, among 630 men with incident prostate cancer and 873 matched control participants participating in the European Prospective Investigation into Cancer and Nutrition (EPIC).We report here findings from a Europe-wide study of the C/T-13910 Between 1992 and 2000, approximately 500,000 individuals  were recruited into the European Prospective Investigation into Cancer and Nutrition (EPIC) from 23 centers in 10 European countries. The methods of recruitment and study design have been described in detail elsewhere.Dietary intake during the year before enrolment was measured by country-specific validated food frequency questionnaires or diet histories, as previously described.26This study includes prostate cancer cases occurring after blood collection and individually matched male control participants from the eight participating countries which recruited men: Denmark, Germany, Greece, Italy, the Netherlands, Spain, Sweden and the United Kingdom (UK).via self-reported questionnaires; self-reported incident cancers are verified through medical records. Data on vital status in most EPIC study centers were collected from mortality registries at the regional or national level, in combination with data collected by active follow-up (Greece). The 10th Revision of the International Statistical Classification of Diseases, Injuries and Causes of Death (ICD) was used, and cancer of the prostate was defined as code C61. For each EPIC center closure dates of the study period were defined as the latest dates of complete follow-up for both cancer incidence and vital status .Follow-up for diagnosis of prostate cancer is provided through record linkage with population-based cancer registries in six of the participating countries: Denmark, Italy, the Netherlands, Spain, Sweden and the UK. In Germany and Greece, follow-up is active and is achieved through checks of insurance records and cancer and pathology registries as well as Case patients were men who developed prostate cancer after the date of blood collection and before the end of the study period, defined for each study center by the latest date of follow-up. The cases with no available blood sample and those participants who had missing information on the date of the blood donation or who had a history of another cancer (except nonmelanoma skin cancer) at the time of the blood collection were excluded. After these exclusions, at the time of genotyping for the current study, DNA was available for approximately 600 men with prostate cancer who had had their DNA extracted for the EPIC component of the Breast and Prostate Cancer Cohort Consortium.i.e. coded as moderately or as well differentiated) and 122 (17.4%) were classified as high-grade .Data on the stage and grade of disease at diagnosis were collected from each center, where possible. A total of 480 cases (76.7%) had information on tumor stage; of these 328 (52.6%) were classified as localized , and 152 (24.1%) were classified as advanced . Information on histological grade was available for 423 cases (65.2%); of these, 301 (47.8%) were classified as low-grade  at the time of diagnosis of the index case. An incidence density sampling protocol for control selection was used, such that controls could include participants who became a case later in time, while each control participant could also be sampled more than once. Matching criteria included: recruitment center, age at enrolment (±6 months), time of day of blood collection (±1 hr) and time between blood draw and last consumption of food or drinks . While these matching criteria are not all necessary for analyses of genotype, they are applied to allow the same sets to be used for analyses of multiple markers of risk, such as nested case control analyses of circulating concentrations of hormonal and nutritional biomarkers.lactase variant (rs4988235) was conducted using the TaqMan assay (Applied Biosystems) at Imperial College, London. The internal quality of genotype data was assessed by 2% blinded samples in duplicate and an intralaboratory concordance rate of greater than 97.2% was observed. Empty wells (containing water only) were also included on each plate. Hardy–Weinberg Equilibrium (HWE) checks have been performed among the controls, stratified by country. No deviation in HWE was observed (p > 0.05). The SNP was successfully genotyped in 97.8% of samples. In total, genotype data for the current analysis were available for 630 cases: 79 cases in Denmark, 179 in Germany, 9 in Greece, 50 in Italy, 22 in the Netherlands, 69 in Spain, 84 in Sweden and 138 in the UK.Genotyping of the C/T-13910 Measurements of circulating concentrations of several nutritional and hormonal biomarkers made for previous nested case control studies of prostate cancer in EPIC were available for a subset of participants in the current study. These analytes were phytanic acid, 25-hydroxyvitamin D, insulin-like growth factor 1 (IGF1), insulin-like growth factor binding protein 3 (IGFBP3), androstenedione, androstanediol glucuronide, testosterone, sex hormone binding globulin (SHBG), calculated free testosterone, enterodiol and enterolactone and details of the laboratory assays have been described elsewhere.26LCT genotype were compared using analyses of variance and multinomial logistic regression models for continuous and categorical variables, respectively, with adjustment for center of recruitment.The baseline characteristics of participants by lactase C/T polymorphism, analyses of variance were conducted for LCT genotypes, with adjustment for recruitment center, in relation to consumption of milk, yoghurt, cheese, butter, dairy based deserts (including ice-cream), total dairy products, dairy protein, total fat, fat from dairy products, calcium intake and circulating concentrations of nutritional and hormonal analytes. Nonconsumers of dairy milk are defined as persons consuming <5 g/day milk and milk beverages.To investigate dairy product intake by the lactase C/T genotype. Likelihood ratio chi-square tests were used to test the main effect of genotype on risk (comparing models with genotype terms with a model with no genotype terms), and tests for trend (trend tests of genetic effect) were obtained by scoring LCT genotypes as 0, 1 and 2, respectively, according to the number of variant T alleles, and with homozygotes for the C allele as the reference group. The effects of potential confounders, other than matching criteria, which are controlled for by design, were examined by including additional regression terms in the logistic regression models. Potential confounders were chosen a priori as factors that may be associated with the risk of prostate cancer developing or being detected and were smoking , body mass index , physical activity  (16), alcohol intake , marital status (married/cohabiting or not married/cohabiting) and education level . For each of these variables a small proportion of values were unknown; these values were included in the analyses as a separate category.Conditional logistic regression models were applied to calculate the relative risks (odds ratios) for prostate cancer in relation to the lactase C/T polymorphism with risk of prostate cancer across subgroups and by case characteristics, we used likelihood ratio tests to compare models with a cross-product term between the genotype trend test variable and subgroup membership with models without the cross-product term. Participants were divided into subgroups according to prostate tumor stage ; histologic grade (low grade or high grade); time to diagnosis ; age at blood collection (<60 or ≥60 years); and country of recruitment (8 countries). For tests of heterogeneity of risk by case characteristic , the controls in each matched set were assigned the characteristics of their case.For tests of heterogeneity in associations of the lactase genotypes compared with those with the CC genotype, with weights determined by the inverse of the variance of each relative risk.To put the results of this study into the context of previous research, we conducted a meta-analysis of our results together with the results of previously published studies. Studies were identified by searching PubMed and the reference lists of relevant articles by using the search terms lactase and prostate cancer. Summary relative risks were estimated as the weighted average of the study-specific RRs for men with the TC or TT p values below 0.05 were considered significant.Statistical analyses were performed with the Stata 10 statistical software package.630 men diagnosed with prostate cancer from recruitment until the end of follow-up and 873 matched participants without prostate cancer were included in the analyses. Their median age at blood collection was 60 years (range: 43–76 years). Prostate cancer diagnosis followed blood collection by a median of 3.5 years (range: <1 to 9.5 years) and the median age at diagnosis was 64 years (range: 47–82 years).lactase genotypes in the eight countries participating in the study. Genotype frequencies followed the Hardy–Weinberg equilibrium (HWE) within each country (p > 0.05). Genotype frequencies varied markedly across Europe. In Greece none of participants and in Italy 5.6% of participants were homozygous for the T allele and 15% and 29% of participants, respectively, had at least one copy of the T allele. In contrast, in Sweden and Denmark, 55.6% and 63.3%, respectively, were homozygous for the T allele, and 95% and 94% of participants, respectively, had at least one copy of the T allele. Similarly, there was significant variation in allele frequencies between the countries, with frequencies of the T allele ranging from 7% and 17% in Greece and Italy, respectively, to 75% in Sweden and 79% in Denmark  was low in all LCT genotype groups, and while there was a statistically significant association between LCT genotype and ice cream intake , with greater intake among heterozygotes, there was no significant trend in intake by genotype (p trend = 0.4).The intake of dairy products and selected nutrients by lactase genotype. After adjustment for regional center, there was significant variation by genotype in the circulating concentration of phytanic acid and borderline significant variation in circulating concentrations of 25-hydroxyvitamin D and enterodiol, respectively, with higher levels of phytanic acid and 25-hydroxyvitamin D being observed among men with more copies of the LCT T allele and lower levels of enterodiol among carriers of the T allele. No significant association was observed between circulating concentrations of IGF1, IGFBP3, sex hormones, SHBG or enterolactone and LCT genotype.lactase T allele was 40% and in control participants it was 40.5%. lactase genotype. We observed no statistically significant association between risk for prostate cancer and lactase genotype, with or without adjustment for potential confounders in the recessive, codominant (additive) or dominant models. The adjusted odds ratios among CT heterozygotes and TT homozygotes compared with CC homozygotes were 1.03 (95% CI: 0.72–1.46) and 1.10 (0.76–1.59), respectively. There was no statistical evidence of heterogeneity in the trends in risk for prostate cancer by genotype according to the age of the men at blood collection, country of recruitment, prostate tumor stage, histological grade, or time to diagnosis (data not shown). The T allele frequencies were particularly low in Italy and Greece and therefore, in a sensitivity analysis, we also investigated the associations between the LCT variant and prostate cancer risk after excluding Greece and Italy; findings were not materially altered (data not shown).In participants with prostate cancer, the frequency of the LCT variant and prostate cancer risk,lactase variant was not associated with a significantly increased risk of prostate cancer.lactase T allele compared to men with no copies was 1.12 (95 % CI: 0.96–1.32).Results from the one previous study of the lactase gene in relation to intake of dairy products and risk for prostate cancer in a large, European study (EPIC). Our results provide evidence for a significant association of the C/T-13910 lactase variant with intake of milk but no evidence for a large association between the polymorphism and risk for prostate cancer.We investigated common genetic variation in the LCT allele frequency across Europe, both between and within countries, which we and others have observedLCT genotype and dairy product intake across Europe may be due to this concomitant cultural variation. Even in the absence of a true diet-genotype association, confounding due to this population stratification  might give rise to an apparent association between diet or biomarker concentrations and lactase genotype in EPIC overall. However, even after adjusting for the regional recruitment center we found that milk consumption, total dairy product intake and calcium intake were related to LCT genotype, with evidence for a dose–response relationship with increasing milk and calcium intake with a higher number of T alleles. Our observations of a slightly weaker trend in the intake of dairy protein by LCT genotype is consistent with the hypothesized mechanism of lactose intolerance given that dairy product intake predominantly comprises milk by weight, whereas dairy protein as a percentage of energy intake comprises both protein from lactose-rich milk and protein from the protein-dense but low lactose cheese.The marked gradient in lactase variant and milk intake are relatively limited and inconsistent. Our results are in accord with data from 1673 men in the Swedish CAPS study, which reported lower milk intake in CC homozygotes (221 g/day) compared to men carrying the T allele (348 g/day).lactase genotype.LCT genotype is due to residual confounding within center, particularly for large centers recruiting over wide geographical areas within which there may be variation in the frequency of the lactase C/T allele. However, our findings of no heterogeneity in the relationship between genotype and milk intake by recruitment center, and of associations among men from regional centers which recruited from geographically limited areas, such as EPIC-Norfolk, provide evidence in support of a true relationship between LCT genotype and milk consumption.Previously published epidemiological data on the While the traditional view has been that lactase-persistence is an autosomal dominant trait, our results suggest a stepwise relationship, with a higher milk intake being observed with increasing number of T alleles. Our findings are consistent with those from a clinical study of 52 adults, in which lactase expression in intestinal biopsy samples was found to follow a trimodal distribution.lactase variant was associated with circulating concentrations of a number of nutritional and hormonal biomarkers that were available for men in the current study, including phytanic acid, 25-hydroxyvitamin D, IGF1, enterodiol and enterolactone.LCT genotype; higher concentrations were observed in TT homozygotes than in heterozygotes and CC homozygotes. These findings are consistent with the fact that phytanic acid is predominantly obtained from foods high in ruminant fat  and provide further indirect support for an association between lactase genotype and dairy food intake. We also observed borderline significant associations between lactase genotype and circulating concentrations of 25-hydroxyvitamin D and enterodiol; a higher concentration of 25-hydroxyvitamin D was observed with increasing number of copies of the LCT T allele and a lower concentration of enterodiol was observed among carriers of the T allele compared to CC homozygotes. Given the multiple statistical tests these may be chance findings and require confirmation in other large studies. In the one previous report on circulating vitamin D levels, no association was found with lactase genotype in two elderly Dutch populations .LCT C allele. There might also be some degree of general malabsorption associated with the C allele, which means that there is lower absorption of dietary vitamin D into the body. An association between the lactase variant and enterodiol is also possible, given that differences in the digestion of lactose due to the LCT variant may alter the activity or composition of the gut microflora, which is responsible for the production of enterodiol from the plant lignan secoisolariciresinol.lactase genotype and serum concentrations of IGF1 and IGFBP3.We also assessed whether the LCT genotype and prostate cancer risk are consistent with those from the only previously published study of the LCT variant in relation to risk for prostate cancer, which reported no significant associations in nested case control studies among Finnish men  and Swedish men .lactase genotype is a marker of intake of lactose-rich dairy products  rather than being a marker of dairy product intake per se, and is not correlated with dietary factors such as intake of cheese or butter.Our findings of no significant association between lactase gene-variant in relation to prostate cancer has been one of the specific hypotheses discussed with respect to the application of Mendelian Randomization (MR) to assess relationships between environmental exposures and risk for disease.lactase genotype is modest, even in this large prospective study and with a relatively common allele of interest , there is relatively limited power to detect an association between the lactase genotype and the disease. Based on previous findings from a prospective cohort analysis in EPIC1 for example, in which a 35 g per day increment in dairy protein intake was associated with an approximately 32% increase in risk for prostate cancer, the 2.2 g per day difference in dairy protein intake between CC and TT homozygotes would be estimated to result in only a 2% elevated risk among TT homozygotes compared with CC homozygotes. With the LCT genotype frequencies observed in EPIC, a study of approximately 30,000 cases and 30,000 controls would be needed to detect a relative risk for prostate cancer of this magnitude with 80% power.Dairy intake and the lactase gene is associated with intake of milk but provide no evidence for a large association with risk for prostate cancer. The data presented illustrate the limitations of applying Mendelian Randomization as a research strategy to explore the relationship between dairy product consumption and cancer risk and the need for very large prospective studies with both genetic and dietary data in such studies of genetic proxies of nutritional exposures.The results from this large prospective study in European men suggest that variation in the


Diet is a major source of cadmium intake among the non-smoking general population. Recent studies have determined that cadmium exposure may produce adverse health effects at lower exposure levels than previously predicted. We conducted a meta-analysis to combine and analyze the results of previous studies that have investigated the association of dietary cadmium intake and cancer risk.We searched PubMed, EMBASE, and MEDLINE database for case-control and cohort studies that assessed the association of dietary cadmium intake and cancer risk. We performed a meta-analysis using eight eligible studies to summarize the data and summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated using a random effects model.Overall, dietary cadmium intake showed no statistically significant association with cancer risk . However, there was strong evidence of heterogeneity, and subgroup analyses were conducted using the study design, geographical location, and cancer type. In subgroup analyses, the positive associations between dietary cadmium intake and cancer risk were observed among studies with Western populations  and studies investigating some hormone-related cancers .Our analysis found a positive association between dietary cadmium intake and cancer risk among studies conducted in Western countries, particularly with hormone-related cancers. Additional experimental and epidemiological studies are required to verify our findings. Cadmium has been recognized as a carcinogen for many decades based on studies of occupationally exposed individuals . FindingDiet is the main source of environmental cadmium among non-occupationally exposed non-smokers . Additioin vitro cell culture and in vivo animal studies demonstrated that cadmium exposure results in cell transformation and induces cancer in various organs ; 2) exposure ; 3) outcome ; and 4) covariates used in multivariate analysisP-values less than 0.05 were considered statistically significant. We estimated the summary association between dietary cadmium intake and cancer incidence using a random effects model. The Q-statistic and I2 statistics were calculated to estimate heterogeneity. Potential sources of heterogeneity were determined via subgroup or sensitivity analyses. The data were stratified by study design (case-control/cohort), geographic location (Western/Asian), and cancer type . We also performed sensitivity analyses to determine the effects of individual studies on the summary estimate by repeating the meta-analysis. For each subgroup analyses, we used a fixed or random effects model based on the results of the Q-statistics to calculate the summary RRs and 95% CIs [P < 0.05 for heterogeneity. We also conducted a cumulative meta-analysis to evaluate whether the trend of summary RRs (95% CIs) changed over time as more data were collected. Studies were added one at a time according to the publication year. The results were summarized as each new study was added. Publication bias was examined using analyses described by Egger [All statistical analyses were performed using STATA software , and two-sided  95% CIs ; we usedby Egger  and Beggby Egger  and a viOverall, the meta-analysis conducted in this manuscript contained eight studies, including two case-control studies (746 cases and 1069 controls) ,16 and sP = 0.020; I2 = 58%). Therefore, we calculated the summary estimate using a random effects model. Overall, dietary cadmium intake showed no statistically significant association with cancer risk . To identify the source of heterogeneity, we conducted subgroup analyses based on study design, geographic location, and cancer type . The funnel plot of studies was shown in We also conducted a cumulative meta-analysis based on publication year. The association between dietary cadmium intake and cancer risk did not change significantly as more data were collected 3. AdditDiet is the major source of cadmium for general populations that are not exposed to cadmium occupationally and do not live in cadmium polluted areas. We identified eight studies that investigated the role of dietary cadmium intake, but the findings of these studies are inconsistent. Several studies have investigated the role of cadmium in cancer development in female reproductive organs -12. In aMany studies have investigated the role of cadmium in hormone-related cancers  in non-occupationally exposed populations using biomarkers -30 TablS2. Dietin vitro cell culture or in vivo animal models provide evidence of the estrogenic or androgenic effects of cadmium on cell growth and gene expression [+) breast tumor but not an estrogen receptor negative (ER-) breast tumor in a cohort of postmenopausal women [It has been suggested that cadmium may induce cancer through multiple pathways, such as via aberrant gene expression, inhibition of oxidative stress, inhibition of DNA damage repair, or inhibition of apoptosis . Recent pression -35. Furtpression . Initialal women . Severalal women ,12,13 oral women . Howeveral women . Additioal women .Several factors may influence the role of dietary cadmium in cancer development. Therefore, it is important to identify the high-risk population for cadmium-induced carcinogenesis―a population that is defined by increased exposure to cadmium or a higher absorbed dose of cadmium. First, dietary habits affect the level of cadmium exposure. Individuals who regularly eat crustaceans, mollusks, and cephalopods or consume large amounts of whole grains and vegetables have the highest exposure to dietary cadmium . AlthougTo the best of our knowledge, this is the first meta-analysis combining the results of existing studies that have investigated the effect of dietary cadmium on cancer risk. Most are population-based cohort studies, which may eliminate recall and selection biases. However, we recognize several limitations in interpreting our results. The most important limitation is the validity of the estimated cadmium intake values. Estimates of dietary cadmium intake could vary widely among the populations studied based on the method of diet assessment and the cadmium database used . FFQ mayOur meta-analysis supports the findings of existing studies regarding the role of dietary cadmium intake in hormone-related cancer risk in Western countries. We cautiously suggest that chronic exposure to cadmium and other metalloestrogens may partly explain the risk of developing hormone-related cancers, particularly in Western populations. To reduce cadmium-induced cancer risk, it is important to identify the high-risk population  and to provide an appropriate medical intervention. Although this meta-analysis of epidemiological studies suggests a link between cadmium and hormone-related cancers, more experimental and epidemiological studies using diverse populations are needed to establish a causal association, as well as to verify the underlying mechanisms.Table S1The association between environmental cadmium exposure and breast cancer risk in studies using biomarkers.(DOCX)Click here for additional data file.Table S2The association between environmental cadmium exposure and prostate cancer risk in studies using biomarkers.(DOCX)Click here for additional data file.


Background Several studies have reported that HLA-DRB1 may be correlated with pemphigus vulgaris (PV), but most have been based on small samples and the results remain inconsistent and unclear.Objectives To investigate the correlation between DRB1 and PV by a meta-analysis of case–control/nonfamily studies.Methods PubMed, Wiley Online Library, ScienceDirect, Google Scholar, Cochrane Library, Chinese National Knowledge Infrastructure and Wanfang databases were searched for studies including: (i) ‘pemphigus’; and (ii) ‘human leukocyte antigen’, ‘HLA’, ‘major histocompatibility complex’, ‘MHC’ or ‘DRB1’. Eighteen selected studies were used in meta-analyses to evaluate DRB1 alleles and phenotypes by calculating the respective odds ratios (ORs) and 95% confidence intervals (CIs). Stratified meta-analyses and meta-regression analysis were also conducted.Results The frequencies of three genotypes  were significantly increased in PV: DRB1*04 , DRB1*08  and DRB1*14 . Three others  were significantly decreased in PV: DRB1*03 , DRB1*07  and DRB1*15 . Ethnicity partially explained the heterogeneity of DRB1*07, DRB1*08 and DRB1*14 phenotypes.Conclusions Our findings suggest that DRB1*04, DRB1*08 and DRB1*14 are statistically significant susceptibility factors for PV. Conversely, DRB1*03, DRB1*07 and DRB1*15 may be negatively associated with PV. Specific HLA-DRB1 types may influence the susceptibility or resistance to PV, which needs further investigations. Pemphigus is a rare and sometimes fatal autoimmune bullous disorder that manifests as flaccid, painful, nonhealing blisters or ulcerations on the skin and mucosal surfaces.,26, Leu67 and Val86 and hydrophilic amino acid residues at positions 70 and 71 on the HLA-DR β chain.Pemphigus onset usually occurs between the 4th and 6th decades of life and has been reported in various populations. Worldwide annual incidence has been estimated at 0·76–6·7 cases per million.,,,The demonstrated association of PV with HLA class II has been supported by serology, genotyping and sequencing in cases from different ethnicities. For example, alleles of HLA-DR4  independently reviewed all abstracts for study relevance, retrieved the selected full texts, extracted data using a standardized form, and assessed study quality. Disagreements were resolved by discussion and by consulting a third investigator (K.Z.). Studies were selected according to the following inclusion criteria: (i) an independent case–control design; (ii) primary study  in English or Chinese; (iii) sufficient information to calculate the odds ratio (OR); (iv) unrelated cases and controls; (v) molecular-type detection methods (including high or low resolution level); and (vi) definite diagnosis of PV, based on histopathology or immunopatho-logy. In addition, studies were excluded based on the following features: (i) incomplete raw data; (ii) repetitive reporting of a dataset ; (iii) insufficient materials and methods; (iv) exclusive focus on haplotype or single nucleotide polymorphism; or (v) exclusive focus on HLA-DR4 or DR14.The following information was collected from each of the selected studies: authors, publication year, ethnicity of study population, detection assay type, PV diagnostic criteria, and numbers of cases and controls for each genetic variation. The genetic data were categorized as allelic data  or phenotype data .et al.P-values); (iii) the results were comprehensive and objective (with negative results included); and (iv) a statement about regular heredity or Hardy–Weinberg equilibrium testing was included. Each paper was scored for these criteria on a scale of 0–10, with ≥ 5 indicating high quality and < 5 indicating low quality.In consideration of the various and complex nature of observational studies, we evaluated the internal validity of each selected article from different aspects. After referring to the treatise of Chalmers http://www.cochrane.org) was used to conduct the meta-analysis. The heterogeneity among different studies was estimated by the χ2 test, the Q-statistic test and the I2 test. If the P-value for heterogeneity (Ph) was > 0·10 or I2 < 50%, then heterogeneity was statistically insignificantP-value for comparability (Pc) was < 0·05 (two-tailed test) and the 95% CI of OR was exclusive of 1·0, then the result was statistically significant. In order to avoid type II errors, Bonferroni adjustment of the P-values was not performed for multiple comparisons.,The effect of DRB1 in PV was measured by using the Mantel–Haenszel method to calculate the ORs and 95% confidence intervals (CIs). Initially, numerical data were extracted directly and frequency data were multiplied by the total sample number and converted to a numerical statistical value.Pc-value ≤ 0·05 but high heterogeneity, then subgroup (by RevMan 5·0) and meta-regressionhttp://www.stata.com).In addition, the two categorical results of a selected gene were comparatively analysed. If both results were consistent in the direction of 95% CI and had ,Funnel plot analysis was carried out by evaluating the symmetry of a scatter diagram. As more than five studies and experiential interpretation are required, we used Begg’s rank correlation test and Egger’s linear regression testet al.http://www.pemphigus.org.uk/). A variety of ethnicities was represented by the 18 studies: Asians,,,,,n=5; caucasians,,,,,–n =8; other nationalities,,,,–n =6; mixture of caucasians and noncaucasians,n =1. In addition, the 18 studies collectively provided data for 27 comparisons between different DRB1 types and PV.In total, 233 nonrepetitive articles were identified by the initial database search. After restrictive selection according to the inclusion and exclusion criteria , 18 stud,,,,,–,,–,,,–P ≤0·05), suggesting a protective role.The susceptibility or resistance correlations of HLA-DRB1 and PV are summarized in P ≤0·05). A random-effects model was used based on the detected heterogeneity in the test results . Furthermore, stratified meta-analyses (I2 = 0%). In the sensitivity analysis, the ORs and 95% CI directions remained stable, suggesting that the results were consistent to some extent.In both allele and phenotype analyses, the overall gene frequency of DRB1*04 was significantly higher in patients with PV  than in controls   and phenotype  analyses, but heterogeneity (I2 = 54%) was observed in the allele group. Ethnicity-stratified meta-analyses implied that DRB1*08 increased significantly only for caucasians. In the sensitivity analysis, three studies,,DRB1*08 frequencies were significantly higher in patients with PV than in controls in both the allele . However, significant heterogeneity  was found to exist among the studies. Meta-regression analysis . The comparability of results did not change after a sensitivity analysis was conducted by sequentially omitting each study.In both allele and phenotype analyses, DRB1*14 showed a remarkably high risk for PV occurrence  and phenotype  analyses. No significant heterogeneity was detected in either analysis .DRB1*03 showed a strong protective effect against PV in both the allele  occurred in the allele analyses, despite the random-effects model having been used. Stratified meta-analyses (I2 = 16%) and other mixed ethnicities (I2 = 13%). Moreover, there was not significant heterogeneity (I2 = 0%) among the studies assessed as low quality. For DRB1*15, results were consistent among studies of other ethnicities (I2 = 0%) and those of low quality (I2 = 0%). A sensitivity analysis revealed that the DRB1*15 phenotype data in Niizeki et al.Both DRB1*07 and DRB1*15 were significantly negatively correlated to the incidence of PV. Nevertheless, high-level heterogeneity . DRB1*14 was the only notable exception, with P =0·049 for Begg’s test and P =0·034 for Egger’s test. The publication bias of DRB1*10/12/16 phenotypes was incalculable, with only one article left due to automatic rejection of zero events in the arithmetic.All the funnel plots were inspected for geometrical symmetry and most were found to be roughly symmetrical. Only the plots of DRB1*12 phenotype, and DRB1*14 allele and phenotype were asymmetrical. The funnel plots confirmed the absence of publication bias  and 4, wExtensive research has been carried out to determine the function of HLA in the pathogenesis of PV; however, the findings to date have been inconsistent and controversial. Therefore, we performed a meta-analysis to investigate more comprehensively the potential association between HLA-DRB1 and PV, the first of its kind in the literature, to our knowledge.P >0·05) in STATA/SE 11.2 software. According to the majority of earlier studies, pemphigus is most often associated with DR4 and DR14, regardless of ethnicity.,,,,–,,,,,,,Our study revealed that DRB1*04, DRB1*08 and DRB1*14 were susceptibility factors for PV, whereas DRB1*03, DRB1*07 and DRB1*15 may be negatively associated with PV across racial lines. When the patients and controls were stratified into subgroups by ethnicity, DRB1*07 frequencies were found to be significantly lower in caucasian and other mixed ethnicities and DRB1*08 was obviously increased in caucasians. In addition, DRB1*04, DRB1*14 and DRB1*15 were strongly correlated with PV incidence, despite remarkable heterogeneity. Meta-regression analysis by ethnicity and study quality could not explain the between-study variance assessed by Knapp–Hartung modification . The loss of tolerance to target autoantigens is considered to involve HLA class II molecules, the initiating autoantigenic peptide(s), and T-cell receptors (TCRs).,Meta-analysis is an established and effective strategy to increase the sample size by pooling data from individual studies to enhance the statistical power of the analysis.Nevertheless, research to determine the primary role of some regions of the HLA locus in the pathogenesis of PV may have value in subsequent prospective studies to uncover the underlying mechanisms. Ethnic-specific PV alleles may influence the susceptibility or resistance to PV by attributing to a direct involvement of the HLA molecules as an antigen presenter or a neighbouring linked gene.Various alleles of the HLA-DRB1 gene have been associated with pemphigus vulgaris (PV), but studies of these genes have been largely carried out in small populations and the results from different studies have not been consistent.To the best of our knowledge, this is the first meta-analysis on the association between HLA-DRB1 and PV.DRB1*04, DRB1*08 and DRB1*14 may act as susceptibility factors for PV, while DRB1*03, DRB1*07 and DRB1*15 were found to be significantly negatively associated with PV.The roles of DRB1*07, DRB1*08 and DRB1*14 phenotypes are partially dependent on ethnicity.