The pooled odds ratio (OR) and its corresponding confidence interval (CI) at 95% were assessed through the random- or fixed- effect model.A meta-analysis consisting of 12 individual studies, including a total of 6425 participants, was carried out in order to investigate the association of adiponectin −11377CG gene polymorphism and T2DM under allelic , recessive , dominant , additive , and homozygous genetic models . No significant association was found between them under the heterozygous genetic model .A significant relationship was observed between Adiponectin −11377CG gene polymorphism was significantly associated with T2DM risk susceptibility. G allele carriers are predisposed to T2DM risk. The epidemic of type 2 diabetes mellitus (T2DM) is considered a major public health problem in China, as it can lead to premature cardiovascular morbidity and death. T2DM is associated with a complicated interaction between genetic mutants and environmental factors. Adipose tissue, as an energy storage depot, is an active endocrine organ that secretes various proteins involved in the regulation of glucose, lipid metabolism, and energy homeostasis Adiponectin is a specific protein secreted by adipocytes; it participates in the regulation of glucose and lipid metabolism, amelioration of insulin resistance (IR), improvement of the insulin sensitivity, and has anti-inflammation and anti-atherosclerosis effects adiponectin gene, located in 3q27, spans 16 kb and contains 3 exons and 2 introns. The adiponectin rs266729 locus point, −11377CG mutation in the proximal promoter is cytosine (C), which is substituted by guanine (G).Adiponectin is encoded by one of the most abundant adipose gene transcripts (ADIPOQ), also referred to as the 30 kDa adipocyte complement-related protein (ACRP30) and 28 kDa gelatin binding protein (GBP28). Adiponectin comprises 244 amino acids. The adiponectin −11377CG gene polymorphisms contributed to T2DM in Swedish Caucasians adiponectin −11377CG gene polymorphisms and T2DM have been carried out domestically, the individual studies results were found to be controversial.Ye et al. (2008) observed that adiponectin −11377CG gene polymorphism was associated with the serum adiponectin level, which suggested that this locus polymorphism might increase the T2DM hereditary risk in the Shanxi Chinese population adiponectin −11377CG gene variant conferred a risk of T2DM in one Fujian Chinese population adiponectin −11377CG gene polymorphism and T2DM in a northern Chinese population Gu et al. reported that adiponectin −11377CG gene polymorphism and T2DM in the Chinese population  was conducted to determine whether there was a relationship between pulation .The words as “adiponectin,” “−11377,” “type 2 diabetes mellitus,” and “polymorphism” were used to search electronic databases, including PubMed, Embase, Web of Science, China National Knowledge Infrastructure, and China Biological Medicine Database. The last research was updated on January 26, 2013 with publication years ranging from 2007 to 2011.The selected studies had to be in accordance with the following major criteria. a) The adiponectin −11377CG gene polymorphism and T2DM must be evaluated. b) The T2DM diagnosis criteria were derived from the American Diabetes Association fasting plasma criteria (2005). The fasting plasma glucose level was ≥7.0 mmol/L, and the 2 h plasma glucose of oral glucose tolerance test was ≥11.1 mmol/L. In addition, there must be no genetic relationships among participants in the individual studies. c) The individual studies should be case-control or cohort studies published in the official journals or peer-reviewed postgraduate dissertations. d) The study should be in agreement with the Hardy-Weinberg equilibrium (HWE).The data were abstracted according to a standard protocol. Three investigators conducted the meta-analysis; two of whom sought out parallel studies, and the third investigator served as the arbitrator to resolve the disagreement between the other two investigators. Studies that did not follow the inclusion criteria, those considered double publications, or those that provided inadequate data were excluded. If the same data appeared in different studies, the data were used only once. The abstracted data comprised the following items: the first author's name, publication year, region, number of genotypes, genotyping, study design, matching criteria, and total number of cases and controls.adiponectin −11377CG gene polymorphism), recessive (GG vs. CC+CG), dominant (CG+GG vs. CC), homozygous (GG vs. CC), heterozygous (CG vs. CC), and additive (G vs. C). The odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were used to compare the association between adiponectin −11377CG gene polymorphism and T2DM. Chi-square-based Q-tests were used to calculate the heterogeneity between the individual studies with significance set at the P<0.05 level P<0.05 level.Six genetic models were used, including allelic , recessive , dominant , additive , and homozygous genetic models . No significant association was found between them under the heterozygous genetic model  (There was a significant relationship between = 0.140) –5.heterogeneity = 0.002, 2I = 62.2%) and the heterozygous  genetic models. Meta-regression was performed subsequently to explore the heterogeneity source.Significant heterogeneity was observed under the additive (PP = 0.002), CC genotype number of control group , and CG genotype number of the T2DM group . According to T1, the entire population was also divided into two subgroups. The studies with T1<205 were encompassed in subgroup 1 and other studies with T1>205 were categorized into subgroup 2. In the subgroup analysis, significantly increased T1DM risk was only observed in subgroup 2  and not in subgroup 1 . Heterogeneity was distinctly reduced, although it was still significant in both subgroups   .P = 0.004), study region (P = 0.026), CG1 (P = 0.003), total number of control group , and CC0 (P = 0.002). According to T0, the studies with T0<110 were included in subgroup 1 and other studies with T0>110 were categorized into subgroup 2. In the subgroup analysis stratified by T0, the association between adiponectin −11377CG gene polymorphism and T2DM was strengthened but not significant in subgroup 1  and in subgroup 2 . Meanwhile, heterogeneity was not weakened in both subgroups   . AlthougP = 0.338).Funnel plot and Egger's test were used to assess the publication bias of the individual studies. No visual publication bias was observed in the funnel plot . No signadiponectin −11377CG gene polymorphism and T2DM under the allelic (OR: 1.150), recessive (OR: 1.450), dominant (OR: 1.071), additive (OR: 1.280), and homozygous genetic models (OR: 1.620). No significant association was found between them under the heterozygous genetic model (OR: 1.640). Based on the current study indicating that adiponectin −11377 G allele might increase T2DM risk, it can be concluded that the G allele might confer T2DM susceptibility to the Chinese population.The current meta-analysis showed a significant relationship between heterogeneity<0.05), meta-regression was performed to seek the heterogeneity source. In the subsequent heterogeneity source analysis, under the additive genetic model, the heterogeneity was found to be large and T1 partly explained the heterogeneity. With regards the heterozygous genetic model, T0 was the main heterogeneity source (P<0.05). Moreover, T1 or T0 should be better matched in the individual studies to decrease the heterogeneity.Given that there was heterogeneity under the additive and heterozygous genetic models Click here for additional data file.Supplement S2PRISMA 2009 Flow Diagram.(DOC)Click here for additional data file.


XRCC1) is crucial to proper repair of DNA damage such as single-strand DNA breaks. A non-synonymous polymorphism in XRCC1, 399 G → A, has been shown to reduce effectiveness of such DNA repair and has been associated with the risk of certain cancers. The known risk for glioma from high dose ionizing radiation makes associations between this polymorphism and glioma of particular interest.The x-ray cross complementing group 1 gene  which was found to be disproportionately driven by a single study. Exclusion of this study, in an influence analysis, produced no statistically significant evidence of association with glioma , and no evidence of publication bias.XRCC1 399 G → A polymorphism in influencing risk of glioma among Caucasians. Future studies should report data separately for glioma subtypes to permit stratified analyses for Grade III and Grade IV glioma and examine other polymorphisms in this gene.This meta-analysis does not suggest a major role of the  TERT, CCDC26, CDKN2A-CDKN2B, RTEL1, PHLDB1, and EGFR. This was supplemented by a query of the HuGE Literature Finder based on a search of (glioma OR brain tumor) for gene XRCC1. Reference lists of identified studies were reviewed in order to identify additional relevant articles.A systematic literature search of the PubMed, EMBASE and Scopus databases was performed on October 25Included studies were required to meet all of the following conditions: 1) study employed a case–control design of human subjects; 2) outcome was microscopically-confirmed malignant glioma; and 3) data were presented on the genotype counts of cases and controls for the 399 G → A polymorphism in XRCC1. No language restriction was implemented, and corresponding authors were contacted in an attempt to obtain unreported genotype counts if studies were otherwise eligible. Genotype counts for cases and controls for the study by Liu et al.  were proThe following data were extracted from each eligible article: last name of first author, date of publication, country in which study was performed, ethnicity of subjects, genotype counts of cases and controls, genotyping method and quality control, glioma subtype (grade III and/or grade IV), and age and gender composition of subjects. There was no blinding to the names of authors, journals, institutions, or funding sources.P < 0.05 was considered significant). Assuming a fixed effects model, the inverse variance method was used to estimate separate genotype-specific summary odds ratios (OR) and 95% confidence intervals for the association between 399 G → A and risk of glioma. A fixed effects model was used due to the exhaustive nature of the literature review and a detailed exploration of possible sources of heterogeneity, as opposed to a random effects model which is not a solution for heterogeneity and assumes that identified studies are a subset of a larger pool of studies. Three pooled ORs were calculated: AA versus GG (OR1), AG versus GG (OR2), and AA versus AG (OR3). The resulting ORs were used to determine the most appropriate genetic model using a previously described approach [Deviation from Hardy-Weinberg equilibrium in control subjects was tested using a chi-squared goodness-of-fit test  If OR1 = OR2 ≠ 1 and OR3 = 1, a dominant model is suggestedb) If OR2 = 1/OR3 ≠ 1 and OR1 = 1, an over dominant model is suggestedc) If OR1 > OR2 > 1 and OR1 > OR3 > 1 (or OR1 < OR2 < 1 and OR1 < OR3 < 1), a co-dominant model is suggestedd) If ORI2 statistic [After determination of the most appropriate genetic model, heterogeneity across studies was assessed using the tatistic . To explThe initial database search yielded 25 articles, and four additional articles were retrieved from a search of the reference lists of the originally identified articles. Screening of the titles and abstracts of these 29 articles for study eligibility led to the initial exclusion of 18 articles which did not meet eligibility requirements, leaving 11 full articles for review ,25-34. OP < 0.001) and was consequently excluded from the meta-analysis. Thus, six studies [Of the seven studies retained for review, three were conducted in the United States ,27,32, t studies ,32,34 we1, OR2, and OR3 were 1.33 , 1.14 , and 1.16 , respectively. As these genotype-specific odds ratios are most suggestive of a dominant model, genotypes AG and AA were collapsed and the studies were meta-analyzed using a dominant model (AA + AG versus GG).For the association between variants in 399 G → A and glioma, genotype-specific odds ratios ORP = 0.006), with indication of high among-study heterogeneity (I2 = 87%). Data were available to explore potential sources of this heterogeneity through stratification by gender, glioma subtype (Grade III vs. Grade IV), study country (US vs. other), genotyping method (PCR-RFLP vs. other), and study size (n < 500 vs. n ≥ 500), and results of these analyses are presented in Table P < 0.001), but this stratification was only feasible for one study [P < 0.001), studies conducted outside of the US , and studies employing PCR-RFLP genotyping , it was clear that these associations were being driven by results of the study by Yosunkaya et al. [XRCC1 399 G → A polymorphism and glioma after removing this study from the meta-analysis , and there were no significant associations detected upon repeating previous subgroup analyses except for that among females as described above  with high corresponding among-study heterogeneity (I2 = 87%). However, an influence analysis conducted by sequentially removing each study and recalculating the association and heterogeneity demonstrated that the study by Yosunkaya et al. [P = 0.10) among Caucasians, reduced heterogeneity (I2 = 7%), and there were no notable associations in stratified analyses.Given the association of 399 G → A polymorphisms with other cancers  and the a et al. , the smageneity I = 87%. HWhile it is not possible to rule out the potential for bias in the identified studies, the five studies on which the final meta-analysis was based were deemed to be free of any major sources of bias which would compromise their validity. All studies were sufficiently clear in their description of recruitment methodology and participant characteristics, with the exception of reporting participant age in three studies ,27,30. AXRCC1 399 G → A polymorphism that may be pertinent to one subtype but not the other. Future investigators should report genotype counts for glioma subtypes separately to permit stratified analyses. Despite these potential limitations, the current literature suggests no statistically significant association between the XRCC1 399 G → A polymorphism and glioma.Although there was no indication of systematic bias among the final eligible studies as described above, this meta-analysis may have been limited by the small sample sizes of some of the included studies, as well as the lack of data for some planned subgroup analyses. In particular, despite research indicating that the genetic landscape of Grade III versus Grade IV gliomas may differ considerably , only twThe authors declare that they have no competing interests.Both authors conceived and designed the study, performed the statistical analysis and interpretation, drafted the manuscript, revised for important intellectual content, and read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2350/13/97/prepub


X-ray repair cross-complementing protein 3 (XRCC3) is an essential gene involved in the double-strand break repair pathway. Published evidence has shown controversial results about the relationship between XRCC3 Thr241Met polymorphism and clinical outcomes of non-small cell lung cancer (NSCLC) patients receiving platinum-based chemotherapy.A systematic review and meta-analysis was performed to evaluate the predictive value of XRCC3 Thr241Met polymorphism on clinical outcomes of advanced NSCLC receiving platinum-based chemotherapy. Response to chemotherapy, overall survival (OS) and progression-free survival (PFS) were analyzed.heterogeneity  = 0.618). The XRCC3 Thr241Met polymorphism was not associated with OS  or PFS . Additionally, no evidence of publication bias was observed.A number of 11 eligible studies were identified according to the inclusion criteria. Carriers of the variant XRCC3 241Met allele were significantly associated with good response to platinum-based chemotherapy (ThrMet/MetMet vs. ThrThr: OR  = 1.509, 95% CI: 1.099–2.072, PThis systematic review and meta-analysis shows that carriers of the XRCC3 241Met allele are associated with good response to platinum-based chemotherapy in advanced NSCLC, while the XRCC3 Thr241Met polymorphism is not associated with OS or PFS. Lung cancer is the major public health problem worldwide, which causes more than one million deaths each year Platinum agents are known to function through the formation of DNA adducts that inhibit DNA synthesis and transcription. Proposed mechanisms of resistance to platinum-based chemotherapy include inactivation of platinum compounds through the glutathione metabolic pathway and increased tolerance to DNA damage as a consequence of enhanced DNA repair capacity. Previous studies have demonstrated that single nucleotide polymorphisms (SNPs) influence DNA repair activity and removal of DNA adducts In this systematic review and meta-analysis, we comprehensively evaluated the correlation between XRCC3 Thr241Met polymorphism and clinical outcomes  of advanced NSCLC patients receiving platinum-based chemotherapy.Online databases of PubMed and EMBASE were searched to retrieve potentially relevant studies. A comprehensive search were conducted using combination of key words and medical subheadings of “X-ray repair cross complementing protein 3” or “XRCC3”, “single nucleotide polymorphism” or “SNP” or “polymorphism”, and “lung cancer” or “lung tumor” or “neoplasm, lung”. There was no limitation of research and the latest research was performed on April 2013. References of related studies and reviews were manually searched for additional studies.Records retrieved were primarily screened by titles and abstracts. Then, potentially relevant full-text articles were retrieved and further assessed for eligibility. Eligible studies were identified according to the following criteria: 1) patients with NSCLC and treated with platinum-based chemotherapy; 2) investigating the association between XRCC3 Thr241Met polymorphism and clinical outcomes, i.e. response, overall survival (OS) and progression free survival (PFS); 3) published studies with available full-text articles. All records were screened by two investigators independently (SXY and LFZ) with disagreement resolved by discussion.Data from eligible studies was collected independently by two investigators (SXY and LFZ) using a standard data collection form and they reached consensus on each item. The following data was extracted: first author, year of publication, the country where the study conducted, age, male, ethnicity, number of patients, TNM stage, chemotherapy regimens, genotype distribution among responders and non-responders, hazard ratios (HR) and corresponding 95% confidence intervals (CI) for OS and PFS. Ethnicity was simply classified as Asian, Caucasian and Mixed. Response to chemotherapy was assessed with RECIST criteria The association strength of XRCC3 Thr241Met polymorphism with response to platinum-based chemotherapy was estimated with odds ratio (OR) and 95% CIs in 4 comparison model: homozygote comparison (MetMet vs. ThrThr), heterozygote comparison [ThrMet vs. ThrThr], dominant model (ThrMet/MetMet vs. ThrThr) and recessive model (MetMet vs. ThrMet/ThrThr), assuming the dominant and recessive effect of the Met allele, respectively). For OS and PFS, the pooled HR and 95% CIs were calculated with HRs and 95% CIs extracted from eligible studies and only homozygote comparison and heterozygote comparison were performed.Heterogeneity between studies was detected using chi-square by Q test, and p<0.1 indicated significant heterogeneity The detailed process of study identification was shown in Egger  = 0.907, PBegg  = 1; XRCC3 Thr241Met polymorphism and response to platinum-based chemotherapy was investigated in 8 heterogeneity  = 0.112; ThrMet vs. ThrThr, OR  = 1.162, 95% CI:0.802–1.683, Pheterogeneity  = 0.009, heterogeneity  = 0.198; ThrMet vs. ThrThr, OR  = 0.831, 95% CI: 0.642–1.075, Pheterogeneity  = 0. 927). Since the number of studies in the analyses of OS and PFS was too little, sensitivity analysis, Egger's test and Begg's test were not performed.Survival of advanced NSCLC and XRCC3 Thr241Met polymorphism was reported in 6 studies In this meta-analysis, we provided evidence that the XRCC3 241Met allele indicated good response to platinum-based chemotherapy, while the XRCC3 Thr241Met polymorphism was not associated with OS or PFS.Platinum compounds, such as cisplatin and carboplatin, are activated intracellularly, binding to DNA to form bulky DNA adducts, block DNA replication and lead to cell death ultimately. Previous studies have suggested that suboptimal DNA repair capacity may lead to decreased removal of platinum-DNA adducts and favorable clinical outcomes It has been documented that XRCC3 is integral to DNA DSB repair and the Thr241Met polymorphism has been associated with the level of bulky DNA adducts For survival of NSCLC patients, we found no association of XRCC3 Thr241Met polymorphism with OS or PFS. However, de las Peñas and colleagues In this systematic review and meta-analysis, we identified 11 eligible studies and 2201 NSCLC patients and provided a systematic overview of current studies. No significant heterogeneity was observed in the process of quantitative synthesis. Additionally, results of sensitivity analysis, Egger's test and Begg's test also confer the reliability and stability of our results. However, limitation to this meta-analysis should be noted. First, the number of studies was relatively small in that sub-group analyses were not available to explore the effect of chemotherapy regimens. Second, the association strength of XRCC3 Thr241Met and survival was based on small number of studies. Third, our results were based on raw data and was not adjusted for certain confounding factors, such as gender, age, TNM stage, histology type of NSCLC and chemotherapy regimens.To summary, results of this systematic review and meta-analysis suggest that, in patients with advanced NSCLC, carriers of the XRCC3 241Met polymorphism is associated with good response to platinum-based chemotherapy. While the XRCC3 Thr241Met polymorphism is not associated with OS or PFS. However, future studies with large sample sizes and well designs are warranted to confirm these findings.Table S1PRISMA checklist.(DOC)Click here for additional data file.


Objective. Our aim in this paper was to investigate the possible genetic association between three Ser563Asn, Leu125Val and Arg670Gly polymorphisms of the PECAM-1 gene and periodontitis. Methods. Genomic DNA was isolated from whole blood of 105 periodontal patient (52 with chronic periodontitis and 53 with aggressive periodontitis) and 101 healthy individuals. Samples were genotyped and analyzed for the three single-nucleotide polymorphisms (SNPs) of PECAM-1 using polymerase chain reaction with sequence-specific primers (PCR-SSPs). Results. A statistically significant difference was found between the genotypic distribution of the Ser563Asn polymorphism in patients with periodontitis compared to controls (P = 0.02). But there were no statistically significant difference between the allele frequencies in the different groups (P = 0.05). The other two polymorphisms did not show a statistically significant difference in their allele and genotype frequencies between the groups. There was no statistically significant difference found for any of the polymorphisms allele and genotype distribution in aggressive and chronic periodontitis either. Conclusions. No significant association was found between the polymorphism tested and the subgroups of periodontitis, further research is still necessary to determine whether this polymorphism can be used as a genetic marker of periodontitis. Genetic associations have been claimed to be effective in predisposition of individuals to periodontitis and have been investigated widely in recent years. Periodontal diseases are a result of destructive inflammatory processes affecting the supporting structures of the teeth, causing resorption of alveolar bone, and formation of periodontal pockets . Not eveSeveral aminoacid polymorphisms have been identified in PECAM-1. These are located in exon 3 codon 80 altering a valine to a methionine (V80M), exon 3 at codon 125 altering a leucine to a valine (L125V), in exon 8 at codon 563 altering an serine to a asparagine (S563N), and in exon 12 at codon 670 altering an arginine to a glycine (R670G). The latter three polymorphisms are in a strong linkage disequilibrium .These polymorphisms were investigated in the present paper. They have been previously associated with diseases such as ischemic heart diseases, coronary artery disease, stenosis, myocardial infarction (MI), and arthrosclerosis in a number of studies –14. Since these diseases are similar to periodontitis, since they all are inflammatory in nature, and no study has yet been undertaken on the possible association between these polymorphisms and periodontal disease, we evaluated the contribution of them in susceptibility to periodontal diseases.In this case, control studies a total of 206 nonsmoking subjects were recruited. 105 patients with periodontitis  consisting of 53 patients with aggressive periodontitis (AgP), 52 patients with chronic periodontitis (CP), and 101 healthy individuals. Periodontitis was diagnosed based on of three clinical parameters, probing depth (PD), clinical attachment loss (CAL), and bleeding on probing index (BPI) and radiographic findings. None of patients had a history of current manifestations of systemic diseases. Patients with severe medical disorders , use of orthodontic appliances, needing pre-medication for dental treatment, chronic usage of anti-inflammatory drugs, present acute necrotizing ulcerative gingivitis, and pregnant or lactating woman were excluded from the study.μM concentration (5′-GCC TTC CCA ACC ATT CCC TT and 5′-TCA CGG ATT TCT GTT GTG TTT C-3′) was used to amplify a 796 bp segment of HLA-DR4 gene. The PECAM-1 Ser563Asn polymorphism was identified by the sequence-specific forward primers and in combination with the consensus reverse primers 5′-CTCTCCCTCCTGTTCCTTGT-3′ and 5′- CGGTGGATGAGGTCCAGATT-3′, respectively. Sequence-specific forward primers in combination with the consensus reverse primers 5′TAGGTCACAATGACGATGTCA-3′ and 5′-GTGGGAAATTATCCACAGTCC-3′, respectively were used to identify the PECAM-1 Arg670Gly polymorphism and the 5′-TGCTGTTCTATAAGGATGACA-3′ forward primer and the 5′-GACTCACCTTCCACCAACAC-3′ common reverse primer were used for investigation of the Leu125Val polymorphism.The diagnostic criteria of CP were the following: (1) the amount of periodontal destruction was consistent with the presence of local factors such as plaque and calculus; (2) at least two sites had probing depth −5 mm and clinical attachment loss −1 mm in every quadrant; the number of the teeth with alveolar bone absorption more than 2/3 root length was less than eight. The clinical criteria of AgP were eight or more teeth, at least 3 of those were other than central incisors or first molars, had a probing depth −5 mm and clinical attachment loss −3 mm. Subjects, even at young ages not reporting familial aggregation of the disease, were not classified as aggressive periodontitis cases and not included in the present paper. In addition, 101 healthy volunteers, without any periodontal disease, systemic inflammatory disease and surgical treatment in the last four weeks were considered as control. The absence of periodontitis was determined according to the following criteria: (1) a minimum of 22 teeth in situ, (2) having no sites with >3 mm probing depth, and (3) the absence of clinical attachment loss. None of the control subjects had a history of periodontitis or tooth loss because of pathogenic tooth mobility. Furthermore, there was no bleeding on probing or radiographic evidence of bone loss in these subjects. All subjects signed an informed consent form before enrolment into the study. 10 mL of venous blood was collected from each subject into tubes containing 50 mM of EDTA. Genomic DNA was isolated from anticoagulated peripheral blood buffy coat using Miller's salting out method . Then thμM that contained 100 ng of genomic DNA, 1 mM each allele-specific primer pair, 200 μM dNTP, 10 mM Tris-HCl (PH = 8.3), 50 mM KCl, 1.5 mM MgCl2, and 0.5 IU Taq DNA polymerase. The reaction was carried out as follows; initial denaturation at 94°C for 2 min, followed by 30 cycles of amplification at 96°C for 20 S and annealing at 64°C for 50 S, with extention for 40 S at 72°C, with a final extention for 2 min at 72°C. The amplified PCR products were analyzed by 2% agarose gel electrophoresis followed by 0.5 μg/mL ethidium bromide staining and ultraviolet visualization. The agarose gels were reported by an investigator unaware of the samples.Amplification was carried out using a DNA Technology MTC 400 in a total volume of 15 P Value < 0.05 was considered statistically significant.The study was approved by the Ethics Committee of University. Written informed consents were obtained before entering the study.Allelic and genotypic frequencies were obtained by direct counting. Contingency tables were used with chi-square tests to compare observed genotype frequencies with those expected under Hardy-Weinberg equilibrium. Chi-square and Fisher's exact tests were used to test for differences in genotype and allele distribution between the groups with the help of SPSS version 13 software. The odds ratio (OR) was calculated along with its 95% CI, and We investigated the genetic variability of the PECAM-1 gene in 101 healthy controls and 105 patients with a mean age of 33.34 ± 9.8 and 29.12 ± 7.71, respectively.The results for the Leu125Val and Arg670Gly Allele and genotype frequencies in patients and controls showed no statistically significant difference Tables .P = 0.05). There was a statistically significant difference in the genotype distribution of this polymorphism. The homozygous genotype combination of Ser/563 was 23.8% in controls, 13.3% in patients (P = 0.02) and the homozygous/Asn563 was 4% in controls, 12.4% in patients (P = 0.02)  .In addition, as shown in Tables P = 0.05), but a statistically significant difference in the genotype distribution of this polymorphism was found (P = 0.02). Therefore, we cannot totally rule out the association of this polymorphism with periodontitis, but certainly further investigations are needed. Although such polymorphisms usually do not affect the gene expression, it results in an aminoacid change from Ser to Asn in the functional Ig-like domain of PECAM-1, but its role is not yet fully understood. It has been shown that the nutrophil specific antigen (CD177) is involved in transmigration of PMN via their attachment to this domain [Periodontitis is an inflammatory disorder characterized by connective tissue and alveolar bone destruction. The correlation of known polymorphisms in components of the human immune system with phenotypes for certain patient groups currently appears to provide the most promising application of genetic determinants of periodontitis. In this paper we investigated the three most popular SNPs of the PECAM-1 gene. The Ser563Asn polymorphism codes the extracellular domain of the PECAM-1 molecule. We found no significant allele frequency distribution difference between the patients and controls for this polymorphism , and arthrosclerosis , 13, 14.PECAM-1 creates its hemophilic bonds through its first or second Ig-like (d1/2) extracellular domain , 19, andSince the Leu125Val (C + 373G) polymorphism is in the first and second domain of PECAM-1 and the importance of this domain and also previous findings showing the association of this polymorphism with diseases such as coronary artery disease, atherosclerosis, and ischemic heart diseases; , 14 we dP = 0.61 and P = 0.81). We found no similar study to compare our results.The results of our paper showed no statistically significant association between allele and genotype frequency in periodontal patients and controls (PECAM-1 appears to interact both with it (hemophilic adhesion) and with non-PECAM-1 ligands (heterophilic adhesion).The cytoplasmic domin of this molecule has an important role in regulating its cellular adhesion behavior and is coded by exons 10–16 .Although the exact role of the exon 12 cytoplasmic domin is not clear yet, the Arg670Gly polymorphism in this exon has been found to be related to diseases such as ischemic heart diseases, MI and Stenosis , 12.Considering the similar immunologic and inflammatory basis of these diseases and periodontitis, we decided to evaluate the possible role of this polymorphism in periodontitis.However, we found no statistically significant association between the different genotype and allele frequency distribution of this polymorphism and periodontitis.Taken together, this paper showed no statistically significant relation between these polymorphisms and periodontitis, but further studies are still recommended.No significant association was found between the polymorphism tested and the subgroups of periodontitis, further research is still necessary to determine whether this polymorphism can be used as a genetic marker of periodontitis.


The n-3 polyunsaturated fatty acids eicosapentaenoic acid and docosahexaenoic acid, which are present in fish, are protective against myocardial infarction. However, fish also contains methylmercury, which influences the risk of myocardial infarction, possibly by generating oxidative stress. Methylmercury is metabolized by conjugation to glutathione, which facilitates elimination. Glutathione is also an antioxidant. Individuals with certain polymorphisms in glutathione-related genes may tolerate higher exposures to methylmercury, due to faster metabolism and elimination and/or better glutathione-associated antioxidative capacity. They would thus benefit more from the protective agents in fish, such as eicosapentaenoic+docosahexaenoic acid and selenium. The objective for this study was to elucidate whether genetic polymorphisms in glutathione-related genes modify the association between eicosapentaenoic+docosahexaenoic acid or methylmercury and risk of first ever myocardial infarction.GCLC and glutamyl-cysteine ligase modifier subunit, GCLM) or glutathione-conjugating  genes were genotyped in 1027 individuals from northern Sweden . The impact of these polymorphisms on the association between erythrocyte-mercury (proxy for methylmercury) and risk of myocardial infarction, as well as between plasma eicosapentaenoic+docosahexaenoic acid and risk of myocardial infarction, was evaluated by conditional logistic regression. The effect of erythrocyte-selenium on risk of myocardial infarction was also taken into consideration.Polymorphisms in glutathione-synthesizing (glutamyl-cysteine ligase catalytic subunit, GCLM-588 TT genotype displayed a lower risk relative to the CC genotype in all but one tertile; in most tertiles the odds ratio was around 0.5 for TT. However, there were few TT carriers and the results were not statistically significant. The results were similar when taking plasma eicosapentaenoic+docosahexaenoic acid, erythrocyte-selenium and erythrocyte-mercury into account simultaneously.There were no strong genetic modifying effects on the association between plasma eicosapentaenoic+docosahexaenoic acid or erythrocyte-mercury and risk of myocardial infarction risk. When eicosapentaenoic+docosahexaenoic acid or erythrocyte-mercury were divided into tertiles, individuals with GCLM-588 TT genotype may have an impact, but a larger study is necessary for confirmation.No statistically significant genetic modifying effects were seen for the association between plasma eicosapentaenoic+docosahexaenoic acid or erythrocyte-mercury and risk of myocardial infarction. Still, our results indicate that the relatively rare  The toxic compound methylmercury (MeHg) from fish may increase the risk of myocardial infarction (MI), possibly due to induction of oxidative stress, a risk factor for MI. High mercury (Hg) levels in hair (proxy for MeHg retention) ,2 and toS-transferases (GSTs), which conjugate GSH to a wide variety of electrophilic compounds [C→T nucleotide substitution at position -129 in GCLC (GCLC-129) [C→T nucleotide substitution at position -588 in GCLM [GSTP1 [Unigene [GCLC, GCLM and GSTP1 may thus modify the MeHg-induced oxidative damage.MeHg is eliminated in the bile as a glutathione (GSH) conjugate ,11. The ompounds ,14, may CLC-129) ,16 and a in GCLM . Glutath[Unigene -20. FurtGSTP1 polymorphisms GSTP1-105 or GSTP1-114 had lower levels of Ery-Hg at high plasma EPA+DHA, compared with individuals with no variant alleles, indicating a faster elimination of MeHg for variant-allele carriers. Also, TT homozygotes for the GCLM-588 polymorphism demonstrated higher Ery-Hg than the other GCLM-588 genotypes. Polymorphisms in GCLC, GCLM and/or GSTP1 have been associated with body burden of Hg in other studies [In our previous study , we eval studies ,21,22.The present study is an extension of a study by Wennberg et al , which eThe study population is part of an individually matched case-control study nested within three prospective health surveillance cohorts in Västerbotten, Northern Sweden: the Västerbotten Intervention Program (VIP), the WHO's Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) Study in northern Sweden, and the Mammography Screening Project (MSP). Both VIP and MONICA are health examination programs for CVD and diabetes. The cohorts, sampling and other variables are described more thoroughly in Wennberg et al. . MedicalThe determination of Ery-Hg was made in acid-digested samples using cold vapor atomic fluorescence spectrometry ,7,23. PlMore detailed information, such as limit of detection, coefficients of variance, and reference material are thoroughly described in Wennberg et al. .GCLC-129, GCLM-588, GSTP1-105 and GSTP1-114 [The Taqman allelic discrimination assay  was performed to analyze all four single nucleotide polymorphisms (SNPs) separately; STP1-114 ,7. ThereSTP1-114 ) for theGCLC-129, GCLM-588, GSTP1-105 and GSTP1-114). Effects of dual-polymorphisms for the GSTP1 gene (GSTP1-105 and GSTP1-114) were also analyzed, where genotype was categorized as the total number of variant alleles for both polymorphisms. Individuals with two or more variant alleles were pooled into one group. The genotypes were used as categorical variables in all analyses. Since this study is an extension of the study by Wennberg et al [Hardy-Weinberg equilibrium was tested for the controls using the conventional Chi-square test. Because the effects of P-EPA+DHA, Ery-Se and Ery-Hg on MI risk were in the same direction for men and women , both geA schematic overview of the statistical analyses are shown in Figure GSTP1-105 and GSTP1-114 combination, the group with individuals with 0 variant alleles was used as reference.Firstly, we evaluated whether genotype in itself had any effect on MI risk . All tests were two-sided and p ≤ 0.05 was considered statistically significant.When genotype was not taken into account, P-EPA+DHA indicated a decreasing MI risk (p = 0.15), while Ery-Hg was statistically significantly associated with decreasing MI risk (p = 0.014) .There were significant effects on MI risk by smoking  and ApoB/ApoA1  and these two variables were thus included in the multivariate analyses.GCLM-588 (p = 0.030).All polymorphisms were in Hardy-Weinberg equilibrium  except for GCLM-588 TT genotype (GCLM-588 CC was used as reference) was 0.60 .When evaluating the effect of genotype alone on MI risk  for the GCLM-588 polymorphism had a lower MI risk relative to wildtype homozygotes (CC) in all P-EPA+DHA and Ery-Hg tertiles .There were no statistically significant genetic modifying effect of the associations between P-EPA+DHA or Ery-Hg and MI risk Figures  and 3. TGSTP1 (combination of GSTP1-105 and GSTP1-114), carriers of two or more variant alleles showed the lowest risk in all Ery-Hg tertiles .Similar patterns as in Wennberg et al.  were seeGCLM-588 TT genotype had a lower risk relative to the CC genotype in all P-EPA+DHA or Ery-Hg tertiles except for one (intermediate tertile for Ery-Hg) , but these findings were not statistically significant. The lack of statistically significant results in this study may be due to a small number of individuals for some genotypes, in particular GCLM-588 TT, yielding a too low power to detect statistically significant effects. The effect estimates (ORs) for GCLM-588 TT were strongly deviant from the CT genotype, which prevented us from pooling these two genotypes. In our previous study, the GCLM-588 TT genotype demonstrated the highest levels of Ery-Hg [GCLM-588 TT genotype had the highest levels of Ery-Hg also among the controls in this study, although this was not significant. GCLM-588 TT carriers displayed the lowest risk of MI in each P-EPA+DHA tertile in this study. However, it is important to note that this interpretation is based on few individuals and needs to be confirmed.We found that the polymorphisms studied had no effect on MI risk by themselves. When P-EPA+DHA or/and Ery-Hg was taken into account, the f Ery-Hg . The GCLGCLM-588 was in Hardy-Weinberg disequilibrium. The allele frequencies reported here were similar to another study, analyzing Danish and Swiss populations, where Hardy-Weinberg equilibrium was reported [The reported . The prereported ,7 also sreported ,28. Ther(GPX1), glutaredoxin (GLRX), gamma-glutamyl transferase 1 (GGT1), or in any of the other GSTs. It is also possible that thioredoxin (TXN) and TXN-related genes affect the metabolism of MeHg [(CAT), paroxonases (PONs) and superoxide dismutase (SOD).To our knowledge, no other studies have assessed gene-environment interactions (for any gene) on the association between MeHg or n-3 polyunsaturated fatty acids and MI risk. There may, however, also be other genetic traits that can influence these associations, e.g. polymorphisms in other GSH-related genes, such as glutathione peroxidase  of MeHg . In addiGCLM-588 T-allele has been associated with a higher risk of MI . The T- with MI . HoweverGCLM-588 TT genotype may have an impact, but a larger study is necessary for testing this hypothesis.There was no statistically significant genetic modifying impact on the association between P-EPA+DHA or Ery-Hg and MI risk. Still, our results indicate that the relatively rare GCLC: Glutamyl-cysteine ligase catalytic subunit; GCLM: Glutamyl-cysteine ligase modifier subunit; GSH: Glutathione; GST: Glutathione-S-transferase; GSTP1: Glutathione-S-transferase Pi 1; Hg: Mercury; MeHg: Methylmercury; MI: Myocardial infarction; OR: Odds ratio; SD: Standard deviation; Se: Selenium; SNP: Single nucleotide polymorphism.ApoB/A1: Apolipoprotein B/A1 ratio; BMI: Body mass index; CI: Confidence interval; DHA: Docosahexaenoic acid; EPA: Eicosapentaenoic acid; Ery-Hg: Erythrocyte total mercury concentration; Ery-Se: Erythrocyte selenium concentration; GCL: Glutamyl-cysteine ligase; The authors declare that they have no competing interests.KSE. contributed to data preparation, designed and carried out the data analyses, participated in interpretation of data, drafting and finalizing of the manuscript. MW contributed to data preparation, participated in interpretation of data, drafting and finalizing of the manuscript. US was advisor for the statistical analyses, contributed to interpretation of data, drafting and finalizing of the manuscript. IAB participated with input in the manuscript writing and analysis of the data. GH participated in the discussion initiating the study, collection and administration of data. TL carried out chemical analysis of Ery-Hg and Ery-Se. MN participated in the discussion initiating the study, collection and administration of data. GR performed genotyping analyses. BV carried out chemical analysis of fatty acids. SS participated in the discussion initiating the study, participated in data analyses, interpretation of data and drafting and finalizing of the manuscript. JHJ established the case-control study population. KB participated in the discussion initiating the study, participated in data analyses, interpretation of data and drafting and finalizing of the manuscript. All authors have read and approved the final manuscript.


Osteosarcoma is a primary bone malignancy that typically occurs during adolescence but also has a second incidence peak in the elderly. It occurs most commonly in the long bones, although there is variability in location between age groups. The etiology of osteosarcoma is not well understood; it occurs at increased rates in individuals with Paget disease of bone, after therapeutic radiation, and in certain cancer predisposition syndromes. It also occurs more commonly in taller individuals, but a strong environmental component to osteosarcoma risk has not been identified. Several studies suggest that osteosarcoma may be associated with single nucleotide polymorphisms in genes important in growth and tumor suppression but the studies are limited by sample size. Herein, we review the epidemiology of osteosarcoma as well as its known and suspected risk factors in an effort to gain insight into its etiology. Osteosarcoma, the most common primary bone malignancy, typically during the adolescent growth spurt but there is a second, smaller peak in the elderly . There aOsteosarcoma represents approximately 55% of child and adolescent malignant bone tumors in the US . It is rIn the US, using population data from the Surveillance, Epidemiology, and End Results (SEER) program, osteosarcoma incidence has been shown to vary by race based on the age of onset : 1) in  in 1]. AIt has been reported that, when a wide range of ages are combined, males are affected with osteosarcoma more frequently than females , 19–21. Osteosarcoma occurs most frequently in the lower long bones , 7, 21 . In younThe anatomic site distributions do not vary significantly by sex or race in young patients  but therSurvival rates vary by age, gender, disease stage, and anatomic site . For chiFemales have higher survival rates than males , 33, 40.Older patients may have unique tumor biology, for example, more axial tumors or other factors associated with a poorer prognosis, such as Paget disease (see below) and response to therapy due to age-related adjustments in therapeutic regimens, which could contribute to their worse overall survival , 29, 37.Studies of environmental exposures and rare cancers, such as osteosarcoma, are challenging and often limited by sample sizes. Most studies are case-control, ecologic, and/or descriptive in nature. This is because the extremely large cohorts required to study these cancers are nearly impossible to conduct. For example, even in a cohort of one million individuals, only 4 or 5 would be expected to develop osteosarcoma. Studies of environmental exposures and osteosarcoma are often combined with studies of other bone tumors, including Ewing sarcoma and others. This makes separating the potentially etiologic clues even more challenging. The reader is referred to a recent, comprehensive review of these studies . Two welin vitro data which suggested that fluoride could act as a mitogen on osteoblasts [Many years ago, it was hypothesized that fluoride could contribute to osteosarcoma risk. This was based, in part, on the fact that it is taken up by and stored in bones and on eoblasts . Studieseoblasts ). A moreeoblasts  but cauteoblasts .Therapeutic radiation is a proven risk factor for osteosarcoma. It was noted to occur more frequently than expected in survivors of Hodgkin disease who received therapeutic radiation , 49. IncSince osteosarcoma occurs most commonly during puberty, a time of rapid bone growth and remodeling, it is highly plausible that factors related to growth and development play a role in osteosarcoma etiology. Case reports of osteosarcoma occurring in individuals with acromegaly, a growth disorder caused by over production of growth hormone, lent further support to this hypothesis . Early sIGF2) and loss of IGF2 imprinting occurs in diverse cancers [IGF2R as potential risk factors for osteosarcoma (see below) [Osteosarcoma incidence is highest during puberty when endogenous sex hormones, growth hormones, and insulin-like growth factor 1(IGF1) levels are at their highest, so this biological pathway is likely to play an important role in osteosarcoma etiology. Insulin-like growth factors (IGFs) play critical roles in carcinogenesis and circulating levels are associated with risk of several cancers , includi cancers , furthere below) .The association between taller stature and increased risk of developing osteosarcoma was first reported in 1967 . That stPtrend < 0.0001).A recent meta-analysis of height and osteosarcoma compiled individual osteosarcoma patient data on 1067 osteosarcoma cases derived from 5 published , 67, 73 The meta-analysis , and a separate study of 962 patients with osteosarcoma , which wNumerous epidemiologic studies have evaluated associations between high birth weight and cancer. This is based on the hypothesis that high birth weight may be the result of multiple factors that are also associated with cancer. For example, IGFs are important in fetal development  and are Review of the literature identified five published studies that evaluated the potential association between birth weight and osteosarcoma; four were null , 79, 87,Paget disease of bone is a relatively common metabolic bone disorder that typically occurs in older individuals , 89. It κB signaling pathway [SQSTM1, a downstream scaffold protein in this pathway, are associated with familial Paget disease [SQSTM1 gene [κB signaling pathway which promotes osteoclastogenesis and formation.The co-occurrence of osteosarcoma in the setting of abnormal bone remodeling due to Paget disease of the bone suggests that osteosarcoma may be etiologically related to abnormal bone remodeling , 91. Thi pathway . Mutatio disease . Many, bTM1 gene . UbiquitChromosomal aneuploidy is common in osteosarcoma cells which suggests that somatic or germline chromosomal instability could potentially predispose an individual to osteosarcoma , 94. TheInherited cancer predisposition syndromes are a heterogeneous group of disorders. There are several disorders in which higher rates of osteosarcoma are noted . StudiesTP53 [TP53 mutation. Additional clinical descriptions and criteria for mutation testing in individuals with suspected LFS are reviewed in [TP53, is crucial for normal cell growth, apoptosis, DNA repair, and numerous other cellular processes. The p53 gene is mutated in a majority of somatic tumor tissues, many of which disrupt the DNA-binding domain and result in a loss of tumor suppressor function [TP53 mutations but these have not consistently been correlated with disease stage or prognosis [The careful characterization of families with high rates of breast cancer, sarcomas, and other cancers by Li and Fraumeni Jr. in 1969 led to the recognition of the syndrome now known as Li-Fraumeni syndrome (LFS) , 102. ThTP53  althoughfunction . Many, brognosis . RB1 tumor suppressor gene [RB1 gene encodes the Rb protein which is critical in normal cell cycle and differentiation processes. Loss of normal Rb function is noted in several sporadic human tumors, including apparently sporadic osteosarcoma. In addition, osteosarcoma is the most common second tumor in patients with retinoblastoma. It occurs more frequently than expected in individuals with RB1 mutations whether or not they had radiation therapy [RB1 mutation, and this may also be the case in apparently sporadic osteosarcoma. Retinoblastoma is a malignant retinal tumor that typically occurs prior to the age of 5. It is caused by mutations in the sor gene . The RB1 therapy , 108. ThRECQL4 , Werner syndrome, and Bloom syndrome. RTS is a rare, autosomal recessive disorder caused by mutations in the DNA helicase iewed in , 110). Iiewed in . The rolBLM helicase, also has a characteristic rash, but not true poikiloderma [BLM mutations in osteosarcoma somatic cells is not well described.Bloom syndrome, caused by autosomal recessive inheritance of mutations in the iloderma . Individiloderma . While oWRN DNA helicase and inherited in an autosomal recessive manner. Individuals with Werner syndrome typically have characteristic “bird” facies, short stature, parental consanguinity, cataracts, atrophic skin, and signs of premature aging such as atherosclerosis. They are at increased risk of osteosarcoma as well as other malignancies [Werner syndrome is a premature aging syndrome which typically presents after the first decade of life , 114. Itgnancies , 116. RPS19, RPL5, RPL11, RPL35A, RPS24, RPS17, or RPS7). Osteosarcoma was noted in three of the 354 patients in the DBA registry in 2001 [Diamond Blackfan anemia (DBA) is another inherited disorder associated with increased risk of osteosarcoma . DBA is  in 2001 . The rolMDM2 gene increases the affinity of the Sp1transcription factor which results in higher MDM2 levels and p53 pathway attenuation [The inherited disorders caused by rare, highly-penetrant mutations and associated with osteosarcoma described above explain only a very small percentage of all osteosarcoma cases. It occurs more often in individuals without a family history of cancer or other medical problems. Several studies have been conducted in an effort to understand the contribution of common genetic variants, such as SNPs, to osteosarcoma risk  althoughenuation . a priori hypotheses that the genes of interest were potentially important in osteosarcoma biology. The first such study evaluated three SNPs in the promoter of the Tumor Necrosis Factor-α (TNF) gene in 63 osteosarcoma cases and 111 controls from Spain [TNF-238G>A was inversely associated with osteosarcoma. The TNF-308G>A variant was not associated with osteosarcoma. The authors also evaluated these genotypes in 47 individuals with Ewing sarcoma but did not find an association. Most of the studies of SNPs and osteosarcoma conducted to date have been limited by sample size and therefore should be considered exploratory in nature . These som Spain . The TNFESR1), vitamin D receptor (VDR), and/or collagen 1α1 (COL1A1) gene could be osteosarcoma risk factors. Variants in ESR1 could be important in osteosarcoma since estrogen is critical during puberty which is the key time of risk for osteosarcoma. The VDR and COL1A1 genes are required for proper bone formation and thus, if aberrations are present, could be associated with osteosarcoma. A total of 72 osteosarcoma cases and 143 controls were evaluated. Ruza et al. found that the Ff genotype of VDR was associated with increased risk of osteosarcoma  [ESR1 or COL1A1 were not associated with osteosarcoma.In a second study, the same group hypothesized that variants in the estrogen receptor (= 0.048) . VariantTP53 cause LFS and osteosarcoma is a defining tumor of the syndrome, SNPs in TP53 were evaluated as potential osteosarcoma risk factors in the Bone Disease and Injury Study of Osteosarcoma (BDISO), a hospital-based study of 104 cases and 74 controls [Since mutations in controls . SubjectTP53 and the MDM2 -309 promoter SNP  in 201 osteosarcoma cases and 250 controls from Italy [TP53 has been associated with risk of several cancers, including lung and breast cancer  SNP in om Italy . The Proiewed in ). In addiewed in . The MDMf cancer . In addi cancers . This osIGF2R, rs998075 and rs998074) were associated with increased risk of osteosarcoma  [IGF2R protein function is not known. As noted above, the IGFs are potential regulators of carcinogenesis in several cancer types and IGF1 levels have been associated with cancer risk. Followup of these findings in osteosarcoma is needed to better understand how genetic variation in IGF2R contributes to its etiology. The first study to evaluate SNPs in growth-related genes did so based on the hypothesis that since osteosarcoma most commonly occurs during a period of active growth, that variants in genes that regulate pubertal growth could be important osteosarcoma risk factors. Common SNPs in 13 growth-related genes were also evaluated as candidate risk modifiers in the BDISO. Of the 52 SNPs evaluated, two correlated SNPs in insulin-like growth factor receptor 2 (29–3.24) . One of SNPs in the 8q24 chromosomal region are being intensely studied because genome-wide association studies (GWAS) have consistently found them to be associated with risk of adult onset cancers, including prostate, breast, colon, and others –125. TheFAS, or TNFRSF6) is a member of the TNF receptor superfamily and plays a central role in programmed cell death. Genetic variants in FAS have been associated with increased risk of several cancers, such as melanoma, gastric, and renal cell cancer [FAS may be osteosarcoma risk factors. They evaluated four SNPs in FAS in 123 osteosarcoma cases and 510 controls from the US [The Fas protein  is a multi-institutional, international collaborative group of childhood cohort studies that is working to better understand the etiology of childhood cancer . HoweverTP53 and RB1 suggest that the genetic contribution to what appears to be sporadic osteosarcoma may also be important. Understanding potential environmental contributions to osteosarcoma risk is very challenging because of its rarity and the fact that a single environmental exposure is not likely to be the primary cause. Numerous studies are underway which seek to improve our understanding of osteosarcoma etiology and through this understanding we will be better equipped to counsel patients and refine treatment strategies.Like many cancers, the etiology of most osteosarcoma remains unknown. Epidemiology studies have provided many important clues, such as associations with puberty, height, and disorders of bone growth and remodeling. The genetic clues derived from the occurrence of osteosarcoma in the setting of germline mutations in genes such as


Single nucleotide polymorphisms (SNPs) may affect the development of diseases. The -2518A/G polymorphism in the regulatory region of the monocyte chemo-attractant protein-1 (MCP-1) gene has been reported to be associated with cancer risk. However, the results of previous studies were inconsistent. Therefore, we performed a meta-analysis to obtain a more precise estimation of the relationship between the -2518A/G polymorphism and cancer risk.heterogeneity = 0.08; GG vs. AG/AA: OR = 1.29, 95%CI = 1.02–1.64, Pheterogeneity = 0.14). In addition, the increased risk of GG genotype was also observed in Caucasians .We performed a meta-analysis, including 4,162 cases and 5,173 controls, to evaluate the strength of the association between the −2518A/G polymorphism and cancer risk. Odds ratio (OR) and 95% confidence intervals (95% CIs) were used to assess the strength of association. Overall, the results indicated that the −2518A/G polymorphism was not statistically associated with cancer risk. However, sub-group analysis revealed that individuals with GG genotypes showed an increased risk of cancer in digestive system compared with carriers of the A allele (GG vs. AA: OR = 1.43, 95%CI = 1.05–1.96, PThis meta-analysis suggests that the MCP-1 −2518A/G polymorphism may have some relation to digestive system cancer susceptibility or cancer development in Caucasian. Large-scale and well-designed case-control studies are needed to validate the findings. Cancer is a major public health problem and one of the principal causes of death worldwide Monocyte chemo-attractant protein 1 (MCP-1), also known as CCL-2 (CC chemokine ligand 2), is a member of the CC chemokine family which plays an important role in inflammation, and is encoded by the CCL-2 gene which locates on 17q11.2-q12 Several MCP-1 polymorphisms have been reported to be associated with disease susceptibility or severity A systematic search of PubMed and China National Knowledge Infrastructure (CNKI) database (last search updated in June 2013) was carried out to identify case-control studies that investigated the association between the −2518A/G polymorphism and cancer risk. The search strategy was based on combinations of “MCP-1”, “CCL-2”; “cancer”, “carcinoma”, “tumor”; “polymorphism”, “variant”, “SNP”. In order to minimize potential publication bias, citations in original studies were also screened by manual search to identify additional relevant publications. The selection criteria of the retrieved articles in our meta-analysis were as follows: (1) a case–control design; (2) investigating the −2518A/G polymorphism and cancer risk; (3) sufficient data available to calculate an odds ratio (OR) with 95% confidence interval (CI). The major reasons for exclusion of studies were (1) investigations in subjects with cancer-prone disposition; (2) overlapping data; (3) not published in English and Chinese.The following information was collected independently by two of the authors (Da and Zhang) for each eligible study: name of first author, published year, country of origin, ethnicity, source of control, cancer type, genotyping method, total number of genotyped cases and controls, genotype frequencies in cases and control, and Hardy–Weinberg equilibrium (HWE) of controls. Ethnicity was categorized as Asian, Caucasian and mixed population. Cancer types were classified as bladder cancer, prostate cancer, digestive system cancer , and other cancers. All studies were defined as hospital-based (HB) or population-based (PB) according to the source of control. The final results of data extraction were compared carefully, and any disagreements were discussed until reaching conformity on all items among all authors.2-test and a P<0.05 was considered as significant disequilibrium. The strength of the associations between the −2518A/G polymorphism and cancer susceptibility was measured by OR with its 95%CI. The pooled ORs and the 95% CIs in each comparison were calculated using the following models: homozygote model (GG vs. AA), heterozygote model (AG vs. AA), dominant model (GG/AG vs. AA) and recessive model (GG vs. AG/AA), respectively. Between-study heterogeneity was assessed by the chi-square based Q test and the heterogeneity was found to be significant when P<0.10P value was >0.10. Otherwise, the random-effects model (DerSimoniane-Laird method) was utilized P<0.05 was considered to be representative of statistically significant publication bias For each study, deviation from HWE among controls was evaluated by Pearson's χAfter careful retrieve and selection, 18 eligible articles were identified according to inclusion and exclusion criteria. The study selection procedures were shown in Out of the 19 applicable studies, 17 were published in English and 2 were written in Chinese, 10 of them were studies of Asians, 8 studies of Caucasian and one study of mixed population. According to the source of control, 10 studies were hospital-based and 9 were population-based. The genotype distributions in the controls were in agreement with HWE except for two studies  and recessive model , recessive model  and dominant model . However, the cancer cases and controls did not significantly differ in the subgroup analyses according to the source of control.Further, in the stratified analyses by sample size and source of control, we observed a significantly increased risk in “large” studies in three genetic models: homozygote model , but not ethnicity, source of control and sample size (P>0.05) contributed to source of heterogeneity.Between-study heterogeneity was obvious in each model . Meta-reP = 0.67), and the results of Egger's test also indicated no risk of publication bias (GG vs. AG/AA: P = 0.96)A one-way sensitivity analysis was performed to assess the stability of the results of the meta-analysis. Statistically similar results were obtained after sequentially excluding individual studies, which confirmed the robustness of the meta-analysis (data not shown). For publication bias, as shown in The impacts of MCP-1 activation on tumor cells have been demonstrated in a variety of malignancies Sub-group analysis was conducted to detect the effects of confounding factors. When stratified by ethnicity, there was a significantly increased cancer risk among Caucasians but not in Asians. The differences may be explained by genetic diversities, different risk factors in life styles, and the exposure to different environmental factors. However, it was noteworthy that an increased cancer risk was found in the recessive model for Caucasians, and only two “large” studies were included in this subgroup. It was reported that small size may decrease statistical power and even may produce a fluctuated risk estimate. Therefore, this relationship needs to be further confirmed in larger size, well-designed prospective studies.In the subgroup analysis by cancer type, no significant association was found except for homozygote model and recessive model comparison of digestive system cancer. This could be explained by the following two reasons: one may be that this polymorphism may play a different role in different cancer sites. The other possible reason is that most studies in this subgroup were “large” studies which have sufficient statistical power to investigate a slight effect compared with “small” studies. In consistent with this explanation, there was a significantly increased cancer risk in “large” studies in three genetic models, but no significant association was observed in “small” studies in any comparison.P = 0.02), but not ethnicity, source of control or sample size (P>0.05) contributed to the source of heterogeneity. In fact, numerous other factors including age, sex ratio, family history and lifestyle may also explain the heterogeneity. Unfortunately, we can not conduct a meta-regression utilizing these variables because detail information was not available.Finally, attention should be paid to the relatively huge heterogeneity in this meta-analysis. Meta-regression indicated that cancer type  date was included in this meta-analysis. As we know, as compared to the candidate-gene approach, GWAS have revolutionized the field of genetic susceptibility and provided a powerful approach to identify the common genetic variants. Therefore, this powerful and comprehensive approach have contributed to unprecedented advances in our understanding of the role of common genetic variation in various cancersIn conclusion, this meta-analysis suggests that the MCP-1 −2518A/G polymorphism may have some relation to digestive system cancer susceptibility or cancer development in Caucasian. To further confirm the results, large scale case-control studies with different ethnic groups and multiple cancer types are needed.Checklist S1PRISMA checklist.(DOC)Click here for additional data file.


Many studies have been carried out to test the hypothesis that the NQO1 C609T polymorphism might be associated with the risk of esophageal cancer. However, the results are poorly consistent, partly due to genetic or other sources of heterogeneity. To investigate the association between this polymorphism and the risk of esophageal cancer, a meta-analysis was performed.2) were used to check heterogeneity. Egger’s test and an inverted funnel plot were used to assess the publication bias.We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of association. The frequency of the putative risk allele in the controls was estimated by the inverse-variance method. Cochran’s Q statistic and the inconsistency index . Regarding histological type, more significant evidence was found for esophageal squamous cell carcinoma (ESCC)  than esophageal adenocarcinoma (EAC)  under a recessive model.The meta-analysis suggests that the NQO1 C609T polymorphism considerably increases the risk of esophageal cancer. Esophageal cancer is a malignancy of the esophagus, the muscular tube through which food passes from the throat to the stomach. Esophageal tumors usually lead to dysphagia, pain and other symptoms, and are diagnosed by biopsy. Generally, esophageal cancer has two subtypes, squamous cell cancer (ESCC) and adenocarcinoma (EAC). Squamous cell cancer arises from the cells that line the upper part of the esophagus. Adenocarcinoma arises from glandular cells that are present at the junction of the esophagus and the stomach .NAD(P)H quinone oxidoreductase 1 (NQO1) is a member of the NAD(P)H dehydrogenase (quinone) family and encodes a cytoplasmic 2-electron reductase, which is a cytosolic flavoenzyme that protects cells from oxidative damage . The NQOSome studies have shown that this polymorphism in the NQO1 gene affects the translation of the NQO1 protein. Compared to the homozygous wild type (C/C), expression of the NQO1 protein encoded by the heterozygous phenotype (C/T) is decreased approximately three-fold. In addition, the homozygous mutant (T/T) phenotype causes a complete lack of enzyme activity ,5-7. TheAll original studies published in English on the NQO1 C609T polymorphism and esophageal cancer were considered in our meta-analysis. HuGENet, Embase and PubMed were searched up to August 8 2011, using the following terms:  and  and (“NQO1” or “NAD(P)H: quinine oxidoreductase 1” or “NAD(P)H dehydrogenase, quinone 1” or “DHQU”).Included studies had to fit the following criteria: (1) sufficient data regarding allele frequency; (2) an association analysis between the NQO1 C609T polymorphism and esophageal cancer risk; and (3) independent case-control studies.The following information was extracted by three investigators  from each study: the first author, year of publication, country, race, sample size, outcome, characteristics of controls, case and control diagnostic criteria, genotyping method, allele frequencies, genotype distribution in cases and controls, pathology status of esophageal cancer and the esophageal cancer risk factors. Results were compared and different opinions were resolved by a discussion.2) were used to check heterogeneity [2 < 25%, heterogeneity did not exist among the studies [Hardy-Weinberg equilibrium  and chi-square test methods were used to test the distribution of genotypes in the control group of each study. The frequency of the putative risk allele in the controls was estimated by the inverse-variance method -18. Cochogeneity ; if P >  studies . If ther studies :If OR1 = OR2 ≠ 1 and OR3 = 1, the dominant model was selected.If OR1 = OR3 ≠ 1 and OR2 = 1, the recessive model was accepted.If OR2 = 1/OR3 ≠ 1 and OR1 = 1, the overdominant model was taken.If OR1 > OR2 > 1 and OR1 > OR3 > 1(or OR1 < OR2 < 1 and OR1 < OR3 < 1), the codominant model was adopted. Finally, the results were pooled again under the appropriate genetic model.Egger’s test and an inverted funnel plot was used to assess publication bias . HWE wasTen relevant studies describing the association between NQO1 C609T and esophageal cancer were identified. However, after reading the full text, we excluded two of these ten studies due to overlapping ,23. FinaAmong the included articles described in Table In addition, among these eligible studies, two included populations that were selected from ESCC patients ,29, fourOverall, the eligible studies included 1,124 cases and 1,510 controls that were genotyped. The prevalence rates of TT in C609T variants were 19.1% in the controls of Asian descent and 4.1% in the controls of Caucasian descent. The prevalence rates of CT for controls of Caucasian and Asian decent were 45.5% and 31.7%, respectively. For histological type, the prevalence rates of TT were 8.6% and 7.3% in controls of ESCC and EAC patients, respectively, while CT were 40.9% and 34.0% in controls of ESCC and EAC patients, respectively. The genotype distribution and all the P-values for HWE testing are shown in Tables The results of the included studies regarding the association between the NQO1 C609T polymorphism and esophageal cancer were conflicting, as seen in Table After sensitivity analysis, Hamajima et al  and MartUsing the inverse variance fixed effects model, the ORs of the pooled NQO1 T allele frequencies were 1.32 (95% CI: 1.08-1.62) for Caucasians and 1.32 (95% CI: 1.08-1.60) for Asians. In total, the summary OR for all the studies was 1.32 (95% CI: 1.15-1.52). It was shown that the T allele was related to susceptibility to esophageal cancer.2 = 0.0%, P = 0.48). In addition, Egger’s test showed that publication bias was not significant under the recessive model (P = 0.69).According to the principle of genetic model selection by Thakkinstian , the recSix case-control articles reporting an association between the NQO1 C609T polymorphism and the histological type of esophageal cancer were included in our research, but their results were debatable. For EAC, Martino et al  and Zhan2 = 0.0%, P = 0.44). Finally, Egger’s test showed that publication bias was not significant under the recessive model (P = 0.74).The recessive model was selected according to the principle of Thakkinstian . The sumTo test whether heterogeneity of the samples affected the results of the meta-analysis, we performed additional analysis. We only used the samples from Germany and China to test the ethnicity effect. The ORs of Germany and China were 1.68 (95% CI: 1.13-2.51) and 1.96 (95% CI: 1.36-2.82), respectively. There was no obvious difference in the results from Caucasian and Asian patients.NQO1 acts as an imperative part of the cellular antioxidant defense system by detoxifying quinines and can prevent the formation of reactive oxygen species. NQO1 gene mutations are linked to tardive dyskinesia, which increases the risk of hematotoxicity after exposure to benzene, and susceptibility to various forms of cancer. Many studies have been carried out to test the hypothesis that the NQO1 C609T polymorphism might be linked to the risk of esophageal cancer, but the results are controversial. This meta-analysis, involving a total of 1,217 esophageal cancer patients and 1,560 controls from eight case-control studies, examined the association of one polymorphisms of the NQO1 gene with esophageal cancer risk. The OR of the pooled NQO1 T allele frequencies for all the studies was 1.32 (95% CI: 1.15-1.52). In addition, significant evidence was found for a correlation between the NQO1 C609T variant and esophageal cancer under the recessive model . Similar to our study, other reports have also shown an association of NQO1 609C > T polymorphism with susceptibility to esophageal tumors. Marjani et al  observedDifferent enzymes encoded by varying NQO1genotypes may affect enzyme activities, and the lack of NQO1 activity encoded by the homozygous TT genotype might result in reduced detoxification of exogenous carcinogens. Traver et al  confirmehttp://www.hapmap.ncbi.nlm.nih.gov): 18.6% in Europeans (CEU) and 50% in Asian populations (HCB).A heterogeneity evaluation is always conducted in statistical analysis in meta-analysis. However, we found low statistical power during heterogeneity testing. Therefore, several subgroup meta-analyses were performed according to ethnicity, control source and case classification. In the racial subgroups, there was a statistically significant asssociation between the NQO1 polymorphism and esophageal cancer. The ORs for Caucasians and Asians were 2.03 (95% CI:1.14-3.61) and 1.53 (95% CI:1.10-2.14), respectively. This showed a possible role of ethnic divergence. Wang et al  also notThe results of this meta-analysis should be interpreted with some caution because there were limitations in our analysis. First, selection bias was a possible major source of heterogeneity from uncontrolled confounders and bias inherent in the study design. For example, there was not an identical criterion for cases and controls among all the included articles. Second, different genotype ratios may have a potential impact on the outcomes. The rate of the TT genotype was very low in Caucasian subjects , but showed a moderate distribution in Asians . Third, we only considered the NQO1 C609T polymorphism in esophageal cancer. However, there may be a possible interaction between the NQO1 C609T polymorphism and other environmental factors.In summary, the present meta-analysis provides information that the NQO1 C609T polymorphism considerably increases susceptibility to or prognosis of esophageal cancer, especially in ESCC patients. Additional population-based studies in large sample sizes should be conducted before its clinical application.The authors declare that they have no competing interests.YH collected the literature data, developed the statistical model, carried out the software implementation and drafted the manuscript. WH collected the literature data, read the full text articles, and checked the model and results. YZ collected the literature data, read the full text articles and drafted the manuscript. XL helped with the discussion in theoretical developments, as well as in drafting the manuscript. MC helped with the discussion both in the theoretical development and English copyediting. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2350/14/31/prepub


The present study was aimed to investigate whether the polymorphism also influences susceptibility and progression of renal cell cancer (RCC) in a Chinese population.Survivin is an inhibitor of apoptosis protein and is involved in the occurrence and progression of human malignancies. Recently, a functional polymorphism  in the promoter of We genotyped this polymorphism using the TaqMan assay in a case-control study comprised of 710 RCC patients and 760 controls. The logistic regression was used to assess the genetic association with occurrence and progression of RCC.P = 0.006, adjusted odds ratio (OR) = 1.38, 95% confidence interval (CI) = 1.08–1.76]. The polymorphism was associated with risk of developing advanced stage  and moderately differentiated  RCC. Furthermore, the patients carrying the CC genotype had a significantly greater prevalence of high clinical stage disease (trendP = 0.003). Similar results were also observed when we restricted the analysis to clear cell RCC, a major histological type of RCC.Compared with the genotypes containing G allele (GG and GC), we found a statistically significant increased occurrence of RCC associated with the CC genotype [survivin may influence the susceptibility and progression of RCC in the Chinese population. Large population-based prospective studies are required to validate our findings.Our results suggest that the functional −31G>C polymorphism in the promoter of  Renal cell cancer (RCC) accounts for more than 90% of all renal malignancies Dysregulation of apoptosis has been implicated in carcinogenesis through abnormally prolonging cell survival and facilitating the accumulation of transforming mutationssurvivin promoter, has been demonstrated to influence survivin expression by modifying the binding affinity of the CDE/CHR repressor survivin could be a potentially genetic marker to predict RCC risk and progression. To test this hypothesis, we genotyped this polymorphism in a case-control study comprised of 710 cases and 760 controls in a Chinese population and assessed the genetic association with occurrence and progression of RCC using logistic regression analysis.Recently, a −31G>C (rs9904341) single-nucleotide polymorphism, which is located at the cell cycle-dependent elements (CDE) and cell cycle homology regions (CHR) repressor binding site of the The study was approved by the Institutional Review Board of the Nanjing Medical University, Nanjing, China. At recruitment, written informed consent was obtained from all participants involved in this study.This is an ongoing molecular epidemiologic study of RCC conducted in the First Affiliated Hospital of Nanjing Medical University, Nanjing, China, from May 2004. The design of the study and the inclusion criteria of the subjects were previously described elsewhere Total genomic DNA was extracted from the peripheral blood by proteinase K digestion and phenol–chloroform extraction. The genotyping of the −31G>C polymorphism (rs9904341) was carried out using predesigned TaqMan SNP Genotyping Assays . The primer and probe sequences are summarized in P value of less than 0.05 was considered as statistically significant. All the analyses were carried out with the software SAS 9.1.3 .The differences in categorical variables such as gender, smoking status, drinking status, and in the frequency distribution of −31G>C alleles and genotypes between the cases and controls were evaluated by Pearson's chi-square test. The differences in continuous variables such as age and BMI were tested by Student's t-test. Before analysis, allele frequencies of the −31G>C polymorphism in the controls was tested against departure from the Hardy-Weinberg Equilibrium (HWE) using the Goodness-of-fit Chi-square test. Associations between the −31G>C polymorphism and RCC risk were evaluated by computing odds ratios (ORs) and 95% confidence intervals (CIs) from unconditional logistic regression analysis with the adjustment for possible confounders. A two-side P = 0.753 and 0.832, respectively). Moreover, no significant differences were observed between the cases and controls with regards to BMI and drinking status . However, more smokers, hypertension patients and diabetics were presented in the cases compared with controls . The majority of patients (84.8%) had the conventional clear cell cancer. When stratified according to the clinical stage, 62.8%, 19.6%, 7.3% and 10.3% of the patients had stage I, II, III and IV disease, respectively. The percent of nuclear grade from I to IV was 19.2%, 48.0%, 24.5%, and 8.3%, respectively.The selected characteristics between the RCC patients and control subjects are presented in P = 0.467 and 0.610, respectively). The frequencies of the GG, GC and CC genotypes among cases were significantly different from those among controls (P = 0.015). The difference in the frequencies distribution of G and C allele among case and controls was also significant (P = 0.006). Compared with individuals carrying G allele (GG/GC), individual with CC genotype had a significantly increased susceptibility to RCC occurrence . Furthermore, the variant −31C allele was also associated with an increased risk for RCC, compared with the −31G allele . Similar results were observed when we restricted the analysis to clear cell RCC . We then examined the effects of the polymorphism on the progression of RCC. As presented in P = 0.021 for RCC and P = 0.018 for ccRCC) in a dose–response manner (Ptrend = 0.003). However, no association between this polymorphism and tumor grade in cases was observed .We then evaluated the effect of the polymorphism on RCC risk stratified by age, BMI, sex, smoking status, smoking level and drinking status. The results were summarized in survivin and risk and progression of RCC. We found that individuals with the −31CC genotype had a significantly increased RCC risk of 1.50 and 1.38, compared with those with GG or GG/GC genotypes, respectively. The polymorphism was also associated with risk of developing advanced stage and moderately-differentiated RCC. Besides, we found that RCC patients carrying the CC genotype had a significantly greater prevalence of high clinical stage disease, compared with those with GG/GC genotypes. To the best of our knowledge, this is the first study to investigate the role of the survivin -31G>C polymorphism in the etiology of RCC.In the present study, we evaluated the associations between the functional −31G>C polymorphism in the promoter of et al. have demonstrated that the expression of survivin was elevated both in RCC cell lines and in tumor tissues survivin promoter −31G>C polymorphism could modulate the expression of survivin survivin −31G>C polymorphism may possess a decreased apoptotic capacity to eliminate cells with DNA damage which may contribute to the occurrence of malignancies. Therefore, it is biologically plausible that the survivin promoter −31G>C polymorphism confers individuals susceptibility to RCC.As a unique inhibitor of apoptosis protein, survivin reduces the susceptibility of tumor cells to apoptotic stimuli and thereby promotes tumor cell survival during tumor development and progression survivin −31G>C polymorphism and cancer risk survivin −31CC genotype and increased cancer risk has been identified by several other studies survivin −31CC genotype was associated with increased risk of other urinary system cancer, such as urothelial carcinoma  survivin −31G>C polymorphism in the development of urinary system cancer. Most recently, a meta-analysis study has been conducted by Srivastava et al. to clarify the associations of this polymorphism and cancer risk survivin −31C allele was associated with 1.27 fold increased risk of cancer. The magnitude of RCC risk found with the C allele or CC genotype in the present study  were similar to the risk observed in the meta-analysis. However, the survivin −31G>C polymorphism was not identified as susceptibility locus for RCC by the recently published genome-wide association studies in European populations survivin −31G>C polymorphism was not included in the GWAS conducted by Purdue et alP = 0.220, OR = 1.07, 95%CI = 0.96–1.18). According to the HapMap database, the rs3764384 is in complete linkage disequilibrium with the survivin −31G>C polymorphism in both Chinese Han populations and Caucasian populations ; the minor allele frequency of −31G>C  in Chinese Han population in Beijing is 0.477, which is dramatically different from that in European population (0.717). Therefore, we speculate that ethnicity differences might play a role in causing the disparity.To date, a number of studies have attempted to evaluate the associations of the survivin was a biomarker to predict RCC progression and prognosis survivin −31CC genotype was associated with progression of RCC, but these results should be interpreted cautiously since there is the possibility that the associations with poor prognosis are due to a late stage at diagnosis. Therefore, if confirmed by additional studies, this polymorphism may help to accurately predict the clinical course of RCC patients. RCC is characterized by high intra-tumor vascularity and, so far several anti-angiogenesis drugs  have proven benefit in treating advanced RCC survivin −31G>C polymorphism, the efficacy of these drugs may be further enhanced. However, lack of available information on the drug treatment of our RCC patients and long-term follow-up restricts our study to explore the influence of the survivin −31G>C polymorphism on the efficacy of these drugs. Therefore, we urge that it be investigated in other studies which focus on the treatment of RCC patients.It has been proposed that expression level of When interpreting our results, another limitation should also be concerned. Because our case-control study was a hospital-based study, we could not rule out a possibility of selection bias of subjects that may have been associated with a particular genotype. However, the −31C allele frequency in our controls was similar to that in the HapMap database for Han Chinese in Beijing (46.4% vs. 48.8%) and was also similar to that in another population-based case-control study of Chinese population (46.4% vs. 47.6%). Besides, the genotype distributions of the polymorphism in our controls conformed to HWE. Therefore, the selection bias in terms of genotype distributions would not be substantial.survivin have a significant influence on the occurrence and progression of RCC in Chinese population. Although the associations appeared to be statistically significant in our population, these initial findings should be independently verified by other large independent population-base studies. Besides, polymorphisms often vary between ethnic groups; therefore, additional studies are also required to clarify the association of this polymorphism with RCC risk in diverse ethnic populations.In conclusion, our case–control study indicates that the −31G>C polymorphism in the promoter of Table S1The sequences of the primers and probe used to genotype the survivin −31 G>C polymorphism.(DOC)Click here for additional data file.Table S2Survivin −31G>C genotypes and risk of RCC in cases and controls.Stratification analyses between (DOC)Click here for additional data file.