Schizophrenia is a heritable disorder, however clear genetic architecture has not been detected. To overcome this state of uncertainty, the SZGene database has been established by including all published case-control genetic association studies appearing in peer-reviewed journals. In the current study, we aimed to determine if genetic variants strongly suggested by SZGene are associated with risk of schizophrenia in our case-control samples of Japanese ancestry. In addition, by employing the additive model for aggregating the effect of seven variants, we aimed to verify the genetic heterogeneity of schizophrenia diagnosed by an operative diagnostic manual, the DSM-IV.Each positively suggested genetic polymorphism was ranked according to its p-value, then the seven top-ranked variants (p < 0.0005) were selected from DRD2, DRD4, GRIN2B, TPH1, MTHFR, and DTNBP1 . 407 Schizophrenia cases and 384 controls participated in this study. To aggregate the vulnerability of the disorder based on the participants' genetic information, we calculated the "risk-index" by adding the number of genetic risk factors.No statistically significant deviation between cases and controls was observed in the genetic risk-index derived from all seven variants on the top-ranked polymorphisms. In fact, the average risk-index score in the schizophrenia group (6.5+/-1.57) was slightly lower than among controls (6.6+/-1.39).The current work illustrates the difficulty in identifying universal and definitive risk-conferring polymorphisms for schizophrenia. Our employed number of samples was small, so we can not preclude the possibility that some or all of these variants are minor risk factors for schizophrenia in the Japanese population. It is also important to aggregate the updated positive variants in the SZGene database when the replication work is conducted. Schizophrenia is a highly heritable disorder, but even its genetic architecture still remains unclear . In ordeBased on the information in SZGene as of February 2007, each positively associated genetic polymorphism in the database was ranked according to its p-value from a chi-square test of association with the disorder. The p-values of the seven top-ranked polymorphisms were all less than 0.005 Table . We chosWith regard to the genotyping procedure, Single nucleotide polymorphisms (SNPs) on the genomic DNA extracted from venous blood were identified by FRET method  according to the manufacture's protocol. The 120 bp Tandem Repeat polymorphism in DRD4 was detected by restriction fragment length polymorphism. Each primer and probe was provided on demand.In addition to the analysis of each single polymorphism, we sought to aggregate the vulnerability of the disorder based on the participants' genetic information. The risk alleles of each of the seven top polymorphisms shown in SZGene were summated, such that an individual homozygous for a polymorphism's risk alleles was quantified as having a value of "2". The heterozygous genotype was given the value of "1", and the homozygote of non-risk alleles was coded "0". This scoring imparted an additive effect onto each variant, which was supported by the meta-analytic results in SZGene . Each of the participants was additively scored from 0 to 14 according to their genetic vulnerability information from across all seven variants. This score was then entered as a predictor of case status in a logistic regression model, with the type-I-error rate fixed at 0.05.The distribution of no single polymorphism was significantly different between schizophrenia and control groups at a p-value less than 0.05  are quite low , which has adverse effects on the inferential power to detect the effects of those variants. Furthermore, this negative impact on power is likely to be compounded when investigating the joint effects of the seven SNPs. However, the direction of the effects identified in our sample was, for five of the variants , in the opposite direction of that documented in SZGene. Thus, even with the addition of more subjects, our sample likely would not yield any semblance of significant association for these five variants. For the remaining two variants (120bpTR on DRD4 and rs6277 on DRD2) our detected effects were in the same direction as those reported in SZGene, suggesting that our data may in fact be consistent with the hypothesis of some effect of these variants on risk for the disorder in a global sense (though not necessarily a significant effect in our sample).Chiefly, our failure to find significant associations could be a result of insufficient sample size and less-than-optimal statistical power. Our average power was 6.72% on the assessment of Genetic Power Calculator . It could be suspected that the mode of inheritance of schizophrenia is not simply additive, however no definitive model is identified so far ,5,6. Re-A third caveat regarding interpretation of our study is the ancestry of our sample. All of our subjects were derived from a sample of Asian ancestry, Japanese, although the top seven variants were selected based on their collective evidence from all ancestral groups (though SZGene represents more Caucasian samples than Asian ones). Given the possibility that the current lack of detection derived from this discrepancy, we recalculated the top variants in SZGene from samples of only Asian ancestry. Within the seven variants, the majority of variants (four out of seven) were still significant in the Asian-only subsamples, and the other three variants had only been examined in Asian-ancestry samples once or twice previously, precluding definitive answers. These data imply that the investigated variants were deserving of further research both in general and in Asian samples specifically. Nevertheless our currently employed samples will not generalize to all samples evaluated by the schizophrenia geneticists so far.With regard to the deviation from Hardy-Weinberg Equilibrium (HWE), the current result of genotyping in cases for 120bp Tandem Repeat in DRD4, and both in cases and controls for rs1801028 in DRD2 has shown the deviation from HWE  our model further. It is also important to aggregate the updated positive variants in the SZGene database when the replication work is conducted. Much work is needed in a collaborative effort in order to generate power to identify potential genetic markers for schizophrenia that transcend ethnicities and populations worldwide, if such exist. Studies of schizophrenia inevitably inherit the weaknesses of the current psychiatric nosology, which clinical observation (symptomatology) demands when we aimed to select the sample due to the lack of biological markers. Our current findings that there is no statistically significant deviation in the possession of "risk-conferring" alleles between schizophrenia and controls may have a chance to highlight the profound heterogeneity of the disorder of interest.The authors declare that they have no competing interests.TK and SJG designed the study and collaborated in the writing of the final version of the manuscript. SK, AT, and HK wrote the protocol, and managed the genotyping. SK wrote the first draft. HU and SJG undertook the statistical analysis. AH, TK, MM, and JK worked for the sample recruitment. HM, and HY assisted in conceptualizing the study, provided laboratory space and resources for data collection, and collaborated in the writing of the final version of the manuscript. All authors contributed to and have approved the final manuscript.


MTHFR) is a critical enzyme in folate metabolism and is involved in DNA methylation, DNA synthesis, and DNA repair. In addition, it is a possible risk factor in neural tube defects (NTDs). The association of the C677T polymorphism in the MTHFR gene and NTD susceptibility has been widely demonstrated, but the results remain inconclusive. In this study, we performed a meta-analysis with 2429 cases and 3570 controls to investigate the effect of the MTHFR C677T polymorphism on NTDs.Methylenetetrahydrofolate reductase . Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association. Sensitivity analysis, test of heterogeneity, cumulative meta-analysis, and assessment of bias were performed in our meta-analysis.An electronic search of PubMed and Embase database for papers on the MTHFR C677T polymorphism and NTD susceptibility was revealed in our meta-analysis . Moreover, an increased NTD risk was found after stratification of the MTHFR C677T variant data by ethnicity and source of controls.A significant association between the MTHFR C677T polymorphism is a genetic risk factor for NTDs. Further functional studies to investigate folate-related gene polymorphisms, periconceptional multivitamin supplements, complex interactions, and the development of NTDs are warranted.The results suggested the maternal  Neural tube defects (NTDs) are a group of severe congenital malformations with an average worldwide birth prevalence of 1 in 500 Although the cause of NTDs is still poorly understood, accumulated evidence has suggested that genetic and/or environmental factors may contribute to NTD aetiology. Among these factors, maternal nutritional status is a key determinant of pregnancy outcome, and attention has been focused on folic acid, a water-soluble B vitamin that acts as a cofactor in one-carbon transfer reactions and plays a central role in DNA methylation, synthesis, and repair MTHFR plays a key role in the folate metabolism pathway and regulates the intracellular folate pool for synthesis and methylation of DNA MTHFR gene is located at chromosome 1p36.3 and is 2.2 kb in length with a total of 11 exons MTHFR gene have been characterised, with the C677T polymorphism as the most important and best studied The enzyme C677T MTHFR polymorphism and NTD susceptibility. However, these studies have failed to yield a consistent conclusion. Therefore, we performed a meta-analysis of all studies published until January 2012 to explore this inconsistency and to investigate the association between the maternal MTHFR C677T polymorphism and risk of NTDs.In the past decade, studies have investigated the association between the MTHFR,” and “neural tube defects,” “NTD”. All studies were published in English or in the Chinese language, and were human studies only. The related reference articles were searched to identify other relevant publications. Unpublished data and further information were also obtained from the authors.Potentially relevant reports were selected by searching Embase and PubMed  using the main search terms “methylene-tetrahydrofolate reductase,” “MTHFR C677T polymorphism and NTDs; 2) human case-control design; 3) sufficient maternal genotype data for estimating an odds ratio (OR) with a 95% confidence interval (CI); and 4) published in English or Chinese. The criteria for the exclusion of studies are as follows: 1) not related to the MTHFR C677T polymorphism and NTDs; 2) not a primary case-control study; 3) no usable or sufficient maternal genotype data reported: and 4) controls are not mothers with at least one healthy birth.Potential studies were selected following inclusion criteria: 1) Two investigators independently extracted the data from all eligible studies using the selection criteria listed above. Any disagreement was resolved by discussion. We extracted the following information: the first author's name, year of publication, the country in which the study was conducted, the ethnicities of the individuals involved, the source of control groups , the sample size, number of cases and controls with the CC, CT, and TT genotypes.P values less than 0.05 were considered statistically significant. For the control groups of each study, the observed genotype frequencies of the MTHFR C677T polymorphism were assessed for Hardy-Weinberg equilibrium.All statistical analyses were performed using the STATA software (version 11). Two-sided MTHFR C677T polymorphism and NTD risk was evaluated by the odds ratios (ORs) with 95% confidence intervals (CIs). The pooled ORs were calculated for the homozygote comparison (TT versus CC), heterozygote comparison (CT versus CC), dominant model (CT + TT versus CC), recessive model (TT versus CT + CC), and an additive model (2TT + CT versus 2CC + CT). Subgroup analyses were performed based on the source of controls and ethnicity if the data permitted.The strength of the association between the P value. If the heterogeneity test result was P<0.1, the pooled ORs were analysed using the random-effects model (the DerSimonian and Laird method) The evaluation of the meta-analysis results included a test for heterogeneity, an analysis of the sensitivity, and an examination for bias. The chi-squared test-based Q-statistic was calculated to test the heterogeneity between studies and detect the source of heterogeneity by ethnicity, publication year, control source, and sample size. The model used for the analysis of the pooled ORs depends on the MTHFR C677T polymorphism in the case-control design. The characteristics of all reports on the association between the MTHFRC677T polymorphism and NTDs are shown in We included 25 eligible studies MTHFRC677T polymorphism showed pooled odds ratios for homozygote comparison , for dominant model comparison , for recessive model comparison , and for additive model comparison . Overall, there was a significant association between the maternal MTHFR C677T polymorphism and NTDs. The forest plot is shown in In our meta-analysis the CC genotype was used as the reference group. The maternal P = 0.010) for Asian population. The pooled odds ratios were 1.524 , and 2.514  for Caucasian and mixed populations, respectively, under the recessive model. However, we did not find an association between the C677T polymorphism and NTD risk in African groups in any genetic models. The meta-analysis results for the other genetic models are listed in We also performed subgroup analysis stratified by ethnicity and study design. We found that the variant genotypes were associated with a significantly increased NTD risk in Asian, Caucasian and mixed populations. In heterozygote comparison ( CT versus CC), the pooled odds ratio was 1.933  in the population-based control subgroups and 1.951  in the hospital-based control subgroups by homozygote comparison. The meta-analysis results for the other genetic models are listed in Significantly increased risks were also found in the subgroup analysis stratified by the source of the controls. The pooled odds ratios were 2.756 . Data are listed in There was significant heterogeneity in four genetic models: TT versus CC: Pheterogeneity  = 0.002 and heterogeneity chi-squared  = 29.94, Pheterogeneity  = 0.120, before and after removal, respectively. Furthermore, no single study qualitatively changed the pooled ORs, suggesting that the results of this meta-analysis were stable. In the cumulative meta-analysis, the pooled ORs tended to be stable, and the associations tended towards significant associations with the accumulation of more data over time.Sensitivity analyses were conducted to ascertain the primary origin of the heterogeneity. Two independent studies by Relton CLP = 0.034, 95% CI: 0.125, 2.824  in the MTHFR gene have been characterised, the C677T polymorphism is a widely described mutation. Heterozygotes (CT) for the polymorphism have 65% of the normal enzyme activity and 10% lower red blood cell folate level; patients with the homozygous variant (TT) have only 30% of normal enzyme activity and 18% lower red blood cell folate levels 12 levels and increased homocysteine levels MTHFR activity, causing high plasma homocysteine and low plasma folate levels, it contributes to NTDs MTHFR C677T in the pathogenesis of NTDs MTHFR C677T polymorphism and NTDs remains unclear.The folate metabolism pathway plays an important role in DNA methylation, DNA synthesis, cell division, and tissue growth, especially in the rapidly developing cells MTHFR C667T polymorphism and susceptibility to NTDs. Overall, we found that mothers with the homozygous TT genotype showed a significantly increased NTD risk compared with homozygous CC genotype carriers . Our results were consistent with a previous report Our meta-analysis, which included 2429 cases and 3570 controls, explored the associations between the maternal 12, and vitamin B6, some of which may affect NTD development. Finally, analysis of the data from the various ethnic groups might eliminate some bias caused by language because only papers written in English or Chinese were included. Thus, large-scale studies should be performed to validate ethnic differences in the effect of this functional polymorphism on NTD risk.In subgroup analysis stratified by ethnicity, we found that the variant genotypes were associated with a significantly increased NTD risk in Asian, Caucasian and mixed populations. However, we did not found this association in African groups in any genetic model, possibly due to the limited studies and a small sample size. Moreover, the pooled odds ratios of mixed populations were higher than those of Caucasian populations and the overall populations in mothers . Many factors may contribute to the finding that the same polymorphism affects different ethnic populations to a different extent. First, the frequency of the T-allele varies in different ethnicities with different genetic backgrounds When stratified by study design, significantly increased risks were also found in both population-based and hospital-based studies. Nevertheless, population-based studies have a higher risk than hospital-based studies. Hospital-based studies usually have a high risk of producing unreliable results because hospital-based controls may not always accurately represent the general population, especially when the genotypes under investigation are expected to affect disease conditions that might be observed in the hospital-based controls Because heterogeneity is a potential problem when interpreting the results of all meta-analyses, we detected the source of heterogeneity by ethnicity, publication year, control source, and sample size and found that none substantially contributed to the heterogeneity. One possible reason might be the matching status.MTHFR genetic polymorphisms play an important role in the development of NTDs; however, only 13% of NTDs were attributed to the MTHFR C677T mutation MTHFR C677T polymorphism alone cannot be responsible for NTDs. Thus, potential gene-gene, maternal-foetal, genetic-nutritional interactions MTHFR gene may have an association with NTD risk.It is assumed that MTHFR and cystathione-β-synthase (CBS) mutations was reported to have a fivefold increase in the risk for spina bifida compared with each variant alone Folate metabolism is complex and involves several regulatory mechanisms. Genetic variations affecting protein function at any step may alter the balance of metabolites, and gene-gene interactions Maternal variant genotypes were associated with NTD risk, indicating possible maternal-foetal interactions. Using family-based approaches, researchers have found that the OR increased to 4.1  if the mother had a TT genotype and her child a CT genotype and to 6.1  if both the mother and her child had TT genotypes MTHFR mutations and low folate concentrations could lead to a hypomethylation of homocysteine to methionine, enhancing the impairment of folate metabolism and increasing the risk for NTDs MTHFR TT genotype and RBC folate level in the lowest quartile conferred an odds ratio of 13.43  for an NTD case and an odds ratio of 3.28  for having offspring with NTDs The combination of Although these studies were hampered by small sample sizes, they illustrate the existence of potential interactions. Thus, further large-scale studies focusing on these complex interactions with NTD risk should be performed.MTHFR gene showed increased NTD risks, such as A1298CC116TG1793AC677T polymorphism. All these suggest these SNPs can be additional genetic factors for NTDs.Some researchers have demonstrated that other SNPs in MTHFR C677T polymorphisms due to the limited data. Despite the limitations listed above, our meta-analysis has some clear advantages. 1) The well-designed search and selection method significantly increased the statistical power of this meta-analysis. 2) No publication bias was detected, indicating that our pooled results are likely to be reliable.Several potential limitations of this meta-analysis should be discussed. 1) Although the funnel plot and Egger's test showed no publication bias, selection bias may have occurred because only studies in English or Chinese were selected. 2) Our results were based on unadjusted estimates due to the absence of available information, such as supplementation of folic acid, maternal use of drugs, and other factors that are associated with NTD risk. 3) We did not consider the foetal MTHFR C677T polymorphism is a genetic risk factor for NTDs. Because NTDs are the most common congenital malformations worldwide and have a multifactorial aetiology, various genetic and environmental factors as well as their complex interactions implicated in the pathogenesis should be taken into account. Further functional studies to investigate folate-related gene polymorphisms, periconceptional multivitamin supplements, complex interactions and their role in development of NTDs are warranted.In conclusion, our meta-analysis provided evidence that the


Helicobacter pylori infection, host genetic factors contribute to gastric cancer (GC). Recognition of H. pylori is known to involve Toll-like receptors (TLR), which subsequently leads to activation of NF-κB. Thus, the overall aim of this study was to estimate for the first time the pooled effect size of polymorphisms in TLR2, TLR4 and CD14 on GC development through a meta-analysis.In addition to TLR2 -196 to -174del, CD14 -260 C/T and TLR4 rs11536889 using PCR, RT-PCR and mass spectrometry. Case-control studies of TLR2, TLR4 and CD14 polymorphisms and GC were searched up to June 2012. Pooled odds ratios and 95% confidence intervals were obtained by means of the random effects model.A case-control study comprising 284 ethnic Chinese individuals  was conducted for the genotyping of TLR4 rs11536889 C allele increased the risk of GC  while the CD14 -260 T allele was protective . TLR2 -196 to -174 increased the risk of GC only in H. pylori-infected individuals . In the meta-analysis, TLR4 Asp299Gly showed borderline results in the general analysis , nevertheless, stratified analysis by ethnicity showed that the mutant allele was a definitive risk factor for GC in Western populations . There was a potential association between the TLR2 -196 to -174 deletion allele and GC in Japanese . TLR4 Thr399Ile did not provide significant results.In our ethnic Chinese case-control study, the TLR4 rs11536889 and CD14 -260 C/T are associated with non-cardia GC in Chinese. Based on our meta-analysis, the TLR signalling pathway is involved in gastric carcinogenesis, TLR4 Asp299Gly and TLR2 -196 to -174del showing associations with GC in an ethnic-specific manner. Despite a major decline in incidence and mortality rates over several decades, gastric cancer (GC) still remains a major cause of morbidity and mortality worldwide in situ, and finally to invasive GC. Although Helicobacter pylori has been established as the most important aetiological risk factor for GC, the pathogenesis of GC involves the combined effects of bacterial, host and environmental factors H. pylori is initially targeted by the toll-like receptors (TLR) signalling pathway, it is conceivable that functionally relevant polymorphisms in genes of this arm of the immune system could affect the magnitude and direction of the host response against the infection.Chronic inflammation has been associated with an increased risk of developing several human malignancies, including GC H. pylori on gastric epithelial cells H. pylori lipopolysaccharide (LPS) interacts with the monocyte differentiation antigen CD14 (CD14) κB, and cytokines such as TNF-α, IL-1β, IL-6 and IL-12 H. pylori LPS functions as a classic TLR2 ligand and induces a discrete pattern of chemokine expression in epithelial cells which involves the modulation of the expression of signalling protein tribbles 3 (TRIB3), a molecule that has been implicated in the regulation of NF-κB H. pylori LPS is initially targeted by TLR2 as described by others, but, for the first time, showed that this TLR2 activation leads to cell proliferation and TLR4 expression via the ERK1/2-ERK1/2 kinases (MEK1/2) pathway H. pylori can enhance inflammatory reactions mediated by TLR4 agonists such as other bacterial LPS which could contribute to gastric inflammation and carcinogenesis The involvement of the TLR signalling pathway in infectious, autoimmune and inflammatory diseases is well accepted TLR2 is located in the long arm of chromosome 4 comprising two 5′ non-coding exons followed by a third coding exon. A polymorphism that causes a 22-bp deletion, known as TLR2 -196 to -174del, has been shown to influence the promoter activity of TLR2. This polymorphism has not only been associated with GC but also other inflammation-related cancers including gallbladder, bladder, prostate and cervical cancers TLR4 is located in chromosome 9q32–q33 and contains 4 exons. Polymorphisms in TLR4 have been extensively studied in several populations in an attempt to find associations with diverse pathologies such as cancer, atherosclerosis and infectious diseases TLR4 Asp299Gly (rs4986790) and Thr399Ile (rs4986791) are located in the coding sequence resulting in amino acid substitutions that affect the TLR4 extracellular domain. Another functionally relevant polymorphism, identify as TLR4 rs11536889, showed a novel association with periodontitis in Japanese individuals CD14 is encoded by a single-copy gene located at bands 5q23–q31 that consists of approximately 3900 bp harboured in two exons. The most studied polymorphism in this gene involves a C-T substitution at base-pair 260 of the 5′flanking region mainly known as CD14 -260 C/T (rs2569190) but also called CD14 -159 C/T CD14 -260 T allele had decreased affinity for DNA/protein interactions at a GC box containing a binding site for stimulatory protein (SP) 1, SP2 and SP3 transcription factors CD14 transcription and in determining the differential activity of the two variants of the CD14 promoter H. pylori infection, in the current study, we conducted a case-control study and meta-analysis assessing TLR2 -196 to -174del, TLR4 Asp299Gly, TLR4 Thr399Ile, TLR4 rs11536889 and CD14 -260 C/T and their association with gastric carcinogenesis, in an attempt to clarify the limited and current conflicting evidence, and to establish the true impact of the TLR signalling pathway in this pathology. To date, two meta-analyses have been published on TLR4 polymorphisms and risk of cancer in general Given the importance of TLRs in regulation of the innate immune response to This study was approved by the Human Ethics Committee (HREC) of the University of New South Wales (HREC 08115 and HERC 02144). Written informed consent was obtained from each individual recruited to the study.2 receptor antagonists and proton pump inhibitors) in the two-month period prior to recruitment were excluded.All subjects were ethnic Chinese individuals presenting for upper gastrointestinal endoscopy at the Department of Medicine, University Hospital of Malaysia  and The Changi General Hospital (Singapore). Patients known to be infected with the Human Immunodeficiency Virus or who had been prescribed non-steroidal anti-inflammatory drugs (NSAIDs), anti-microbial agents or acid suppressants  based on histological confirmation and recruited during the period January 2004 to April 2007, were invited to participate in the study. The control group comprised 214 individuals diagnosed with functional dyspepsia (FD) over the same period. FD was defined as pain or discomfort centred in the upper abdomen without any identifiable organic disease, in accordance with Rome II classification system Seventy patients newly diagnosed with a primary non-cardia GC . DNA was rehydrated in sterile water and normalised to 10 ng/ µl for customised SNP genotyping of TLR4 rs11536889 through the application of matrix assisted laser desorption ionisation time-of-flight (MALDI-TOF) mass spectrometry, the Sequenom MassARRAY iPLEX™ assay  in a subset of the same ethnic Chinese population. The methodology and results have been published elsewhere We have previously genotyped H. pylori IgG antibodies in GC patients and FD controls was determined by means of an in-house enzyme-linked immunosorbent assay (ELISA), previously described by Mitchell et al. H. pylori negative by ELISA were investigated further by Immunoblot  according to the manufacturer's instructions. These results have been published in part elsewhere The presence of TLR2, TLR4 and CD14 polymorphisms and risk of GC in humans. The search strategy included Medical Subject Headings (MeSH) terms and text words as described in Electronic databases  were searched up to June 2012 for all case-control studies evaluating Studies were selected if they met the following conditions: diagnosis of primary GC based on histological assessment, the study had a case-control design, the selected polymorphisms in the control subjects satisfied the Hardy Weinberg equilibrium (HWE), it supplied sufficient information to calculate the OR and the manuscript was published as a full paper in a peer-reviewed journal, not as an abstract or similar type of summary.H. pylori status (where available), total cases, total controls and number of individuals harbouring each specific allele.The following information was collected from each study: author, year of publication, journal, study population, tumour location (cardia and non-cardia GC), molecular technique, 2). The direct count method was used to estimate the genotype and allele frequencies. The odds ratios (OR) and 95% confidence intervals (CI) were calculated by means of the Fisher's exact probability test . The data was analysed by means of the programs GraphPad Prism version 5.02  and SPSS version 19.0.0 .In our case-control study, deviation from HWE was tested using the chi-square goodness-of-fit test . Due to the low power of this statistical test when meta-analysis includes a small number of studies, the Higginś test (I2) was also used to measure the degree of inconsistency in the results of the studies and to describe the percentage of total variation across studies due to heterogeneity rather than chance. The terms low, moderate and high were assigned to I2 values of 25%, 50% and 75%, respectively For the meta-analysis, the allele frequencies from individual studies were calculated as the number of cases or controls harbouring at least one allele divided by the total number of chromosomes included in each of the corresponding groups. The pooled ORs were calculated by weighting individual ORs by the inverse of their variance. For each polymorphism, this pooled OR as well as the 95% CI were obtained by means of both the fixed and the random effects model. The random effects model was chosen as it assumes that there is a distribution of true effect sizes rather than one true effect, and it assigns a more balanced weight to each study. Heterogeneity was calculated by means of the Cochrańs H. pylori status of the 284 subjects included in our ethnic Chinese case-control study are outlined in Demographics including age, gender and P-value: <0.0001), despite matching for age .The median age of GC patients was significantly higher than that of FD controls .H. pylori infection was found to be present in (67%) of individuals in this study (56/70 GC patients and 134/214 FD controls) .ontrols) . Compari2 values (less than 3.84). Allele and genotype frequencies as well as ORs and 95% CIs are shown in TLR4 rs11536889 C allele and CC genotype markedly increased the risk of GC in these ethnic Chinese individuals showing ORs of 1.89 (95% CI: 1.23–2.92) and 5.29 (95% CI: 1.71–16.34), respectively. Individuals harbouring the CD14 -260 T allele  and TT genotype  were found to be significantly protected against the development of GC. Although the CD14 -260 CT genotype showed a tendency towards protection against GC, this was not statistically significant . No significant association was found between TLR2 -196 to 174del and GC in our case-control study.All polymorphisms genotyped in our case-control study were found to be in HWE in the control group showing non-significant χH. pylori is known to be a major risk factor associated with GC, further analyses were performed to assess the joint effect of TLR2 -196 to -174del, TLR4 rs11536889 and CD14 -260 C/T and H. pylori infection on risk of GC. First, to confirm that no association existed between TLR2 -196 to -174del, TLR4 rs11536889 and CD14 -260 C/T and risk of H. pylori infection, univariate statistical analyses were conducted, showing non significant results . In addition, the TLR2 -196 to -174 deletion allele increased the risk of GC only in individuals infected with H. pylori . In contrast, CD14 -260 C/T analyses did not provide significant results .Given that  results . Second,tagonism . IndividTLR4 Asp299Gly and Thr399Ile in our ethnic Chinese case-control study has been published previously Data on TLR2, TLR4 and CD14 polymorphisms and risk of GC were identified for potential inclusion in the meta-analysis : 3, P-value: 0.429), 2) TLR4 Thr399Ile and risk of GC , and 3) TLR4 rs11536889 and risk of GC . In contrast, potential publication bias was observed in the meta-analyses of CD14 -260 C/T and TLR4 Asp299Gly and risk of GC  and 3.52  for CD14 -260 C/T and TLR4 Asp299Gly, respectively).Funnel plots (not shown) and Eggeŕs regression tests showed that no publication bias existed in the following meta-analyses: 1) TLR2 -196 to -174del and risk of GC, 1364 GC patients and 2487 controls were included. The general analysis showed a potential association to exist between TLR2 -196 to -174del and risk of GC . After performing a stratified analysis by ethnicity an increased risk was observed in Japanese individuals  although did not reach significance . Heterogeneity was high in the general analysis  and moderate in the stratified analysis .For the meta-analysis of ificance . InteresTLR4 Asp299Gly analysis showed a borderline association with GC   .Meta-analysis of the 6 case-control studies (979 GC patients and 1404 controls) included in the 98–2.56) . In addi31–2.65) . Low to TLR4 Thr399Ile included three studies comprising 423 GC patients and 612 controls. Both the general  and stratified by ethnicity  analyses failed to show a statistically significant association between this polymorphism and the risk of GC. In contrast, sensitivity analysis showed significant results after excluding the study by Garza-Gonzalez et al. Q: 5.76, P-value: 0.056, 2I: 65.28%) and high in the stratified analysis .The meta-analysis of TLR4 rs11536889, including 766 GC patients and 1506 controls, showed no significant associations between this polymorphism and GC in the general analysis  or when stratified by ethnicity . Heterogeneity was high in these analyses .Meta-analysis of CD14 -260 C/T and the risk of GC (pooled OR: 0.93 95% CI: 0.76–1.13). Similarly, a further stratified analysis based on ethnicity did not provide significant results . However, borderline results were obtained after performing sensitivity analysis, in which the study by Zhao et al. CD14 -260 C/T meta-analysis .General analysis, which included data from all the studies (1398 GC patients and 1588 controls), failed to show any association between TLR2 -196 to -174del, TLR4 Asp299Gly, TLR4 Thr399Ile, TLR4 rs11536889 and CD14 -260 C/T and H. pylori infection, we performed a meta-analysis with only those case-control studies that provided H. pylori status in relation to the genotype. Six studies, including our ethnic Chinese case-control study, provided sufficient data to calculate the OR and 95% CIs Q: 1.93, P-value: 0.165, 2I: 48.15%; Q: 2.03, P-value: 0.154, 2I: 50.83%; Q: 0.32, P-value: 0.854, 2I: 0% and Q: 4.42, P-value: 0.036, 2I: 77.35% for TLR2 -196 to -174del, TLR4 Asp299Gly, TLR4 rs11536889 and CD14 -260 C/T, respectively).In order to determine the association between H. pylori is a risk factor for the development of non-cardia GC H. pylori is initially recognised by TLR2 and 4, members of the TLR signalling pathway, which initiate an innate immune response in the host. Thus, we postulated that polymorphisms in TLR2, TLR4 and CD14, genes that encode key components of the TLR signalling pathway, might affect the magnitude of the host response against H. pylori infection leading to severe long-term outcomes such as GC. Given that available studies assessing the association between genetic polymorphisms of molecules involved in the TLR signalling pathway and risk of GC were limited and conflicting, we conducted a global meta-analysis to increase the statistical power of our case-control study, to detect the pooled effect size and its magnitude, and to identify potential causes for the previous conflicting findings in other studies. General, sensitivity and stratified analyses were conducted in the current meta-analysis of TLR2 -196 to -174del, TLR4 Asp299Gly, TLR4 Thr399Ile, TLR4 rs11536889 and CD14 260 C/T polymorphisms and the risk of GC.According to extensive epidemiological evidence, TLR2 -196 to -174del. Consistent with these findings, meta-analysis of TLR2 -196 to -174del and risk of GC showed that only in Japanese individuals TLR2 -196 to -174del might be a risk factor for GC. Further case-controls studies are required to establish if this association is present in other ethnic groups including Caucasians. Given that TLR2 is known to stimulate the release of IL-8 in response to H. pylori infection TLR2 -196 to -174 del/del genotype, which has been associated with decreased transcriptional activity Our ethnic Chinese case-control study failed to showed an association with TLR4 polymorphisms provided interesting findings. Although the general analysis of TLR4 Asp299Gly, which included data from all studies, only showed borderline results, stratified analysis by ethnicity indicated that the TLR4 Asp299Gly G allele noticeably increased the risk of developing GC in the subgroup of individuals who belonged to Western populations. The fact that TLR4 Asp299Gly has been shown to disrupt the normal structure of the extracellular domain of TLR4, which has the potential to reduce responsiveness to H. pylori by diminishing the binding affinity of the bacterial ligands, increases the importance of our findings TLR4 Thr399Ile failed to show a significant association with GC in the general analysis, after performing sensitivity analysis, in which the study by Garza-Gonzalez et al. TLR4 Thr399Ile is not involved in gastric carcinogenesis.While TLR4 rs11536889, our ethnic Chinese case-control study showed that individuals harbouring the TLR4 rs11536889 C allele and CC genotype were at an increased risk of developing GC. The finding that this specific polymorphism is only a risk factor for GC in Chinese individuals is consistent with other studies where a number of polymorphisms investigated in Asian and Caucasian individuals have shown different risk associations with GC according to ethnicity TLR4 rs11536889 is located in the centre of the 2818-bp TLR4 3′UTR and therefore, may affect mRNA stability TLR4 rs11536889 and the risk of prostate cancer Although our meta-analysis did not provide significant results for CD14 -260 C/T showed a statistically significant association with GC in our ethnic Chinese case-control study. The results showed that the CD14 -260 T allele and TT genotype conferred protection against the disease in these subjects. In the meta-analysis, while the general and stratified by ethnicity analyses showed that the association between CD14 260 C/T and the development of GC was not statistically significant, sensitivity analysis excluding the study by Zhao et al. CD14 -260 T allele might be a protective factor against the development of non-cardia GC mainly, the main GC subtype in East Asian populations including our ethnic Chinese population. CD14 -260 C/T involves a C-T substitution at base-pair 260 of the 5′flanking region where the promoter, other enhancers and protein binding sites are likely to be located. Currently, there is some controversy regarding the influence of CD14 -260 C/T on the expression of soluble CD14 (sCD14). According to a number of studies, the CD14 -260 T allele is proposed to increase sCD14 production, which leads to increased serum levels of sCD14 H. pylori infection elevated sCD14 levels have been associated with the CD14 -260 CC genotype CD14 -260 CC genotype indeed increases sCD14 serum levels, it could explain why the T allele seems to be a protective factor as shown in our case-control study and meta-analysis. Since the current evidence regarding the influence of CD14 -260 C/T on the expression of soluble CD14 (sCD14) is conflicting, more functional studies are required to clarify this issue.H. pylori is known to be the main risk factor for GC, we also examined the potential interaction between H. pylori and TLR2, TLR4 and CD14 polymorphisms in the development of GC. Our ethnic Chinese case-control study and meta-analysis showed that selected polymorphisms do not increase the risk of H. pylori infection. Furthermore, additional analyses in our ethnic Chinese population showed that the presence of these polymorphisms and H. pylori infection increases dramatically the risk of GC in these individuals. Not only H. pylori-infected subjects harbouring the TLR4 rs11536889 C allele showed the highest risk of all but also H. pylori-infected individuals harbouring the TLR2 -196 to -174 deletion allele were shown to be more susceptible to GC, a phenomenon that is not observed if the bacterium is absent. In contrast, the risk of GC in H. pylori-infected individuals harbouring the CD14 -260 T allele, which was shown to be a protective factor in our initial analyses, was not magnified or reduced in the presence of H. pylori. Overall, these findings are consistent with our hypothesis that given that H. pylori is initially targeted by the TLR signalling pathway, polymorphisms in this branch of the innate immune system could modulate the direction and magnitude of the host response against the infection, explaining why only approximately 1% of H. pylori-infected individuals develop GC.As TLR4 polymorphisms and risk of cancer TLR4 Asp299Gly and Thr399Ile increase the risk of gastrointestinal cancers  showing ORs of 1.64 (95% CI: 1.02–2.64) and 2.01 (95% CI: 1.40–2.89), respectively TLR4 Asp299Gly and this pathology, showed an OR of 1.85 (95% CI: 1.06–3.22). However, the authors included a study in their meta-analysis that did not comply with the inclusion criteria of our meta-analysis since the subjects recruited in that case-control study did not suffer from GC but a “GC phenotype” characterized by corpus-predominant gastritis or pangastritis TLR4 Thr399Ile is associated with cancer in general  showing an OR of 1.81 (95% CI: 1.18–2.77) TLR4 rs11536889 and risk of cancer after analysing prostate, gastric and hepatocellular cancers as a group The results obtained in our meta-analysis differ from those presented by the other two available meta-analyses addressing the association between CD14 -260 C/T and TLR4 Asp299Gly polymorphisms and risk of GC that showed negative results, were not published. Nevertheless, asymmetry tests have limited power when the number of included studies in a meta-analysis is small TLR2 -196 to -174del, TLR4 Thr399Ile and CD14 -260 C/T provided different results compared to the general analysis, these results must be taken with discretion.Our meta-analysis has some limitations. First, publication bias assessment suggested the possibility that studies addressing the association between TLR2 -196 to -174del, TLR4 Asp299Gly, TLR4 rs11536889 and CD14 -260 C/T polymorphisms appear to play an important role in the development of GC inferring that polymorphisms in the TLR signalling pathway are clearly involved in gastric carcinogenesis. Continued research efforts directed towards the identification of major associations between molecules involved in innate immunity and H. pylori-related GC, and subsequent detection of their functional implications, have the potential to provide novel insights into targeted treatment in genetically-susceptible individuals, and thus, improve primary and secondary prevention of H. pylori-related GC, a disease that remains the second-leading cause of cancer-related deaths worldwide.In conclusion, based on our ethnic Chinese case-control study and meta-analysis, Checklist S1PRISMA checklist for reporting systematic reviews and meta-analysis.(DOC)Click here for additional data file.


CLU, CR1 and PICALM loci in association with late-onset Alzheimer's disease (AD). Parkinson disease (PD) shares several clinical and pathologic characteristics with AD; we therefore explored whether these SNPs were also associated with PD risk.Recent GWAS and subsequent confirmation studies reported several single-nucleotide polymorphisms (SNPs) at the CLU locus was associated with PD risk under the recessive model  after adjusting for year of birth, gender, smoking, and caffeine intake. Further adjustment for family history of PD and ApoE ε4 status did not change the result. In addition, we did not find evidence for effect modification by ApoE or known PD risk factors. The association, however, appeared to be stronger for PD with dementia  than for PD without dementia . The two other SNPs, rs6656401 from CR1, and rs3851179 from PICALM region were not associated with PD (p>0.05).791 non-Hispanic Whites cases and 1,580 matched controls were included in the study. Odds ratios (OR) and 95% confidence intervals (CI) were obtained from logistic regression models. rs11136000 at the CLU with PD. This exploratory finding and the role of dementia in explaining this finding needs further investigation.Our exploratory analysis suggests an association of  Alzheimer's disease (AD) and Parkinson disease (PD) are the two most common neurodegenerative diseases among the elderly. These two conditions share several clinical and pathological characteristics. For example, they both are clinically progressive and involve abnormal protein depositions CLU) CR1) PICALM) CLU, rs6656401 for CR1, and for rs3851179 for PICALM) in a large PD case-control study.Recent large genome-wide association studies (GWAS) have reported several novel susceptibility genetic loci for late onset AD, including clusterin  than those diagnosed after 2000 (13.9%).CLU locus was associated with PD risk under the recessive model . Subgroup analyses generally showed similar results . None of the SNPs examined was related to PD risk under the additive models or dominant models; however, rs11136000 at the ve model . After a results . The resCLU locus might be associated with PD, and this association appeared to be stronger for PD patients with dementia. Our analyses also suggest that this relationship was independent of ApoE or known risk factors for PD.In this large case-control analysis, we found preliminary evidence that rs11136000 at the ApoE ε4, the most established genetic risk factor for AD, has been examined in relation to PD in over 30 case-control studies. Most prior studies reported a null association between ApoE ε4 and PD ApoE ε4 in our study sample. We found that while ApoE ε4-carriers had a higher prevalence of dementia than non-carriers among PD patients, ApoE ε4 was associated with a statistically significant lower risk of PD  Several clinical and pathological similarities between PD and AD have led to the hypothesis that these two conditions may share some pathogenic mechanisms or risk factors CLU locus as a risk allele for late onset AD, and the finding was subsequently confirmed in a large case-control study and a meta-analysis Two recent large GWAS CLU with PD dementia. In support of this, we found that the association was stronger for PD dementia than for PD without dementia, although both associations were in the same direction. The presence of dementia in our study was collected only as part of PD diagnostic confirmation and thus we were unable to examine this possibility in details. Therefore, if our finding is confirmed, future studies should also investigate the possibility that the association of CLU with PD might be explained by its potential association with dementia.An alternative explanation is that the finding was mediated by an association of CR1PICALMCR1 encodes complement receptor 1, and may play a role in neuroinflammation and amyloid clearance PICALM encodes a ubiquitously expressed phosphatidylinositol-binding clathrin assembly protein which may affect synaptic neurotransmission and trafficking PICALM locus was only associated with AD risk among ApoE ε4 carriers; our analysis did not reveal a significant interaction between rs3821179, or any other SNPs, and ApoE ε4 allele CR1 or PICALM and PD.To the best of our knowledge, this is the first attempt to examine recent AD GWAS findings in PD pathogenesis. Therefore, our analyses should be considered exploratory and hypothesis generating; accordingly, we explored the associations under different genetic models and did not adjust for multiple comparisons. Although this study is among the larger population based genetic studies on PD, the statistical power was limited. For example, we had only an adequate statistical power for a common SNP  and a moderate association (OR ≤0.69 or ≥1.38) under a recessive model. For this consideration, we only chose the most significant SNPs in previous AD GWAS. Further, it is important to point out that the previous AD GWAS analyses were based on additive model, but our analysis on rs11136000 was only statistically significant under recessive model. Due to these uncertainties, our finding on rs11136000 only suggests a potential link to this genomic locus; future studies with larger sample size and denser SNP coverage are needed to confirm our result, and if confirmed, further investigations would be needed to identify the underlying gene and functional SNPs.In this study, we confirmed the diagnosis of PD with patients' treating physicians, rather than having the diagnosis uniformly made by study related movement disorder specialists. We therefore could not exclude the possibility of a few misdiagnoses. Nevertheless, recent clinicopathological studies showed a 90% accuracy for PD diagnosis made by clinical neurologists PD cases and controls were from the Parkinson's, Genes, and Environment (PAGE) study that was nested within the large prospective cohort: the National Institute of Health (NIH)-AARP Diet and Health Study cohort  DNA was extracted from saliva samples collected with the Oragene™ collection kits. Three SNPs were selected based on their statistical significance as reported in the GWAS, one for each gene region: rs11136000 for CLU, rs6656401 for CR1, and rs3851179 for PICALM. One additional SNP on PICALM was also selected based on information from ALZgene.com; this SNP is in linkage disequilibrium with rs3851179 and the results were also similar, so we did not present detailed data for that particular SNP. Genotyping was performed by BioServe Biotechnologies, Ltd., Beltsville, MD, using MassARRAY iPLEXTM platform . Sequenom is a PCR and mass spectrometry based system. Genotyping assays are custom developed using Mass ARRAY Assay Design 3.1 software. For quality control purpose, we randomly included 51 duplicated saliva DNA samples which were kept blinded to the genotyping laboratory; the genotyping reproducibility was 100%.We examined Hardy-Weinberg equilibrium with chi-square statistics. Odds ratios (ORs) and 95% confidence intervals (CIs) were derived from logistic regression models, adjusting for year of birth (in four groups), gender, smoking status  and daily caffeine intake (quintile). We also further adjusted for family history of PD and ApoE ε4 status. We examined each individual allele in relation to PD first under an additive model and then under dominant and recessive models. We began the analyses with all participants, and then stratified by individual covariates: year of birth (below or above median), gender (men vs. women), smoking status (never vs. ever smokers) caffeine intake (below or above median), family history of PD (Yes vs. No), and ApoE ε4 status (ε4 carriers vs. non- ε4 carriers).To examine the potential influence of bias stemming from the possibility that PD cases with dementia were less likely to participate in the study than PD cases without dementia, we conducted a sensitivity analysis to examine the association of genes with PD separately for cases diagnosed before the year 2000 and diagnosed after the year 2000. We assumed that cases with longer duration of PD (e.g. diagnosed before 2000) were more likely to have dementia than cases with shorter duration, and therefore such a bias would affect the analyses for cases with years of PD more so than for recent cases. With the same reasoning, stratified analysis by age may also help clarify the potential influence of dementia as the prevalence of dementia increases dramatically with age. Finally, we also analyzed rs11136000 at the CLU locus separately in relation to PD with dementia and PD without dementia. Statistical analyses were performed using SAS version 9.2  combined with Plink v1.07. Post-hoc power calculation was performed with Quanto V1.2.4


MicroRNAs (miRNAs) negatively regulate the gene expression and act as tumor suppressors or oncogenes in oncogenesis. The association between single nucleotide polymorphism (SNP) in miR-196a2 rs11614913 and the susceptibility of digestive system cancers was inconsistent in previous studies.An updated meta-analysis based on 15 independent case-control studies consisting of 4999 cancer patients and 7606 controls was performed to address this association. It was found that miR-196a2 polymorphism significantly elevated the risks of digestive system cancers . We also found that variant in miR-196a2 increased the susceptibility of colorectal cancer (CRC) , while the association in recessive model  showed a marginal significance. Additionally, significant association between miR-196a2 polymorphism and increased risk of hepatocellular cancer (HCC) was detected. By stratifying tumors on the basis of site of origin, source of controls, ethnicity and allele frequency in controls, elevated cancer risks were observed.Our findings suggest the significant association between miR-196a2 polymorphism and increased susceptibility of digestive system cancers, especially of CRC, HCC and Asians. Besides, C allele may contribute to increased digestive cancer risks. MicroRNAs (miRNAs) are endogenous, small non-coding and have a length of 18–25 nucleotides RNAs. miRNAs can interact with messenger RNAs (mRNAs) by binding to 3′ un-translated regions (UTRs) and lead to the degradation or translational repression of mRNAs. Studies revealed that miRNAs played key roles in various biological processes including cell growth regulation, differentiation, apoptosis and tumorigenesis As we know, the above-referenced meta-analysis included gastric cancer (GC), HCC and other digestive cancers for the SNP in miR-196a2. However, by the limitation of inadequate publications, they did not calculate pooled ORs of digestive system cancers comprehensively. To improve the efficiency of meta-analysis on digestive cancers and reduce the potential between-study heterogeneity which might derive from various cancers in diverse systems, we focused on digestive system cancers only and added more recent publications on CRC A systematic search in PubMed was conducted using a retrieving query formulation “(microrna 196a2 OR rs11614913) polymorphisms cancer” . We also searched references in published articles and reviews on this topic in PubMed. Eligible studies were selected according to the following explicit inclusion criteria: (a) Study was designed using the methodology of a case-control study. (b) The association between miR-196a2 polymorphism and digestive system cancer risks was explored. (c) There was sufficient data for the computation of odds ratios and corresponding 95% confidence intervals . (d) Cases with carcinomas were diagnosed by histopathology. Moreover, we also contacted some researchers to request unpublished study outcomes and detailed datasets for pooled calculation .Two investigators (Guo and Jin) screened titles, abstracts and full texts independently using a standardized screening guide. Data extraction was carried out independently after the concealment of authors, journals, supporting organizations and funds to avoid investigators' bias. After data abstraction, discrepancies and differences were resolved by consensus and discussion.Characteristics of enrolled studies were assigned to the structured form , includiThree reviewers  independently evaluated the quality of selected studies by scoring according to a set of predetermined criteria  which wa2 index 2 index more than 50%,), we used the random-effects model (DerSimonian and Laird method) Crude ORs and corresponding 95%CIs were calculated to investigate the association strength between miR-196a2 polymorphism and the susceptibility of digestive system cancers. Pooled ORs were obtained from combination of single studies by heterozygote comparison (CT vs. TT), homozygote comparison (CC vs. TT), dominant and recessive models , allelic comparison (C vs. T) respectively. We used chi-square-based Q-test Stratification by tumor site, source of controls, ethnicity and allele frequency in controls was conducted. All cancers were categorized into two groups: digestive tract cancer and digestive gland cancer. Eligible studies were classified into population-based and hospital-based according to control source. The subjects were classified by ethnicity into Caucasian group and Asian group. We also classified the selected studies into C>T  group and C≤T  group by allele frequency in controls.Hardy-Weinberg equilibrium (HWE) in control population was judged by the chi-square test. P-value less than 0.05 was considered to be a state of disequilibrium. Publication bias was diagnosed with Egger's linear regression method http://ims.cochrane.org/revman/download). All P-values were two-sided.The frequency distributions of C allele in Asians and Caucasians were compared using chi-square test. All statistical analysis was implemented with SAS 9.2 software , STATA 11.0  and RevMan 5.1  12 studies were matched for age, sex and/or residence, smoking, alcohol consumption Genotypes in all studies were detected with genetic DNA from blood samples using 4 genotyping methods totally. 13 out of 15 studies checked genotypes for quality control. Genotype distribution of controls in all studies was consistent with HWE, except for Mingwu Zhang's study on CRC.2 decreased from 63% (Ph = 0.0005) to 42% (Ph = 0.05). While the summary OR for allele contrast (C vs. T) still kept significant , and this result was similar to pooled OR without deletion of any study .We found no significant evidence of publication bias  in any comparison model using Egger's linear regression method. Furthermore, the shape of funnel plot for the allele contrast (C vs. T) showed approximately symmetric and inverted funnel-shaped . Begge's2<50% in most genetic comparisons).Between-study heterogeneities and corresponding quantitative degrees in all comparisons and subgroups, were shown in We deleted one single study from the overall pooled analysis each time to check the influence of the removed data set to the overall ORs. Two studies (Wang (ESCC) The association strength between miR-196a2 polymorphism and the susceptibility for digestive system cancers are shown in Tumor site, source of controls, ethnicity and allele frequency in controls were taken into consideration for subgroup analysis. The forest plots of dominant models (CC/CT vs. TT) in different subgroups were shown in Significant association between SNP rs11614913 and increased risks of digestive gland cancers was found in three genetic models , except for recessive model  and allele contrast . Additionally, we demonstrated that this locus polymorphism was significantly linked to higher risks for CRC , but a marginal significance was found in recessive model . We also observed increased susceptibility of HCC in homozygote comparison , dominant model , recessive model  and allele contrast . We just found a marginal significance in homozygote comparison  in HCC study. Compared with CRC and HCC, no significant associations were found in GC, OSCC and PSCC.With consideration of control source, studies with hospital-based controls showed elevated risks in four genetic comparisons  and an edge effect was obtained in recessive model . However, studies with population-based controls presented no significant association.For the Asian group, every genetic comparison produced significantly increased risks  while no significant associations were detected in Caucasian group.In the subgroup of C>T, remarkably elevated cancer risks were found in homozygote comparison  and dominant model . While we did not find significant associations among heterozygote comparison , recessive model  and allele contrast . Meanwhile, significant association between miR-196a2 polymorphism and increased risk of digestive system cancer was also found in the C≤T group .2 = 222.32, P<0.0001 ). A former study reported a parallel observation When we compared C allele frequency in Asians with that in Caucasians, Zhang's study on CRC was excluded due to its HWE disequilibrium in controls. C allele frequency of miR-196a2 ranged from 0.419 to 0.754 across Asian and Caucasian controls. In Asian controls, C allele frequency accounted for 45.60% which was significantly lower than that in Caucasian controls  comparing with TT carriers Further more, SNPs in miRNAs can occasionally disturb the gene or protein expression and result in pathogenicity Our study showed that the presence of C allele significantly increased the risk of digestive system cancers with the comparison to T allele. This finding indicates that the genetic variant in miR-196a2 may crucially modify the susceptibility of digestive system cancers. Previous meta-analysis which described cancers locating in multiple systems of organism supported our finding We found that miR-196a2 polymorphism, in stratified analysis by cancer site, was statistically related with elevated cancer risks in the alimentary tract group and digestive gland group. Moreover, significantly increased risks were found in CRC and HCC. However, we did not observe any significant association between the genetic variant and the susceptibility of GC, OSCC and PSCC. There are some possibilities for this discrepancy among tumor sites. Firstly, the tissue specificity leads to different cancer susceptibilities in different tissues. Secondly, the relative small amount of eligible studies in stratified analysis might induce significant/insignificant association by chance due to insufficient statistical power In the subgroup of ethnicity, we found significant association between miR-196a2 polymorphism and increased risks of digestive system cancers in Asians but not in Caucasians. A former meta-analysis reported a parallel observation to us The majority  of studies with hospital-based controls recruited Asians as tested subjects and we found significantly increased risks in this subgroup. While most  studies with population-based controls investigated Caucasians and we did not found any significant results in this subgroup. So the mentioned ethnic interpretations are available to the inconsistency in control source stratification. And the possible selection bias in controls with different matched criteria and sample size may also be the reasons. Chu's meta-analysis study also reported significantly increased cancer risks in Asians but not in Caucasians Disagreements in the stratification of allele frequency in controls might attribute to above interpretations for ethnic effect to some extent.Some advantages can be highlighted in our study. On one hand, this meta-analysis shed light on the association between miR-196a2 polymorphism and increased risks of digestive system cancers, CRC and HCC comprehensively and systematically. On the other hand, the inclusion of an unpublished study on CRC and the collection of unpublished genotype frequency of OSCC and PSCC strengthened the power and persuasion of our inference. Further more, all included studies had acceptable quality (scored at least 6). Limitations of this study should be noticed at the same time. Firstly, genetic factors, tumor biological characteristics and their interactions with environmental factors produce evident influences to the cancer susceptibility and tumorigenesis. Different cancers have different risk factors and diverse sensitivities to them. For instance, Heliobacter pylori infections and smoking may increase the incidence of gastric cancer. And hepatitis B, C virus infections and exposure of aflatoxin in food are risk to liver cancer In summary, this meta-analysis indicated that miR-196a2 rs11614913 polymorphism may increase the susceptibility of digestive system cancers, especially of CRC and HCC. SNP in this locus may considerably act as a candidate of biomarker for cancer screening, diagnosis and therapy in the future. To confirm our findings, further well-designed studies with large sample size in diverse ethnic populations, more types of digestive system cancers along with tissue-specific biochemical, functional and expressional characteristics are required.Figure S1Funnel plot of publication bias. The standard error of log (OR) is plotted versus OR for each study. Each square represents a separate study for the indicated association by allele contrast (C vs. T). The dotted line in blue indicates the estimated OR.(TIF)Click here for additional data file.Figure S2Forest plots of dominant model (CC/CT vs. TT) in different subgroups. The squares and horizontal lines correspond to OR and 95% CI of specific study, and the area of squares reflects study weight (inverse of the variance). The diamond represents the pooled OR and its 95% CI.(TIF)Click here for additional data file.Table S1Genotype frequency distribution of studies included.(DOC)Click here for additional data file.Table S2Scale for methodological quality assessment.(DOC)Click here for additional data file.Table S3Heterogeneity test.(DOC)Click here for additional data file.Table S4ORs (95% CI) of sensitivity analysis.(DOC)Click here for additional data file.Table S5MOOSE Checklist.(DOC)Click here for additional data file.


The present knowledge on the association of single nucleotide polymorphisms (SNPs) of lysyl oxidase-like 1 (LOXL1) with pseudoexfoliation syndrome (PEXS) and pseudoexfoliation glaucoma (PEXG) is controversial and inconclusive. This meta-analysis sought to derive a more precise estimation of the effects of LOXL1 SNP loci  on PEXS/PEXG. Literature searches were conducted on the PubMed, EMBASE, ISI Web of Science, and Cochrane Library databases through October 2013. Twelve studies describing 1810 cases and 1790 controls met the inclusion criteria. The strengths of the associations found through the meta-analysis were assessed with pooled odds ratios and their 95% confidence intervals (CI). A meta-regression analysis was also used to examine the influence of the study and population characteristics. The results indicated that rs1048661 TT carriers had 92.1% and 40.4% less risk of developing PEXS/PEXG than did the controls in the Caucasian and Asian populations, respectively. Carriers of rs3825942 AA or rs2165241 CC also had significantly less PEXS/PEXG susceptibility than did the non-carriers. Meta-regression showed that in Caucasians, the male proportion  and mean age  of the PEXS/PEXG subjects correlated positively with the effect of rs3825942 on PEXS/PEXG susceptibility. The meta-analysis suggested that LOXL1 rs1048661 TT, rs3825942 AA, and rs2165241 CC were associated with a reduced risk of developing PEXS/PEXG. Pseudoexfoliation syndrome (PEXS) is an age-related systemic disorder that is the most common cause of secondary glaucoma worldwide and the most frequent cause of unilateral glaucoma Despite its worldwide distribution, there is a clear tendency for PEXS to cluster geographically and in certain racial or ethnic subgroups A genome-wide association study identified three common single nucleotide polymorphisms (SNPs) in the LOXL1 gene on chromosome 15q24.1 that were strongly associated with pseudoexfoliation syndrome The PubMed, EMBASE, ISI Web of Science, and the Cochrane Library databases were electronically searched for case-control studies published through October 2013 that examined the association of the LOXL1 gene polymorphisms with the PEXS/PEXG susceptibility. The search strategy was based on a combination of “(lysyl oxidase-like 1 OR LOXL1) AND  AND (pseudoexfoliation syndrome OR pseudoexfoliation glaucoma)”. We also manually searched references in key articles. The language was limited to English.The inclusion criteria were as follows: (a) evaluation of the association of the LOXL1 gene polymorphisms with the PEXS/PEXG risk; (b) case-control studies; (c) sufficient published data for estimating an odds ratio (OR) with a 95% confidence interval (CI); and (d) PEXS was diagnosed as the presence of pseudoexfoliative material on the anterior lens capsule after maximal pupil dilatation. PEXG was diagnosed if patients had typical features of PXFS and all of the following: an initial intraocular pressure of at least 22 mm Hg, glaucomatous optic disc changes, visual field defects consistentent with optic nerve damage, and no evidence of other conditions causing secondary glaucoma To show the relationship between the LOXL1 gene polymorphisms and PEXS/PEXG risk, the most strongly and independently associated SNPs were selected for the analysis . Information regarding the following aspects was retrieved from each study according to a fixed protocol: study design; geographical location; population ethnicity, definition and numbers of cases and controls; DNA extraction and genotyping methods; frequency of the genotypes; mean age of the patients; and proportion of the patients who were male. When the studies included subjects of more than one ethnicity, the genotype data were extracted separately for each ethnic group. The genetic equilibrium of the LOXL1 gene for the control group of each study was evaluated by testing for Hardy-Weinberg equilibrium (HWE) using chi-square analyses A summary OR with a 95% CI was calculated to assess the strength of the association of the LOXL1 gene polymorphisms with the PEXS/PEXG risk. The OR of each study was first calculated in a 2×2 table. Pooled ORs for the risk were then calculated for the allele frequency comparison and the additive, dominant, and recessive models. The between-study heterogeneity was evaluated with a Q statistic, and a P value <0.1 was considered statistically significant t-test suggested by Egger, with P<0.05 considered to represent statistically significant publication bias To consider the possible sources of heterogeneity, we stratified the studies by ethnicity and repeated the analysis separately for each group. Furthermore, we performed a meta-regression analysis to assess the influence of the population characteristics All calculations were performed using the Comprehensive Meta-Analysis computer program version 2 .The first search retrieved 83 articles. After eliminating the 60 studies not related to the topic, 23 potentially relevant studies were identified for further evaluation. In these studies, the titles or abstracts indicated that they evaluated the association between the LOXL1 gene polymorphisms and PEXS/PEXG susceptibility; however, some studies did not meet all of the study inclusion criteria. Ultimately, 11 studies were excluded because they were undesirable article types , had overlapping patient samples (n = 1) Twelve studies evaluated the association between the rs1048661 T/G polymorphism and the risk of developing PEXS/PEXG. For the combined group data, significant associations between rs1048661 and susceptibility to PEXS/PEXG were observed for the additive, dominant, and recessive models, but not for the allele frequency comparison . In a suThe twelve studies contained data regarding the association of the rs3825942 A/G polymorphism with the susceptibility to PEXS/PEXG. In comparison with the control group, the association between rs3825942 and decreased susceptibility to PEXS/PEXG was significant in all genetic models . FurtherEight studies contained data for the rs216524 C/T polymorphism. The association between rs216524 and susceptibility to PEXS/PEXG was significant in all genetic models . FurtherThe Q-test suggested significant between-study heterogeneity for several of the pooled models for each of the SNPs , and 4. The male proportion and mean age of the subjects did not significantly affect the influences of rs1048661 and rs2165241 on PEXS/PEXG susceptibility. In contrast, for the effects of rs3825942 on PEXS/PEXG risk in Caucasians, a significant influence was detected for both the male proportion  rs3825942 TT+TG vs. GG; (B) rs3825942 AA+AG vs. GG; (C) rs2165241 CC+CT vs. TT.(DOC)Click here for additional data file.Checklist S1PRISMA checklist.(DOC)Click here for additional data file.


A meta-analysis of 11 studies with 3882 subjects was conducted. Pooled odds ratios (ORs) for the association between BDKRB2−58T/C gene polymorphism and EH and their corresponding 95% confidence intervals (CIs) were estimated using the random effects model.The objective of this study was to explore the association between BDKRB2−58T/C gene polymorphism was significantly correlated with EH under an allelic genetic model , a dominant genetic model , a recessive genetic model , a homozygote genetic model , and a heterozygote genetic model .The BDKRB2−58T/C gene polymorphism is associated with increased EH risk. The results of this study suggest that carriers of the −58C allele are susceptible to EH.The  The kallikrein–kinin system (KKS) is an important hormonal system that takes part in blood pressure (BP) and renal sodium regulation 1 (BDKRB1) and β2 (BDKRB2) BDKRB2 gene, located in 14q32.1–32.2, spans approximately 4 kb and consists of three exons. In 1996, Braun et al. detected −58T/C variations in the BDKRB2 promoter region and found that these could lead to a reduction in BDKRB2 transcription, which might be associated with the pathogenesis of essential hypertension (EH) The function of bradykinin is mediated by two receptor subtypes, namely, βBDKRB2−58T/C gene polymorphism and EH has been widely studied, but the results remain inconclusive. In 2000, Gainer et al. found that BDKRB2−58C might represent a susceptibility marker for EH in African Americans BDKRB2−58T/C gene polymorphism and EH and concluded that the −58CC genotype is associated with increased EH risk in a Chinese population BDKRB2−58T/C gene polymorphism and EH (Supplement S5).The relationship between 2 receptor”, and “polymorphism”. Studies published before 2012 were obtained .PubMed, EMBASE, Web of Science, China Biological Medicine Database, and China National Knowledge Infrastructure were searched for relevant articles with the terms “essential hypertension”, “bradykinin βBDKRB2−58T/C gene polymorphism and EH was assessed; (b) the diagnosis of EH was in line with the 1999 diagnostic criteria of the World Health Organization in which systolic BP≥140 mmHg, diastolic BP≥90 mmHg, and treatment with antihypertensive medication defined EH, excluding patients with secondary hypertension, cardiomyopathy, valvular heart disease, congenital heart diseases, and renal failure; (c) the Hardy–Weinberg equilibrium (HWE) was followed; and (d) the results of the same data used in different studies were adopted only once. If articles with similar data were published by the same work group, the study with the larger sample size was selected.Studies that met the following major criteria were included: (a) the association between The data were collected according to a standard protocol. Repeated publications, studies against the selection criteria, and work providing insufficient data were excluded from the meta-analysis. Data were recorded as follows: first author’s name, publication year, study region, number of genotypes, genotyping, study design, matching criteria, total number of case patients, and total number of control subjects.BDKRB2−58T/C gene polymorphism and EH reported under these models was analyzed using odds ratios (ORs) with 95% confidence intervals (CIs). Between-study heterogeneity was calculated by χ2-based Q analysis, and significance was set at P<0.05 I2. If heterogeneity among studies was detected, the DerSimonian–Laird random effects pooling method was used Z test was used to determine the pooled OR, and significance was set at P<0.05.Five genetic models  were used. The association between Fisher’s exact test was used to assess the HWE, and P<0.05 was considered statistically significant. Potential publication bias was estimated by funnel plot analysis. The funnel plot asymmetry was assessed by Egger’s linear regression test on the natural logarithm scale of the OR (P<0.05) BDKRB2−58T/C gene polymorphism. No study was excluded for deviating from the HWE. Data were collected from 1947 patients with EH and 1935 control subjects (Supplement S1 and S6) Our literature search yielded 20 relevant articles, 11 of which met the inclusion criteria. Of the 9 excluded studies, 2 were double publications, 2 were reviews, and 5 were not associated with the BDKRB2−58T/C gene polymorphism and EH was found under the allelic , dominant , recessive , homozygote , and heterozygote  genetic models. Subgroup analysis stratified by continent also revealed a significant association between BDKRB2−58T/C gene polymorphism and EH in the Asian subgroup under the allelic , dominant , recessive , homozygote , and heterozygote  genetic models. No significant association was found in the American and European subgroups under any of the genetic models (P>0.05) . In subgroup 2, no significant increase in EH risk was found   (P = 0.036), total sample size of the control group (P = 0.037), and study region (P = 0.045). Based on TT0, the whole population was divided into two subgroups: Subgroup 1 was defined as TT0<30, whereas subgroup 2 was classified as TT0>30. In the subgroup analysis by TT0, under the allelic genetic model, significantly increased EH risk was detected in subgroup 1 , total sample size of the control group (P = 0.033), and TT0 (P = 0.041). The entire population was separated into six subgroups by study region . A significant association was found in the Canadian subgroup , but not in the other five subgroups (P>0.05) , but not in the American and European subgroups (P>0.05). Such variation in the results can be attributed to the ethnic differences between groups.This meta-analysis found a significant association between In the following meta-regression to explore the heterogeneity source under an allelic genetic model, the confounding factors TT0, study region, and total sample size of the control group could partly explain the heterogeneity source, with TT0 being the most important factor. This finding suggested that the heterogeneity among the different studies can be ascribed to the nonuniformity in the sample size of control subjects with the TT genotype. Subgroup analysis according to the number of control subjects with the TT genotype revealed that EH risk was significantly increased only in the TT0<30 subgroup.BDKRB2−58T/C gene polymorphism is associated with increased EH risk, especially in Asians. Carriers of the −58C allele of the BDKRB2 gene might be predisposed to developing EH. In 2010, Niu et al. performed a meta-analysis aiming to provide a comprehensive evaluation of the correlation between BDKRB2−58T/C gene polymorphism and EH. They found that the −58T allele exhibited a protective effect on hypertension only in African Americans (P = 0.04) and had no effect on hypertension in Asians and Caucasians (P>0.05) Research has shown that the BDKRB2 would contribute to EH and other cardiovascular diseases, suggesting that it is a candidate gene for EH. Bradykinin could lower renal vascular resistance and increase the renal blood flow volume, which in turn could increase urine sodium excretion BDKRB2−58T/C mutation could lower the transcription rate of the BDKRB2 gene, constrict vessels, and create an imbalance between water and salt, which all contribute to EH. The results of the current meta-analysis have confirmed these findings.EH is a polygenic disease caused by both environmental and hereditary factors BDKRB2−58T/C gene polymorphism included in the meta-analysis still proved inadequate. BDKRB2 was affected not only by the BDKRB2−58T/C gene polymorphism but also by such environmental factors as tissue injury and inflammation. Lastly, the type of association between BDKRB2−58T/C gene polymorphism and EH could not be easily adjusted. All these represent a weakness of the study.This work was not without limitations. The large-scale studies on the relationship between EH and BDKRB2−58C allele might increase EH risk. This conclusion provides a strong foundation for formulating a strategy for individual therapy in patients with EH. Given the abovementioned limitations, however, this finding warrants further investigation.The results of this meta-analysis suggest that the Supplement S1Characteristics of the investigated studies of the association between bradykinin β2 receptor -58T/C gene polymorphism and essential hypertension.(DOC)Click here for additional data file.Supplement S2Summary of meta-analysis of association of bradykinin β2 receptor -58T/C gene polymorphism and essential hypertension.(DOC)Click here for additional data file.Supplement S3The meta-regression results among 11 studies under an allelic genetic model for -58T/C gene polymorphism of bradykinin β2 receptor.(DOC)Click here for additional data file.Supplement S4The meta-regression results among 11 studies under a dominant genetic model for -58T/C gene polymorphism of bradykinin β2 receptor.(DOC)Click here for additional data file.Supplement S5PRISMA 2009 Checklist.(DOC)Click here for additional data file.Supplement S6PRISMA 2009 Flow Diagram.(DOC)Click here for additional data file.


P53 is a tumor suppressor gene and plays important role in the etiology of breast cancer. Intron 3 sixteen-bp duplication polymorphism of p53 has been reported to be associated with breast cancer risk. However, the reported results remain conflicting rather than conclusive.A meta-analysis including 19 case-control studies was performed to address this issue. Odds ratios (ORs) with 95% confidence intervals (CIs) were adopted to evaluate the association.The overall results suggested that the variant genotypes were associated with a significantly increased breast cancer risk . When stratifying by sample size of studies, a significantly elevated risk was also observed among large sample studies (>500 subjects) but not among small sample studies (≤500 subjects).p53 may contribute to susceptibility to breast cancer. Additional well-designed large studies were required to validate this association in different populations.These results suggested that the 16-bp duplication polymorphism of  Breast cancer is the most commonly diagnosed cancer and a predominate cause of death in female population worldwide p53 tumor suppressor gene, designated as the guardian of the genome, is the most frequently mutated gene in different types of cancers p53 gene is mutated in 20%–30% of the sporadic breast cancer p53 gene. The most informative one is the codon 72 Arg>Pro polymorphism (rs1042522), which results in structural alteration of the p53 protein and consequently affect its functions p53 gene also contains several polymorphisms in non-coding region. Among these, the 16-bp duplication polymorphism (rs17878362) within intron 3 has been widely analyzed as possible cancer susceptibility modifiers . Review articles were hand-searched to find additional eligible studies and only published studies with full-text articles were included. Studies included in our meta-analysis have to meet the following criteria: (1) use a case-control design and (2) contain available genotype frequency. Major reasons for exclusion of studies were: (1) genotype frequency was not reported (2) duplicate of previous publication and (3) abstract, comment and review.To identify all studies that examined the association of Information was carefully extracted from all eligible publications independently by two authors (D.W. and Z.Z.). For each included study, the following information was sought: the first author's last name, year of publication, country of origin, ethnicity, numbers of genotyped cases and controls, source of control groups , genotyping methods, and quality control.2 test. The strength of the association between the SNP rs17878362 and breast cancer risk was measured by odds ratios (ORs) with 95% confidence intervals (CIs). We first estimated the risks of the variant Ins/Del and Ins/Ins genotypes on breast cancer, compared with the wild-type Del/Del homozygote, and then evaluated the risks of (Ins/Ins+Ins/Del) vs Del/Del and Ins/Ins vs (Ins/Del+Del/Del) on breast cancer, assuming dominant and recessive effects of the variant Ins allele, respectively. Stratified analyses were also performed by ethnicity, source of controls and sample size (≤500 and >500 subjects).For control group of each study, the allelic frequency was calculated and the observed genotype frequencies of the SNP rs17878362 were assessed for Hardy-Weinberg equilibrium using the χP>0.05, otherwise a random-effect model (the DerSimonian and Laird method) was used For the heterogeneity test, a fixed-effect model (the Mantel-Haenszel method) Cumulative meta-analysis were conducted to provide a framework for updating a genetic effect from all studies and to measure how much the genetic effect alters as evidence accumulates.P values.Sensitivity analyses were performed to assess the stability of the results, namely, a single study in the meta-analysis was deleted each time to reflect the influence of the individual data set to the pooled OR. Funnel plots and Egger's linear regression tests were used to provide diagnosis of the potential publication bias The flow chart in tPrend<0.001; Pooled ORs and heterogeneity test results for the association of SNP rs17878362 and breast cancer risk were shown in Then, these studies were further divided into two subgroups according to their source of controls. A statistically significantly elevated risk was only found among hospital-based studies in the dominant model   but not among small sample study (≤500 subjects).P = 0.048) and showed a trend of association as published data accumulated . Although the genotype distribution in two studies The leave-one-out sensitivity analysis indicated that the study by Faghani et al. P = 0.882 for Ins/Ins vs Del/Del; Funnel plots and Egger's tests were conducted to estimate the publication bias of literatures. The symmetry plots indicated that there was no publication bias in all pooled studies. The results were further confirmed by Egger's test  examined the association between a commonly studied 16-bp duplication polymorphism within intron 3 of p53 transcript in lymphoblastoid cell lines, suggesting that this polymorphism causes an alteration in messenger RNA (mRNA) processing P53 haplotype  is associated with reduced apoptotic and DNA repair capacity in lymphoblastoid cell lines P53 variants may affect P53 function. Thus, it is reasonable that the 16-bp Ins allele might result in alteration of p53 gene expression and function, leading to decrease of p53 mediated apoptosis of tumor cells. In our present meta-analysis, we found that individuals with the 16-bp Ins allele were associated with higher risk of breast cancer than subjects with the Del allele, which was consistent with experimental findings.It is reported that the 16-bp Ins allele was associated with lower level of Our results showed that the Ins allele may increase risk of breast cancer, which were consistent with a previous meta-analysis of eight studies based on breast cancer In our analysis, many studies did not provide the ethnic background of their participants, which precluded more detailed analysis of this polymorphism in different ethnicities. Thus, more specific ethnical information should be provided in further studies, which should lead to better understanding of the association between the 16-bp duplication polymorphism of p53 and breast cancer risk among different ethnicities.We found an evidence for the association between the 16-bp Ins allele and breast cancer risk among large sample studies (>500 subjects) but not among small sample studies (≤500 subjects). This is probably because studies with small sample size may have limited statistical power to detect a small effect or may have generated a fluctuated risk estimate. Thus, the use of a proper and large sample study is very crucial in reducing biases in such association studies.In this meta-analysis, a thorough sensitivity analysis was carried out by removing each single study from pooled data and the results showed that there was no influence of the individual data on overall results. Moreover, we also calculated the overall pooled ORs on 16-bp duplication with and without the two largest studies Some limitations of this meta-analysis should be acknowledged. First, in the subgroup analyses, the number of Africans and Asians was relatively small, not having enough statistical power to explore the real association. Second, misclassifications on disease status and genotypes may also influence the results, because cases in several studies were not confirmed by pathology, and the quality control of genotyping was also not well documented in several studies. In spite of these, our present meta-analysis also had some advantages. First, substantial number of cases and controls were pooled from different studies, which greatly increased statistical power of the analysis. Second, the quality of case-control studies included in this meta-analysis was satisfactory according to our selection criteria. Third, we did not detect any publication bias indicating that the whole pooled result should be unbiased.p53 gene was significantly associated with an increased risk of breast cancer. Future well-designed large studies were warranted to validate these findings in different ethnic populations.Taken together, this meta-analysis provided evidence that the 16-bp duplication polymorphism within intron 3 of