Vitamin D status may influence the risk of Insulin resistance related diseases such as Type 2 diabetes (T2DM), metabolic syndrome (MetS), and polycystic ovarian syndrome (PCOS). Several studies have assessed vitamin D receptor (VDR) gene polymorphism in relationship with these diseases; however, results remain inconsistent. Our study was conducted to elucidate whether VDR Gene polymorphisms could predict insulin resistance on a large scale.A meta-analysis using MEDLINE and EMBASE, was performed up to December 16th, 2016. Studies reporting association of vitamin D gene polymorphism with incident T2DM, MetS and PCOS outcomes were included and sub-group analysis by pigment of skin and latitude were performed.P = 0.03) for T allele and MetS for G allele  in BsmI was significant association with VDR gene polymorphism. Simultaneously, sub-group analysis showed VDR ApaI rs7975232(G > T)variant was associated with insulin resistance related diseases in Asians (GG/GT + TT)  and population who lived in middle latitude district (30–60°) (GG/GT + TT) , VDR BsmI rs1544410 (A > G)and VDR Taq1rs731236 (T/C) variant were associated with insulin resistance related diseases in Caucasian (dark-pigmented).A total of 28 articles based on four gene variation, and comprising 9232 participants with 5193 Insulin resistance related diseases patients were included. No significant associations of the VDR ApaI, BsmI, FokI and TaqI variant with Insulin resistance related diseases were found. However, sub-group analysis analysis showed that PCOS in TaqI (OR = 1.47, 95% CI = 1.03–2.09, The results suggested that the association between insulin resistance related diseases and VDR ApaI, BsmI, FokI variant was more obvious in dark-pigmented Caucasians and Asians but not in Caucasian with white skin. Vitamin D deficiency as a common health problem is a global problem, thought to be related to lack of sunlight exposure, and usually accompanied by reduced dietary intake . The VitT2DM, MetS, and IFG are common metabolic disorders which are observed with increasing prevalence, and which are caused by a complex interplay between genetic and environmental factors, and these metabolic disorders are all characterized by insulin resistance –13. PCOSVitamin D condition depends mainly on the sunlight and skin. It is both an environmental and biological determinant of health. Skin pigmentation may predispose subpopulations to vitamin D deficiency . Some stTwo investigators  independently searched PubMed and Embase  database using the terms ((Gene polymorphism or gene variation)) AND (((((((diabetes mellitus) OR Diabetes) OR insulin resistance) OR metabolic syndrome) OR polycystic ovarian syndrome)) AND (vitamin D receptor OR VDR)).Furthermore, we reviewed citations in the retrieved articles to search for additional relevant studies. Articles included in meta-analysis were in English or Chinese, with human subjects, published in primary literature and with no obvious overlap of subjects with other studies. The retrieved literatures were then read in their entirety to assess their appropriateness for the inclusion in this meta-analysis. Conference abstracts, case reports, editorials, review articles, and letters were excluded. We defined strict criteria for inclusion of studies. Studies were included if the exposure of interest was the VDR genotype.Two independent authors extracted data and reached a consensus on the author, year of publication, ethnicity, number of patients and controls and disease types.2 test and the inconsistency index (I2) were used to evaluate heterogeneity across the included studies. Random-effects model was applied in all the analysis. OR and their corresponding 95% confidence intervals (CI) were estimated. Z-test was performed to determine the statistical significance of pooled OR, and was considered significant when P < 0.05. We assessed potential publication bias by using a funnel plot and Egger’s test. Sensitivity analysis was performed by sequential removal (statistics of study remove) of individual studies (we did not show these results) [All statistical analyses were performed using Review Manager (Review Manager 5.0 software) and Stata/MP 11.0. Cochran’s wresults) .This study is focusing on VDR ApaI rs7975232 (G > T) variant, BsmI rs1544410 (A > G) variant, Taq1rs731236 (T > C) variant and FokIrs2228570 (C > T) variant and Insulin resistance related diseases susceptibility including . Characteristics of studies investigating the association of the variants with Insulin resistance related diseases susceptibility are presented in Table Of these, 14 case–control studies examined the association of the ApaI rs7975232 (G > T) variant –30 (TablP = 0.37) in the recessive genetic model (G/G vs.G/T or T/T), dominant genetic model in the (G/G or G/T vs.T/T)  and G allele vs. T allele analysis . sub-group analysis indicated that there was no association between VDR ApaI rs7975232 (G > T)variant and T2DM, PCOS patients (Table P = 0.04) and population who lived in middle latitude district (30–60°) (GG/GT + TT) . No publication bias was detected by either the funnel plot or Egger’s tests .Fourteen studies (3212 cases and 3360 controls) examining the association between the VDR ApaI rs7975232 (G > T) variant and Insulin resistance related diseases susceptibility were included. Sub-group analysis (nine studies about T2DM and five studies about PCOS) was performed. All the original data were combined by means of the Random effect model. We found no association of the VDR ApaI rs7975232 (G > T) variant with Insulin resistance related diseases  in the recessive genetic model (A/A vs.A/G or G/G), dominant genetic model in th e (A/A or A/G vs. G/G)  and A allele vs. G allele analysis . sub-group analysis indicated that there was no association between BsmI rs1544410 (A > G) variant and T2DM, PCOS patients. However, significant association was found in MetS sub-group analysis G allele vs. A allele analysis  (Table P = 0.002),  . No publication bias was detected by either the funnel plot or Egger’s tests .Twenty-two studies (4294 cases and 4157 controls) in 17 papers examining the association between the VDR BsmI rs1544410 (A > G) variant and Insulin resistance related diseases susceptibility were included. Sub-group analysis  was performed. All the original data were combined by means of the Random effect model. We found no association of the VDR BsmI rs1544410 (A > G)variant with Insulin resistance related diseases  in the recessive genetic model (T/T vs.T/C or C/C), dominant genetic model in the (T/T or T/C vs. C/C) , T allele . Sub-group analysis indicated significant association between VDR Taq1rs731236 C allele and PCOS in C allele analysis  (Table P = 0.01). No publication bias was detected by either the funnel plot or Egger’s tests .Nineteen studies (3533 cases and 4024 controls) examining the association between the VDR Taq1rs731236 (T/C) variant and Insulin resistance related diseases susceptibility were included. Sub-group analysis  was performed. All the original data were combined by means of the Random effect model. We found no association of the VDR TaqI rs731236 (T/C) variant with Insulin resistance related diseases  in the recessive genetic model (C/C vs.C/T or T/T), dominant genetic model in the ((C/C or C/T vs. T/T)  and C allele vs. T allele analysis . sub-group analysis indicated that there was no association between FokIrs2228570 (C > T) variant and T2DM, PCOS and MetS patients .Eighteen studies (4851 cases and 6174 controls) from 17 papers examining the association between the VDR FokIrs2228570 (C > T) variant and Insulin resistance related diseases susceptibility were included. Sub-group analysis  was performed. All the original data were combined by means of the Random effect model. We found no association of the VDR FokIrs2228570 (C > T)variant with Insulin resistance related diseases , and CaMKs stimulates VDR-Mediated transcription by phosphorylation levels of VDR . Recent To the best of our knowledge, this is the first meta-analysis which takes into account the interaction of individual VDR polymorphisms with in insulin resistance diseases. This meta-analysis, which included a total of 28 articles, examined the associations among four studied polymorphisms in the VDR ApaI variant, VDR BsmI variant, VDR Taq1 variant and VDR FokI variant and insulin resistance related diseases. The results indicated that VDR ApaI variant, VDR BsmI variant and VDR FokI variant were not conspicuous risk factors for insulin resistance related diseases. The result provided no evidence of the association between VDR variant and Insulin resistance related diseases. Yet the results were different when the researches were grouping by skin pigment and living latitude. Sub-group analysis suggested that the association between insulin resistance related diseases and VDR ApaI, BsmI, FokI variant was obvious in dark-pigmented Caucasian population and Asians.However, to make conclusive estimates, many factors should be considered. In complex diseases such as T2DM, complex interactions between genetic and environmental factors have differential effects on disease susceptibility. Further characterization of VDR, in addition to traditional and related risk factors may facilitate early identification of patients at high risk for T2DM, and then elucidate new approaches for prevention and treatment. However, several limitations of the meta-analysis should be addressed. First, lack of the original data of the reviewed studies limited our further evaluation of potential interactions, because the interactions between and even different polymorphic loci of the same gene may influence the risk. Second, our results were based on unadjusted published estimates, and hence, we were unable to adjust them by possible confounders, for example Vitamin D level, and diet did not take into consider. Third, the number of articles and cases taking in this research is relatively small. In order to provide a more precise estimation on the basis of adjustment for confounders, more well-designed studies should be taking into account. Additionally, current evidence from prospective studies on the association between vitamin D gene polymorphism and risk of insulin resistance related diseases was limited by the use of vitamin D gene polymorphism or a single measurement of 25(OH)D concentrations. A single baseline measure of dietary vitamin D may not be able to take into account the within-individual variations of vitamin D levels across seasons or geographical location, as evident in sub-group analysis. Studies are, therefore, needed with geographical location and dietary vitamin D levels to adjust for its variability while quantifying the associations.In summary, this meta-analysis provided evidence of the association between VDR BsmI variant and MetS and supporting that VDR BsmI variant G allele might be a susceptibility marker of MetS. TaqI variant was associated with PCOS for C allele and supporting that VDR TaqI variant C allele might be a susceptibility marker of PCOS. No significant association was found in the rest gene polymorphisms and these diseases related with insulin resistance diseases. The relationship of VDR gene polymorphism was more important with PCOS and MetS than T2DM. However, sub-group analysis showed VDR ApaI variant was associated with insulin resistance related diseases in Asians, VDR BsmI and VDR TaqI variant was associated with insulin resistance related diseases in Caucasian (dark-pigmented).The results suggested that the association between insulin resistance related diseases and VDR ApaI, BsmI, FokI variant was more obvious in dark-pigmented Caucasians and Asians but not in Caucasian with white skin.


VEGF) gene may contribute to osteosarcoma risk, but the results of previous studies have been inconsistent and inconclusive. We conducted a meta-analysis to assess this association more accurately. Relevant studies were collected systemically from three online English databases. Crude odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the associations of three VEGF gene polymorphisms  with osteosarcoma risk. Seven case-control studies involving 1,350 cases and 1,706 controls were selected for the meta-analysis. The pooled OR indicated that the VEGF +936C/T polymorphism was associated with increased risk of osteosarcoma in a Chinese population . A significant association was also found between the −634 G/C polymorphism and osteosarcoma risk . In sum, our meta-analysis suggests VEGF polymorphisms are associated with osteosarcoma susceptibility in the Chinese population. However, further studies that include different ethnicities and larger populations are needed.Polymorphisms in the vascular endothelial growth factor ( Osteosarcoma, one of the most common types of malignant primary bone tumors, is characterised by the direct formation of immature bone or osteoid tissue by tumor cells, and is most prevalent in children and young people , 2. In tRecent molecular studies have suggested that genome dysfunction contributes to tumorigenesis , 8. MutaVEGF is located at chromosome 6p21.3 and comprises a 14-kb coding region with eight exons and seven introns [VEGF polymorphisms, namely +936C/T (rs3025039), +1612G/A (rs10434), and −634G/C (rs2010963), have been investigated for their association with osteosarcoma risk, but the results have been inconsistent. Therefore, we conducted a comprehensive meta-analysis of all published studies to determine the association between VEGF polymorphism and osteosarcoma susceptibility more accurately. Our meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [ introns , 23. Sev introns , 25. Som introns . In 2014 introns . To datetatement , 29. No Forty studies were identified through literature searching. In accordance with the selection criteria described in the Methods, 23 studies were excluded for duplication in the first step of title screening, and 17 studies were excluded for other reasons  during the systematic screening. Ultimately, seven articles were included in this meta-analysis  . Sensitivity analyses were performed by excluding each single study one by one, and the results of pooled ORs still presented stability .In the seven studies examined, a significant increase in osteosarcoma risk was observed in four genetic models    and subsequent subgroup analysis  . Since then, a series of case-control studies have been conducted, but the conclusions have been inconsistent. In 2016, Zhang et al. [VEGF −634 G/C and +936 C/T polymorphisms were significantly associated with osteosarcoma risk. However, their meta-analysis only included three case-control studies. To date, four additional studies have explored the associations between VEGF polymorphisms and osteosarcoma. In our meta-analysis of seven eligible case-control studies, more precise associations between the three most common polymorphisms in VEGF  and osteosarcoma susceptibility were investigated than in the previous meta-analysis. All the results revealed that the VEGF +936 C/T polymorphism significantly increased the risk of osteosarcoma in the Chinese population. Subgroup analyses based on the HWE status and control design also identified similar risks. Interestingly, our results suggested that the VEGF −634 G/C polymorphism protects against osteosarcoma development. However, no significant association between VEGF +1612 G/A and osteosarcoma susceptibility was observed. These inconsistent findings among the three SNP loci indicat that different polymorphisms exert different effects on gene function, even when they are located at the same unit.Studies of osteosarcoma have strongly suggested that higher VEGF expression and activity in primary tumor tissue correlates with increased local microvessel density, faster development of pulmonary metastasis, and poorer prognosis for osteosarcoma patients , 41. An g et al.  conducteVEGF polymorphisms  with osteosarcoma susceptibility. None of the studies evaluated herein displayed significant heterogeneity or publication bias within the three common polymorphism loci. All the pooled data yielded consistent results, which not only confirms the validity of our results, but also supports our statistical methods.Meta-analysis is an effective method of combining the quantitative results of previous studies in order to derive a pooled summary conclusion through statistical measures , 44. ThiVEGF polymorphisms and osteosarcoma susceptibility. Second, all the included studies were conducted with Chinese subjects. Ethnicity bias may exist because a single Asian race was examined, and the conclusions may not be applicable to other races. Third, the interactions among various risk factors, such as smoking, drinking, and other genetic factors, are crucial determinants of cancer formation. Thus, the inherent mechanism could not be explained clearly with unadjusted databases in this meta-analysis. Fourth, deviations from HWE were found in the distribution of controls in some of the included studies, possibly due to the insufficient of sample sizes or genotyping errors in those studies.However, there were some limitations to our meta-analysis. First, only seven eligible studies were collected, and the limited number of studies with small sample sizes may have affected the analysis of the correlation between VEGF polymorphisms and osteosarcoma susceptibility, and suggest that analysis of VEGF polymorphisms may be useful for the early clinical diagnosis and treatment of osteosarcoma.Our meta-analysis contained a large sample size, new research data and high-quality statistics. The results are credible and reliable as a preliminary exploration of the relationship between the VEGF polymorphisms are associated with osteosarcoma susceptibility in the Chinese population. Nevertheless, additional studies including different ethnicities and larger populations are needed for further exploration of these associations.In summary, our meta-analysis suggests that Three online electronic databases  were searched with the following terms: (“osteosarcoma”) AND  AND (“polymorphism” OR “SNP” OR “single nucleotide polymorphism” OR “variant”), from inception to January 2016. Furthermore, all the references of the collected studies were examined so that additional relevant studies could be identified. Only English language full-text case-controls studies were included.VEGF polymorphisms; (3) evaluated the association between VEGF polymorphisms and osteosarcoma risk; (4) presented adequate genotype data or data necessary to calculate the OR and 95% CI; and (5) described SNP loci which were reported in at least five publications. Studies were excluded if they: (1) were review papers; (2) were animal studies; (3) contained insufficient information for assessment of the association; (4) contained repeated or overlapping results from another study .All the selected studies met the following inclusion criteria: (1) case-control studies focused on osteosarcoma; (2) reported on Two reviewers (Hu and Du) independently conducted data extraction using a standardized form. The following information was collected: the first author's name, year of publication, sources of controls, study region or country, ethnicity of subjects (such as Asian or Caucasian), genotyping method and genotype distribution data for cases and controls. Disagreements were resolved by a third author during the analysis.VEGF +936C/T locus. Similar genetic models were also assessed for the other SNPs. Heterogeneity was assessed with Cochran's Q statistic and the I2 method, and P < 0.10 or I2 > 40% were considered to demonstrate substantial heterogeneity [P values, and P < 0.05 was considered statistically significant.HWE was evaluated with the chi-square test using the genotypes of the controls. The association between the genotype distribution and osteosarcoma was evaluated based on the ORs and corresponding 95% CIs. For example, the pooled ORs were obtained for the allele contrast (T vs. C), co-dominant model , dominant model (CT + TT vs. CC), and recessive model (TT vs. CC + CT) in the ogeneity . ORs werogeneity ; otherwiogeneity . Subgrou


NQO1 rs1800566). Furthermore, we provided a database to integrate and analyze the association of genetic variants and HCC risk. To the best of our knowledge, this is the first comprehensive field synopsis and systematic meta-analysis of genetic association with HCC risk. We have provided a useful resource and platform for investigators to explore the association of sequence polymorphisms and HCC risk.Hepatocellular carcinoma (HCC) is one of the most common malignancy in the world. In order to comprehensively examine the association between genetic variants and risk of HCC, a systematic literature search and meta-analyses of the evidences have been performed. With the data from 301 articles, we conducted meta-analyses for 69 polymorphisms involving 46 distinct genes. The result showed that 31 polymorphisms in 25 genes are significantly associated with HCC risk. Cumulative epidemiological evidence for a significant association with HCC risk was graded strong for one polymorphism ( However, our understanding of genetic landscape in HCC is still far from complete and the key drivers of HCC tumourigenesis remain poorly to be understood.Hepatocellular carcinoma (HCC) is the most common malignancy primary cancer and the third-leading cause of cancer mortality worldwide . The preUp to date, numerous works enrolling tens of thousands of subjects have been performed to examine the role of genetic variations in HCC carcinogenesis in the past two decades. Many sequence polymorphisms have been identified as potential genetic factors associated with HCC susceptibility. Notably, many studies might investigate the association between a specific polymorphism with HCC risk, however, the results of these works are not always consistent. Systematic review covering all tested polymorphisms is necessary. Here, we comprehensively evaluate the candidate-gene association studies of HCC risk, and perform meta-analyses for variants with sufficient data. We provided a systematic synopsis of our current understanding of the genetic basis of HCC susceptibility.In this work, we totally identified 505 eligible articles, comprising 282,042 subjects . A total of 255 polymorphisms in 198 genes were eligible in our analysis . The number of subjects enrolled in the meta-analyses ranged from 607 to 14425 . Moderate associations with HCC (ORs 1.5-2.0 0.5-0.8) were identified for 13 polymorphisms  had associations with HCC risk only in Asian people. One polymorphism  only showed significantly association with HCC risk among African people, and one polymorphism  has the association with HCC risk only in Caucasian. Next, we performed ethnicity-specific analyses using either dominant or recessive genetic models to further evaluate the associations of genetic variants with HCC risk. Another 5 significant associated variants in 5 genes were identified using either dominant or recessive models .Detailed meta-analysis results were recorded for each of the polymorphisms. At first, we evaluated these polymorphisms using additive model. Among all the allele contrast meta-analysis, 21 (30%) polymorphisms in 19 genes showed nominally significant associations with HCC risk (ls Table . The resNQO1 rs1800566) was graded strong for evidence of association with HCC risk using Venice criteria result. Moreover, moderate and weak for the evidence of true association with HCC were assigned to 14 and 16 polymorphisms, respectively.To assess the cumulative epidemiologic evidence for significant meta-analysis, Venice criteria  were appPrevious meta-analyses works have independently analyzed the association between genetic variants and risk of HCC –22. Herehttp://donglab.ecnu.edu.cn/databases/HCCdb/.To facilitate HCC related polymorphisms integration and online query, we subsequently constructed a database of HCC-related polymorphisms (HCCdb). Currently, HCCdb contains 69 polymorphisms in 46 genes. The current version of HCCdb provides a user friendly search engine, which allows to search the basic content of gene or literature information. Furthermore, HCCdb provided a module to carry out a direct meta-analysis on the polymorphisms. Users can select the genetic model and effect models when performing online meta-analysis. In HCCdb, the OR and 95% CI can be measured to evaluate the strength of associations between polymorphisms and HCC risk. The database is freely available at NQO1 rs1800566). NQO1 is a cytosolic enzyme and plays an important role in protecting cells against oxidative stress by catalyzing two-electron reduction of numerous quinoid compounds into their less toxic form. Many epidemiological studies have investigated the effect of NQO1 rs1800566 polymorphism on carcinogenesis [NQO1 rs1800566 polymorphism is a critical risk factor for HCC risk (OR=1.34). However, we failed to evaluate the susceptibility of NQO1 rs1800566 polymorphism to HCC in specific populations because of the limited eligible published case–control studies.Sequence polymorphisms in genes have been considered as underlying candidates in hepatocellular carcinogenesis. In this work, we described the results of the first systematic synopsis and meta-analysis in the field of genetic predisposition to HCC. We found that 31 polymorphisms in 25 genes showed significant associations with HCC risk. Our work provided a comprehensive research synopsis of candidate-gene association study of HCC risk. Using Venice criteria results, we graded one polymorphism strong for cumulative epidemiological evidence of association with HCC risk  AND (polymorphism OR polymorphisms)” in title field without language restrictions for studies published up to 18 June 2015. Furthermore, Google scholar was also used to search eligible publications using the same keywords. This search produced 2667 potentially relevant publications. After further evaluation, 505 eligible publications were retained  and then checked by another reviewer (DD). The results of a total of 16 publications have some inconsistent and disagreements. All of these disagreements were encountered because of careless. We collected the disagreements and discuss with DD, and made the final decision after re-performing the work. The study provided enough information for the genotypic or allelic distribution of individual variants for both HCC cases and controls was the one we needed. Following characteristics were collected: first author's surname, publication year, ethnicity , dbSNP I2) and the operation of sensitivity analyses, we performed meta-analyses for the 69 genetic variants with case-control data available containing at least three independent sources. All statistical tests were conducted by STATA, version 12.0. All tests were two-tailed, and only P-value<0.05 was considered significant. To comprehensively analyze the relationship between genetic variants and risk of HCC, we selected three genetic models: additive model, dominant model and recessive model. To illustrate the models, we assume a polymorphism genome locus having two alleles, labeled A and a. A is the high-risk candidate allele and a is the lower-risk allele. Additive model is the same as allele model, represent the effect of the A allele vs. the a allele; dominant model represent the effect of the a/a+A/a vs. the A/A genotypes only when present in two copies of A allele, recessive mode represent the effect of the A/A+A/a vs. the a/a genotypes when present in either one or two copies of A allele. Summary odds ratios (ORs) with 95% confidence intervals (CIs) for alleles or genotypes were used to assess strength of associations between genetic variants and HCC risk by the random-effects method [For the stabilization of heterogeneity test statistic , given that the deviation may denote bias. Moreover, the extent to which the combined risk estimate might be influenced by individual studies was assessed consecutively omitting every study from the meta-analyses . Begg's funnel plots [Heterogeneity assumption was estimated by Chi-square based on Q-test . I2 statogeneity . Generalel plots  and Eggeel plots  were useI2 < 25%, ‘B’ for I2 between 25% and 50%, and ‘C’ for I2 >50%. Protection from bias may be caused by factors that lead to systematic deviations from the true effect of a genetic association. Biases may operate at the level of a single study, a collection of studies , or a research field at large. It can be graded as ‘A’ if there was no observable bias and bias was unlikely to explain the presence of the association, ‘B’ if bias could be present or could explain the presence of the association, or ‘C’ if bias was evident or was likely to explain the presence of the association. Assessment of protection from bias also included consideration of the magnitude of the association; a score of ‘C’ was assigned to an association with a summary OR < 1.15 unless the association had been replicated prospectively by multiple studies with no evidence of publication bias. Cumulative epidemiological evidence was defined as strong, moderate, or weak. If all three grades were A, we considered it was strong. While if one or more grades were C, it was weak. All other combinations was moderate.In order to assess statistically significant associations identified by meta-analyses, Venice criteria was employed in this work. It grades the cumulative evidence at three major criteria: (i) amount of evidence; (ii) replication of results; (iii) publication from bias. Amount of evidence was graded by the sum of test alleles or genotypes among both cases and controls in the meta-analysis; ‘A’ for over 1,000, ‘B’ for 100 to 1,000, and ‘C’ for less than 100. Caution was taken when applying this criterion to rare variants with frequency <1%, as an A grade is unobtainable. Replication was graded by the heterogeneity statistic; ‘A’ for The HCCdb system is based on a three-tier architecture: client, server and database. It includes a user-friendly web interface, PHP's DBI module and MySQL database. HCCdb was developed on MySQL v4.1 with the MyISAM storage engine.


CD44 polymorphisms have been previously associated with cancer risk. However, the results between independent studies were inconsistent. Here, a meta-analysis was performed to systematically evaluate associations between CD44 polymorphisms and cancer susceptibility. A comprehensive literature search conducted in PubMed, Embase, and Web of Science databases through August 10, 2016 yielded 11 eligible publications consisting of 5,788 cancer patients and 5,852 controls. Overall, odds ratios (OR) calculated with 95% confidence intervals (CI) identified a significant association between CD44 polymorphism rs13347 and cancer susceptibility under all genetic models. Additionally, the minor allele of polymorphism rs11821102 was associated with a decreased susceptibility to cancer in allele contrast, dominant, and heterozygous models, while no significant association was identified for polymorphisms rs10836347, rs713330, or rs1425802. Subgroup analysis by ethnicity revealed rs13347 was significantly associated with cancer susceptibility for Chinese but not for Indians. Linkage disequilibrium (LD) between different polymorphisms varied across diverse ethnic populations. In conclusion, the results indicate that CD44 polymorphism rs13347 acts as a risk factor for cancer, especially in Chinese, while the minor allele of polymorphism rs11821102 may be associated with a decreased susceptibility to cancer. Nevertheless, further studies on a larger population covering different ethnicities are warranted. CD44 is a multistructural and multifunctional transmembrane glycoprotein, which functions as a receptor for hyaluronan and many other extracellular matrix components, as well as a coreceptor for growth factors and cytokinesCD44 is involved in many crucial cellular processes, including cell survival, proliferation, differentiation, adhesion, and migration1CD44 has a role in cancer. First, CD44 is found to be widely expressed in various cancers, and its expression correlates with poor prognosis134CD44 has been shown to impede cancer progressionCD44 is a common cancer stem cell (CSC) marker. CSCs are a selected population of tumor cells that display many features of embryonic or tissue stem cells, and likewise, possess the capacity for self-renewal and differentiation. CD44 is in fact a critical player in the regulation of properties of the CSCs, such as self-renewal, tumor initiation, metastasis, and chemo- or radio-resistance1CD44 contributes in part as a downstream target of Wnt, a gene involved in the maintenance of the CSC phenotype, and has been shown to be essential for Wnt-induced tumor progression in cancersCD44 and hyaluronan furthermore promotes protein kinase C activation which leads to phosphorylation and translocation to the nucleus of NANOG, a transcription factor also involved in the maintenance of stem cell characteristicsCD44 has a critical role in epithelial-mesenchymal transition (EMT). EMT is a tightly regulated and highly conserved cellular process in which a cell type changes from an epithelial to a mesenchymal phenotype611Increasing evidence indicates that CD44 and/or function have been under intensive investigation. Recent studies have examined the association of specific single nucleotide polymorphisms (SNPs) in the CD44 gene with cancer risk but the significance of these findings remains unclear. Jiang et al. first discovered that the CD44 rs13347 polymorphism might affect breast cancer development and prognosis by increasing CD44 expression in the Chinese population141516181920CD44 rs13347 polymorphism and risks for gallbladder or breast cancers2223CD44 polymorphisms and the susceptibility to cancer. Eligible studies included diverse forms of cancer and two ethnicities, Chinese and Indian. These results have potential implications for the basis of cancer development as well as for functional consequences of allele specific expression of CD44.Based on these roles in cancer development, molecular mechanisms contributing to the regulation of CD44 polymorphisms with cancer risk in any type of cancer performed up to the date of August 10, 2016. Gene-specific terms (CD44) were combined with polymorphism- (polymorphism or polymorphisms or variation or variations or variant or variants or mutation or mutations or genotype or genotypes) and disease-specific terms (cancer or cancers or tumor or tumors or neoplasm or neoplasms). The search was performed by the method of free-text word combined with the Medical Subject Headings (MeSH) and included the following search terms: “Neoplasms”, “Antigens, CD44” and “Polymorphism, Single Nucleotide”. A thorough review of all referenced materials within retrieved studies was also performed in order to identify additional potentially eligible studies.PubMed, Embase, and Web of Science databases were searched for studies reporting association of CD44 SNPs in cancer risk; (3) articles published in English; (4) studies performed on humans; and (5) in the case of multiple publications from the same study group, the most complete and recent results were used.Inclusion criteria for eligible studies were the following: (1) case-control or cohort study design; (2) sufficient data for the evaluation of The exclusion criteria were defined as the following: (1) abstracts, reviews and animal studies; (2) useless reported data such as genotype number or frequency was not included; and (3) articles published in languages other than English.CD44 gene: rs8193, rs11821102, rs10836347, and rs13347 in the 3′UTR, rs1425802 in the promoter and rs9666607 in exon region. CD44 rs8193 and rs13347 were in high linkage disequilibrium (LD) , so the selection of rs13347 was sufficient to represent the two SNPs. In addition, due to the difficulty in genotyping rs9666607 using MALDI-TOF, the polymorphism rs713330, which is in complete LD with rs9666607  was chosen to replace it1315Previous studies performed bioinformatics analysis with Haploview software 4.2 to analyze the haplotype block based on the Chinese Han Beijing population data of HapMap . Six tagSNPs were found to cover all the potential functional common SNPs (MAF > 0.05) in the Two reviewers (Q.C.Q. and J.W.W.) independently selected studies and extracted the following data from each study: first author’s surname, publication year, ethnicity, cancer types, numbers of cases and controls, and genotype distributions of cases and controls. The results were compared and disagreement was resolved through discussion until consensus was reached. Study design was stratified into population-based studies and hospital-based studies.http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp, maximum score = 9 points) was used to evaluate the methodological quality, which scored studies by the selection of patients, the comparability of the groups, and the quality of the sampling process. Studies awarded a score of 0–3, 4–6, or 7–9 were considered as low-, moderate-, or high-quality studies, respectively.The Newcastle-Ottawa Scale and Agency for Healthcare Research and Quality (P < 0.05) or absence (P > 0.05) of heterogeneity. Sensitivity analysis was conducted by sequentially excluding one study at a time. The Begg’s test and the Egger’s test were performed to assess publication bias. If any possible bias was observed, the trim and fill method was used to identify and adjust for those studies. Data analysis was carried out using Stata software, version 11.0 . P-values < 0.05 were considered to be statistically significant.The meta-analysis assessed associations between polymorphisms and cancer risk under allele contrast, dominant, recessive, homozygous, and heterozygous models. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the strength of associations. Heterogeneity among the included studies was evaluated using the Chi square-based Q statistic. The fixed-effect (Mantel-Haenszel method) or random-effects model (DerSimonian-Laird method) was used to calculate pooled effect estimates in the presence (https://www.ncbi.nlm.nih.gov/variation/tools/1000genomes/) regarding the CD44 polymorphisms evaluated in the current study. Briefly, populations enrolled in the project including African ancestry in Southwest USA (ASW), Utah residents with Northern and Western European ancestry (CEU), Han Chinese in Beijing, China (CHB), Southern Han Chinese, China (CHS), Finnish in Finland (FIN), British in England and Scotland (GBR), Gujarati Indians in Houston, Texas (GIH), Indian Telugu in the UK (ITU), Japanese in Tokyo, Japan (JPT), and Toscani in Italy (TSI). Haploview software 4.2 was used to perform the analysis, and linkage disequilibrium (LD) was evaluated by D’ and r2 statistics in each of the above-mentioned populationsWe extracted data from the 1000 genomes Project Phase III ; dominant model ; recessive model ; homozygous model ; and heterozygous model . Additionally, polymorphism rs11821102 was significantly associated with cancer susceptibility in the allele contrast , dominant , and heterozygous models   . Howevertibility .rs13347, significant between-study heterogeneity was present in all genetic models; therefore, a random-effects model (Der-Simonian Laird) was used. For all other polymorphisms, no significant heterogeneity was found in any genetic model. A fixed-effect model (the Mantel-Haenszel method) was thus applied.For rs13347 polymorphism, the studies consisted of individuals of Chinese or Indian descent. However, for other polymorphisms, individuals from all eligible studies were only of Chinese descent, and the number of studies for each cancer type was less than two. Therefore, stratified analysis on the basis of ethnicity, source of controls, and cancer type was only performed on rs13347 ; dominant model ; recessive model ; homozygous model ; and heterozygous model . No associations were observed between the CD44 polymorphisms examined and Indians. The magnitude of association in hospital-based studies was significantly weakened for all genetic models. However, the magnitude of association in population-based studies was not significantly changed: allele contrast ; dominant model ; recessive model ; homozygous model ; and heterozygous model . When the stratification analysis was conducted based on cancer type, we uncovered that the T allele was significantly associated with an increased susceptibility to colorectal cancer, nasopharyngeal carcinoma, and acute myeloid leukemia in all genetic models, and an increased risk for breast cancer only in recessive and homozygous models.In an ethnicity subgroup analysis, polymorphism rs13347 polymorphism in an allelic comparison and the rs11821102 polymorphism in the heterozygous model are presented in In order to examine the influence of individual data sets on the pooled ORs, single studies were sequentially excluded from analysis. Pooled ORs were persistent, indicating that the results were statistically stable and robust (data not shown). Sensitivity analysis of the rs13347 polymorphism in an allelic comparison and the rs11821102 polymorphism in the heterozygous model are presented in P-values from the two tests are listed in rs10836347. For this polymorphism, publication bias was apparent in the recessive and homozygous models. However, analysis with the trim and fill method demonstrated that the results of our study did not significantly change even after adjusting for the publication bias.The Begg’s and the Egger’s tests were performed to quantitatively evaluate publication bias of the included studies. Asymmetry was not observed in the funnel plots of any of the polymorphisms. The funnel plots for the CD44 polymorphisms evaluated, including rs10836347, rs11821102, rs13347, rs1425803, rs713330, rs8193, and rs9666607  were calculated for ASW populations, while complete LD (D’ > 0.90) was observed for the other ethnic populations examined. The rs713330 polymorphism was in complete LD with rs9666607  for all populations. LD plots for the ASW population yielded a high LD value between rs13347 and rs11821102 polymorphisms, moderate LD values for CEU, FIN, GIH, ITU, and TSI populations, and lower LD values for CHB, CHS, GBR, and JPT populations.In order to investigate the relationship between polymorphisms in the different populations, LD analysis was performed to test for the existence of bins in the region containing the seven s9666607 . RelativCD44. The meta-analysis performed here with data pooled from 5,788 cases and 5,852 controls supports previous findings that a significant association between CD44 polymorphism rs13347 and cancer risk exists under all genetic models. Thus, the T allele emerged as a risk marker for cancers, especially in Chinese, which is a finding consistent with the results of most of the included studies.The genetic basis for the development of cancer involves inherited as well as somatic components. While familial predispositions to cancer have been more easily identified, those genetic factors more generally affecting populations in conjunction with environmental factors have been more difficult to identify. Thus, the focus has become polymorphisms in well-known cancer associated genes, such as CD44 gene is located on chromosome 11 and consists of 20 exons and 19 introns1CD44 gene undergo complicated alternative splicing, which results in many functionally distinct protein isoforms, such as CD44 standard (CD44s) and CD44 variant isoforms (CD44v), which account for the heterogeneity in this protein family14CD44 is expressed as multiple transcriptional variants, but the 3′UTR, which is ~3000 nucleotides long, is in fact relatively conserved2CD44 polymorphism rs13347 has been the subject of intense investigation in cancer susceptibility studies primarily due to its location in the 3′UTR of the CD44 gene/transcripts10131416rs13347 may lead to alterations in mRNA and/or protein levels of CD44 due to the change of the C and the T allele. In transient transfections using a construct in which the reporter gene is modulated by the CD44 3′ UTR, the presence of the rs13347 T allele led to increased transcriptional activity relative to the C allele131516rs13347 variant genotypes (CT and TT) were shown to exhibit dramatically increased CD44 than CC carriers in breast cancer, acute myeloid leukemia, nasopharyngeal carcinoma, and colorectal cancer131516CD44 more strongly in C allele carriers than in T allele carriers1315162930The full-length rs13347 polymorphism, we identified a significant association in all the genetic models for Chinese but not Indians, only in population-based studies. Moreover, we performed LD analyses to determine the LD between the related polymorphisms. The rs713330 polymorphism was in complete LD with rs9666607 for all populations. Similarly, the high LD values between rs13347 and rs9666607 polymorphisms were observed in all populations except the ASW population. LD plots for the ASW population yielded a high LD value between rs13347 and rs11821102 polymorphisms, for CEU, FIN, GIH, ITU, and TSI populations, moderate LD values, and for CHB, CHS, GBR, and JPT populations, lower LD values. The limited number of studies and sample size may account for this discrepancy; therefore, future studies are necessary to verify these results.In addition, when the stratification analyses were conducted based on ethnicity and source of control for the CD44 polymorphism rs11821102 indicate a positive correlation with statistical power associated with cancer; yet pooled analysis demonstrated that the minor allele of rs11821102 polymorphism might be related to a decreased cancer risk in Chinese. The polymorphism rs11821102 is also located in 3′UTR of the CD44 gene13CD44 expression or function to date. The limited number of studies and sample size may account for this discrepancy; therefore, larger, preferably population-based case-control studies, as well as mechanistic studies involving CD44 polymorphism rs11821102, are warranted to validate our findings and to further investigate the role of CD44 in the development of cancer.None of the eligible studies for rs13347 but not in other polymorphisms within all genotype models, and stratified analysis was used to explore the source of heterogeneity. Subgroup analysis by source of controls demonstrated that the between-study heterogeneity was still significant. When subgroup analysis was performed by ethnicity, the heterogeneity was dramatically reduced in Indians but not in Chinese. However, stratified analysis based on cancer type demonstrated that the heterogeneity was not significant in studies performed on nasopharyngeal carcinoma under all genetic models or on breast cancer under recessive and homozygous models. Therefore, the between-study heterogeneity might be mainly attributed to various cancer types. Second, our analysis was limited to individuals of Asian descent, mainly Chinese. LD between different polymorphisms varied across diverse ethnic populations. It, therefore, remains uncertain as to whether the result can be generalized to other ethnic populations.Although we have conducted a comprehensive retrieval for all eligible studies and polymorphisms, which markedly expanded the sample size and revealed some associations not observed in previous work, some limitations in this study exist. First, statistically significant heterogeneity was confirmed in CD44 polymorphisms with cancer risk. In summary, our study suggests CD44 polymorphism rs13347 can serve as a risk factor for cancer, particularly in Chinese. Our findings also indicate that the minor allele of rs11821102 polymorphism may be associated with a decreased susceptibility to cancer in Chinese.To the best of our knowledge, this is the first meta-analysis to date to investigate the associations of How to cite this article: Qi, Q. et al. Associations of five polymorphisms in the CD44 gene with cancer susceptibility in Asians. Sci. Rep.6, 39485; doi: 10.1038/srep39485 (2016).Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


Background: Although endothelial cell protein C receptor (EPCR) gene Ser219Gly polymorphism has been associated with venous thromboembolism (VTE) susceptibility, no clear consensus has yet been reached.Objective and methods: A meta-analysis of 9,494 subjects from 13 individual studies was conducted to better elucidate the potential relationship between the EPCR gene Ser219Gly polymorphism and VTE. Pooled odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were evaluated by using fixed or random effect models.Results: The current meta-analysis suggested that there was a significant association between EPCR gene Ser219Gly polymorphism and VTE under allelic , recessive , homozygous , and additive genetic models .Conclusions:EPCR gene Ser219Gly polymorphism was associated with an elevated risk of VTE and the Gly residue carriers of the EPCR gene might be predisposed to VTE. Venous thromboembolism (VTE) encompasses deep vein thrombosis (DVT) and pulmonary empolism (PE). DVT indicates the formation of a venous thrombus typically in the deep veins of the legs, which may undergo embolization when the clot is dislodged from the underlying endothelium and carried downstream by circulatory system potentially reaching the lungs where it can cause a sudden occlusion of pulmonary circulation, referred to as PE. This event presents as a clinical emergency that can endanger the patient's life. In Western countries, VTE morbidity is around 1–2% in the whole population and rising. The early mortality of the DVT and PE are as high as 3.8 and 38.9%, respectively  expressed on the endothelium of the great vessels to cleave plasminogen to plasmin, a potent anti-coagulant  were associated with an increased risk for DVT as well as its mutant allele G  diagnose DVT by Doppler ultrasonography of the lower extremities, or diagnose PE by compression or ventilation lung ultrasonography, contrast venography, lung ventilation/perfusion scan, conventional pulmonary angiography, or computed tomographic angiography, (c) have control groups at Hardy-Weinberg equilibrium (HWE). The studies must be officially published cohort or case-control studies.The following inclusion criteria had to be met by the selected studies for our meta-analysis. Studies selected must: (a) assess the association of VTE and The data was abstracted according to a standardized protocol by three authors. Two were responsible for removing duplicate studies while the third acted as an arbitrator to resolve any disagreements. Studies that did not meet inclusion criteria, were published repeatedly, or did not supply sufficient data were removed. Similar data sets presented in multiple publications by a single author group were represented once in the current meta-analysis. The listed data table also had to include items such as the first author's name, publication year, region, genotyping method, matching criteria, the genotype number in the VTE and control groups, and sample size of VTE and controls Table .EPCR gene Ser219Gly polymorphism and VTE was compared by using odds ratios (ORs) and their corresponding 95% confidence intervals (CIs). Chi-square-based Q-tests were used to calculate the heterogeneity among the studies with significance set at P < 0.05 level , recessive (GG vs. AG and AA), homozygous (GG vs. AA), and additive (G vs. A). The relationship of Cochran, . If no hCochran, . OtherwiCochran, . Z-test P < 0.05 level. The funnel plot was used to assess the potential publication bias. The Egger's linear regression test on a natural log scale of the OR was used to evaluate the funnel plot symmetry and the significance was set at P < 0.05 level , recessive , homozygous , and additive genetic models , homozygous , and additive genetic models . No significant association was detected under the recessive genetic model .We also analyzed subgroups, stratified by ethnicity. In the Chinese subgroup, we found significant association between P = 0.001), recessive , homozygous , and additive genetic models .In the non-Chinese subgroup, a significant association between them was also observed under allelic . However, allelic and additive genetic models exhibited significant heterogeneity (P > 0.05). In the subgroup analysis, no significant heterogeneity was detected under all of the genetic models in the Chinese population (P > 0.05). Regard to the non-Chinese population, heterogeneity was detected under the additive genetic models (P < 0.05). This suggests that the source of heterogeneity was associated with ethnicity.In the whole population, no significant heterogeneity was detected under recessive or homozygous genetic models , recessive (OR: 2.02), homozygous (OR: 2.24), and additive genetic models (OR: 1.63). This suggests that the EPCR gene Ser219Gly polymorphism is associated with an elevated risk of VTE and that carriers of the G allele of the EPCR gene at the 6,936th or 4,600th position may be predisposed to VTE. Our analysis of the data by ethnicity echoed our initial findings with significant association detected in both the non-Chinese and Chinese ethnicities. Although heterogeneity was detected under allelic, and additive genetic models in the whole population (Pheterogeneity < 0.05), our subgroup analysis found it to be limited to the non-Chinese group, suggesting ethnicity to be the main source of heterogeneity (Pheterogeneity > 0.05).In the current meta-analysis, we found a significant association between the EPCR is primarily expressed on the endothelial apical cell surface of the big vessels, but is also found in relatively high amounts in the placenta, lung, liver, and heart , interleukin-1â (IL-1â), TNF-α, and thrombin. EPCR is also subject to MMP-mediated cleavage with the resultant sEPCR contributing to a pro-coagulation state through two mechanisms. Firstly, it acts as a competitive inhibitor by sEPCR by maintaining its interactions with activated Protein C, but no longer contributing to the thrombin-thrombomodulin (TM) system  (Yin and Jin, This study is not without limitations, however. We still lack the multiple large-scale studies necessary to completely understand the relationship between the EPCR gene Ser219Gly polymorphism was significantly associated with VTE susceptibility. The persons with the Gly residue of EPCR gene Ser219Gly polymorphism might be susceptible to VTE. More studies on the relationship between them should be carried out to further clarify this conclusion.In conclusion, YL and JW researched data. YL and HK wrote manuscript, researched data. YL, HG, and XY reviewed/edited manuscript. YL contributed to discussion, reviewed/edited manuscript. YL and GG researched data, contributed discussion.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Birth weight, a marker of the intrauterine environment, has been extensively studied in epidemiological research in relation to subsequent health and disease. Although numerous meta-analyses have been published examining the association between birth weight and subsequent health-related outcomes, the epidemiological credibility of these associations has not been thoroughly assessed. The objective of this study is to map the diverse health outcomes associated with birth weight and evaluate the credibility and presence of biases in the reported associations.An umbrella review was performed to identify systematic reviews and meta-analyses of observational studies investigating the association between birth weight and subsequent health outcomes and traits. For each association, we estimated the summary effect size by random-effects and fixed-effects models, the 95 % confidence interval, and the 95 % prediction interval. We also assessed the between-study heterogeneity, evidence for small-study effects and excess significance bias. We further applied standardized methodological criteria to evaluate the epidemiological credibility of the statistically significant associations.P < 1 × 10−6. Thirty associations presented large or very large between-study heterogeneity. Evidence for small-study effects and excess significance bias was present in 13 and 16 associations, respectively. One association with low birth weight , two dose-response associations with birth weight  and one association with small-for-gestational age infants with normal birth weight (increased risk for childhood stunting) presented convincing evidence. Eleven additional associations had highly suggestive evidence.Thirty-nine articles including 78 associations between birth weight and diverse outcomes met the eligibility criteria. A wide range of health outcomes has been studied, ranging from anthropometry and metabolic diseases, cardiovascular diseases and cardiovascular risk factors, various cancers, respiratory diseases and allergies, musculoskeletal traits and perinatal outcomes. Forty-seven of 78 associations presented a nominally significant summary effect and 21 associations remained statistically significant at The range of outcomes convincingly associated with birth weight might be narrower than originally described under the “fetal origin hypothesis” of disease. There is weak evidence that birth weight constitutes an effective public health intervention marker.The online version of this article (doi:10.1186/s12916-016-0692-5) contains supplementary material, which is available to authorized users. In early 1990’s, the “fetal origin hypothesis” of adult diseases was suggested to describe the observed associations between low birth weight (BW) and cardiovascular diseases in adult life . Barker,Since then, the importance of the early life and intrauterine environment in relation to later disease has been widely acknowledged and studied , 6–10. BInterpreting associations between BW and the occurrence of health problems later in life is, however, challenging and linked to a series of methodological limitations . DespiteWe performed an umbrella review, which is a comprehensive and systematic collection and evaluation of multiple systematic reviews and meta-analyses performed on a specific research topic . We follTwo independent researchers extracted the data , and in the case of discrepancies, the final decision was that of a third researcher (IT). From each eligible article, we recorded the first author, journal, year of publication, examined outcomes and number of studies included. We also extracted the study-specific effect sizes  along with the corresponding 95 % confidence intervals and the number of cases and controls in each study for each association. Whenever the sample sizes were not available through the meta-analysis, we retrieved the original reports to record them. Further, when multiple comparisons were available for a particular phenotype (e.g. < 2500 g vs. ≥ 2500 g and < 2500 g vs. 2500–4000 g) we always preferred to extract information on < 2500 g versus ≥ 2500 g and > 4000 g versus ≤ 4000 g in the case of low BW and high BW, respectively. However, when this comparison was not available, we extracted the comparison reported by the meta-analysis. For the excluded meta-analyses assessing an overlapping association, we recorded the level of comparison and the summary effect estimate along with the 95 % confidence interval. Additionally, we scrutinized the full-text of the eligible papers to examine whether their authors discussed the potential effect of gestational age in the association of BW with subsequent health outcomes.For each meta-analysis, we estimated the summary effect size and its 95 % confidence interval with both fixed-effects and random-effects models , 29. We 2 metric [2 ranges between 0 % and 100 % and is the ratio of between-study variance over the sum of the within-study and between-study variances [In the case of meta-analyses with continuous outcomes, the standardized mean difference was transformed to an odds ratio with an established formula . Between2 metric . I2 rangariances . Values P value less than 0.10 with a more conservative effect in the largest study than in random-effects meta-analysis was judged to be evidence for small-study effects.We assessed whether there was evidence for small-study effects  with the regression asymmetry test proposed by Egger et al. , 36. A Pt distribution [P < 0.10 [We applied the excess statistical significance test, which assesses whether the observed number of studies with nominally significant results is larger than their expected number . This teribution , 39. ExcP < 0.10 . For fouP < 1 × 10−6, more than 1000 cases, not large between-study heterogeneity (I2 < 50 %), 95 % prediction interval excluding the null value, and no evidence of small-study effects and excess significance bias. Additionally, the associations with a statistically significant effect at P < 1 × 10−6, more than 1000 cases, and a statistically significant effect in the largest study were characterized as having highly suggestive evidence. We considered as suggestive the associations that have more than 1000 cases and a statistically significant effect under the random-effects model at P < 1 × 10−3. The rest of statistically significant associations at P < 0.05 under random-effects model were graded as weak associations.Finally, we identified the associations that had the strongest validity and were not suggestive of bias. Specifically, we considered as convincing the associations that met the following criteria: significance under the random-effects model at The statistical analyses were performed with STATA version 12.0 and the power calculations were performed using STATA version 12.0 and G*Power version 3.1.Overall, the literature search identified 1520 articles, of which 39 articles, published between 2005 and 2015, were deemed eligible  and the same outcome. Overlapping meta-analyses provided concordant results, with the exception of two pairs, which had a summary effect in opposite direction (diastolic blood pressure and overweight) compared to the meta-analysis included in our umbrella review . Six other meta-analyses differed in the summary effect significance compared to the most recent one  and 10 of them had a significant effect at P < 0.001. Only seven meta-analyses, examining the association of low BW with perinatal mortality in developing countries, wheezing disorders in childhood, being overweight or obese in adulthood, coronary heart disease, intelligence in adolescence, all-cause mortality, and chronic kidney disease, were statistically significant at P < 1 × 10−6 under the random-effects model (Table 2 ≥ 50 % and I2 ≤ 75 %), and 10 associations had very large heterogeneity estimates (I2 > 75 %). On bias assessment, seven associations had evidence for small-study effects , and four associations  had hints for excess significance bias , 1574–11,729), while the median number of datasets was 11 . Overall, 21 out of 28 associations had more than 1000 cases, 17 of 28 meta-analyses presented a nominally significant effect  remained statistically significant after the application of a more conservative significance threshold (P < 1 × 10−6). The largest study had a standard error of less than 0.10 in four meta-analyses and a more conservative effect compared to random-effects model in 12 meta-analyses. Only four meta-analyses  had a 95 % prediction interval excluding the null value (Table 2 ≥ 50 % and I2 ≤ 75 %) in seven meta-analyses and only one meta-analysis presented very large heterogeneity (I2 > 75 %). Two associations presented hints for both small-study effects and excess significance bias , another two associations had only small-study effects (bone tumour and non-Hodgkin lymphoma in childhood), and two additional associations had hints for excess significance bias (acute myeloid leukaemia and testicular cancer).Across 18 meta-analyses examining high BW as a dichotomous trait, the median number of cases was 6115 , 16 meta-analyses were supported by more than 1000 cases, and the median number of datasets was 10 . Ten associations presented a significant effect at P < 0.05, but only six associations survived in the application of a more stringent P value (P < 1 × 10−6). The largest study had a standard error of less than 0.10 in 21 meta-analyses and a more conservative effect compared to the random-effects model in 20 meta-analyses. Only six associations  presented 95 % prediction interval excluding the null value  and the median number of datasets was 8 . Overall, 17 associations were significant at P < 1 × 10−6 and 95 % prediction interval excluding the null value  and the risk for acute lymphoblastic leukaemia, childhood stunting and depression. No meta-analyses on large-for-gestational age infants were identified. Under the random-effects model, three associations had a statistically significant effect at Despite the importance of gestational age on BW, only four out of the 36 papers  examining low BW, high BW or dose–response relationships with BW, presented subgroup analyses, including only studies that provided gestational age-adjusted estimates Table  14, 41––41–43. NP < 0.05. Of the remaining 50 associations, only four presented convincing evidence by having more than 1000 cases, not large heterogeneity, 95 % prediction interval excluding the null value, a significant summary effect at P < 1 × 10−6, and absence of small-study effects and excess significance bias (Table P < 1 × 10−6 and largest study with a significant effect). These associations examined perinatal mortality in developing countries, wheezing disorders, being overweight or obese in adulthood, coronary heart disease for the comparison of < 2500 g versus ≥2500 g, intelligence in adolescence for the comparison of low BW versus normal BW, all types of leukaemia, being overweight or obese in adulthood for the comparison of > 4000 g versus ≤ 4000 g, muscle strength and coronary heart disease for the comparison of increase per 1 kg in BW, and maternal cardiovascular mortality and paternal cardiovascular mortality for the comparison of increase per 1 SD in BW. Fourteen associations presented suggestive evidence and 13 associations had weak evidence (Table Twenty-eight of 78 associations (36 %) did not present a significant summary effect at as Table . These aOur work constitutes the first comprehensive mapping and appraisal of the association between BW and the risk of subsequent health outcomes, as provided by published systematic reviews and meta-analyses of observational studies. Overall, 78 associations have been examined, including a diverse range of outcomes: cardiovascular, cancer, metabolic, respiratory and mortality outcomes, and disease traits and biomarkers. Despite common belief that the intrauterine environment as assessed by BW is associated with many diseases and disease traits in adult life , 6–10, oThe associations between BW and cardiovascular disease were amongst the first to be observed in the medical literature –5 and ouP value [The observed increased risk of cardiovascular disease associated with lower BW is likely to be a main contributor to the inverse association of BW with all-cause mortality; an association supported by convincing evidence in our assessment . The higP value . HoweverP value . These dThe association between low BW and low bone mineral concentration in later life is less well studied compared to other outcomes and current data stem from six studies contributing to the meta-analysis . DespiteComparisons between BW and later overweight and obesity do not support a detrimental health effect of low BW. BW less than 2500 g was found to be protective for being overweight or obese, whereas BW greater than 4000 g was linked with an increased risk for being overweight or obese in adult life . These aAlthough 29 associations focused on outcomes related to different types of cancer, high BW was found to be a risk factor only for developing leukaemia . The assDespite intensive research on BW reflected by the large number of meta-analyses identified, there were only three papers that performed meta-analyses of studies assessing low BW in relation to gestational age , 55, 56,In the present study, we applied the umbrella review approach summarising data from already published systematic reviews and meta-analyses. This approach takes full advantage of the existing meta-analyses to perform a standardised methodological process for the assessment of the epidemiological credibility of the findings. However, our study has some caveats. First, the Egger test and excess statistical significance test offer hints of bias, and not proof thereof, while the Egger test is difficult to interpret when the between-study heterogeneity is large. Further, our excess significance estimates were based on the largest study of each meta-analysis and they might be conservative, because often these studies were not necessarily very large or might have had inherent biases themselves. Furthermore, we did not appraise the quality of the primary studies, because this was beyond the scope of this umbrella review. This should be the aim of the original systematic reviews and meta-analyses, which should examine the methodological characteristics of the component studies.Our study maps the current status of evidence on 78 associations of BW with various health outcomes, traits and biomarkers. Of them, only three examined the effects of BW in relation to gestational age through size-at-birth defined phenotypes. Our results show that the range of outcomes associated with BW is narrow and smaller than described under the fetal origin of disease hypothesis. Currently, there is weak evidence that BW constitutes an effective public policy intervention for long-term health and disease.


RR) and corresponding 95% confidence interval (95% CI) of leukemia, comparing hair dye users to nonusers. When data from all 20 studies that met the inclusion criteria were combined, ever use of hair dye was associated with a nonstatistically significant increased risk of leukemia, meta‐RR = 1.09 (95% CI: 0.97–1.22). When restricted to studies that adjusted for smoking, ever use of hair dye was not associated with leukemia, meta‐RR = 0.99 (95% CI: 0.76–1.29). A statistically significant increased risk of leukemia was associated with permanent hair dye use (meta‐RR = 1.19 [95% CI: 1.07–1.33]), dark hair dye use (meta‐RR = 1.29 [95% CI: 1.11–1.50]), hair dye use among males (meta‐RR = 1.42 [95% CI: 1.01–2.00]), hair dye use pre‐1980 (meta‐RR = 1.49 [95% CI: 1.21–1.83]), and hair dye use for ≥15 years (meta‐RR = 1.35 [95% CI: 1.13–1.62]). Overall, findings suggest that ever use of hair dye is not a significant risk factor for leukemia. Certain hair dye use characteristics were associated with a statistically significant increased risk, but further research is required to determine whether these associations truly reflect a risk of leukemia due to methodological limitations in the underlying studies.The objective of this study was to examine the association between personal use of hair dyes and the risk of leukemia. We conducted a systematic literature review of epidemiology studies reporting leukemia‐specific cancer risks among hair dye users, and estimated the meta‐relative risk (meta‐ The prevalence of the use of hair dye, a mixture of chemical compounds used to treat hair for cosmetic purposes, has increased worldwide, with an estimated 50–80 percent of women in the United States, Japan, and European Union reporting to have used hair dye in their lifetime Hair dye products include a range of over 5000 chemical compounds and are composed of dye intermediates and dye couplers that interact with each other in the presence of hydrogen peroxide to form pigment molecules The association between personal use of hair dye (involving self‐application) and cancer endpoints has also been evaluated, and inconsistent findings have been reported that vary by cancer type Leukemia, a type of hematopoietic cancer that arises in the bone marrow, is classified by the rate of growth (acute or chronic) and cell line of origin (lymphocytic or myeloid). According to the Surveillance, Epidemiology, and End Results Program (SEER), rates for new leukemia cases have been rising on average 0.3 percent per year over the last 10 years, with over 60,000 new cases of leukemia projected to occur in 2016 Since the meta‐analysis of Takkouche in 2005, ten studies have been published in which the association between personal hair dye use and the risk of one or more leukemia subtypes was evaluated We followed standardized PRISMA protocol and performed a systematic literature review to estimate the pooled relative risk of leukemia among personal hair dye users. Studies were identified by electronic database searching of PubMed, Web of Science, and Embase from their respective inception dates, using the search terms “hair” and (“dye” or “color” or “colour”) and (“leukemia” or “leukaemia” or “myeloid” or “lymphocytic” or “myelogenous” or “lymphoblastic”). Findings were supplemented with references manually obtained from the search results. Furthermore, we systematically reviewed studies that cited the articles that met our inclusion criteria. The latest search was conducted in May 2017.Two independent individuals reviewed and screened the title and abstract results to identify potentially relevant articles Fig. . SelectiData on study design, study population, primary exposure, subexposure, health outcome, risk estimates, confidence intervals, country of study, time period of diagnoses, time period of hair dye use data, number of cases and controls, cohort size, participation rate, and adjusted covariates were collected for each article. Study‐specific data were abstracted by one reviewer and assessed for quality control by an independent reviewer.Each study was critiqued and analyzed for validity of study design and completeness of information based on potential for confounding, participation rate, loss to follow‐up, methodology of interviews or questionnaires, and selection protocol. Sensitivity analyses were performed to determine the effect of study exclusion.P < 0.05]) models were employed to estimate the pooled relative risk (meta‐RR) of all types of leukemia among all hair dye type users with 95% CI, weighted by the inverse of the study variance. Stratified analyses were performed by leukemia group (lymphocytic and myeloid), leukemia subtype , duration of hair dye use (≤10 years or ≥15 years), time period of hair dye use (pre‐1980 and post‐1980), dark hair dye , light hair dye (blonde or classified as light in paper), use of permanent hair dye, and gender. In these analyses, gender‐, type‐, and time period‐specific risk estimates were included in the models when studies reported separate measures of association by males and females, permanent and semi‐permanent hair dyes, and decade of hair dye use. No hair dye use was used as the reference group, and a minimum of four studies were required per stratified analysis. Cochran's Q test was used to examine study heterogeneity. Funnel plots (log relative risk and standard error) and Egger's test were performed to assess the potential of publication bias. All statistical analyses were performed using Stata software, version 14.2.Fixed‐effect and random‐effects (in the presence of heterogeneity [n = 2), Serbia (n = 1), China (n = 3), Denmark (n = 1), Italy (n = 4), Greece (n = 1), Spain (n = 1), United States (n = 7), and multiple countries (n = 5). The studies examined all leukemia types grouped together, as well as various subtypes of lymphocytic and myeloid leukemia.A total of 33 papers met the inclusion criteria for full paper review from the original 206 abstracts Fig. . The KapDue to the presence of overlapping cohorts, Thun 1994 and Zhang 2008 were removed from the analyses, with preference given to the more comprehensive analyses of Altekruse 1999 and Slager 2014, respectively Based on 20 studies, ever use of any type of personal hair dye was associated with a nonstatistically significant increased risk of leukemia, when compared to no use of hair dye, meta‐RR = 1.09 (95% CI: 0.97–1.22) , meta‐RR = 1.17 (95% CI: 1.03–1.34), and a meta‐RR = 1.06 (95% CI: 0.93–1.20) for myeloid leukemia . No statistically significant associations were observed when models were separated by AML, CLL, and ALL subtypes individually (Table P = 0.53), and did not indicate the presence of publication bias , and meta‐RR = 1.19 (95% CI: 1.07–1.33), respectively, while the use of light hair dye, meta‐RR = 1.13 (95% CI: 0.95–1.34), and semi‐permanent or nonpermanent hair dye, meta‐RR = 1.05 (95% CI: 0.86–1.29), were not. Additionally, use of hair dye prior to 1980 was associated with a statistically significant increased risk of leukemia, meta‐RR = 1.49 (95% CI: 1.21–1.83), while use of hair dye after 1980 was not, meta‐RR = 1.06 (95% CI: 0.81–1.38). Finally, use of hair dye for ≥15 years was associated with a statistically significant increased risk of leukemia, meta‐RR = 1.35 (95% CI: 1.13–1.62), while use of hair dye for ≤10 years was associated with a meta‐RR of 0.94 (95% CI: 0.80–1.11). A funnel plot and Egger's test did not show evidence of asymmetry , time period of use , duration of use , and male gender, are associated with a statistically significant increased risk of leukemia. However, the observed findings may be due to the introduction of bias and confounding by smoking, study design limitations, and historical formulations of hair dye products.An unstratified meta‐analysis indicated that use of any type of hair dye was associated with a nonstatistically significant increased risk of all types of leukemia, meta‐RR 1.09 (95% CI: 0.97–1.22)  into hair dye formulations that were shown to produce mutagenic activity and dermally penetrate humans, resulting in regulatory action in 1978 to ban certain aromatic amine compounds in the European Union The implication of these time‐varying exposures is that hair dyes prior to reformulation are potentially more carcinogenic than more recent hair dye formulations after the removal of certain mutagenic ingredients. Specifically, this study found that individuals who used hair dye products prior to 1980 were at a statistically significant increased risk of leukemia, which was not observed in individuals that used hair dyes after 1980 Table . All undThis analysis also provided evidence that duration of use may be a factor in the risk of leukemia, as use of hair dye for ≥15 years was associated with an increased risk of leukemia, while use of hair dye for ≤10 years was associated with a decreased risk of leukemia Table . All undLymphocytic leukemia develops from lymphocytes while myeloid leukemia arises from primarily granulocytes or monocytes. Similar to Takkouche, we report that hair dye use was associated with an increased risk of lymphocytic leukemia Table . This trFindings also suggest that male users of hair dye are at an increased risk of leukemia, which is an area of research that requires further investigation. This may be due to different hair dye use exposure patterns ; however, as there were only four studies that provided male‐specific risk estimates, we were unable to further stratify subanalyses by gender. It should be noted that all studies involving men were case–control studies.The main strength of this study is that it provides a pooled estimate of leukemia risk among hair dye users across various study populations. Additionally, the inclusion of more studies allowed for the further investigation of exposure characteristics, including hair dye type and duration/time period of use. A methodological limitation was less accurate exposure classification in studies that assessed the risk of leukemia due to a suite of past occupational and lifestyle exposures, and therefore only collected limited data on the history of lifetime hair dye use This analysis is also limited by the studied disease classifications, with some studies reporting risk estimates for all leukemia types combined rather than by specific leukemia subtypes. The most informative summary risk measures should be analyzed by leukemia subtype due to different etiologies. However, we were unable to perform meta‐analyses for all leukemia subtypes, and were unable to further stratify subtype meta‐analyses by hair dye type, gender, etc. This body of literature would benefit from additional studies by specific leukemia subtypes. Additionally, the underlying studies did not provide data that enabled us to perform a robust dose–response analysis. While we used duration of use as a proxy of cumulative dose to assess the dose–response relationship, future studies should attempt to characterize different dose levels.The issue of dependency also arises during the analysis of underlying case–control studies. In studies that calculated risk estimates for non‐Hodgkin lymphoma, multiple myeloma, and leukemia, the same control populations were used in all calculations despite differing disease outcomes. Therefore, these calculations in the underlying studies may not be considered independent, and multiple comparisons may result in observed statistically significant associations that do not exist Findings suggest that personal hair dye use is not a significant risk factor for leukemia when data from all studies were combined. Additionally, statistically significant associations were observed when studies were stratified by exposure profile characteristics, including hair dye type, gender, and duration/time period of use. While statistically significant, the clinical significance of these findings remains unclear. Further research is required to determine whether the aforementioned stratified associations truly reflect a risk of leukemia in certain users of hair dye, due to the potential for methodological limitations in the underlying studies  to overestimate the true effect.The authors declare that there are no conflicts of interest.  The authors are employed by Cardno ChemRisk, a consulting firm that provides scientific advice to the government, corporations, law firms, and various scientific/professional organizations. Cardno ChemRisk has not performed consulting work for hair dye manufacturers, and this analysis was designed, conducted, and funded exclusively by Cardno ChemRisk.


HDAC9) gene is associated with stroke, but the reliability of these findings remains controversial, particularly for the data derived from different ethnicities and geographical locations. Therefore, we performed a meta-analysis to explore the associations between HDAC9 polymorphisms and the risk of stroke in the Chinese population. All eligible case-control studies that met the search criteria were retrieved from multiple databases, and six case-control studies with a total of 2,356 stroke patients and 3,420 healthy controls were included. The pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated to assess the strengths of the associations of 3 HDAC9 gene polymorphisms with stroke risk. Our results revealed statistically significant associations of the rs2107595 (T/C) polymorphism with an increased risk of stroke in the allele, codominant and dominant models. Additionally, the rs2389995 (G/A) polymorphism was found to be significantly associated with a decreased risk of stroke in all genetic models. In conclusion, this meta-analysis suggested that the T allele of rs2107595 in HDAC9 increases the risk of stroke but that the G allele of rs2389995 decreases the risk of stroke in the Chinese population.Several recent genome-wide association studies (GWASs) have suggested that the histone deacetylase 9 ( HDAC9) as being significantly associated with ischaemic stroke567Stroke is a leading cause of death and long-term adult disability throughout the worldHDAC9 is a member of the HDAC gene family that plays essential roles in the organization of chromatin structure and subsequent transcriptional regulationHDAC9 polymorphisms have been reported to be associated with coronary artery disease (CAD)713HDAC9 gene polymorphisms and the risk of stroke have been intensively investigated5675HDAC9 is significantly associated with large-vessel ischaemic stroke in European populationsHDAC9 is not polymorphic and claimed significant associations of rs2389995 and rs2240419, which are the other two SNPs of the HDAC9 gene, with large-vessel stroke. Hence, we designed this meta-analysis to quantify the overall genetic effects of these three HDAC9 polymorphisms on the risk of stroke in the Chinese population.HDAC9 were possibility of partial overlapping but this possible partial overlapping would not affect the final results  for the three SNPs, and minor allele frequencies (MAF) of the 3 SNPs in the Chinese Han population in Beijing (HCB) were estimated from the 1000 Genomes. The present samples indicated that 96% power for rs2107595 (MAF = 0.301), 75% power for rs2389995 (MAF = 0.180), and 80% power for rs2240419 (MAF = 0.218). The power analysis indicated that these recruited samples could provide sufficient power in identifying the association between the 3 SNPs and stroke in the Chinese Han population.As illustrated in P < 0.01; in the codominant model, TT vs. CC, OR = 1.29, 95% CI: 1.04–1.60, P < 0.05; CT vs. CC, OR = 1.18, 95% CI: 1.04–1.36, and P < 0.05; in the dominant model, TT + CT vs. CC, OR = 1.22, 95% CI: 1.05–1.40 and P < 0.01; and the recessive model was not significant   .P < 0.01); codominant ; dominant ; and recessive   .P = 0.16; TT vs. CC: OR = 1.48, 95% CI = 0.76–2.89, P = 0.25; CT vs. CC: OR = 1.28, 95% CI = 0.96–1.69, P = 0.09; TT + CT vs. CC: OR = 1.33, 95% CI = 0.93–1.89, P = 0.12; and TT vs. CT + CC: OR = 1.32, 95% CI = 0.77–2.26, P = 0.32). Remarkable between-study heterogeneity was present, and thus a random-effects model was used to calculate the pooled estimates However, no significant relationship of the rs2240419 polymorphism with IS risk was found in any of the four genetic models . There were no significant differences for the pooled ORs before or after using the “trim and fill” method in the codominant model (TT vs. CC) of rs2240419  of HDAC9 and the stroke risk in the Chinese Han population. To the best of our knowledge, this is the first meta-analysis to explore the relationships between HDAC9 gene polymorphisms and stroke susceptibility in a Chinese population. Six case-control studies816171819HDAC9 gene polymorphisms.Recently, several GWASs identified a novel association between HDAC9 are 0.301, 0.180 and 0.218, respectively, in the Chinese Han population in Beijing (HCB), whereas the MAFs are 0.367 0.210 and 0.290, respectively, in the southern Han Chinese population (CHS) based on the data from the 1000 G. Besides, the MAFs of the 3 SNPs rs2107595, rs2389995 and rs2240419 are 0.168, 0.006 and 0.244, respectively, in the European population (EUR), and it may be one possible reason for the inconsistent result between the Chinese and the European. Additionally, the linkage disequilibrium patterns in alleles between the different ethnic populations might also contribute to this phenomenon, for instance, the low linkage disequilibrium between the rs2389995 and rs2240419 has been found in the Chinese Han population in Beijing (HCB), as indicated by an r2 value of 0.059 and a D’value of 0.274, whereas an r2 value of 0.108 and a D’value of 0.409 was described in the southern Han Chinese population (CHS) based on the data from the 1000 G. Finally, significant heterogeneity was observed among all genetic models of rs2240419, and factors, such as genotyping method, subtype of stroke, gender distribution, personal history, past medical history and other, might be potential sources of heterogeneity.In our meta-analysis, the main finding was that the T allele of rs2107595 confers the risk of stroke in all the three models  in the Chinese population, whereas the G allele of rs2389995 decreases the risk of ischaemic stroke in all of the comparison models, and no significant association of the rs2240419 T/C polymorphism and the risk of stroke was observed. Our results have some differences from the previous studies. A possible explanation for this phenomenon is that the previous single studies of stroke had small samples size, and thus the significance of current work may not be justified; thus, further studies are needed to clarify the effects of the 3 SNPs on the risk of stroke. Furthermore, the differential allele frequencies of the 3 SNPs exerted disproportionate levels of influence on the stroke risks in different populations. For example, the minor allelic frequencies (MAFs) of the 3 SNPs rs2107595, rs2389995 and rs2240419 of Additionally, the genotype distributions of the controls did not deviate from HWE in any study. The NOS results indicated that the included studies were credible. Moreover, sensitivity analysis was conducted, and it did not significantly alter the combined ORs. Additionally, no evidence of publication bias was identified by either Begg’s or Egger’s tests with the exception of the codominant model of rs2240419. However, there was no significant difference for pooled ORs before and after using the ‘trim and fill’ method in the codominant model of rs2240419. Taken together, the results of this meta-analysis are reliable and stable.HDAC9 and subsequent strokes. Fourth, only articles in English and Chinese language were included; thus, studies of other ethnicities and those written in other languages were neglected. Finally, three non-English (Chinese) articles were included in this analysis. Although inclusion of non-English articles may be difficult for non-native speakers to read and understand, it is essential for ensuring the generalizability of systematic analysis.There were some limitations in the current study. First, the sample sizes of the studies included in our meta-analysis were relatively small, which made it difficult to perform subgroup analysis to evaluate the heterogeneity among the included studies. Second, the heterogeneity detected in all genetic models of rs2240419 might have affected the precision of outcome even though we used the random-effects model to calculate pool ORs. Third, stroke is a multi-factorial disorder that is associated with genetic and environmental factors, such as diet, life style, and climate. However, none of the original studies accounted for gene-environment interactions. Further studies are needed to clarify whether these environmental factors affected the polymorphism of HDAC9 gene on chromosome 7p21.1 are implicated in stroke riskHDAC9 region are associated with the risk of stroke is still unclear. Recent studies have suggested that a deficiency of the HDAC9 gene attenuates atherosclerosis10HDAC9 can increase risk by altering brain ischaemic responses and neuronal survivalHDAC9 expression. Further studies are required to clarify the roles of these variants in ischaemic stroke.It is now accepted that the SNPs within the HDAC9 gene increases the risk of stroke in the Chinese population, whereas the minor G allele of rs2389995 may be associated with a decreased risk of stroke. No association of stroke risk with the rs2240419 polymorphism was identified. Due to the above-mentioned limitations, a well-designed large-scale study that includes ethnicities and considers both genetic and environmental factors is required to confirm and expand these findings.In summary, our meta-analysis suggested that the T allele of rs2107595 in the HDAC9”) AND  AND . Furthermore, the references of selected articles and the abstracts presented at related conferences were also checked by hand to identify additional potential studies. The languages were limited to English and Chinese.In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statementHDAC9 gene polymorphisms and ischaemic stroke cerebrovascular disease in Chinese populations; (2) studies in which the diagnoses of IS were confirmed by computed tomographic (CT) or magnetic resonance imaging (MRI); (3) case-control studies; (4) the genotype distributions in both the cases and controls were available to calculate the OR and 95% CI; and (5) the genotype distribution in control group was consistent with Hardy-Weinberg equilibrium (HWE). Additionally, we excluded reviews, abstracts, and redundant and animal studies.The inclusion criteria for the studies were as follows: (1) studies of the association between HDAC9 genotype distributions and alleles in the case and control groups.Two independent investigators extracted the relevant data from all included studies based on the inclusion criteria, and a third investigator verified the data. The following information from eligible studies was extracted: the first author’s name, publication year, ethnicity, geographical location (province or city), sample size, genotyping method, and the Two investigators independently assessed the qualities of the included studies in accordance with the Newcastle-Ottawa scale (NOS)2 statistic. When I2 > 50% or PQ ≤ 0.1, which suggest substantial heterogeneity, a random-effects model (DerSimonian-Laird method)2 test, P < 0.05 was considered statistically significant. The power analysis was calculated by using the Power and Sample Size Program softwareP < 0.05 was considered statistically significant. If publication bias existed, the non-parametric ‘trim and fill’ method was used to adjust for the bias. All analyses were conducted using the RevMan 5.1 and STATA 12.0 software packages.The associations of the rs2107595, rs2389995, and rs2240419 polymorphisms with the risk of stroke were assessed by the pooled ORs with the corresponding 95% CIs under the following genetic models: allele model, codominant model, dominant model, and recessive model. The heterogeneity between studies was determined by the Cochrane’s Q-statistic testHow to cite this article: Zhou, X. et al. The association between HDAC9 gene polymorphisms and stroke risk in the Chinese population: A meta-analysis. Sci. Rep.7, 41538; doi: 10.1038/srep41538 (2017).Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.