Stroke is the second most common cause of death and major cause of disability worldwide. The SNP 83 in PDE4D gene has been suggested as a risk factor in ischemic stroke, but direct evidence from genetic association studies remains inconclusive even in Chinese population.Meta-analysis of case-control studies on the relationship between SNP 83 in PDE4D gene and susceptibility to ischemic stroke in Chinese population published domestically and abroad from January 2003 to September 2012.9 case-control studies were selected. Meta-analysis results showed that the significant association between SNP 83 and ischemic stroke was found under the dominant model  and recessive model  in Chinese population. In subgroup meta-analysis, SNP 83 and atherothrombotic stroke, rather than lacunar stroke, showed the significant association under the dominant model  and recessive model .The results suggest that SNP 83 in PDE4D gene is significantly associated with susceptibility to ischemic stroke in Chinese population. Stroke is the second most common cause of death and major cause of disability worldwide. The phosphodiesterase 4D (PDE4D) gene is at the locus on chromosome 5q12 and encodes cAMP-specific 30, 50-cyclic phosphodiesterase 4D, belonging to a superfamily of phosphodiesterases (PDE4 family). Even in Chinese population, the conclusions have not reached an agreement. Several studies have reported a positive or null relation between SNP 83 in PDE4D gene and ischemic stroke in Chinese population, but findings have been controversial. Electronic databases including MEDLINE, CBMdisc, CNKI , Chinese VIP database and Chinese WanFang database were searched from January 1, 2003 to September 30, 2012 for all case-control studies evaluating the association of SNP 83 in PDE4D gene with ischemic stroke in Chinese population. The following terms were used in our search strategies: PDE4D/phosphodiesterase 4D and stroke/cerebral infarction/brain infarction/cerebrovascular disease and polymorphism/gene/genotype/variant/allele. The equivalent Chinese terms were used in the Chinese databases. The “related articles” option in MEDLINE, as well as reference lists of all retrieved studies, were checked to search for other relevant articles that were not initially identified. The articles were selected without language restrictions. The entire literature search was performed by two independent researchers.The studies had to meet the following criteria: (1) The association of SNP 83 in PDE4D gene with ischemic stroke was examined based on case-control design; (2) The population of the studies was restricted to Chinese population. The studies were excluded if one of the following existed: (1) The genotype frequency was not reported, (2) For duplicate publications, the smaller dataset was discarded.The two of the authors independently extracted data from each relevant study. Disagreements were reconciled through group discussion.The following information was collected from each study: (1) first author, journal, year of publication, region, (2) total number, characteristics of cases and controls, subtype of ischemic stroke, distribution of genotypes and alleles in all groups.I2 statistic and I2>50% indicates significant heterogeneity between the studies. Based on the test of heterogeneity, a pooled OR was calculated by using fixed or random effect model, along with the 95% confidence interval (CI) to measure the strength of the genetic association. Publication bias was examined by the visual inspection of funnel plot, Begg’s test and Egger’s regression test .Data were analyzed and processed using Review Manager 5.0 and Stata 10.0. Heterogeneity among studies was examined with the 105 studies were identified by the literature search, among which 9 studies met the inclusion criteria. Of the 96 excluded studies, 7 were duplicate publication, 36 were reviews, editorials or comments, 32 were from other ethnic populations, 4 were not involved with SNP 83, 17 were other irrelevant articles. A flow diagram schematized the process of selecting and excluding articles with specific reasons, as shown in A total of 9 case-control studies of Chinese population were included in the meta-analysis comprising 2751 patients with ischemic stroke and 3233 controls. The ischemic stroke in most studies of our meta-analysis was confirmed by CT or MRI, except one study in which the definition of stroke was not mentioned. 2I statistic, was not significant under the dominant model (2I = 0) and recessive model (2I = 31%). Therefore, the fixed effect model was used for calculating the pooled OR for the both models. A significant association between SNP 83 and ischemic stroke was found under the dominant model  and recessive model , as shown in For SNP 83, the heterogeneity among the studies, measured by I2<0.5) and the fixed effect model was used for calculating the pooled OR. The sensitivity analysis demonstrated that the significant positive association between SNP 83 and ischemic stroke was found under the dominant model  and recessive model , as shown in The sensitivity analysis was performed with 7 case-control studies whose genotype frequencies in the control group were consistent with Hardy-Weinberg equilibrium (HWE). p<0.00001) and recessive model . The remaining pooled OR from SVO subgroup was not significant under the dominant or recessive model (p>0.05), as shown in Subgroup analysis was performed for SNP 83 in PDE4D gene and ischemic stroke in Chinese population by the subtypes of ischemic stroke. 5 studies were selected in the subgroup of large-artery atherosclerosis (LAA) p = 0.602 for dominant model and p = 0.076 for recessive model, respectively). In Egger’s regression test, there was no statistical evidence of publication bias under the dominant model, but not for the recessive model .For SNP 83,the distribution of the ORs from individual studies in relation to their respective standard deviation in funnel plot, as shown in Case-control studies are commonly used to find the association between the candidate genes and the complex human diseases. However, the data from the genetic association studies indicates that susceptibility loci for common disease have a small effect. This means that genetic association studies need to test many cases and controls to have a reasonable chance of finding an effect. Our meta-analysis showed that the risk of developing ischemic stroke in carriers with C allele on SNP 83 was 1.34-fold higher than individuals without C allele in Chinese population. Also, the risk in individuals with CC genotype was 1.45-fold higher than individuals without CC genotype. In case-control studies, a control group that is representative of the general population is expected to be in HWE for the studied locus. Therefore, we selected the case-control studies whose genotype frequencies in the control group were consistent with HWE for sensitivity analysis. The results of sensitivity analysis were close to the results of the meta-analysis before the sensitivity analysis. So it suggests that the combined results of our meta-analysis are reliable.In 2008, Bevan et al. How can we explain the association between SNP 83 in PDE4D gene and ischemic stroke in Chinese population? 1) PDE4D selectively degrades the second messenger cyclic adenosine monophosphate (cAMP) in vascular smooth muscle cells and activated macrophages, which is a key signaling molecule mediating cell proliferation and migration related to atherosclerosis and plaque stability. According to TOAST classification, ischemic stroke can be divided into five subtypes: 1) LAA, 2) SVO, 3) cardioembolism (CE), 4) stroke of other determined etiology, and 5) stroke of undetermined etiology. The present meta-analysis should be interpreted within the context of its limitations. 1) All included studies of our meta-analysis have followed a retrospective case-control design. It may be more subject to bias and artifact than prospective studies. 2) If another variant in or near the SNP 83 in PDE4D gene was the causal variant, the true association could easily be missed. Different linkage disequilibrium patterns with the causal variant may lead to variable results in different populations. 3) We only focused on SNP 83 in PDE4D gene, while did not evaluate other genes or environmental factors. It is possible that the potential roles of SNP 83 in PDE4D gene are diluted or masked by other gene-gene or gene-environment interactions. 4) Publication bias refers to the decreased likelihood of studies’ results being published when they are near the null, not statistically significant. Publication bias is one of the most important sources of bias in meta-analysis, which can cause the false positive results. In our meta-analysis, under the dominant model, we found no evidence of publication bias by the visual inspection of funnel plot, Begg’s test or Egger’s regression test. However, under the recessive model, we found publication bias by the visual inspection of funnel plot and Egger’s regression test. Hence, the caution is indicated when interpreting the association of SNP 83 with ischemic stroke under the recessive model.In conclusion, our meta-analysis suggests that SNP 83 in PDE4D gene is associated with developing ischemic stroke in Chinese population. Given the limitations in the present meta-analysis, the results need to be interpreted with caution. Well-designed case-control studies with large sample sizes regarding the association of SNP 83 in PDE4D gene and ischemic stroke need to be performed on different ethnic population in the future.File S1PRISMA 2009 Checklist.(DOC)Click here for additional data file.


MDR) 1 gene encodes a 170-kDa membrane transporter called P-glycoprotein, which plays an important role in protecting cells against lipophilic xenobiotics by the way of an ATP-dependent cellular efflux mechanism. Three polymorphisms of MDR1, 3435C > T located in exon 26, 1236C > T in exon 12 and 2677G > T/A in exon 21 were the most extensively studied and were identified functionally important and ethnically diverse mapping to the gene region. Considering the potential influence of altering MDR1 activity, it is plausible that MDR1 polymorphisms might play a role in the development of cancer. Although the effects of MDR1 polymorphisms on susceptibility to human cancer have been investigated in many studies, the results still remain conflicting.The multidrug resistance  for 3435C > T polymorphism, 10 studies (2101 cases and 2842 controls) for 1236C > T polymorphism and 18 studies (3585 cases and 4351 controls) for 2677G > T/A polymorphism.The stratified analyses for 3435C > T polymorphism, individuals with T-allele in 3435C > T had significantly higher ALL risks ; significantly elevated risks were observed among Caucasian populations . When restricting the analysis to the source of controls, we found that HB  genetic models had higher risks , as well as in PB (population-based) genetic models .The T/A-allele frequency of 2677G > T/A polymorphism was associated with higher risk of cancer , significantly elevated risks were observed among Asian populations , and elevated risks could be associated with PB models .Our meta-analysis suggested that 3435C > T polymorphism and 2677G > T/A polymorphism were associated with cancer risk when all studies were pooled together, while 1236C > T polymorphism not. MDR1 or ABCB1) gene encodes a 170-kDa membrane transport protein called P-glycoprotein. For minimizing the exposure of potential toxic compounds to the cellular homeostasis, P-glycoprotein is expressed primarily in regions that act as epithelial barriers or perform excretory functions, including blood-tissue barrier, the gastrointestinal tract, liver and kidney. Therefore, P-glycoprotein can play the role of sweeper by extruding several exogenous and endogenous substances, using ATP-dependent efflux pump pyrene and chemokines involved in inflammation seem to be the substrates of P-glycoprotein, which leading P-glycoprotein to be a potential cause of inflammation-induced carcinogenesis. MDR1 also seems to play a role in preventing early apoptosis in tumor cells.ATP-binding cassette (ABC) is one of the largest families of active importers and exporters that are located mainly in tissues acting as a barrier or having an excretory function. Most of the ABC transporters play a role in cell defense against environmental attacks generated by xenobiotics and intraceullar metabolic waste. The multidrug resistance 1 MDR1 gene heterogeneity, namely multiple mutations in the ABCB1/MDR1 gene has been demonstrated in previous studies. Analysis of all 28 exons of the ABCB1/MDR1 gene demonstrated at least 48 single-nucleotide polymorphisms (SNPs) to date, including promoter and the intron–exon region. The most frequent SNP MDR1 2677G > T/A in exon 21 (RefSNP ID: rs2032582), leads to amino acid exchange from Ala to Ser or Thr. The silent mutation in exon 26 MDR1 3435C > T (RefSNP ID: rs1045642) is associated with altered protein function. The third common polymorphism of ABCB1/MDR1 gene is a silent mutation in exon 12 MDR1 1236C > T (RefSNP ID: rs1128503). These three polymorphisms are closely related to linkage disequilibrium (LD). It was suggested that SNP is connected with susceptibility to many cancer types, such as renal epithelial tumors and acute lymphoblastic leukemia and CRC.Significant MDR1 3435C > T polymorphism is associated with cancer risk when all studies were pooled together . In the stratified analysis by cancer type, the results indicated that individuals with T-allele in 3435C > T had significantly higher ALL risks , otherwise no significant association was found between higher CRC risks and T-allele in 3435C > T, neither was between breast cancer and T-allele in 3435C > T. When stratified by ethnicity, significantly elevated risks were observed among Caucasian populations, whereas significantly elevated risks were not observed among Asian populations . When restricting the analysis to the source of controls, we found that HB genetic models had higher risks , and association was detected in PB genetic models also .Our results showed that MDR1 played in different cell types or tissues. We’ve found the association between MDR1 3435C > T polymorphism and ALL risk in subgroup analyses, as well as subgroup based on HB and PB genetic models. And in the stratified analysis by ethnicity, individuals carrying the T-allele in 3435C > T were significantly associated with elevated cancer risk in Asian as well as Caucasian populations compared with C-allele carriers.Inconsistent results might be attributed to the different roles We also found that T/A-allele frequency of 2677G > T/A polymorphism was associated with higher risk of cancer . In the subgroup analysis by ethnicity, significantly elevated risks were observed among Asian populations , however no significantly elevated risks were observed among Caucasian populations. When stratified by the source of controls, we couldn’t find association between HB genetic models and higher cancer risks, but elevated risks could be associated with PB models .The combined result based on all studies showed that there was no statistically significant link between cancer risk and 1236C > T .It should be considered that the apparent inconsistency of these results may be caused by differences in disease prevalence, lifestyle, as well as possible limitations due to the relatively small sample size. The current knowledge of carcinogenesis indicates it is a process developed step by step, as well as influenced by multiple factors that involve various genetic alterations and several signaling pathways. Thus, it is unlikely that risk factors of cancer work in isolation from each other. Besides, even the same polymorphisms may act distinct roles in each cancer type, for different genetic backgrounds may contribute to the cancer discrepancy. And more importantly, the appearance determined by polymorphisms may largely depend on synthetically interaction with each polymorphism or a particular environmental exposure. Thus, it is possible that the effects of DNA repair function on cancer risk may be modified by multiple genetic polymorphisms. Also should we consider the chance findings as another plausible reason for the inconsistency of the results.MDR1 polymorphism and cancer risk as possible as we can, there still exists some limitations. First, when stratified by the source of controls, our results indicated that studies using hospital-based controls rather than population-based controls had a significantly increased risk. The reason may be that the hospital-based studies have some biases because such controls may contain certain other diverse diseases which can cause different risks of developing into cancer of various organs and may not be so representative as the general population. Therefore, using proper and more representative cancer-free control subjects are crucial for reducing biases in such case–control studies. Second, our results were based on single-factor estimates without adjustment for other risk factors such as age, smoking and drinking status, environmental factors and other variables, which might have caused serious confounding bias. Third, some inevitable publication bias might exist. Finally, the number of the published studies was not sufficiently large for a comprehensive analysis, particularly for the 1236C > T polymorphism. Hence we had to give up subgroup analysis for the polymorphism. For these limitations, our results should be interpreted with caution.Although we have put considerable resources and efforts into discovering the association between MDR1 polymorphism between cancer risks is more powerful than any single study. Second, the quality of eligible studies included in current meta-analysis was satisfactory and met our inclusion criterion. Third, we did not detect sufficient publication bias indicating that the whole results might be unbiased.Our meta-analysis also has several strengths. First, statistically, a systematic review of the association of MDR1 3435C > T and 2677G > T/A polymorphism may contribute to genetic susceptibility of cancers. And the results support that the minor T-allele of the MDR1 3435C > T polymorphism is associated with a higher risk of acute lymphocytic leukemia, and significantly elevated risks were observed among Asian and Caucasian populations as well as HB and PB subgroups. And in the 2677G > T/A polymorphism, those who carry the T-allele and A-allele were associated with higher cancer risks among Asians and PB subgroup. However, it is necessary to conduct large sample studies using standardized unbiased genotyping methods, homogeneous cancer patients and well-matched controls. Moreover, further studies estimating the effect of gene–gene and gene–environment interactions may eventually lead to our better, comprehensive understanding of the association between the MDR1 polymorphism and cancer risk.In conclusion, our meta-analysis suggests that the 95% CI: 95% confidence interval; OR: Odds ratio; ALL: Acute lymphoblastic leukemia; HL: Hodgkin lymphoma; HB: Hospital-based; PB: Population-based; PCR-RFLP: Polymerase chain reaction-restriction fragment length polymorphism; MAF: Minor allele frequency; APEX: Arrayed primer extensions.The author declares that there are no competing interests and that this work has not been published or submitted concurrently for publication elsewhere.LHW contributed solely to the writing and submission of this work. All authors read and approved the final manuscript.


Additionally, this polymorphism modified the overall survival of DIA patients . Like tumor grade, XRCC4 codon 247 polymorphism was an independent prognostic factor influencing the survival of DIA. These results suggest that XRCC4 codon 247 polymorphism may be associated with DIA risk and prognosis among the Guangxi population.The DNA repair gene X-ray cross-complementary group 4 (XRCC4), an important caretaker of the overall genome stability, is thought to play a major role in human tumorigenesis. We investigated the association between an important polymorphic variant of this gene at codon 247 (rs373409) and diffusely infiltrating astrocytoma (DIA) risk and prognosis. This hospital-based case-control study investigated this association in the Guangxi population. In total, 242 cases with DIA and 358 age-, sex-, and race-matched healthy controls were genotyped using TaqMan-PCR technique. We found a significant difference in the frequency of XRCC4 genotypes between cases and controls. Compared with the homozygote of XRCC4 codon 247 Ala alleles (XRCC4-AA), the genotypes of XRCC4 codon 247 Ser alleles (namely XRCC4-AS or -SS) increased DIA risk . Furthermore, XRCC4 polymorphism was correlated with tumor dedifferentiation of DIA ( In relaDIA varies considerably in its epidemiological features, morphologic attributes, growth patterns, genetic profiles, and clinic behavior. Histopathologically, this tumor is divided into three groups: low-grade astrocytoma , anaplastic astrocytoma (WHO Grade III), and glioblastoma (WHO Grade IV) . DespiteWhile DNA repair gene x-ray repair cross-complementary Group 4, a key component of NHEJ pathway, is found to restore DNA double-strand break repair and has the ability to support V(D)J recombination –16. The 2.2.1.p > 0.05). According to the WHO grading standard of DIA, cases with IV-grade tumors accounted for 58.7% (142/242), whereas the frequencies of II-grade, and III-grade cases were 19.4% (47/242) and 21.9% (53/242), respectively.Our final analysis included 242 DIA cases and 358 controls. The demographic characteristics of all cases and controls are shown in 2.2.p < 0.01), resulting in an Ser allele frequency of 22.3% in cases and 11.3% in controls. Logistic regression analysis showed that the adjusted odds ratio (OR) for DIA for those individuals carrying XRCC4-AS compared with those exhibiting the homozygote for Ala alleles (XRCC4-AA) was 1.82 , and the corresponding OR for those featuring XRCC4-SS was 2.89 . These results showed that DIA risk was associated with the number of codon 247 Ser alleles.The genotypic distribution of XRCC4 codon 247 for both tumor patients and controls is summarized in Pinteraction > 0.05; To assess possible interactive effects of matching factors and XRCC4 codon 247 polymorphism on DIA risk, we performed a series of bivariate stratified analyses by matching factors , and did not find that these factors modulated the effect of this polymorphism on DIA risk ] or the non-risk genotype (XRCC4-AA) and the clinical pathological characteristics of DIA was first performed separately. Significant differences in the distributions of the genotypes were observed with respect to different tumor grades but not with respect to age, gender, and minority status (data not shown). Spearman r test next exhibited that XRCC4 codon 247 polymorphism was positively related to a higher grade of DIA . These results suggest that XRCC4 codon 247 polymorphism may have functional significance in DIA.et al. [p = 0.023). Recently, a large hospital-based case-control epidemiologic study has also shown that this polymorphism increases the risk of hepatocellular carcinoma [XRCC4, located on chromosome 5q14.2, is an important DNA repair gene involved in the NHEJ pathway ,22. The et al.  investigarcinoma . FurtherTaken together, those results suggest that XRCC4 codon 247 polymorphism may alter the normal protein function and, consequently, may be associated with a reduction in DNA repair capacity . Thus, tBecause previous studies had shown that XRCC4 codon 247 polymorphism may modify tumor outcome ,21, we aIn the present study, to control the effects of confounders such as age, gender, and race, we used an individually matched design. In the stratified analysis, no interactive effects were found, suggesting that these factors do not modify the correlation between XRCC4 codon 247 polymorphism and DIA.However, there were several limitations to our study. Potential selection bias might have occurred because the selection of control subjects in our study was hospital-based. Despite the analysis of the XRCC4 codon 247 polymorphism, we did not analyze other polymorphisms of this gene possibly able to modify the risk of DIA. Our findings were based on relatively small numbers and limited by small number subjects in part of the genotype strata. Therefore, more genes deserve further elucidation based on a large sample and the combination of genes.4.4.1.Between January 2004 and December 2009, incident DIA cases were recruited at the affiliated hospitals of two main medical universities in Guangxi, Guangxi Medical University and Youjiang Medical College for Nationalities. All cases were histopathologically confirmed and previously treated with chemotherapy or radiotherapy. There were no age, sex, race, or tumor stage restrictions. Each new patient was screened with a brief eligibility questionnaire that assessed prior tumor therapy and willingness to participate in this study by the instituted staff interviewers. If the patient was willing to participate, the interviewer accompanied the study participant to a private room to conduct the interview. Healthy control subjects without a history of cancer were randomly selected from a pool of healthy volunteers. Because of the routine scheduled physical exams, volunteers visited the general health check-up centers of the same hospitals. The controls were individually matched (1:1 or 2:1) to cases based on ethnicity , sex, and age (±5 years). Every potential control was first surveyed by using a short questionnaire to elicit willingness to participate in the study and to provide preliminary demographic data for matching. A total of 242 cases and 358 controls, representing 95% of eligible cases and 98% of eligible controls, were enrolled and interviewed. After giving written consent, demographic information and clinical pathological data were collected in the hospitals using a standard interviewer administered questionnaire and/or medical records. At the same time, 4 mL of peripheral blood was obtained for DNA extraction. This study was approved by the ethics committees of the hospitals involved in this study. All activities involving human subjects were carried out under full compliance with government policies and the Helsinki Declaration.4.2.DNA was extracted from peripheral blood samples from all tumor patients and control subjects in a 1.5 mL microcentrifuge tube for deparaffinization and proteinase K digestion, as described by standard procedures . DNA was stored at 4 °C until additional analysis.4.3.Genotypes were analyzed by using a previously published TaqMan-PCR technique ,19. Brie4.4.All DIA patients were followed for at least 3 years for medians and ranges. The last follow-up day was 30 September 2013, and the survival status was confirmed by patients or family contacts. In this study, the duration of overall survival was defined as the time from surgical resection to death or to the date on which the patient was last known to be alive.4.5.2 test was used to test the differences between the cases and the control subjects in the distribution of gender, age, ethnicity, and XRCC4 genotypes. The Spearman r test was used to analyze the correlation between XRCC4 genotypes and tumor grade of DIA. As the present study was based on an individually matched design, we did conditional logistic regression to elucidate odds ratios (ORs) and 95% confidence intervals (CIs) for risk of DIA. Kaplan–Meier survival analysis with the log-rank test was used to evaluate the relationship between XRCC4 codon 247 polymorphism and DIA prognosis. Hazard ratios (HRs) and 95%CIs for XRCC4 genotypes were calculated from a multivariate Cox regression model (with step-wise forward selection based on the likelihood ratio test). In this study, a p-value of <0.05 was considered statistically significant.All analyses were performed with the statistical package for social science (SPSS) version 18 . The Pearson’s χ5.In summary, to the best of our knowledge, this is the first report investigating an association between XRCC4 codon 247 polymorphism and the risk and prognosis of DIA in Guangxi patients. We have found evidence suggesting that the genotypes of XRCC4 with codon 247 Ser alleles may be correlated with increased risk and poor prognosis for DIA, and that the decreasing NHEJ capacity may play an important role in the tumorigenesis of this type of tumor.


CXCR1 gene causes a conservative amino acid substitution (S276T). This single nucleotide polymorphism (SNP) seemed to be functional as it was associated with decreased lung cancer risk. Previous studies of our group found association of haplotypes in the IL8 and in the CXCR2 genes with the multifactorial disease chronic periodontitis. In this study we investigated the polymorphism rs2234671 in 395 Brazilian subjects with and without chronic periodontitis.The chemokine receptor 1 CXCR-1  is a specific receptor for the interleukin 8 (IL-8), which is chemoattractant for neutrophils and has an important role in the inflammatory response. The polymorphism rs2234671 at position Ex2+860G > C of the Similar distribution of the allelic and genotypic frequencies were observed between the groups (p > 0.05).CXCR1 gene was not associated with the susceptibility to chronic periodontitis in the studied Brazilian population.The polymorphism rs2234671 in the  The human chemokine receptor CXCR-1  is a specific receptor for the chemokine interleukin 8 (IL-8) . Cellula+ ) in exon 2, and +827 (starting from the initiation of the ATG codon in exon 2 of [GenBank: L19592.1]), respectively. The variant position 860G > C is based on the [NCBI: NM000634.2] exon 2 initiations, however it is important to be clear that all these different positions at the CXCR1 gene refer to the same polymorphism (G > C), which results in a conservative amino acid substitution from serine to threonine at the 276 amino acid residue of the CXCR-1  protein. Here, we preferred to use the reference sequence number [refSNP ID: rs2234671] in NCBI's Entrez system (http://www.ncbi.nlm.nih.gov/SNP).The 860G > C (S276T) SNP in ta banks ,13. ThesInterleukin 2 (IL2) [IL4 [IL6 [IL10 [IL8 and in the CXCR2 genes with CP [CXCR1 gene would also influence the host susceptibility to CP.Predominantly in the last decade, many candidate-gene investigations have been conducted in order to find genetic risk factors associated with chronic periodontitis (CP). Epidemiological studies indicate that CP is an important cause of teeth loss in adults, since 5% to 15% of any population suffers from this disease . CP is a 2 (IL2) ,18, IL4 L2) [IL4 -21, IL6 IL4 [IL6 ,23 and IL6 [IL10 ,25. Rece with CP ,27. BecaCXCR1 gene in a Brazilian population with chronic periodontitis.In this regard, the aim of this study was to investigate the association of the rs2234671 SNP in the In total, 395 individuals in good general health and having similar socioeconomic status were recruited from the patient pool of the School of Dentistry at Araraquara, São Paulo State University - UNESP between November 2004 and May 2007. The study was approved by the Committee for Ethical Affairs of the São Paulo State University (Protocol number 57/04).To verify statistical power of our sample, we used the G*POWER 3 software  with theInformation on smoking status was obtained using a self-reported questionnaire, and subjects were classified as a "smoker" or "nonsmoker" according to Kornman et al..DNA was obtained from buccal epithelial cells, extracted with sequential phenolchloroform/isoamyl alcohol (25:24:1) solution and precipitated with a salt ethanol solution. The SNP was identified using the sequence-specific primer-polymerase chain reaction method (SSP-PCR) according to Renzoni et al. . The PCRThe chi-squared test was used to determine whether the groups were composed of patients with the same proportion of males and females and whether they had similar smoking habits. Onset age distribution between the two groups was evaluated by Students't-test. Those statistical analyses, as well as deviations from Hardy-Weinberg equilibrium, were performed using BioEstat software version 5.0 .CXCR1gene and periodontal disease susceptibility and the other covariates. This multivariate logistic regression modeling was executed using the R statistical package . Differences were considered to be significant when p < 0.05.In addition, a forward stepwise multiple logistic regression analysis was used for estimating the relationships between the SNP rs2234671 in the CXCR1 gene was consistent with the assumption of the Hardy-Weinberg equilibrium for the control (p = 0.1719) and CP groups (p = 0.2777).The power calculations showed that the sample size of 395 individuals demonstrated a power of 93%. Therefore, the number of subjects enrolled in this study is large enough to detect association with an acceptable level of confidence. The population investigated here was composed mainly of female subjects (59.7%) and nonsmokers (84.8%) and the mean age of the individuals was 39.49 years Table . The minSignificant associations between age and periodontitis were observed by univariate analysis, mainly considering the ORs for age groups 30-39 to the 50-59. We consider that besides the 60-69 and > 70 age groups showed significant OR values they were uncommon and demonstrated a wide range of CI. Significant association was also found between smoking status and periodontitis (OR = 3.8). Therefore, age and smoking status were considered confounding factors. Even though gender was not found to be associated with periodontitis, we included it in the confounding factors in the multivariate analysis, to adjust for any small confounding effects. To more accurately evaluate the strength of any association and to eliminate the distortion caused by confounding effects, multivariate analysis was performed. The multiple logistic regression analysis demonstrated that neither genotypes nor alleles were associated with periodontitis, even after adjusting for covariates, including age, gender and smoking status Table . TherefoCXCR1 gene was investigated regarding the CP. Single nucleotide polymorphisms are mainly useful in studies of human population genetics and candidate-gene studies for disease association [To our knowledge, this is the first time that the rs2234671 SNP in the ociation . This maociation . If the ociation .Another important point to be considered in studying genetic variations is about the functionality of a polymorphism. Considering that the rs2234671 SNP causes a conservative amino acid substitution (S276T) in the third extracellular loop of the CXCR-1 protein, one can suppose whether this event would influence the ligand/binding interaction of the chemokine receptor. This speculation was raised by Liu and colleagues , which fRelevant factors known to influence the pathogenesis of periodontitis were assessed by multivariate analysis. Regarding age, there is evidence that both the prevalence and severity of periodontitis increase with increasing age . This caWe did not take into account ancestry in our study because we only obtained the skin color information. Although Brazilian population is admixtured, the skin color is not related with ancestry according to Pena et al., Parra eCXCR1 gene would be associated with susceptibility to chronic periodontitis, the obtained results showing a lack of association permit us to conclude that this SNP was not useful as a genetic risk factor for CP in the studied Brazilian population.In regards to our hypothesis whether the rs2234671 SNP in the IL-8: Interleukin 8; SNP: Single Nucleotide Polymorphism; CP: Chronic Periodontitis; PPD: Probing Pocket Depth; CAL: Clinical Attachment Loss; BOP: Bleeding on Probing.The authors declare that they have no competing interests.RMSC conceived and coordinated the study, performed statistical analysis and wrote the manuscript. KMCC, RR, PMS: carried out the molecular reactions and helped analyze the results. GA: helped with the statistical analysis and helped wrote the manuscript. ACV, YJK: examined and selected the patients and extracted the DNA. SRPO, JAC: participated in the study design, defined the clinical criteria of the studied groups and helped wrote the manuscript. All authors read and approved the final manuscript.This study was supported by CAPES and FAPESP grants .


CHRNA3 gene: rs1051730 and AGPHD1 gene: rs8034191) on 15q25.1.The association between polymorphisms on 15q25.1 and lung cancer has been widely evaluated; however, the studies have yielded contradictory results. We sought to investigate this inconsistency by performing a comprehensive meta-analysis on two polymorphisms . For rs1051730-G/A, carriers of A allele had a 36% increased risk for lung cancer , without heterogeneity (P = 0.258) or publication bias (EggerP = 0.462). For rs8034191-T/C, the allelic contrast indicated that C allele conferred a 23% increased risk for lung cancer , with significant heterogeneity (P<0.0005), without publication bias (EggerP = 0.682). Subgroup analyses suggested that the between-study heterogeneity was derived from ethnicity, study design, matched information, and lung cancer subtypes. For example, the association of polymorphisms rs1051730 and rs8034191 with lung cancer was heterogeneous between Caucasians  and East Asians  under the allelic model, and this association was relatively strengthened under the dominant model. There was no observable publication bias for both polymorphisms.The two polymorphisms followed Hardy-Weinberg equilibrium for all studies (CHRNA3 gene rs1051730-A allele and AGPHD1 gene rs8034191-T allele might be risk-conferring factors for the development of lung cancer in Caucasians, but not in East-Asians.Our findings demonstrated that  Lung cancer is the most common malignancy and the first-leading cause of cancer mortality, with an estimated 1.3 million new cases diagnosed annually in the world CHRNA3 gene and rs8034191 in the AGPHD1 gene and lung cancer risk or related phenotypes has been widely investigated. As stated by McClellan and King, many if not most of the genetic polymorphisms that are reported to be associated with common disorders in GWA studies are factually spurious associations caused by subtle differences in ancestry between the populations being studied (known as “cryptic population stratification”) The chromosome 15q25.1 region has been identified as a hotspot for lung cancer susceptibility by recent genome-wide association (GWA) studies We performed this analysis in accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement We searched the PubMed and EMBASE databases for articles published before January 2012, using the Boolean combinations of subject terms (CHRNA3 OR AGPHD1 OR LOC123688) AND (lung cancer OR carcinoma OR neoplasm) AND . Articles were restricted to English-language and human studies. The full text of the retrieved articles was scrutinized to decide whether information on the topic of interest was included. Reference lists of these retrieved articles and systematic reviews were also checked for citations of articles not initially identified. For articles involving more than one geographic or ethnic heterogeneous group, each group was treated separately. When genotype frequency was not reported, we contacted the authors to obtain the relevant information.CHRNA3 gene rs1051730 polymorphism and/or AGPHD1 gene rs8034191 polymorphism were associated with lung cancer risk; 2) followed a nested case-control or case-control or cross-sectional study design; and 3) provided sufficient information on genotype/allele counts between cases and controls to estimate the odds ratio (OR) and the corresponding 95% confidence interval (95% CI). The relatively complete and recent results were extracted when there were multiple articles involving the same population.Articles were included in this meta-analysis if they 1) examined the hypothesis that The following information was extracted independently and entered into separate databases by two authors (MG and WN) from each qualified study: first author's last name, publication date, population ethnicity, study design, baseline characteristics of the study population including age, ethnicity, sex, smoking status, and the genotype counts in cases and controls. Any encountered discrepancy was adjudicated by a discussion until a consensus was reached.The study quality was assessed by using a quality assessment score developed for genetic association studies by Thakkinstian et al 2 or Fisher's exact test in control groups. Irrespective of between-study heterogeneity, a random-effects model using the DerSimonian and Laird method was implemented to bring the individual effect-size estimates together, and the estimate of heterogeneity was taken from the Mantel-Haenszel model Data management and statistical analyses were conducted using STATA software . Deviation from Hardy-Weinberg equilibrium was tested by χI2 statistic (ranging from 0 to 100%), which was documented for the percentage of the observed between-study variability due to heterogeneity rather than by chance, with higher values suggesting the existence of heterogeneity Between-study heterogeneity was assessed by the inconsistency index Cumulative meta-analysis was conducted to identify the influence of the first published study on the subsequent publications, and the evolution of the combined estimates over time according to the ascending date of publication. To identify potentially influential studies, we performed influential analysis  by removing an individual study each time to check whether any of these estimates biased the overall estimate.I2 and Egger's statistic, for which a significance level was defined as <0.1.The funnel plot and Egger's test were applied to assess publication bias CHRNA3 gene rs1051730 and/or AGPHD1 gene rs8034191 polymorphisms with lung cancer risk Based on our search strategy, the primary screening produced 40 potentially relevant articles, of which 12 met the inclusion criteria in an attempt to evaluate the association of P>0.05). Ten of 16 qualified studies were matched on age or sex or smoking status between cases and controls CHRNA3 gene rs1051730-A allele ranged widely between Caucasians and East Asians with African-Americans in between. For example in control groups, the rs1051730-A allele ranged from 29.45% to 37.14% in Caucasians, from 1.39% to 3.3% in East Asians, and from 16.15% to 19.85% in African-Americans. The observation was similar for AGPHD1 gene rs8034191-C allele, with frequencies ranging from 23.04% to 39.47% in Caucasian controls, from 1.82% to 3.72% in East Asian controls, and from 16.15% to 31.44 in African-American controls.The baseline characteristics of all qualified studies are summarized in Due to the sparseness of the mutant alleles of both studied polymorphisms in East Asians and to maximize the statistical power to detect an association, we considered the risk effect of two polymorphisms under both allelic and dominant models.CHRNA3 gene rs1051730-A allele yielded a remarkably increased risk for lung cancer  relative to the rs1051730-G allele; however, there was moderate evidence of between-study heterogeneity . The risk magnitude was slightly potentiated under the dominant model , but heterogeneity was absent   with heterogeneity . The risk magnitude was slightly weakened under the dominant model   . Likewis<0.0005) .P = 0.742 and 0.682 for rs1051730 and rs8034191, respectively). Further evidence of selective publication suggested that there were no missing studies required to make the funnel plot symmetrical for both polymorphisms .In view of significant heterogeneity and to seek for its potential sources, we performed a panel of subgroup analyses on ethnicity, matched information, study design, and disease type.CHRNA3 gene rs1051730 polymorphism    , and AGP= 0.043) . In cont= 0.043)  and 3, aP = 0.012; and rs8034191: OR = 1.31, 95% CI: 0.96–1.79, P = 0.092), whereas under dominant model, this association was potentiated in population-based studies . Restricting analysis to the non-small-cell lung cancer observed no evidence of heterogeneity, and found that the risk magnitude was significant but relatively weakened under allelic model , whereas this magnitude was significantly strengthened under dominant model .In subgroup analysis by study design, association of both studied polymorphisms with lung cancer was potentiated in hospital-based studies under allelic model  and AGPHD1 gene rs8034191  polymorphisms with lung cancer risk was observed in cases with a high smoking rate under the allelic model , sex , and smoking rate (percentage of current and former smokers). Among these variables, the association of ic model .CHRNA3 gene rs1051730-A allele and AGPHD1 gene rs8034191-T allele might be risk-conferring factors for the development of lung cancer in Caucasians, but not in East-Asians. Although potential sources of heterogeneity could not be easily eliminated, the present study, to our knowledge, is the first meta-analysis to date dealing with the association of these two polymorphisms with lung cancer susceptibility.Via a comprehensive meta-analysis, we evaluated the association of two common polymorphisms on 15q25.1 with the risk of lung cancer. Overall results demonstrated that CHRNA3 gene rs1051730-A allele and AGPHD1 gene rs8034191-C allele between Caucasians and East Asians, making it very difficult to detect the weak association in Asians unless examining a very large population. This suggests that different genetic backgrounds may cause this discrepancy or that different populations may have different linkage disequilibrium patterns. The studied polymorphisms may be in linkage with another causal variant in one ethnic population but not in another CHRNA5 gene We identified ethnicity as a potential source of between-study heterogeneity by subgroup analysis. Genetic heterogeneity is inevitable in disease identification strategy Besides the disturbing influence of ethnicity on overall estimate, any estimate should be treated with caution when studies were stratified by study design. In this meta-analysis, for both polymorphisms, the risk estimates in hospital-based studies were stronger than that in population-based studies. Besides the relatively small sample size, drawbacks of hospital-based studies should not be disregarded, as population stratification remains an important issue CHRNA3 gene were associated with an increased risk of smoking initiation, indicating a potential genotype-phenotype interaction Furthermore, our meta-regression analysis found an association of two studied polymorphisms with lung cancer risk in patients with a higher smoking rate. We defined smoking rate based on the percentage of current and former smokers if available. This definition is unlikely to undermine our observation since the exclusion of ever-smoking might lead to an underestimation of the risk for lung cancer. Moreover, our data on smoking and other confounders were extracted from recent publications (after the year 2008) from professional cancer journals as reflected by the high quality score. Additionally, smoking is by far the major contributor to lung cancer, accounting for about 90% of the lung cancer incidence The strengths of this study include the relatively large sample size, no deviation from Hardy-Weinberg equilibrium, and the high quality of the qualified studies. However, our current study should be interpreted with several technical limitations in mind. Firstly, most of the studies in this meta-analysis were case-control studies, which are susceptible to selection bias by including only nonfatal cases. Secondly, because only published studies in English were retrieved and the “grey” literature (articles in languages other than English) was not included, publication bias might be possible, even though our funnel plots and statistical tests did not show it. However, asymmetry in the funnel plot, being either visually interpreted or statistically tested, may result from an essential difference between the small and larger studies that arises from inherent between-study heterogeneity CHRNA3 gene rs1051730-A allele and AGPHD1 gene rs8034191-T allele might be risk-conferring factors for the development of lung cancer in Caucasians, but not in East-Asians. We have strengthened the previous findings on the association of high smoking rate with increased lung cancer risk. Further studies should investigate the markers on and adjacent to 15q25.1 to clarify whether the present association is causal or due to linkage disequilibrium.Taken together, we have expanded previously individual studies by providing the convincing evidence that Table S1CHRNA3 gene rs1051730 polymorphism and AGPHD1 gene rs8034191 polymorphism with lung cancer.Criteria for quality assessment of genetic association of (DOC)Click here for additional data file.Flowchart S1PRISMA flowchart.(PDF)Click here for additional data file.Checklist S1PRISMA checklist.(DOC)Click here for additional data file.


Homocysteine is a risk factor for atherosclerosis, and the level of homocysteine in plasma is known to be strongly influenced by genetic factors—not only rare variants, but also common polymorphisms. This report describes a comprehensive postgenomic strategy for elucidating useful genetic information about homocysteine metabolism. The standard method for gathering such information is the candidate gene approach, which is an effective method based on known biological information. After collecting evidence from independent research projects, a critical epidemiological review permits a determination as to whether a putative association is true or not. A genome-wide association study (GWAS), which requires no biological information, can identify new candidates and confirm associations suggested by the candidate gene approach. The importance of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, which was shown in a randomized controlled trial conducted by the present author, and in other studies, was independently confirmed by a large-scale GWAS. GWASs have also identified new candidate genes, but these must be confirmed by independent studies. In homocysteine metabolism, the classical candidate gene approach was sufficiently robust to detect the true association. However, candidate markers newly discovered by GWAS need to be confirmed by well-designed epidemiological studies to determine their significance. International statements, such as CONSORT and STREGA, provide useful principles for conducting such research. McCully firstly reported the vascular pathology of severe inherited homocysteinemia, in 1969.2 Since then, hyperhomocysteinemia has been extensively studied, and elevated plasma total homocysteine (tHcy) level has been identified as a risk factor for atherosclerotic vascular diseases in many persuasive systematic reviews.3–5Several novel risk factors for atherosclerosis have been proposed by Ridker et al6,7An important determinant of plasma homocysteine concentration is dietary intake of folate, which enhances the importance of homocysteine as a biomarker because the level of homocysteine can be lowered by eating more green vegetables and by folic acid supplementation.Investigations at the genetic level have also progressed, and have identified not only rare mutations that cause severe inherited homocysteinemia, but also common polymorphisms that result in moderate elevation of homocysteine level.This short report presents a comprehensive strategy to elucidate the useful genetic information in the postgenomic era, using the example of homocysteine metabolism.A candidate gene approach, based on known biological information, is an established and effective method of genetic research. It is natural to focus on the gene involved in the biological mechanisms of the target phenotype. For example, in the metabolic pathway of homocysteine, there are 3 key enzymes: methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MS), and cystathionine beta-synthase (CBS) Figure .8 This TT genotype was known to cause mild hyperhomocysteinemia more frequently than the major allele homozygote, and its allele frequency approaches 30% in many ethnic groups.9MTHFR is a key enzyme in the metabolic pathway of homocysteine. Single nucleotide polymorphisms (SNPs) have been identified in the genes of related enzymes. The present author investigated these candidate SNPs and focused on a common C to T substitution at position 677 of the MTHFR gene (MTHFR C677T polymorphism), which results in an alanine to valine amino acid substitution in the protein and leads to a 30% decrease in enzyme activity in heterozygotes and a 60% decrease in homozygotes.10 the present author investigated the MTHFR C677T polymorphism, which is common and functional8,9; 210 healthy males were enrolled in the study. After excluding those who were taking folic acid or drugs known to effect folic acid metabolism, 203 healthy males remained. The mean age and body mass index (BMI) were 45.8 ± 11.5 years and 23.7 ± 3.66 kg/m2 (mean ± SD), respectively, which are typical values for healthy Japanese male workers. Genotyping for the MTHFR C677T polymorphism was performed by using a polymerase chain reaction (PCR) technique and restriction fragment length polymorphism (RFLP) analysis. The intervention in this randomized controlled trial (RCT) consisted of oral folic acid 1 mg/day, or an identical-looking placebo, for 3 months, because reduction in total homocysteine is known to be maximal at a folic acid dosage of 1 mg/day (one study reported that a minimum of 0.8 mg/day was necessary to achieve maximum reduction in tHcy level).6In a previous study,11,12 Among the participants receiving folic acid, there was a significant difference in the decrease in plasma tHcy between MTHFR C677T genotypes.10 The TT homozygote group showed the largest decrease in plasma tHcy at both 1 month and 3 months after starting the intervention. Based on consistent results observed twice during the course of the intervention, the effect size of the tHcy reduction in TT homozygotes was estimated to be 2.4 times that of the wild type. There were significant linear trends between the allele number and the decrease in plasma tHcy at 1 month and 3 months (P < 0.01 for both). The results of these trend tests remained statistically significant after adjustment for age, BMI, smoking status, and alcohol consumption at 1 month and 3 months (P < 0.01 for both). Thus, in an RCT prepared in accordance with the Consolidated Standards of Reporting Trials (CONSORT) statement,13 MTHFR C677T genotype was shown to influence the plasma level of homocysteine and the response to folic acid intake.The genotyping results were in Hardy-Weinberg equilibrium and were consistent with results previously reported for another Japanese population.P < 0.01).14 The haplotype information obtained was not more informative than that obtained by grouping according to the single SNP C677T, which strongly influences enzyme activity. This indicates that, from the perspective of informatics, increasing the number of typed SNPs does not necessarily provide more information.Our previous study showed that the MTHFR C677T minor allele homozygote was associated with a 2.4-fold beneficial decrease in plasma homocysteine level, as compared with the other genotypes. Next, we performed additional genotyping over the whole sequences of this gene. Of 52 SNPs on the MTHFR gene, 4 SNP loci encompassing more than 80% of the relevant information were selected, and haplotypes were estimated. The haplotypes were classified into 3 groups  on the basis of the number of times the most frequent haplotype was present. The decrease was greater in Hap2 (6.61 µmol/L) than in the other haplotypes  of homocysteine was published,From a methodological standpoint, GWASs are ideal, because they employ a purely statistical approach that requires no biological information. Rapid advances in genotyping technology have made it possible to use a large number of genetic markers in a straightforward way. GWASs have become increasingly used in the United Kingdom and the United States. This method involves identifying genetic variations associated with a particular disease by screening markers across the complete genomes of many individuals. Confirmation of the findings, using a different method, enhances the accuracy of the results.15 Figure P value. The most significant variant was in the MTHFR gene, on chromosome 1. This variant reached genome-wide significance with a Bonferroni-corrected threshold. This is the C677T polymorphism itself, the significance of which was shown in our RCT using the candidate gene approach.Since 2003, during which the first 3 GWASs were reported, the number of articles on genomic meta-analysis and the GWAS has been increasing  initiative was introduced to extend the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement, and provides additions to 12 of the 22 items on the STROBE checklist.16–22 The publication of these guidelines in major journals is important because I believe sound epidemiological design should be emphasized in genetic studies. As Thelle has pointed out, the STREGA checklist does not itself provide new ideas, but instead emphasizes the need for systematic and transparent reports using guidelines that, although well known to epidemiologists, may not be widely known among molecular biologists and geneticists.23 Using such guidelines, the quality of genetic association studies is likely to increase, and better reporting of such studies would facilitate the synthesis of evidence from different reports. This synthesis of knowledge is crucial if evidence-based genomics is to be integrated with the practice of medicine and public health. In this context, I believe that epidemiology is needed by genomics, even if not vice versa.Recently, the 24 They underscored the need for a broad-based ecological approach to human health and identified 8 specific content areas that are needed to address new challenges (the first two of these areas are informatics and genomics). Although human genome studies are still in the development stage, I would like to contribute to public health by encouraging epidemiological studies that highlight new techniques in genomics and informatics.The US Institute of Medicine released a report regarding the future of public health.


Evidence is accumulating that chronic inflammation may have an important role in prostate cancer (PCa). The COX-2 polymorphism rs2745557 (+202 C/T) has been extensively investigated as a potential risk factor for PCa, but the results have thus far been inconclusive. This meta-analysis was performed to derive a more precise estimation of the association.A comprehensive search was conducted to identify all case-control studies of COX-2 rs2745557 polymorphism and PCa risk. We used odds ratios (ORs) to assess the strength of the association, and 95% confidence intervals (CIs) give a sense of the precision of the estimate. Statistical analyses were performed by Review Manage, version 5.0 and Stata 10.0.A total of 8 available studies were considered in the present meta-analysis, with 11356 patients and 11641 controls for rs2745557. When all groups were pooled, there was no evidence that rs2745557 had significant association with PCa under co-dominant, recessive, over-dominant, and allelic models. However, our analysis suggested that rs2745557 was associated with a lower PCa risk under dominant model in overall population . When stratifying for race, there was a significant association between rs2745557 polymorphism and lower PCa risk in dominant model comparison in the subgroup of Caucasians , but not in co-dominant, recessive, over-dominant and allelic comparisons.Based on our meta-analysis, COX-2 rs2745557 was associated with a lower PCa risk under dominant model in Caucasians. PCa is one of the most frequently diagnosed malignancies and a common cause of cancer mortality in men in the Western hemisphere ,2. IdentCOX, also known as prostaglandin-endoperoxide synthase (PTGS), catalyzes the rate-limiting step in the formation of inflammatory prostaglandins. COX is an integral membrane bifunctional enzyme, which metabolizes arachidonic acids to many biologically active eicosanoids. COX-2 gene located on chromosome 1q25.2-q25.3 is a candidate gene for PCa susceptibility . COX-2 iSeveral polymorphisms in the COX-2 gene have been described, such as rs5277, rs689466, rs2206593, rs689470, and rs2745557. rs2745557 polymorphism in intron 1 has been brought to our attention. The functional impact of rs2745557, an intronic variant, on COX-2 activity is not yet known. Several studies were conducted to investigate the associations of COX-2 rs2745557 with PCa susceptibility -24. HoweWe searched the articles using the terms "COX-2" or "PTGS2", "prostate", "carcinoma" or "cancer" or "tumor", and "polymorphism" or "variation" in PubMed, Cochrane Library and Embase electronic databases, and all eligible studies were published before November 15, 2011. We evaluated all associated publications to retrieve the most eligible literatures. The reference lists of reviews and retrieved articles were hand searched at the same time. We did not include abstracts or unpublished reports. When overlapping data of the same patient population were included in more than one publication, only the most recent or complete study was used in this meta-analysis. Articles were limited to English language papers.The following inclusion criteria were used to select literatures for the meta-analysis: (1) information on the evaluation of COX-2 rs2745557 polymorphism and PCa susceptibility; (2) case-control studies; and (3) sufficient genotype data were presented to calculate the OR with 95% CI. Major reasons for exclusion of studies were: (1) no controls; (2) reviews and duplication of the previous publication; and (3) no usable data reported.All data were extracted independently by two investigators according to the prespecified selection criteria. Disagreement was resolved by discussion. The following data were extracted: the name of the first author, publication year, ethnicity of the population, available genotype, number of prostate cancer cases and controls studied and results of studies. Different descents were categorized as Caucasian, Asian, and African American. For case-control studies, data were extracted separately for each group whenever possible.2-test test were both performed to evaluate the between-study heterogeneity of the studies. In our study, two models of meta-analysis were applied for dichotomous outcomes: the fixed-effects model and the random-effects model. The fixed-effects model assumes that studies are sampled from populations with the same effect size, making an adjustment to the study weights according to the in-study variance. The random-effects model assumes that studies are taken from populations with varying effect sizes, calculating the study weights both from in-study and between-study variances, considering the extent of variation, or heterogeneity. A P-value ≥0.10 for the Q-test indicated lack of heterogeneity among the studies, and so the summary OR estimate of each study was calculated by the fixed-effects model [2 statistic can be used to quantify heterogeneity irrespective of the number of studies.The strength of the association between COX-2 rs2745557 polymorphism and PCa risk was measured by ORs, whereas a sense of the precision of the estimate was given by 95% CIs. The significance of the summary OR was determined with a Z-test. We first examined rs2745557 genotypes using co-dominant model , recessive (TT vs TC + CC), over-dominant (TC vs TT + CC) and dominant (TT + TC vs CC) genetic models. Then, the relationship between the allele and susceptibility to PCa was examined . Stratified analyses were also performed by ethnicities. A chi-square-based Q-statistic test and an Its model . Otherwits model . I2 statThe significance of the pooled OR was determined by the Z-test and P < 0.05 was considered as statistically significant. To explore the reasons of heterogeneity, subgroup analyses were performed by ethnicity. The one-way 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. To investigate whether publication bias might affect the validity of the estimates, funnel plot were constructed. An asymmetric plot suggests a possible publication bias. Funnel plot asymmetry was assessed by the method of Egger's linear regression test, a linear regression approach to measure funnel plot asymmetry on the natural logarithm scale of OR. The significance of the intercept was determined by the t-test suggested by Egger . All statistical tests were performed with Review Manage, version 5.0 and Stata 10.0 using two-sided P-values.According to the inclusion criteria defined above, we identified 8 independent studies in 7 eligible reports -24, inclIn overall population, there was significant heterogeneity in COX-2 rs2745557 for dominant model comparison, heterogeneous co-dominant model, over-dominant model and allelic model comparison, except for the homogeneous co-dominant model and recessive model comparisons. After subgroup analyses by ethnicity, the heterogeneity was effectively removed under allelic model in Caucasians. The data suggested that rs2745557 was associated with a lower PCa risk under dominant model in overall population , confirming the stability of the results. Hence, results of the sensitivity analysis suggest that the data in this meta-analysis are relatively stable and credible.Begg's funnel plot and Egger's test were performed to assess the publication bias. The shape of funnel plots did not reveal any evidence of obvious asymmetry in all comparison models, and the Egger's test was used to provide statistical evidence of funnel plot symmetry. The results did not show any evidence of publication bias. The detailed data were present in Table We consider the COX-2 gene highly interesting in the search for susceptibility genes for PCa. Previous study results suggested that single nucleotide polymorphisms (SNPs) are the most common sources of human genetic variation, and they may contribute to an individual's susceptibility to cancer . In the In order to provide the comprehensive and reliable conclusion, we performed the present meta-analysis of 8 independent case-control studies -24, inclHeterogeneity is a potential problem when interpreting the results of the present meta-analysis. In overall analysis, significant between-study heterogeneity existed in dominant model, heterogeneous co-dominant model, over-dominant model and allelic model comparisons. After subgroup analyses by ethnicity, the heterogeneity was removed under allelic model in Caucasians. In this meta-analysis, high levels of heterogeneity were observed in some comparisons. There are some factors that could have contributed toward the high heterogeneity. First, there is likely to be considerable genetic heterogeneity between the samples that were drawn from geographically diverse populations. It is known that genotype distributions differ across populations, and genotype-phenotype associations may also depend on population stratification. Second, definition of control group is different in different studies, the definition differences of the controls could have contributed to the high heterogeneity observed in our meta-analysis. Third, we attempted to determine if the high heterogeneity might also be explained by other variables such as stages of PCa, smoking status, and environmental factors included in the different studies, but are unable to provide a reliable answer to this question because we did not have access to individual level data for these variables.Some limitations of this meta-analysis should be acknowledged. First, because only published and English articles were included in the meta-analysis, publication and potential English language biases may have occurred, even though it was not found by making use of statistical test. Second, the result should be cautiously interpreted because controls were not uniformly defined. Non-differential misclassification bias was possible because these studies may have included controls that had different risks for developing PCa. Third, only one study analyzed Asian population and another one African American population in this study. So it is quite important to have more studies and sample of Asians, Africans, and African Americans in the future so that more precise conclusion about the associations between rs2745557 polymorphism and PCa risk could be achieved. Fourth, our results were based on unadjusted estimates, while a more precise analysis should be conducted adjusted by other factors like smoking, drinking status and environmental factors. In addition, our analysis did not consider the possibility of gene-gene or SNP-SNP interactions or the possibility of linkage disequilibrium between polymorphisms. Further investigations of the haplotypic effect of a gene and the study of multiple polymorphisms in different genes are needed.In conclusion, our meta-analysis suggested that there was an association between rs2745557 polymorphism and lower PCa risk in Caucasians. Due to limitations showed above in this analysis, it is critical that larger and well-designed multicenter studies are needed to confirm our results.PCa: Prostate cancer; PTGS: Prostaglandin-endoperoxide synthase; OR: odds ratio; CI: Confidence interval; vs: Versus; R: Random effect model; F: Fixed effect model.The authors declare that they have no competing interests.ZH carried out the publication search, participated in data analysis and drafted the manuscript. XY carried out publication search, and revised the manuscript. ZZ and LR participated in the publication search and helped to draft the manuscript. MB participated performed the statistical analysis. All authors read and approved the final manuscript.


Previous studies have found that common genetic variants on chromosome 8q24 are associated with the risk of developing colorectal neoplasia. We conducted a hospital-based case-control study, including 435 cases and 788 unrelated controls to investigate the associations between common variants on 8q24 and the risk of colorectal cancer in a Chinese population. We also evaluated the association of rs6983267 with colorectal neoplasia in the published literature via a meta-analysis study. We found that rs6983267 was significantly associated with the risk of colorectal cancer in the Chinese population, with an adjusted odds-ratio (OR) for the GT heterozygotes and GG homozygotes of 1.30  and 1.66 , respectively, compared to the TT homozygotes, with a P-trend value of 0.003. No association was found for the other three loci . In the meta-analysis of the published genetic association studies, the rs6983267 variant was found to be associated with an increased risk of colorectal neoplasia. The heterozygous GT carriers showed a 20% increased risk of colorectal neoplasia  with a summary OR for homozygous GG carriers of 1.39  compared to the TT genotype carriers. We found no significant differences between the association of rs6983267 and colorectal cancer and colorectal adenomas. In summary, our study confirms that the variant rs6983267 is a risk factor for colorectal neoplasia in various populations, including the Chinese population. APC, MLH1, MSH2, TGFBR2 and SMAD4) have been identified Colorectal cancer (CRC) is the third most common cancer and the fourth most frequent cause of cancer death worldwide et al genotyped six variants in 1,124 individuals with invasive CRC and 4,573 controls that had been previously identified as having an underlying risk for prostate cancer due to alterations on 8q24 et al conducted a genome-wide association study of 550,000 tag SNPs in 930 familial colorectal cancer patients and 960 controls and found that rs6983267 had the strongest association with CRC risk e.g. rs6983267, rs10808556 and rs10505477) were associated with CRC risk. The variations in the other regions were found to be associated with prostate, breast and ovarian cancers Among these loci, variants on 8q24 have shown strong evidence of an association with the risk of CRC in different populations. Haiman The constantly improving standard of living in China has brought about extensive changes to the lifestyle and diet of the average Chinese citizen over the past three decades, and has led to a corresponding increase in the incidence and mortality of CRC in China Most of the participants in the study have been described previously A 5-mL peripheral venous blood sample was obtained from each subject after written informed consent was obtained. Each participant was personally interviewed by trained interviewers to complete a Semi-quantitative Food Frequency Questionnaire (SQFFQ), which collected demographic information and information about dietary, and smoking habits , alcohol use  and other lifestyle factors The study was approved by all of the ethics committees of the participating hospitals . All of the samples were collected with a written informed consent provided by the participants, and all protocols were approved by the human research ethics committees of the participating hospitals.2 = 0.95) according to the Hapmap database, and they were also found to be associated with an increased risk of prostate, breast and ovarian cancers in many population studies Genome-wide association studies and gene-based candidate studies have confirmed that chromosome 8q24 is a susceptibility region for CRC. It has also been shown that specific loci on 8q24 are associated with specific cancers Genomic DNA was extracted from 2.5-mL of whole blood with a Promega DNA Purification Wizard kit according to the manufacturer's instructions. The genotyping methods have been reported previously In order to explore the association between rs6983267 and the risk of colorectal neoplasia, a meta-analysis was conducted. We performed a comprehensive and systematic bibliographic search updated to February of 2011 based on the MEDLINE and PubMed databases. We used the terms “8q24” and “rs6983267” in combination with “colorectal neoplasia”, “colorectal cancer” or “colorectal adenoma” to search the database to identify the studies regarding the association between the rs6983267 polymorphism and the risk of colorectal cancer. References were also checked to identify any missing studies. The details of the studies were thoroughly examined in order to exclude potentially overlapping data. If the same participants were used in different papers, only the largest and most complete study was included here. The studies included were those that provided data about rs6983267 and the risk of colorectal cancer or colorectal adenomas and could be case-control, cohort or cross-sectional studies that were reported in English. The studies included should also provide sufficient data about the frequency of the genotypes. Individual authors were also contacted for further data when the criteria were not met. The flow chart that tracks the selection process for the studies and the reasons for exclusion is presented in etc), they were considered individually. Pooled allelic effects were estimated both under a fixed effects model and a random effects model, and the pooled OR with its 95% CIs was used as the summary measurement.For each study, the following information was recorded: first author, publication year, study design, study location, study population/ethnicity, total number and sources of cases and controls, sub-group and disease categories, total number of cases and controls, and the allele frequency in the study. When there were sub-group studies described in the paper  and Student's t-test (for continuous variables) were used to evaluate the differences in demographic characteristics and selected variables. Hardy-Weinberg Equilibrium (HWE) was assessed by the χ2 test (1 degree of freedom (d.f)). The common homozygote was used as the reference to calculate the genotype-specific odds ratio (OR) and its 95% confidence intervals (CI) with or without adjustment for age, sex, smoking status and alcohol use under the unconditional Logistic regression statistic model. The statistical powers of the study were calculated using the Power software under the assuming of two sided test with alpha level is 0.05 with the log-additive genetic model The prevalence of each of the alleles was measured in cases and controls. The χ2 statistic. Publication bias was graphically represented by funnel plotting and was assessed both by Egger's linear regression http://www.r-project.org/).For meta-analysis, the pooled OR and its 95% CI were calculated using the standard inverse variance weighting method for the fixed effects model and the DerSimonian-Laird method for the random-effects model. Heterogeneity between studies was assessed using the Cochrane Q-test in combination with the IThe characteristics of cases and controls are given in Statistically significant associations were obtained only for the previously reported SNP rs6983267 . Compare2 = 0%), and no evidence of a significant publication bias was found . For the GG homozygotes, we noted that there was a significant increase in colorectal neoplasia, with the SOR of 1.40 (95% CI = 1.33–1.46) under the fixed effects model and 1.39 (95% CI  = 1.32–1.48) under the random effects model compared to the TT carriers (2 = 33.2%). However, there still no significant publication bias . Sensitivity analyses were also performed by removing the individual studies sequentially, and we found that none individual studies dramatically affected the overall polled ORs.For the meta-analysis regarding the association between colorectal cancer risk and the variant rs6983267, we identified twenty-three reports regarding the association between rs6983267 and colorectal neoplasia. After detailed evaluation, sixteen studies including a total of 36,761 cases and 38,901 controls were used for the meta-analysis  [5], [11carriers . HoweverTo determine whether the association between variant rs6983267 and colorectal neoplasia could differ for colorectal adenomas and colorectal cancer, we examined the association between the variant and colorectal cancer and the variant and colorectal adenomas. Among the fourteen identified reports, two examined the association between the variant and colorectal adenomas, with a total of 4,197 cases and 5,109 controls et al that there are five different haplotype blocks within this region. The rs6983267 locus and its highly correlated locus, rs10505477 (r2 = 0.95 in CHB population for Hapmap database), which are located between a 128.47 and 128.54 Mb region, have been found to be associated with prostate, colorectal and ovarian cancers Variants on 8q24 (position 128.14 Mb to 128.62 Mb) were found to be associated with various types of cancer. It was reported by Ghoussaini In the meta-analysis of rs6983267 and colorectal neoplasia, sixteen eligible papers that examined the risk of colorectal carcinoma, including two that also reported the association between the locus and colorectal adenomas risk were examined. We found that the GT heterozygotes had a 20%  and the GG homozygotes showed a 39%  increased risk of colorectal neoplasia. The SORs determined for colorectal neoplasia were similar in magnitude to those observed for colorectal cancer and colorectal adenomas . These fAlthough the variant rs6983267 had been found to be associated with an increased susceptibility to colorectal neoplasia, whether the rs6983267 SNP is the causal locus is still uncertain. Several recently published studies have shown that rs6983267 is located within a transcriptional enhancer region and affects a binding site for TCF4 , a transcription factor which is activated in most CRCs. TCF4 interacts with β-catenin to activate the transcription of Wnt target genes, which are part of a key pathway involved in CRC initiation There are several potential limitations to the current study. First, for a hospital-based case-control study, subjects were recruited based on their outcome (with CRC or without CRC) rather than their exposure. The potential CRC risks for the controls are immeasurable, and may have caused a cause bias in studying the etiology of the disease. It could also have led to spurious results in the gene/environmental interaction studies. Second, the sample size was relatively small. We cannot exclude the possibility there is an association between rs16901979, rs1447295 and rs7837688 and colorectal cancer in the Chinese population due to the inadequate statistical power of our study , although many other studies have also reported no significant association for these loci with CRC in other populations In summary, we observed a statistically significant association between SNP rs6983267 on 8q24 and the risk of colorectal cancer in a Chinese population. Moreover, a meta-analysis of previous studies conducted in different populations confirmed the association between this locus and colorectal neoplasia risk in different populations and ethnic groups. These results provide a more complete picture of the role of this polymorphism in the risk of colorectal neoplasia, and may give genetic insight into possible strategies for prevention of colorectal neoplasia.


Ethnicity was identified as a potential source of between-study heterogeneity. In conclusion, this meta-analysis demonstrated that common variations are a risk factor associated with increased BC susceptibility, but these associations vary in different ethnic populations.Several genome-wide association studies on breast cancer (BC) have reported similar findings of a new susceptibility locus, 5p12. After that, a number of studies reported that the rs10941679, rs4415084, and rs981782 polymorphism in chromosome 5p12 has been implicated in BC risk. However, the studies have yielded contradictory results. To derive a more precise estimation of the relationship, a meta-analysis of 131,983 BC cases and 200,314 controls from 24 published case–control studies was performed. Overall, significantly elevated BC risk was associated with rs10941679, rs4415084, and rs981782 risk allele when all studies were pooled into the meta-analysis. In the subgroup analysis by ethnicity, significantly increased risks were found for the rs10941679 and rs4415084 polymorphism among Caucasians and East Asians, while no significant associations were observed for the two polymorphisms in African and other ethnic populations. For 5p12-rs981782, significant associations were only detected among Caucasians. In addition, we found that rs10941679 and rs4415084 on 5p12 confer risk, exclusively for estrogen receptor (ER)-positive tumors with per-allele OR of 1.16 (95% CI: 1.11–1.21; P<10 BRCA1, BRCA2, PTEN and TP53) have been identified to be associated with familiar breast cancer Breast cancer (BC) is one of the most common malignancies among women worldwide FGFR2 (rs2981582) at 10q26.13 and near the 5′ end of the TOX3 gene at 16q12.1 (rs3803662) Recently, spectacular advance was made in identifying susceptible genes involved in breast cancer through genome-wide association strategy (GWAS) Genetic association studies published before the end of March 2013 on breast cancer and polymorphisms in the chromosome 5p12 were sought by computer-based searches from databases including MEDLINE, PubMed, EMBASE, ISI web of science and CNKI  without language restriction. Search term combinations were keywords relating to the chromosome 5p12  in combination with words related to breast cancer . We replaced one term each time until all possible combination mode were searched to avoid any missing literature. The titles and abstracts of potential articles were screened to determine their relevance, and any clearly irrelevant studies were excluded. The full texts of the remaining articles were read to determine whether they contained information on the topic of interest. Furthermore, reference lists of primary studies and review articles were also reviewed by a manual search to identify additional relevant publications.The included studies have to meet the following criteria: (1) original papers containing independent data, (2) identification of breast cancer patients was confirmed histologically or pathologically, (3) genotype distribution information or odds ratio (OR) with its 95% confidence interval (CI) and P-value, (4) case–control or cohort studies. The major reasons for exclusion of studies were (1) overlapping data, (2) case-only studies, (3) family based studies, and review articles.Data extraction was performed independently by two reviewers and differences were resolved by further discussion among all authors. For each included study, the following information was extracted from each report according to a fixed protocol: first author, publication year, definition and numbers of cases and controls, frequency of genotypes, age, cigarette smoking, alcohol drinking, ethnicity, Hardy–Weinberg equilibrium (HWE) status, source of control, estrogen receptor (ER) status, progesterone receptor (PR) status and genotyping method. Studies with different ethnic groups were considered as individual studies for our analyses.2 based Q test followed by subsidiary analysis or by random-effects regression models with restricted maximum likelihood estimation Deviation from HWE for controls was examined by χ2 tests. OR with 95% CIs was used to assess the strength of association between the 5p12 polymorphisms and breast cancer risk. The per-allele OR of the risk allele was estimated. Then we estimated the risks of the heterozygous and homozygote genotypes on breast cancer, compared with the wild-type homozygote. Random-effects and fixed-effect summary measures were calculated as inverse-variance-weighted average of the log odds ratio. The results of random-effects summary were reported in the text because it takes into account the variation between studies. Heterogeneity across individual studies was calculated using the Cochran χThe combined search yielded 109 references. −5; heterozygous: OR = 1.10, 95% CI: 1.06–1.15, P<10−5; homozygote: OR = 1.12, 95% CI: 1.05–1.20, P<10−5). Similar significant associations were also observed for East Asians with per-allele OR of 1.05 . However, no significant association was found for African and other ethnic populations in all genetic models  = 0.02] versus ER-negative tumors   <10 = 0.49] .Significant heterogeneity was present among the 33 data sets (P<0.05). In meta-regression analysis, sample size (P = 0.13), genotyping method (P = 0.37), mean age of cases (P = 0.25) and controls (P = 0.61), did not significantly explained such heterogeneity. By contrast, ethnicity (P = 0.001) was significantly correlated with the magnitude of the genetic effect.−5; Significant heterogeneity was present among the included studies of the rs4415084 polymorphism (P<0.05). Ethnicity (P = 0.007) and sample size (P = 0.03) explained a large part of the heterogeneity, whereas genotyping method (P = 0.58), mean age of cases (P = 0.18) and controls (P = 0.32) explained little heterogeneity. In the overall analysis, the rs4415084 polymorphism on chromosome 5p12 was significantly associated with elevated BC risk for Caucasians with a per-allele OR of 1.10  = 0.004] than ER- breast cancer   <10 = 0.65] .For Caucasian populations, the overall per-allele OR of the T variant for breast cancer was 1.05 . The shape of the funnel plots was symmetrical for these polymorphisms –S7. The The association between polymorphisms of 5p12 and breast cancer risk had been originally reported by Easton et al Genetic heterogeneity is inevitable in disease identification strategy Because ER status is one of the major markers of breast cancer subtypes, we further performed analyses to test for differences in the associations of these polymorphisms with breast cancer risk with respect to different ER status. The findings that 5p12-rs10941679 and 5p12-rs4415084 largely affect ER-positive disease are confirmed by our meta-analysis of all available data. The pooled OR estimate is consistent with little or no effect of the two SNPs on ER-negative disease. These findings provide further support for the notion that ER-negative and ER-positive tumors result from different etiologic pathways, rather than different stages of tumor evolution within a common carcinogenic pathway BRCA1 or BRCA2 is plausibly explained by a polygenic model in which a large number of “low-penetrance” variants act in combination to cause wide variation in risk in the population FGFR2XRCC1SLC4A7. These studies greatly contribute to the understanding of the genetic as well as the pathological basis of the development of breast cancers.Large sample and unbiased epidemiological studies of predisposition genes polymorphisms could provide insight into the in vivo relationship between candidate genes and complex diseases. Nevertheless, small sample sized association studies lack statistical power and have resulted in apparently contradicting results. The interpretation of these studies has been further complicated by the use of different ethnic populations and phenotypic heterogeneity. An alternative therefore is to pool data from a range of studies via meta-analysis, thus enhancing the statistical power of the analysis for the estimation of genetic effects. The familial excess in risk not accounted for by Several potential limitations of the present meta-analysis should be taken into consideration. Firstly, the subgroup meta-analyses dealing with interactions between the 5p12 polymorphisms and Africans or other ethnic populations are based on the small number of studies where such information is available. As studies among the African or other ethnic populations are currently limited, further studies including a wider spectrum of subjects should be carried to investigate the role of these variants in different populations. Secondly, our results were based on unadjusted estimates, while a more precise analysis should be conducted if all individual raw data were available, which would allow for the adjustment by other co-variants including age, cigarette consumption, alcohol drinking, menopausal status, and other lifestyle. Thirdly, the single locus–based nature of meta-analysis precluded the possibility of gene-gene and gene-environment interactions, as well as haplotype-based effects, suggesting that additional studies assessing these aspects are necessary.In summary, findings from this meta-analysis indicate that 5p12 rs10941679, rs4415084, and rs981782 polymorphism is significantly associated with an increased risk of breast cancer, particularly in Caucasian and East Asian populations. More work is needed to further investigate the association of these polymorphisms across different histological types or tumor staging of breast cancer. Besides, future studies are recommended to identify the possible gene-gene and gene-environmental interactions in this association.Figure S1Study selection process.(TIF)Click here for additional data file.Figure S2Forest plot from the meta-analysis of breast cancer risk and 5p12 rs10941679 polymorphism.(TIF)Click here for additional data file.Figure S3Forest plot from the meta-analysis of breast cancer risk and 5p12 rs4415084 polymorphism.(TIF)Click here for additional data file.Figure S4Forest plot from the meta-analysis of breast cancer risk and 5p12 rs981782 polymorphism.(TIF)Click here for additional data file.Figure S5Begg’s funnel plot for publication bias in studies on 5p12-rs10941679 polymorphism and breast cancer.(TIF)Click here for additional data file.Figure S6Begg’s funnel plot for publication bias in studies on 5p12-rs4415084 polymorphism and breast cancer.(TIF)Click here for additional data file.Figure S7Begg’s funnel plot for publication bias in studies on 5p12-rs981782 polymorphism and breast cancer.(TIF)Click here for additional data file.Checklist S1(DOC)Click here for additional data file.


The base excision repair (BER) pathway removes DNA damage caused by ionizing radiation, reactive oxidative species and methylating agents. ADPRT and APE1 are two important genes in the BER pathway. Several studies have evaluated the association between polymorphisms in the two BER genes  and breast cancer risk. However, the results are inconsistent.In this study, we conducted a meta-analysis to derive a more precise estimation. A total of 8 studies were included in the meta-analysis . For ADPRT Val762Ala polymorphism, no obvious associations were found for all genetic models . For APE1 Asp148Glu polymorphism, also no obvious associations were found for all genetic models . In the subgroup analysis by ethnicity or study design, still no obvious associations were found.This meta-analysis indicates that ADPRT Val762Ala and APE1 Asp148Glu polymorphisms are not associated with increased breast cancer risk. Breast cancer is currently the most common cancer and one of the main causes of cancer-related death in the world, which has become a major public health challenge The BER pathway consists of at least 11 DNA damage specific glycosylases and more than 20 further proteins Several original studies have investigated the association between ADPRT Val762Ala and APE1 Asp148Glu polymorphisms and risk of breast cancer, but the results remain inconsistent, partially due to insufficient power in each of published studies which have been based on relatively small sample sizes. To explore a more precise estimation of the association between the two polymorphisms and risk of breast cancer, a meta-analysis was performed.A literature search of Pubmed and Embase (updated to 2011/08/01) was conducted without a language limitation, using the following keywords and subject terms: “ADPRT or PARP1”, “APE1 or APEX1”, “polymorphism”, and “breast”. All searched studies were retrieved, and their bibliographies were checked for other relevant publications. Review articles and bibliographies of other relevant studies identified were hand-searched to find additional eligible studies. Only published studies with full text articles were included. When more than one of the same patient population was included in several publications, only the most recent or complete study was used in this meta-analysis. If necessary, we attempted to contact the corresponding authors of retrieved articles to acquire additional information.The following criteria were used for the study selection: (1) evaluation of the polymorphism and breast cancer risk; (2) study designed as case-control; and (3) sufficient published data for calculating odds ratios (OR) with their 95% confidence interval (95% CI).Information was carefully extracted from all eligible publications independently by two investigators according to the inclusion criteria listed above. For conflicting evaluation, an agreement was reached following discussion. For each study, the following characteristics were collected: first author's name, year of publication, ethnicity, study design (control source and matching), genotyping results of cases and controls. We did not define any minimum number of patients to include in our meta-analysis.2 test. If the P value is greater than 0.10 for the Q test which indicates a lack of heterogeneity among studies, the pooled OR estimate of the each study was calculated by the fixed-effects model (the Mantel–Haenszel method) 2<25%: no heterogeneity; 25%<I2<50%: moderate heterogeneity; 50%<I2<75%: high heterogeneity; I2>75%: extreme high heterogeneity). Subgroup analyses were performed by ethnicity and study design. Sensitivity analyses were also performed to identify the influence of the individual studies on the combined OR. Hardy-Weinberg equilibrium (HWE) was tested by the χ2 . The minor allele frequency (MAF) was also calculated for the controls. Publication bias was assessed by performing funnel plots qualitatively, and estimated by Egger's test  A statistical test for heterogeneity was performed based on the Q test and IA total of 22 articles were achieved by literature search from PubMed and EMBASE. As shown in As shown in The associations between APE1 Asp148Glu and breast cancer risk are also shown in Sensitivity analysis was carried out by deleting any single study each time. The pooled ORs were not significantly altered (data not shown), indicating that the results were robust.Funnel plots and Egger's test were performed to assess potential publication bias of the literatures. The shape of the funnel plots showed that the dots nearly symmetrically distributed, predominantly within pseudo 95% confidence limits  and EggeAn increasing number of articles on genetic association studies, genome-wide association studies (GWASs), and relate meta-analyses have been published to clarify the association between gene polymorphisms and breast cancer ADPRT plays an important part in DNA repair and cellular stress response. Its role in single-strand breaks through the BER pathway has been studied The APE1 Asp148Glu is the most extensively studied polymorphism in APE1. A study showed that APE1 Asp148Glu had no impact on endonuclease and DNA binding activities Some limitations might be included in the meta-analysis. First, although we collected all the eligible studies, the sample size of the included studies was not large enough, which could decrease the statistical power to better evaluate the association between the two gene polymorphisms and breast cancer susceptibility. Second, the overall outcomes were based on unadjusted estimates, while a more precise evaluation should be adjusted by other co-variants including age, body mass index, menopausal status, ethnicity, smoking status, alcohol consumption, and environment factors if individual data were available. Third, most of the included studies had conducted on Caucasians, and a few on Asians and Africans. Thus, more samples should be collected from Asians and Africans. Fourth, the genotyping method and the select criteria of controls in the studies were different. Finally, case-control studies with small sample size (<100 cases or 100 controls) might be reporting inflated ORs.In conclusion, this meta-analysis suggests that ADPRT Val762Ala and APE1 Asp148Glu polymorphisms may not contribute to breast cancer risk. Large-sample studies of different ethnic groups with carefully matched cases and controls are needed to clarify the role of the two gene polymorphisms in the BER pathway and breast cancer susceptibility in the future.Checklist S1(DOC)Click here for additional data file.