P(Z) <10−5, P(Q) <10−4; dominant model: OR = 1.21, 95%CI = 1.14–1.27, P(Z) <10−5, P(Q) <10−4; recessive model: OR = 1.18, 95%CI = 1.12–1.24, P(Z) <10−5, P(Q) = 0.04]. In addition, our data revealed that rs2046210 conferred greater risk in estrogen receptor (ER)-negative tumors  than in ER-positive ones . When stratified by ethnicity, significant associations were found in Caucasian and Asian populations, but not detected among Africans. There was evidence of heterogeneity (P<0.05), however, the heterogeneity largely disappeared after stratification by ethnicity. The present meta-analysis demonstrated that the rs2046210 polymorphism may be associated with increased BC susceptibility, but this association varies in different ethnicities.Genome-wide association studies (GWAS) have identified several genetic susceptibility loci for breast cancer (BC). One of them, conducted among Chinese women, found an association of rs2046210 at 6q25.1 with the risk of BC recently. Since then, numerous association studies have been carried out to investigate the relationship between this polymorphism and BC risk in various populations. However, these have yielded contradictory results. We therefore performed a meta-analysis to clarify this inconsistency. Overall, a total of 235003 subjects based on 13 studies were included in our study. Significantly increased BC risk was detected in the pooled analysis [allele contrast: OR = 1.13, 95%CI = 1.10–1.17,  BRCA1 and BRCA2, have been identified as risk factors for BC, but only account for less than 5% of overall BC cases ESR1 gene, which encodes estrogen receptor α (ERα) and may be involved in the development of BC. Therefore, numerous studies have been carried out to investigate this susceptibility subsequently. However, a proportion of them have produced conflicting results, which may be caused by the restriction of sample size or ethnic diversity. And individual studies may have insufficient power to achieve a reliable conclusion.Breast cancer (BC) is the most common cancer among women worldwide To clarify this inconsistency, we therefore performed the first comprehensive meta-analysis to determine the overall effect of the rs2046210 polymorphism on the risk of BC.Eligible literatures in English language published before January 10th 2013 were identified by a search of PUBMED, EMBASE and ISI Web of Science using combination of following keywords: breast cancer, 6q25.1, rs2046210, single nucleotide polymorphism (SNP or polymorphism). All the references cited in these studies and previous review articles were reviewed to identify additional relevant publications.P-value; (4) the studies described the genotyping methods, equipment and protocol used or provide corresponding reference to them; (5) the diagnosis of BC patients was confirmed histologically or pathologically. The major reasons for exclusion of studies were (1) used overlapping samples; (2) were case-only studies or review articles.For inclusion, eligible studies had to meet all of the following criteria: (1) the studies were published in peer-reviewed journals and were original papers having independent data from other studies; (2) the studies investigated the association between rs2046210 and BC risk using either case–control or cohort design; (3) the studies have sufficient data to calculate the odds ratio (OR) with its 95% confidence interval (CI) and For each study, the following data were extracted independently by two participants: first author’s surname, year of publication, diagnosis criteria, age, ethnicity, study site, study strategy, Hardy-Weinberg equilibrium (HWE) status, genotyping method, source of control, estrogen receptor (ER) status, total number of cases and controls, and genotype frequency among cases and controls. The results were compared and disagreements were discussed and resolved by consensus.2) test was used to test for deviation from Hardy-Weinberg equilibrium (HWE). Odds ratio (OR) with its 95% confidence interval (CI) was used to assess the strength of association between rs2046210 and BC risk. We used allele contrast (A vs. G), dominant (AA+AG vs. GG) and recessive (AA vs. GG+AG) genetic models to examine the relationship between risk allele or genotypes and BC susceptibility. Cochran’s Chi square-based Q statistic test was performed to assess possible heterogeneity across studies. If heterogeneity existed (P<0.05), the random effects model was adopted to calculate the overall OR value Z test.The chi-square .Subgroup analyses were performed according to ethnicity , ER-positive/negative status, sample size (<5000 and ≥5000), and source of controls. In addition, sensitivity analysis was performed to assess the stability of the results by removing each study in turn from the total and re-analyzing the remainder. Funnel plot and Egger’s regression test were used to assess publication bias. All The literature search yielded 127 references, and the study selection process is shown in P(Z) <10−5, P(Q) <10−4; dominant model: OR = 1.21, 95%CI = 1.14–1.27, P(Z) <10−5, P(Q) <10−4; recessive model: OR = 1.18, 95%CI = 1.12–1.24, P(Z) <10−5, P(Q) = 0.04] as shown in P(Z) <10−5, P(Q) = 0.03; dominant model: OR = 1.12, 95%CI = 1.10–1.14, P(Z) <10−5, P(Q) = 0.10; recessive model: OR = 1.14, 95%CI = 1.11–1.18, P(Z) <10−5, P(Q) = 0.99] and Asians . However, there was no evidence indicating significant association among African population in any genetic model (Main results of our study investigating the effect of the rs2046210 polymorphism on BC risk are listed in ic model .P(Z) <10−5, P(Q) <10−4] than ER-positive tumors  .Each study included in the meta-analysis was removed from the total each time to reflect the influence of individual data set to the pooled ORs. According to the result of sensitivity analysis, the pooled ORs were not qualitatively altered after the removal of any data set, even for two studies by Cai et al. The rs2046210 polymorphism was first identified as a risk variant for BC by Zheng et al In the stratified analysis by ethnicity, significant associations were found among Caucasians and Asians in all genetic models, while no association was detected in African population. In fact, the frequency of the risk-associated A-allele was substantially higher in African population (e.g. 69% in HapMap YRI) than in Caucasian (e.g. 29% in HapMap CEU) or Asian populations (e.g. 38% in HapMap CHB). It has been reported that the A-allele may consist of different haplotypes with different risk associations in African population. The study by Ruiz-Narváez et al. Meta-analysis is often dominated by a few large studies, which may remarkably reduce the evidence from smaller studies. However, in the stratified analysis according to sample size, significantly increased BC risk was found in both large and small studies for all genetic models. In the subgroup analysis based on control source, we also found significant associations in all the subgroups , and there was no obvious difference between these subgroups. In addition, our data indicated that rs2046210 was more closely related to ER-negative BC, which is consistent with previous reports in Chinese women ESR1 gene (29 kb upstream of the first untranslated region and 180 kb upstream of the first coding exon) ESR1 encodes estrogen receptor α (ERα), which regulates signal transduction of estrogen, a sex hormone that plays a central role in the etiology of BC. Elevated estrogen levels have been reported to be associated with increased BC risk ESR1 and ESR2, have been the focus of numerous epidemiologic studies on BC risk ESR1, the rs2046210 polymorphism or SNPs in LD with it may modulate the expression of ESR1 and alter its downstream signaling, and then is likely to affect BC susceptibility. Interestingly, it is found in a recent GWAS study that the 6q25.1 locus is associated with bone mineral density, which is also a phenotype affected by estrogen This polymorphism is located upstream of the Despite our efforts to investigate the relationship between rs2046210 and BC risk, some limitations should be acknowledged. First, the subgroup meta-analysis examining the interaction between the ER status and the effect of rs2046210 on BC susceptibility was performed based on limited studies with such information available. Therefore, selection bias may have occurred and the corresponding result may be over inflated. In this context, more reliable result can be expected if relevant statistical data are available for a pooled analysis. Second, results in this meta-analysis were based on unadjusted estimates. If all the individual raw data were provided, a more precise analysis could be conducted which would allow for the adjustment by other covariates including age, drinking status, cigarette consumption and other lifestyles. Third, there was substantial between-study heterogeneity found in the overall pooled analysis. However, the heterogeneity was effectively decreased after stratification by ethnicity. In spite of these limitations, no publication bias was observed, and the large number of study subjects still guarantees the statistical power of our analyses.To conclude, this meta-analysis showed that the rs2046210 polymorphism was significantly associated with increased rick of BC, particularly in Caucasian and Asian populations. Further studies with more accurate phenotype and genotype data, detailed individual information, larger sample size of different ethnic populations and standard statistical methods will be needed to validate our results. Moreover, the interactions between rs2046210 and other SNP loci which are in LD with it should also be evaluated to further elucidate the underlying relationship between this polymorphism and the risk of BC.Figure S1Flow diagram of the literature selection process.(DOCX)Click here for additional data file.Figure S2Funnel plot of the association between rs2046210 and breast cancer risk .(DOCX)Click here for additional data file.Figure S3Funnel plot of the association between rs2046210 and breast cancer risk (dominant model).(DOCX)Click here for additional data file.Figure S4Funnel plot of the association between rs2046210 and breast cancer risk (recessive model).(DOCX)Click here for additional data file.PRISMA Checklist S1(DOC)Click here for additional data file.


Human papillomavirus (HPV) infection is considered the major cause of cervical cancer (CC), but a number of infected women do not develop invasive lesions, suggesting the role of genetic susceptibility and environmental co-factors for cancer outbreak. Glutathione S- transferases (GSTs) are multifunctional enzymes that play a key role in the detoxification of varieties of both endogenous products of oxidative stress and exogenous carcinogens.MEDLINE, EMBASE, and Cochrane databases were searched. All studies evaluating the association between GSTM1 polymorphisms and cervical cancer were included. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using fixed-or random-effects model.A total of 23 case-control studies were included in the meta-analysis. The overall result showed that the association between GSTM1 null genotype and risk for cervical cancer was statistically significant . Subgroup analyses were performed based on ethnicity, smoking and HPV infection. Our results showed that smokers with null GSTM1 genotype had higher risk of cervical cancer . For the ethnicity stratification, significant increased risk of null GSTM1 genotype was found in Chinese and Indian population, but no increased risk in other population was found.this meta-analysis provided strong evidence that the GSTM1 genotype is associated with CC development, especially in Chinese and Indian populations. Smoking and HPV infection modified the association between the null GSTM1 genotype and CC. Cervical cancer (CC) is the second most common gynecologic malignancy in the world and the seventh most frequent overall malignancy According to several epidemiological and biological studies, human papilloma virus (HPV) infection is the dominant etiological event in CC development; however, it is insufficient as a causal agent because this virus is also detected at a certain frequency among women who are cytologically normal, and CC occurs in only a fraction of HPV-infected women. Additional features of the host, including an active sexual history, weakened immune function, and cigarette smoking, have been confirmed as risk factors for CC Previous studies have shown that genetic variations in the glutathione S-transferases (GSTs) affect human phase II detoxification enzymes involved in the detoxification of various exogenous and endogenous reactive species GSTM1 facilitates the excretion of a wide range of carcinogens, reactive oxygen species, and chemotherapeutic agents with a variety of substrate specificities. Its allelic variant *0  caus7es a completely lack of enzymatic activity to bind genotoxic substrates such as epoxides derived from aflatoxin and PAHs This meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines We followed the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) The inclusion criteria were as follows: case-control studies that investigated the association between GSTM1 polymorphisms and the risk of CC and studies that presented original data and the numbers of null GSTM1 genotypes among the cases and controls.Exclusion criteria included the following: duplicate publications; case reports; insufficient data to construct a 2×2 table of the test result; precancerous lesions included among the cases; lack of a control group; and abstracts, reviews, talks, and review class documentations.The data extracted from each study included the authors, publication year, country of origin, average ages of cases and controls, number of null GSTM1 genotypes among the cases and controls, and the adjusted ORs of the selected studies. Smokers were defined as those with a lifetime history of smoking more than 100 cigarettes and who had smoked continuously for at least 1 year until the time of diagnosis; non-smokers were defined as those who had never smoked. The 2×2 tables were reconstructed. Two (Z.S. and H.C.M.) authors independently assessed the articles according to the inclusion/exclusion criteria and referred to Corresponding Author (B.L.H.) in cases of disagreement. When important data were not provided, the authors contacted the article authors via e-mail.The study quality was assessed according to the revised tool for the quality assessment of diagnostic accuracy studies  or absence (p>0.1 and I2<50%) of heterogeneity Data analysis was performed using Review Manager (version 5.0) and STATA software .The association between the GSTM1 gene polymorphisms and CC was estimated by calculating the pooled odds ratios (ORs) with 95% confidence intervals (CIs). ORs were used to analyze the results, and their corresponding 95% CIs were estimated. Cross-study heterogeneity was estimated using the IA flow diagram of the study selection process is shown in 2 = 67% for GSTM1), and therefore, a random-effects model was used. The overall result showed that the GSTM1 null allele was related to an increased risk of CC .The forest plot of the GSTM1 meta-analysis is shown in 2 = 28.9% for non-smokers and P = 0.734, I2 = 0% for smokers). In the ethnicity stratification, a moderately significant increase in risk was associated with the null GSTM1 genotype in Chinese  and Indian populations , but the risk observed in other populations was not significant , while no significant increased risk was observed in non-smokers . After snificant . In the 2of 0%. Further studies are needed to confirm the roles of ethnicity and study design with regard to heterogeneity.Significant cross-study heterogeneity was present in both the overall and subgroup analyses. We explored several possible sources of this cross-study heterogeneity, such as ethnicity, the DNA genotyping sample source, sample size, and quality score. However, none of these variables could explain the heterogeneity, which could have been caused by the limited number of included studies. Regardless of the p value, ethnicity and study design were thought to play important roles. Next, we filtered 3 studies (American population and study design are population-based) and obtained an IDespite CC being among the most common cancers worldwide, the etiology is not yet clearly understood. The present and related studies show that the GST-null genotype is associated with an increased cancer incidence. Moreover, GSTs also play an important modulatory role in the induction of other enzymes and proteins involved in cellular functions such as DNA repair Cigarette smoking, which decreases the ability to clear oncogenic infections, has been found to be an independent risk factor of CC In previous decades, a few meta-analyses that investigated the association between GST polymorphisms and CC found that this association is, however, affected by an important limitation Our meta-analysis included some limitations. First, heterogeneity was a major problem in this meta-analysis. We explored several possible sources of heterogeneity, including the sample size and DNA source. However, we failed to find a clear reason, indicating that a conservative manner should be adopted when interpreting these results. Second, some control sources were population-based In conclusion, this meta-analysis provided strong evidence that the GSTM1 genotype is associated with CC development, especially in Chinese and Indian populations. Smoking and HPV infection modified the association between the null GSTM1 genotype and CC. Studies with large sample sizes should be performed to confirm this finding. Additionally, further studies that investigate the effects of gene–environment interactions on CC risk are required.Checklist S1PRISMA checklist.(PDF)Click here for additional data file.Checklist S2PRISMA Flow Diagram.(PDF)Click here for additional data file.


TERT rs2736100 single nucleotide polymorphism (SNP) and cancer risk has been studied by many researchers, but the results remain inconclusive. To further explore this association, we performed a meta-analysis.The association between the TERT rs2736100 polymorphism and cancer risk was performed and the genotype data were analyzed in a meta-analysis. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association. Sensitivity analysis, test of heterogeneity, cumulative meta-analysis and assessment of bias were performed in our meta-analysis.A computerized search of PubMed and Embase database for publications on the TERT rs2736100 polymorphism and cancer susceptibility was revealed by the results of the meta-analysis of the 25 case-control studies . Moreover, increased cancer risk in all genetic models was found after stratification of the SNP data by cancer type, ethnicity and source of controls.A significant association between the TERT rs2736100 polymorphism and cancer risk was significant. This meta-analysis suggests that the TERT rs2736100 polymorphism may be a risk factor for cancer. Further functional studies between this polymorphism and cancer risk are warranted.In all genetic models, the association between the  Cancer is a multifactorial disease, which is the result of complex interactions between inherited and environmental factors. Lung cancer is the most common malignancy and the leading cause of cancer deaths for women and men worldwide -3. ThereTERT gene product contains three distinct structural domains: the RNA-binding domain (TRBD), the reverse transcriptase domain and the carboxy-terminal extension (CTE), which represents the putative thumb domain of TERT [Telomeres are special nucleoprotein structures located at the ends of eukaryotic chromosomes and are essential for protecting chromosomal termini against degradation, end to-end fusion and rearrangement . Telomer of TERT . Tumor c of TERT , and tel of TERT . Activat of TERT .TERT and cleft lip and palate transmembrane 1 like (CLPTM1L) gene regions are associated with susceptibility to many types of cancer [rs2736100 polymorphism is localized to intron 2 of the TERT gene. McKay et al. [TERT rs2736100 polymorphism may contribute to an increased risk of lung cancer. Since then, several research groups have reported associations between this SNP and cancer risk, but with inconclusive results [In the past decade, many investigators have explored factors contributing to inherited susceptibility to cancer . The seqf cancer . The rs2y et al.  publishe results -31. ConsTERT OR "telomerase reverse transcriptase") AND polymorphism and using the limits, Humans, English, Cancer. The related reference articles were searched to identify other relevant publications. Unpublished data and further information were also obtained from the authors. The case-control studies were selected if data were available on the role of the TERT rs2736100 polymorphism in cancer risk.Eligible studies were identified by searching PubMed, Embase, CNKI, and the Chinese Biomedicine Database , using the following search terms  case-control design, and (3) sufficient genotype data for estimating an odds ratio (OR) with a 95% confidence interval (CI). Articles that were not about cancer research, contained duplicated previous research, or did not include usable genotype data were excluded.In our meta-analysis, the following inclusion criteria were used for selecting the studies: (1) articles about the Two investigators independently extracted the data from all eligible publications using the selection criteria listed above. Any disagreement was resolved by discussion. We extracted the following information from each study when available: the first author's name, year of publication, country, patient ethnicity (composed of either European or Asian), cancer type, source of control groups ), genotyping method and number of cases and controls with the TT, TG, and GG genotypes.P values less than 0.05 were considered statistically significant. We first assessed Hardy-Weinberg equilibrium in the control groups of each study. The OR and 95% CI in each case-control study were employed to assess the strength of the associations between the TERT rs2736100 polymorphisms and cancer risk. The OR and the 95% CI in each comparison were assessed in a codominant model , a dominant model (GG + GT versus TT), a recessive model (GG versus GT + TT) and an additive model (2GG + TG versus 2TT + TG). Subgroup analyses were performed based on cancer type, the source of controls and ethnicity. The chi-square test-based Q-statistic was calculated to test the heterogeneity between studies. If the result of this heterogeneity test was P < 0.05, then the pooled ORs were analyzed using the random effects model (the DerSimonian and Laird method) [P > 0.05, indicating that the between-study heterogeneity was not significant, then the fixed-effects model was selected (the Mantel-Haenszel method) [2 I(2 = 100% × (Q-df)/QI) statistic was then used to quantitatively estimate heterogeneity, with 2 I<25%, 25-75% and >75% representing low, moderate or high degrees of inconsistency, respectively [Z test . Additionally, sensitivity analyses were performed after sequential removal of each study. Cumulative meta-analyses were performed through an assortment of all eligible cancer studies with case sample size. Finally, the Begg's funnel plot and Egger's test were performed to analyze the publication bias statistically (P < 0.05 was considered a significant publication bias) [All statistical analyses were performed using the STATA software . Two-sided  method) . Otherwi method) . The I2 ectively ,35. The In total, 11 articles including 25 case-control studies in English with 23032 cases and 38274 controls met the inclusion criteria. The characteristics of the studies are listed in Table TERT rs2736100 polymorphism among the controls across different ethnicities. For European populations, the G allele frequency was 51.0% (95% CI = 49.6-52.4), which was significantly (P <0.001) higher than that in the Asian populations   were pooled into the meta-analysis, and a significantly increased cancer risk was found for all genetic models based on the studies . Figure TERT rs2736100 polymorphism and cancer risk in the recessive model.As shown in Table TERT rs2736100 polymorphism were stratified by cancer type: the lung cancer subgroup, the glioma subgroup and the other cancers subgroup. The pooled odds ratios for the lung cancer, glioma, the other cancers were 1.39 , 1.34  and 1.22 , respectively, when we use a recessive genetic model. The meta-analysis results for the other genetic models are listed in Table Specific data for the In the stratified analysis by source of controls, significantly increased risks were also found. The pooled odds ratios were 1.38 95% CI 1.29, 1.47) in the population-based controls subgroup and 1.33  in the hospital-based controls subgroups in a recessive genetic model. The meta-analysis results for the other genetic models are listed in Table 9, 1.47 iWe stratified the studies by the ethnicity of the participants into two subgroups, Asian and European, and the pooled odds ratios were 1.40  and1.31 95% CI 1.22, 1.41), respectively, in a recessive genetic model. The meta-analysis results for the other genetic models are listed in Table 2, 1.41, TERT rs2736100 polymorphism and risk of lung adenocarcinoma .Among the 25 studies, many investigators also have established an association between the TERT rs2736100 polymorphism and cancer susceptibility, the results suggested that the significance of the pooled ORs was not influenced by any single study in a recessive genetic model. Sensitivity analyses indicated that the independent study contributing the most to heterogeneity was conducted by Kohno et al. [P heterogeneity = 0.062; 2 I= 32.3%) and 1.35  before and after removal, respectively.Sensitivity analyses were performed after sequential removal of each eligible study. When we investigated the o et al.  . When patients were stratified based on ethnicity, heterogeneity disappeared in the European . In the analysis of the cancer type subgroups, heterogeneity disappeared in the glioma .Significant heterogeneity existed in four genetic models  of the Cumulative meta-analyses were also conducted using the eligible studies sorted by case sample size Figure . There it = 1.03, P = 0.313 for GG versus GT + TT), and the 95% confidence interval  included zero, indicating no publication bias. Additionally, in all genetic models, the results did not show evidence of publication bias.The Begg's funnel plot and Egger's test were performed to assess the publication bias Figure . The resrs2736100 located in intron 2 of TERT, has been hypothesised to be associated with the risk of cancer development by many researchers, however, the results are conflicting and heterogeneous. Here, we analyzed pooled data from case-control studies to determine the role of TERT rs2736100 polymorphism in cancer susceptibility. In the meta-analysis conducted on 23032 cases and 38274 controls, TERT rs2736100 polymorphism was found to be associated with a significantly increased cancer risk. In the subgroup analyses by cancer type, ethnicity and source of controls, increased cancer risk in all genetic models was also found.It is well known that single nucleotide polymorphisms (SNPs) are the most common sources of human genetic variation, which may contribute to an individual's susceptibility to cancer . Thus geTERT gene) in cancer risk at several different sites; lung cancer, basal cell carcinoma and pancreatic cancer show strong associations, while bladder, prostate and cervical cancer as well as glioma show risk alleles in this region [TERT makes it a compelling candidate gene for factors that influence cancer risk [TERT gene has been recognized as one of the most common tumor markers. The TERT gene is located on the short (p) arm of chromosome 5 at position 15.33 which is the reverse transcriptase component of telomerase and the expression of the functional TERT protein is a prerequisite for acquisition of telomerase activity. Telomerase is a ribonucleoprotein enzyme that synthesizes the TTAGGG telomeric repeat sequences that are essential for genomic stability [TERT may have an important role in lung tumorigenesis [A number of well-designed genome-wide association studies (GWAS) have implicated variants at the 5p15.33 locus  and shorter telomere length has been recently reported [rs2736100 was not clear. TERT rs2736100 polymorphism may contribute directly to disease predisposition by modifying the function of TERT or is in highly linkage disequilibrium (LD) with other nearby biologically plausible and disease-causing mutations.Telomerase and the control of telomere length are intimately linked to the process of tumourigenesis in humans . The assreported . The typreported . HoweverTERT rs2736100 polymorphism and adenocarcinoma in all genetic models. TERT gene amplification occurred in 57% of NSCLCs, but was more common among ADCs (75%). TERT gene amplification is responsible for TERT mRNA overexpression in a majority of ADCs, while epigenetic factors at the transcriptional or post-transcriptional levels significantly affect TERT expression in NSCLC cells [Adenocarcinoma is the most common histologic type of lung cancer and the relative proportion of ADC has steadily risen. The strongest risk association was observed between the LC cells . The re-LC cells .There are some limitations of this meta-analysis that should be discussed. First, misclassifications of the histologic type of the cancers reported may influence the results. Second, the lack of detailed information, such as age and sex of the patients, in some studies limited further stratification, and a more accurate OR would be corrected for age, sex and other factors that are associated with cancer risk. Third, in our meta-analysis, the origins of heterogeneity may include many factors, such as the differences in control characteristics and diverse genotyping methods. In addition, the small sample size (<100 cases and controls) studies appear to overestimate the true association because of deficiencies in statistical power.P > 0.01) in all studies. Third, the results did not show any evidence of publication bias.Based on the limitations of the present study listed above, detailed studies are warranted to confirm our findings. Nevertheless, our meta-analysis has some advantages. First, the well-designed search and selection method significantly increased the statistical power of this meta-analysis. Second, the distribution of genotypes in the controls was consistent with Hardy-Weinberg equilibrium (TERT rs2736100 polymorphism is associated with cancer risk. Further functional studies between this polymorphism and cancer risk are warranted.The overall results of this meta-analysis have shown that the The authors declare that they have no competing interests.PZ participated in collection of data and manuscript preparation. GJ and LZ performed the statistical analysis. PZ and AG participated in study design and critically revised the manuscript. PZ and AL participated in study design and manuscript preparation. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/12/7/prepub


The role of matrix metalloproteinase (MMP) gene polymorphisms in the development of chronic obstructive pulmonary disease (COPD) has been reported with inconsistent results. This meta-analysis was performed to assess the association of MMP-1 -1607G/GG and MMP-9 -1562C/T promoter polymorphisms with COPD susceptibility.Published case-control studies from Pubmed and China National Knowledge Infrastructure (CNKI) databases were retrieved. Data were extracted and pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated.A total of fourteen case-control studies were included in this meta-analysis. Pooled effect size showed an association of MMP-9 -1562 C/T with the risk of COPD . However, no correlation with COPD was revealed in MMP-1 -1607G/GG polymorphism. When stratified by ethnicity, results indicated MMP-1 -1607G/GG  and MMP-9 -1562 C/T  were correlated with COPD susceptibility among Caucasians and Asians respectively. According to source of controls, signifiant association of MMP-9 -1562 C/T  with COPD susceptibility was revealed in the subgroup with smoker-based controls. However, in the aforementioned risk estimates, only the association of MMP-9 -1562 C/T (additive and dominant models) with the risk of COPD in the subgroup with smoker-based controls persisted significantly after Bonferroni correction for multiple testing. Moreover, after excluding the studies without Hardy–Weinberg equilibrium and/or with small sample size, the pooled results were robust and no publication bias was found in this study.This meta-analysis suggests, when using healthy smokers as controls, MMP-9 -1562 C/T, but not MMP-1 -1607 G/GG polymorphism is associated with the risk of COPD. Chronic obstructive pulmonary disease (COPD) is a worldwide disease, characterized by not fully reversible and progressive airflow limitation. To date, although the underlying mehanisms of COPD have not been fully understood, a genetic predisposition of COPD has been strongly evidenced Matrix metalloproteinases (MMPs), members of the metzincin group of proteases, have an important part in COPD, owing to their functions as degradation of components of extracellular matrix and regulators of extracellular signaling networks In the past decade, the association of MMP-1 -1607 G/GG and MMP-9 -1562 C/T polymorphisms in the promotor region with COPD susceptibility have been reported with diverse results http://www.cnki.net/). CNKI database was found by Tsinghua University of China in 1996 and includes over 8000 Chinese journals covering natural and social sciences. The languages were limited to English and Chinese. The following search terms were utilized: matrix metalloproteinase or MMP, and gene polymorphism or polymorphism, and chronic obstructive pulmonary disease or COPD. The PRISMA flow diagram   not case-control genetic study, 2) duplicated report, 3) no useful data reported, 4) other MMP polymorphisms except MMP-1 -1607 G/GG and MMP-9 -1562 C/T. Unpublished data were not considered. Disagreement was resolved by discussion before reaching a consensus. If more than one article was published by the same group using the same cases, the study with higher sample size was selected.In the present meta-analysis, three genetic models were used as follows: 1) additive ; 2) dominant ; 3) recessive . Categorical variables were presented as odds ratio (OR) with 95% confidence interval (CI). Pooled ORs with 95% CI were calculated and p<0.05 was accepted with statistical significance. Heterogeneity was checked by the Q test. Meta-analysis was done with the fixed-effects model when there was no heterogeneity (p≥0.1). Otherwise, the random-effects model was used. Subgroup analysis was performed by enthinity and source of controls to assess the effect of possible clinical heterogeneity on the summary ORs. Bonferroni correction was utilized for multiple testing. Because multiple comparisons in the two polymorphisms were performed 15 times respectively, the P value lesser than 0.05/15 (0.0033) was accepted for statistical significance after Bonferroni correction. Pearson's χ2 test was used to determine whether the observed frequencies of genotypes in controls conformed to the Hardy–Weinberg equilibrium (HWE). Studies with controls that depart from HWE (p<0.05) and/or with a small number cases (n≤60) were subjected to a sensitivity analysis in order to check the consistency of the overall effect size. Funnel plots, as well as the Begg's rank correlation test and Egger's linear regression test, was used to inspect the potential publication bias, and p<0.05 was considered significant publication bias. All analyses were conducted using Revman 5.0  and Stata 11.0 .Thirty-nine studies were relevant to the search terms. After reviewing the titles, abstracts and articles, twenty-five studies were excluded and thus a total of fourteen studies matched the inclusion criteria Figure 1.Combined results indicated significant association of MMP-9 -1562C/T with an increased risk of COPD using a dominant model , However, no association was found between MMP-1 -1607G/GG and the risk of COPD. In the ethnicity-specific subgroup analysis, MMP-1 -1607G/GG polymorphism had a higher risk for COPD in Caucasians in a recessive model , however, the same pattern of result was found for MMP-9 -1562C/T polymorphism in Asians using a dominant model . Moreover, according to source of controls, signficant association of MMP-9 -1562C/T with COPD risk was revealed in the subgroup with smoker-based controls in the additive   and recessive  models.Significant heterogeneity was revealed between all studies in the meta-analysis, and the source of heterogeneity was detected by ethnicity and source of controls. When stratified by ethnicity, using the three genetic models, no heterogeneity was observed in the studies on both polymorphisms in Caucasians, but not Asians (data not shown). According to source of controls, no significant heterogeneity for MMP-1 -1607G/GG and MMP-9 -1562C/T was revealed in the subgroup with population-based controls, while there was significant heterogeneity in smoker-based control subgroups except for MMP-9 -1562C/T in the additive  were lack of HWE and/or smaller sample size, which had a potential to influence the robustness of the present meta-analysis. However, exclusion of these studies did not significantly alter the pattern of the pooled effect size in both polymorphisms (data not shown).The funnel plots showed no sigificant asymmetry in studies on both polymorphisms (data not shown). Moreover, publication bias was not suggested by Begg's rank correlation test  and Egger's linear regression test .MMP-1 and MMP-9, major members of MMPs, contribute to the development of cigarette-induced emphysema In this meta-analysis, MMP-9 -1562C/T, but not MMP-1 -1607G/GG, was found to be correlated with COPD in a dominant model, indicating individuals carrying at least a T allele may have a higher risk for COPD than those carrying C homozygote. Interestingly, in the included studies, minor allele frequency (MAF) for MMP-1 -1607 G/GG was dramatically different between Asians and Caucasians, while MAF for MMP-9 -1562C/T in Caucasians was within the range of that in Asians, which manifested MMP-1 -1607 G/GG polymorphism for COPD was probably in an ethnicity-specific pattern and the variability of MMP-9 -1562C/T for COPD might be across different ethnicities or geographic locations. However, significant heterogeneity was revealed between all studies. To identify the source of heterogeneity, subgroup analysis was performed according to ethnicity and source of controls. Pooled ORs by meta-analysis suggested an ethnicity-dependent results that MMP-1 -1607G/GG in Caucasians (recessive model) and MMP-9 -1562C/T in Asians (dominant model) were risk factors for COPD. Noticeably, no heterogeneity was observed in the studies on both polymorphisms in Caucasians. Futhermore, according to source of controls, there was a signficant association of MMP-9 -1562C/T with COPD risk in the subgroup with smoker-based controls, with no heterogeneity in the additive and recessive models. However, the same pattern of result was not observed in the analysis of MMP-1 -1607G/GG polymorphism. These data suggested different ethnicity and source of controls may account for the overall heterogeneity. Noticeably, after Bonferroni correction for multiple testing, only the association of MMP-9 -1562C/T polymorphism (additive and dominant models) in the subgroup of smoker-based controls and COPD risk persisted significantly, while no other associations were found. In the assessment of the robustness of this meta-analysis, no significant alteration of the total effect size in both polymorphisms was detected with exclusion of the studies for departure from the HWE and/or smaller sample size. Publication bias was not suggested in the present study, possibly owing to the deliberate search strategy and data extraction.However, some limitations should be considered. First, the pooled estimates in this meta-analysis were not based on adjustment by confused factors, such as sex, age, smoking history. Second, some of the studies had small sample size and did not have adequate power to detect the risk for COPD. Third, lack of the original data in the studies limited our further analysis of the potential interactions between gene and gene, or gene and environment, which might modulate COPD risk.In conclusion, although the pooled estimates should be interpreted with caution, our meta-analysis suggests, when using healthy smokers as controls, MMP-9 -1562C/T, but not MMP-1 -1607G/GG polymorphism is associated with the risk of COPD. However, large sample size studies with unbiased genotyping methods, standardized defined COPD cases and matched controls in different populations, and more detailed data about individual and environment are warranted. Additionally, investigators should pay more attention to the combined effects on gene-gene and gene-environment interactions that may lead to a better understanding of the association of MMP gene polymorphisms with COPD risk.Figure S1The PRISMA flow diagram.(DOC)Click here for additional data file.Table S1PRISMA Checklist.(DOC)Click here for additional data file.


KCNQ1 rs2237892 C→T gene polymorphism is reportedly associated with T2DM susceptibility, but various studies show conflicting results. To explore this association in the Asian population, a meta-analysis of 15,736 patients from 10 individual studies was performed. The pooled odds ratios (ORs) and their 95% confidence intervals (CIs) were evaluated using random-effect or fixed-effect models. A significant relationship between the KCNQ1 rs2237892 C→T gene polymorphism and T2DM was observed in the Asian population under the allelic , recessive , dominant , and additive  genetic models. In the subgroup analysis by race, a significant association was found in Chinese, Korean and Malaysia population, but not in Indian population. KCNQ1 rs2237892 C→T gene polymorphism was found to be significantly associated with increased T2DM risk in the Asian population, except Indian population. The C allele of the KCNQ1 rs2237892 C→T gene polymorphism may confer susceptibility to T2DM.The  Diabetes mellitus (DM) has become a major public health problem in China. About 9.7% of Chinese adults currently suffer from DM, which is not even diagnosed in 60.7% of these cases. Moreover, 15.5% of Chinese adults have pre-diabetes, which is an important risk factor for the progression of overt DM and cardiovascular diseases KCNQ1) gene has been identified as a novel gene susceptible to T2DM in the Genome-Wide Association Studies (GWAS) by Unoki et al. et al. KCNQ1 with T2DM was replicated in populations with Korean, Chinese and European ancestry as well as in two independent Japanese populations.Type 2 diabetes mellitus is a polygenic metabolic disorder with genetic heterogeneity. The voltage-gated potassium channel or KQT-like subfamily member 1  that is being substituted with thymine (T).KCNQ1 rs2237892 C→T gene polymorphism and T2DM have been performed, the results of the individual studies were inconsistent. Lee et al. KCNQ1 rs2237892 C→T gene polymorphism conferred a risk of T2DM in the Korean population. Similarly, Liu et al. KCNQ1 rs2237892 C variants in a Chinese population. By contrast, Chen et al. KCNQ1 rs2237892 gene locus in another Chinese population.Although many studies on the relationship between KCNQ1 rs2237892 C→T gene polymorphism with T2DM in the Asian population (Data S1).As the genotype distribution is different between continents, this study involved the meta-analysis of 7607 T2DM patients and 8129 controls to determine the relationship of KCNQ1’, ‘rs2237892’, ‘T2DM’, and ‘polymorphism’. The last research was updated on 10 September 2013, with the date of publication ranging from 2008 to 2012.The electronic databases as PubMed, Embase, Web of Science, China National Knowledge Infrastructure, and China Biological Medicine Database were searched using the terms ‘i) Evaluation of the KCNQ1 rs2237892 C→T gene polymorphism and T2DM; (ii) the diagnosis of T2DM was according to the American Diabetes Association fasting plasma criteria (2005), which requires that the fasting plasma glucose levels of patients be ≥7.0 mmol/l or that the 2 hrs plasma glucose level be ≥11.1 mmol/l; (iii) the studies should be case–control or cohort studies published in the official journals; and (iv) the studies should be consistent with the Hardy–Weinberg equilibrium (HWE).The selected studies had to meet the major criteria: , the recessive (TT versus CC+CT), the dominant (CC versus CT+TT) and the additive (C versus T) genetic models, were used. The association of KCNQ1 rs2237892 C→T gene polymorphism and T2DM was compared by using ORs and their corresponding 95% CIs. The heterogeneity between the individual studies was calculated using Chi-square-based Q-tests and the significance level was set at P < 0.05 P < 0.05.Four genetic models, which include the allelic , recessive , dominant , and additive genetic models . The subsequent meta-regression was carried out to explore the source of the heterogeneity. Under the dominant genetic model, the heterogeneity could be explained by CC genotype number of the T2DM group sample size , total T2DM group sample size , CT genotype number of the T2DM group , TT genotype number of the T2DM group , CC genotype number of the control group sample size  and CT genotype number of the control group sample size . Based on T0, the whole population was divided into two subgroups. The studies with T0 < 600 belonged to subgroup 1 and the remaining studies with T0 > 600 belonged to subgroup 2. In the following subgroup analysis stratified by T0, significant T2DM risk increases were detected in the two subgroups . Nevertheless, the heterogeneity was significantly reduced in subgroup 1  and was even higher in subgroup 2 than in the entire population  (Significant heterogeneity existed under the dominant genetic model = 73.1%)  and 3..1%  and KCNQ1 rs2237892 C→T gene polymorphism and T2DM was observed in the Chinese subgroup under the allelic , recessive , dominant , and additive genetic models . A significant association was also found between KCNQ1 rs2237892 C→T gene polymorphism and T2DM in the Korean subgroup under the allelic , recessive , dominant , and additive genetic models . In the Malaysian subgroup, a significant association was also observed under the allelic , dominant  and additive genetic models . However, no significant association was found between KCNQ1 rs2237892 C→T gene polymorphism and T2DM under the recessive genetic model .In the subgroup analysis stratified by race, a significant association between KCNQ1 rs2237892 C→T gene polymorphism and T2DM under the allelic , recessive , dominant  and additive genetic models    and 4.KCNQ1 rs2237892 C→T gene polymorphism and T2DM (OR = 1).A logistic regression on multivariable adjusted risks such as age, sex, body mass index (BMI), ethnicity and sample size have been carried out. These risk factors were found to have no effect on the association of T = 1.27, P = 0.241).The publication bias of the individual studies was assessed using the funnel plot and Egger's test. No visual publication bias was found in the funnel plot , and no KCNQ1 rs2237892 C→T gene polymorphism and T2DM under allelic (OR: 1.350), recessive (OR: 0.650), dominant (OR: 1.450) and additive genetic (OR: 1.346) models in the Asian population. In conclusion, the present results showed that the KCNQ1 rs2237892 C allele may increase T2DM risk and confer T2DM susceptibility to Asians.In the current meta-analysis, a significant relationship existed between heterogeneity < 0.05), the meta-regression has been carried out to find the heterogeneity source. In the subsequent heterogeneity source analysis under the dominant genetic model, T0 was shown to be the main possible heterogeneity source (P = 0.001), while in the additive genetic model, the confounding factor CC0 could explain the heterogeneity source (P = 0.008).Taking into account that the heterogeneity existed under the dominant genetic model (PI2 = 0%) and strengthened in the subgroup 2 (I2 = 73.1%). Hence, T0 mainly caused the heterogeneity under the dominant genetic model. Moreover, the total control group sample size should be better matched between the individual studies to further reduce the heterogeneity.Under the dominant genetic model, the subgroup analysis stratified by T0 demonstrated that although increased T2DM risks were observed in both subgroups, the heterogeneity was weakened in the subgroup 1 (KCNQ1 rs2237892 C→T gene polymorphism and T2DM in Chinese, Korean, and Malaysian subgroups but not in the Indian population. The varying results between the different races were probably associated with different ethnicities. The consequences of these racial differences might have on the results and conclusions. Additionally, the number of manuscripts included in the Korean, Indian and Malaysian subgroups was relatively small, which might have caused the difference among the races. More studies should be carried out in the future to verify the association between KCNQ1 rs2237892 C→T gene polymorphism and T2DM in Asian populations.In the subgroup analysis stratified by race, a significant relationship existed between the KCNQ1 rs2237892 C→T gene polymorphism and T2DM has not yet been elucidated. KCNQ1 gene encodes for the pore-forming subunit of the voltage-dependent potassium ion channel, which is required for the repolarization of the cardiac action potential and for water and salt transportation in epithelial tissues. Previous studies have shown that KCNQ1 variants led to cardiac long-QT syndrome and sudden infant death syndrome KCNQ1 is produced in the pancreatic islets, and the specific KCNQ1 blocker 293B stimulates insulin secretion et al. et al. KCNQ1 gene might have an effect on T2DM through factors other than weight gain. In the current meta-analysis, the KCNQ1 rs2237892 C allele increased the T2DM risk, which may be associated with insulin hyposecretion. However, this hypothesis needs to be verified by more studies.At present, the exact mechanism of the association of et al. KCNQ1 rs2237892 C→T gene polymorphism and T2DM, and they concluded that the KCNQ1 rs2237892 C allele increased the T2DM risk. Although the conclusion was similar to that obtained from the current meta-analysis, the current meta-analysis was more superior as compared with their work. Zhou's paper was published in 2010, while the current meta-analysis included literature published from 2010 up to the present. In addition, only the dominant and recessive genetic models were adopted in Zhou's work, while in the current meta-analysis, four genetic models were used namely, the allelic, dominant, recessive and additive genetic models. Hence, the conclusion of this study must be more objective and credible than theirs. Meanwhile, Unoki et al. et al. et al. KCNQ1 rs2237892 using genome-wide association studies and obtained positive results. However, concrete data were not available and cannot be adopted. Moreover, with regard to the study of Tan et al. et al. et al. KCNQ1 rs2237892 C→T gene polymorphism and T2DM afterwards. Although they obtained positive results, the number of genotypes in the aforementioned manuscripts could not be retrieved yet and neither of their conclusions was credible. In the current meta-analysis, the data extraction process was stricter than theirs, and the results and the corresponding conclusion must be more objective than the previous meta-analyses. Furthermore, considering that the difference races might influence the research results, the subgroup analysis stratified by races have been performed in the current meta-analysis and it was shown that there was a significant association of T2DM with KCNQ1 rs2237892 C→T gene polymorphism in Chinese, Korean and Malaysia population and not in the Indian population. However, in those previous meta-analyses, such subgroup analysis has not been carried out. Hence, the conclusion deduced from the present meta-analysis should be more comprehensive than those from the previous meta-analyses.In 2010, Zhou KCNQ1 rs2237892 C→T gene polymorphism and T2DM in the current research, the KCNQ1 expression level was influenced by other genetic factors. As T2DM is a multigenic heredity disease, KCNQ1 rs2237892 C→T gene polymorphism might be associated with the gene linkage disequilibrium of KCNQ1 rs2237895 A→C, rs2237897 C→T and rs2074196 G→T gene polymorphisms, which might increase the T2DM risk However, the present meta-analysis has some limitations. Large-scale studies on the association of T2DM with KCNQ1 rs2237892 C→T gene polymorphism were still not adequate. Although logistic regression has shown that age, sex, BMI, ethnicity, or sample size has no effect on the association of KCNQ1 rs2237892 C→T gene polymorphism was markedly associated with increased T2DM risk in the Asian population, except Indian population. People with the C allele might be susceptible to T2DM risks. The current conclusion might help us to formulate individual T2DM therapy strategies. Given the limitations, more large-scale studies are needed to clarify the significance of the conclusion.


Leukemia is the most prevalent childhood cancer, and Acute Lymphoblastic Leukemia (ALL) constitutes 75% of all cases. Some epidemiological studies have shown a relationship between socioeconomic status (SES) and some childhood cancers. In the present study, an attempt was made to assess socioeconomical status in a case-control study.In 2010, a case-control study was conducted on 100 cases of acute lymphoblastic leukemia aged 1 to14 years in Department of Pediatric Oncology of Dr.Sheikh Hospital in Mashhad – Iran and matched age and sex with 400 healthy controls. Data was collected by interview using a questionnaire. Ninety five percent confidence intervals were used to measure the relationship between childhood Acute Lymphoblastic Leukemia and parental education, income status, father's job (Socioeconomic status), number of children, birth score and paternal smoking. There was a significant difference in parental education level, income status, and number of children, birth score, father's job and paternal smoking between two groups. Regression analysis showed that the risk of childhood ALL associated with paternal smoking, and father's high risk job. Fifty percent cases and thirty five percent of control groups located in upper lower and lower middle class of socioeconomic status, respectively. There is a meaningful different between socioeconomic status in two groups. But the risk of childhood ALL did not associate with socioeconomic status.The results suggest that paternal smoking and father’s high risk job are related to risk of childhood leukemia. It should be considered for planning support. In the US, the incidence of ALL is roughly 6000 new cases per year, or approximately 1 in 50,000. ALL accounts for approximately 70 percent of all childhood leukemia cases (ages 0 to 19 years), making it the most common type of childhood cancer. ALL is slightly more common in males than females  and some childhood cancers, such as lymphoma or leukemia. In the present study, an attempt was made to assess socio-economical class in a case-control study investigating childhood leukemia. Over the last years, the interest in assessing social inequalities and health has increased substantially. Socioeconomic characteristics are associated with morbidity and mortality discrepancies in many developed countries . The relationship between social inequalities and cancer has been well studied for adults but less extensively for childhood cancer. Childhood leukemia seems to be unique in this aspect, as earlier it was reported that childhood leukemia was more frequent among individuals of low socioeconomic status (SES). A comprehensive review on the association between SES and childhood leukemia was recently published and the authors have pointed out that this association is likely to vary according to time, place and study design .There are more positive associations  in older studies and negative associations in newer ones. Overall, studies conducted in Europe have shown a positive association between childhood ALL and SES, while North-American studies reported negative ones. Registry-based and record-based studies generally presented positive associations, whereas interview-based case–control studies showed negative associations , 6. The A case-control study was conducted on 100 cases of acute lymphoblastic leukemia age 1 to 14 years in department of pediatric oncology of Dr.Sheikh Hospital in Mashhad – Iran and matched on age and sex to 400 healthy controls. The control group consisted of four hundred children between the ages of 1 to 14 years without any malignancy, hematologic or chronic disorders, who were seen in the outpatient clinics for mild infectious diseases. The diagnosis of ALL was confirmed by an oncologist. Data was collected by interview using a questionnaire. We measured socioeconomic status by kuppuswamy’s socioeconomic status scale. In this scale, parental education, income status and father's job were measured and classified in five classes .Statistical analysisData analyzed by chi-square test and regression analysis. 95% confidence intervals were used to measure the relation between childhood ALL and parental education, income status, father's job (Socioeconomic status), number of children, birth score and paternal smoking.Out of 100 patients with ALL, 23 % (n=23) had uneducated fathers, 55% (n=55) had Primary and secondary school, 18% (n=18) had diploma and4% (n=4) had above diploma. While of 400 children in controls, 8% (n=32) had uneducated fathers, 43% (n=172) had Primary and secondary school and 28% (n=112) had a diploma and 21% (n=84) had above diploma. There was a significant difference in father's education level between two groups by chi-square test .Out of 100 patients with ALL, 34% (n=34) had uneducated mothers, 45% (n=45) had Primary and secondary school, 21% (n=21) had a diploma and no one had above diploma. While of 400 children in controls, 7% (n=28) had Uneducated mothers, 50 % (n=200) had Primary and secondary school and 26 % (n=104) had diploma and 17 % (n=68) had above diploma. There was a significant difference in mothers’ education level between two groups by chi-square test .Family income state in two groups was significantly different by chi – square test . Eighty one % (n=81) of cases in ALL group and 21 % (n=84) of case group have low incomes. Also 19 % (n=19) of cases in ALL group and 79% (n=316) of case group were in the intermediate and high income category.Among case fathers, 40 % reported having smoke, compared with 5 % of control fathers. Forty percent of parents of children in the study were smokers, while this was 5 % for fathers in control group There was a significant difference in paternal smoking between two groups by chi-square test .Number of children in two groups was significantly different by chi-square test . The number of children in 26 % of cases and 38 % of controls were three and one respectively.Birth score in two groups was significantly different by chi-square test . Birth score of children in 30% of cases and 59% of control were one.There was significant difference between father′s high risk jobs in two groups . 27% (n=27) of patients in case and 3 % (n=12) in control group had fathers with high risk jobs. The type of high risk job in most of the ALL group were 74 % (n=20) farming and 26% (n=7) painting.Regression analysis showed the risk of childhood ALL associated with paternal smoking  and father's job .Overall, studies utilizing area-based socioeconomic measures have demonstrated an increased risk of ALL among people with high SES . In Yorkshire, England, an ecological study performed on 248 children (<15 years) revealed a marked reduction in incidence of ALL for the highest quintile of deprivation  , income status  and father's job (0.002) between two groups (case and control). The risk of childhood ALL was associated with paternal smoking , alcohol drinking  and addiction  . The association between parental smoking and risk of childhood acute lymphoblastic leukemia (ALL) was investigated in an Australian population-based case-control study that included 388 cases and 868 controls aged <15 years, recruited from 2003 to 2006. Data was analyzed by logistic regression. Maternal smoking was not associated with risk of childhood ALL, but the odds ratio for paternal smoking of ≥15 cigarettes per day around the time of the child's conception was 1.35 . Study results suggest that heavier paternal smoking around the time of conception is a risk factor for childhood ALL , individual-level and ecological-level measures may represent different risk factors, we advise researchers to report these measures separately rather than in summary indices of social class .The frequency of leukemia in children whose fathers were painters or farmers is higher than normal children. So people with these occupations should pay more attention and should be protected against these risk factors.


CYP2C9 gene, namely CYP2C9*2 and CYP2C9*3, differ from wild-type CYP2C9*1 by single amino acid substitutions. These mutated alleles encode enzymes with altered properties that are associated with impaired metabolism. In the past decade, a number of case-control studies have been carried out to investigate the relationship between the CYP2C9 polymorphism and CRC susceptibility, but the results were conflicting. To investigate this inconsistency, we performed a meta-analysis of 13 studies involving a total of 20,879 subjects for CYP2C9*2 and *3 polymorphisms to evaluate the effect of CYP2C9 on genetic susceptibility for CRC. Overall, the summary odds ratio of CRC was 0.94  and 1.00  for CYP2C9 *2 and *3 carriers, respectively. No significant results were observed in heterozygous and homozygous when compared with wild genotype for these polymorphisms. In the stratified analyses according to ethnicity, sample size, diagnostic criterion, HWE status and sex, no evidence of any gene-disease association was obtained. Our result suggest that the *2, *3 polymorphisms of CYP2C9 gene are not associated with CRC susceptibility.CYP2C9 enzyme activity is involved in the metabolism of substances related to colorectal cancer (CRC), and it is functionally linked to a genetic polymorphism. Two allelic variants of the  Colorectal cancer (CRC) is the third most common type of cancer in the western world and is responsible for approximately 50,000 deaths per year CYP2C9*2 (R144C) and *3 (I359L) produce slow-metabolizing enzymes compared with wild-type CYP2C9*1 CYP2C9 gene may be a good candidate for genetics studies on CRC.Specific components of the western diet including meat consumption (particularly red and/or well-done meat) and dietary fat (particularly polyunsaturated fatty acids) have been proposed as risk factors which influence susceptibility to colorectal cancer CYP2C9 polymorphisms and CRC risk among various populations. But the results are not always consistent. There are several possible explanations for this discordance, such as small sample size, ethnic background, uncorrected multiple hypothesis testing, and publication bias. Meta-analysis is a statistical procedure for combining the results of several studies to produce a single estimate of the major effect with enhanced precision. It has become important in cancer genetics because of rapid increases in the number and size of datasets. The aim of the present study is to perform a comprehensive meta-analysis to evaluate the association between the CYP2C9 *2 and *3 polymorphism and CRC.Over the past few years, considerable efforts have been devoted to exploring the relationships between the CYP2C9 polymorphisms and CRC risk published before the end of May 2012. The following keywords were used: “colorectal” or “colo*,” “cancer” or “tumor” or “carcinoma,” and “CYP2C9” or “cytochrome P450 2C9”. Additional studies were identified by a hand search of references of original studies and review articles on the association between the CYP2C9 polymorphism and CRC. No language restrictions were applied.We searched the PubMed, Embase, and ISI Web of Science for all articles on the association between CYP2C9 *2 or *3 polymorphism and CRC risk and (iii) genotype distribution information in cases and controls or odds ratio (OR) with its 95% confidence interval (CI) and P-value. Major reasons for exclusion of studies were (i) review, or editorial, or comment; (ii) duplicated studies; (iii) no sufficient data were reported.We reviewed abstracts of all citations and retrieved studies. The following criteria were used to include published studies: (i) identification of colorectal cancer cases was confirmed histologically or pathologically, (ii) case–control or cohort studies to evaluate the association between Two investigators extracted information from all eligible publications independently according to the inclusion criteria listed above. Disagreements were resolved by discussion with co-authors. For each included study, the following information was extracted from each report according to a fixed protocol: first author's surname, publication year, definition and numbers of cases and controls, diagnostic criterion, frequency of genotypes, source of controls, gender, age, Hardy–Weinberg equilibrium (HWE) status, ethnicity and genotyping method.CYP2C9 *2 and *3 polymorphism was estimated using ORs, with the corresponding 95% CIs. For the *2 polymorphism, we first estimated the risks of the *2 heterozygous and *2 homozygote genotypes on CRC, compared with the wild-type *1 homozygote. The risk of *2 carrier versus *1 on cancers was then evaluated in dominant model. The same evaluation was carried out for the *3 polymorphism.We first assessed HWE in the controls for each study using goodness-of-fit test (chi-square or Fisher's exact test) and a P<0.05 was considered as significant disequilibrium. The strength of the association between CRC and the 2 statistic to quantify the proportion of the total variation due to heterogeneity Both the Cochran's Q statistic In order to assess the stability of the results, one-way sensitivity analyses were performed by removing each individual study in turn from the total and re-analyzing the remainder. Egger's regression test and funnel-plot analysis were used to assess publication bias CYP2C9 polymorphism and CRC were included in the current meta-analysis CYP2C9 *2 polymorphism, including a total of 9154 cases and 10900 controls, and for the *3 polymorphism 12 studies were identified covering a total of 7701 cases and 9287 controls. Characteristics of studies included in the current meta-analysis are presented in There were 63 papers relevant to the searching terms. The study selection process is shown in CYP2C9 *2 polymorphism is shown in CYP2C9 *2 polymorphism (P>0.05). The combined OR from the fixed-effects model was not significant with OR of 0.94  for the variant carriers. Similarly, no significant associations were found for heterozygous  and homozygous  when compared with wild genotype. Subgroup analysis for CRC risk of CYP2C9 *2 was also performed to explore the sources of heterogeneity. In the subgroup analyses by ethnicity, sample size, HWE status, diagnostic criteria and sex, no significant results were found in almost all genetic models .CYP2C9 *3 were not associated with CRC risk when compared with the wild-type *1 homozygote . Similarly, no associations were observed in the dominant genetic model , gender of cases (P = 0.34) and controls (P = 0.37), diagnostic criteria (P = 0.91) and the status of Hardy–Weinberg equilibrium (p = 0.05) did not significantly explained such heterogeneity. By contrast, ethnicity (P = 0.001) were significantly correlated with the magnitude of the genetic effect.A single study involved in the meta-analysis was deleted each time to reflect the influence of the individual dataset to the pooled ORs, and the corresponding pooled ORs were not qualitatively altered, suggesting that the results of this meta-analysis are stable  and S3. CYP2C9 is a polymorphic gene in the human population; the genetic variations have been studied with respect to a variety of cancer types. In recent years, a number of molecular epidemiologic studies have been conducted to evaluate the role of *2 and *3 polymorphisms in the CYP2C9 gene on CRC risk; however, the results remain conflicting rather than conclusive. As a powerful statistical method, meta-analysis can provide a quantitative approach for pooling the results of different research on the same topic, and thus a quantitative assessment of association between CYP2C9 polymorphism and CRC risk was of great value. The present meta-analysis, including 9463 cases and 11416 controls from 13 case–control studies, explored the association between the *2 and *3 polymorphism of CYP2C9 gene and CRC risk. To the best of our knowledge, this is the first comprehensive meta-analysis concerning the relationship between CYP2C9 polymorphism and CRC susceptibility. Overall, we did not find any significant association between CYP2C9 *2, *3 polymorphism and CRC susceptibility. In the stratified analysis by ethnicity, sample size, HWE status, diagnostic criteria and sex, significant associations were still not observed in all genetic models. CYP2C9 genotype was not found to be a determinant of colorectal cancer susceptibility according to the results of present meta-analysis.A number of factors predict CRC; however, detailed mechanisms of CRC remain a matter of speculation. However, accumulative evidences have suggested an important role for genetics in determining risk for CRC CYP2C9*3 encodes a protein with approximately 5–30% of the activity of the common reference allele CYP2C9*3 allele carriers have reduced carcinogen activating ability and thus reduced disease risk. However, the increased CRC risk associated with CYP2C9*2 genotype in earlier studies suggests that the enzyme may play a more important role in detoxification of carcinogens.Although CYP2C9 is active in the metabolism of several commonly prescribed drugs, including warfarin, phenytoin and non-steroidal anti-inflammatory drugs (NSAIDs) CYP2C9 and UGT1A6 has been reported among Caucasian population UGT1A6 and CYP2C9, aspirin or ibuprofen use, and CRC risk were determined in 2295 CRC cases and 2903 controls. Their data showed the enhanced effect of slower-metabolizing CYP2C9 variants on the chemopreventive activity of ibuprofen against CRC, and CYP variants were more effective in individuals with wild-type rather than variant UGT1A6CYP2C9 polymorphism to CRC etiology.Epidemiological data indicated the use of NSAID is inversely associated with the risk of developing colorectal cancer CYP2C9 *2, *3 polymorphism and the risk of CRC, the associations between CYP2C9 polymorphism and CRC risk might be modified when exposed to some factors such as tobacco smoking CYP2C9 genotypes modified the CRC risk associated with smoking status. Women with variant genotypes who smoked >20 pack-years had a 2.5-fold greater odds of adenoma compared with women with wild-type genotypes who smoked ≤20 pack-years. Because of limited data in primary studies, we could not quantitatively analyze the modification effects of smoking on the relationships between CYP2C9 polymorphisms and CRC risk.Although there is no association between CYP2C9 polymorphism and these covariates and CRC is needed in order to determine clearly the impact of CYP2C9 polymorphism on the etiology of CRC. Thirdly, meta-analysis is a type of retrospective study, and the recall and selection bias might exist. In spite of these, our meta-analysis also had some advantages. First, substantial numbers of cases and controls were pooled from different studies, which significantly increased the statistical power of the analysis. Second, no publication bias was detected; indicating that the whole pooled result may be unbiased.Limitations also inevitably existed in this meta-analysis. Firstly, most studies were conducted in Caucasian population. Therefore, it could be under powered to detected the interaction among Asian population in subgroup analysis. Hence, 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 since we did not have original data. Therefore, we were not able to take into account other factors like obesity, inflammation, aspirin/NSAID use, vitamin D and vitamin E intake, which may modify the risk estimates, as reported in previous publications. Thus, assessment of the association between CYP2C9 *2 and *3 polymorphism is not associated with altered susceptibility to CRC. As studies among other populations are currently limited, further studies including a wider spectrum of subjects should be carried to investigate the role of these variant in these populations, which should lead to better, comprehensive understanding of the association between the CYP2C9 polymorphism and CRC.In conclusion, this meta-analysis evaluates the relation-ship between genetic polymorphism and CRC risk and reveals that This meta-analysis is guided by the PRISMA statement .Figure S1The association study selection process.(TIF)Click here for additional data file.Figure S2Result of sensitivity analyses for CYP2C9*2 carrier and CRC risk.(TIF)Click here for additional data file.Figure S3Result of sensitivity analyses for CYP2C9*3 carrier and CRC risk.(TIF)Click here for additional data file.Figure S4Funnel plot for the association between and CYP2C9 *2 carrier and colorectal cancer risk; Egger's test was also performed to investigate the symmetry of the funnel plot (P = 0.96).(TIF)Click here for additional data file.Figure S5Funnel plot for the association between and CYP2C9 *3 carrier and colorectal cancer risk; Egger's test was also performed to investigate the symmetry of the funnel plot (P = 0.95).(TIF)Click here for additional data file.Checklist S1PRISMA 2009 Checklist.(DOC)Click here for additional data file.


Debate is ongoing about what role, if any, variation in the serotonin transporter linked polymorphic region (5-HTTLPR) plays in depression. Some studies report an interaction between 5-HTTLPR variation and stressful life events affecting the risk for depression, others report a main effect of 5-HTTLPR variation on depression, while others find no evidence for either a main or interaction effect. Meta-analyses of multiple studies have also reached differing conclusions.To improve understanding of the combined roles of 5-HTTLPR variation and stress in the development of depression, we are conducting a meta-analysis of multiple independent datasets. This coordinated approach utilizes new analyses performed with centrally-developed, standardized scripts. This publication documents the protocol for this collaborative, consortium-based meta-analysis of 5-HTTLPR variation, stress, and depression.Study eligibility criteria: Our goal is to invite all datasets, published or unpublished, with 5-HTTLPR genotype and assessments of stress and depression for at least 300 subjects. This inclusive approach is to minimize potential impact from publication bias.Data sources: This project currently includes investigators from 35 independent groups, providing data on at least N = 33,761 participants.The analytic plan was determined prior to starting data analysis. Analyses of individual study datasets will be performed by the investigators who collected the data using centrally-developed standardized analysis scripts to ensure a consistent analytical approach across sites. The consortium as a group will review and interpret the meta-analysis results.de novo results obtained from all available data, using variables and analyses determined a priori. Primary analyses, based on the original 2003 report by Caspi and colleagues of a GxE interaction will be supplemented by secondary analyses to help interpret and clarify issues ranging from the mechanism of effect to heterogeneity among the contributing studies. Publication of this protocol serves to protect this project from biased reporting and to improve the ability of readers to interpret the results of this specific meta-analysis upon its completion.Variation in 5-HTTLPR is hypothesized to moderate the response to stress on depression. To test specific hypotheses about the role of 5-HTTLPR variation on depression, we will perform coordinated meta-analyses of  Large-scale, collaborative meta-analysis has the potential to clarify complex scientific questions by increasing sample size, harmonizing variables, and conducting uniform analyses. In this paper, we describe the protocol for a collaborative, consortium-based meta-analysis to increase understanding of the role of 5-HTTLPR variation and stress in depression. The publication of this protocol serves several important purposes. First, we document our study protocols, design, and primary analysis decisions prior to conducting and publishing our study of 5-HTTLPR variation, stress, and depression, which will avoid biased reporting later. Second, publication of these details will improve the ability of other researchers to interpret the results of this specific meta-analysis upon its completion. Finally, publishing our detailed protocol may be helpful to future consortia by detailing key analysis strategies and as a standard for transparency and commitment to analytic plans set prior to meta-analysis.5-HTT). This gene encodes an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons, which terminates the action of serotonin. The repeat length polymorphism has been shown to affect the rate of serotonin uptake )Second, the diathesis-stress model would predict that an alternative approach might be to study a population that was uniformly exposed to a specific stressor. A minority of the studies in our consortium are of this type (e.g. ASPIS (military conscription), Heart and Soul (coronary heart disease), Intern Health Study , POUCH (pregnancy)).Third, limiting the sample size to 300 was done for practical reasons. On the other hand, the small published studies were in their majority those with positive findings ). Small Fourth, although we will perform a number of specific heterogeneity tests, it is impossible to test all combinations.Hence, although we will include many possible confounds and expect to have power to detect a robust effect of genotype, a negative finding does not exclude the possibility that a genetic effect exists that is very sensitive to timing or to the method of measuring depression or stress., 5-HTTLPR variation plays in depression. Various studies have argued for  or agair  the pro●5-HTT: Serotonin transporter gene.SLC6A4, location: 17q11.2. Also known as HTT; 5HTT; OCD1; SERT; 5-HTT; SERT1; hSERT.●Official name: ●Summary: This gene encodes an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. The encoded protein terminates the action of serotonin and recycles it in a sodium-dependent manner. This protein is a target of psychomotor stimulants, such as amphetamines and cocaine, and is a member of the sodium:neurotransmitter symporter family.●5-HTTLPR: serotonin-transporter-linked polymorphic region. Summary: A repeat length polymorphism in the promoter of the 5-HTT gene that has been shown to affect the rate of serotonin uptake. The short (“s”) allele is associated with lower transcriptional efficiency of the promoter compared to the long (“l”) allele.●GxE: Gene-environment interaction.The authors have no competing interests to declare.LJB and NB initially conceived of the study. RCC recruited the participating studies, led the protocol design discussions, and drafted the protocol. All authors contributed to the design of the protocol. LB and RCC drafted the manuscript. All authors helped edit the manuscript and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-244X/13/304/prepubInvited groups that are not currently participating.Click here for fileVariables used for the analyses.Click here for fileHuman Research Protection Review for participating studies.Click here for file


Diabetic nephropathy (DN) is one of the life-threatening disorders characterized by persistent albuminuria, raised arterial blood pressure, a lowered glomerular filtration rate, and high risk of cardiovascular morbidity and mortality. The vascular genes ACE (Angiotensin-converting enzyme), and PPARG (peroxisome proliferator activated receptor gamma) are involved in alterations in vascular endothelium, and are suggested to play a role in the susceptibility of diabetic nephropathy.The aim of our study was to find out the role of ACE ID and PPARG P12A polymorphisms in genetic susceptibility of diabetic nephropathy in south Indian population.A total of 54 cases with diabetic nephropathy and 67 control subjects with diabetes were enrolled for our study. DNA was isolated from peripheral blood leucocytes, and genotyped using PCR-electrophoresis (ACE ID) or PCR-RFLP (PPARG P12A) methods.2 test was applied for the analysis of genotypic distributions in genotypic and dominant models. Odds ratios were also calculated. No significant differences in genotype frequencies of ACE ID and PPARG P12A polymorphisms were found on comparing patients with diabetic nephropathy with diabetic controls. The synergistic role of ACE ID* PPARG P12A interaction, did not show any association in patients with diabetic nephropathy when compared to diabetic controls.ACE ID genotypes followed Hardy-Weinberg equilibrium in both cases and controls. But P12A genotypes deviated from Hardy-Weinberg equilibrium in diabetic controls. ChiIn conclusion, the ACE and PPARG genes do not have a key role in conferring risk for diabetic nephropathy. Diabetic nephropathy (DN) is one of the life-threatening disorders characterized by persistent albuminuria, raised arterial blood pressure, a lowered glomerular filtration rate, and high risk of cardiovascular morbidity and mortality . The preAngiotensin-converting enzyme  is an exopeptidase which participates in the renin-angiotensin system (RAS), and mediates various physiological functions. Intron 16 of the ACE gene harbors an insertion-deletion (ID) polymorphism . The perThe present study is aimed to evaluate the role of ACE ID and PPARG and polymorphisms in relation to type-2-diabetes induced nephropathy in south Indian population.Individuals for the study were recruited among patients visiting Sri Ramachandra Medical Centre, Chennai. About 67 unrelated individuals with diabetes for more than 10 years who have not developed nephropathy were considered as controls. 54 individuals with type 2 diabetes and nephropathy were considered as cases. All participants underwent detailed clinical evaluation, and followed by biochemical investigations such as serum creatinine, fasting and postprandial blood glucose, and 24 h urinary albumin excretion. Patients with persistent urine albuminuria (> 300 mg/L) in two consecutive measurements with or without renal failure (serum creatinine > 1 mg/dL) were considered as cases with diabetic nephropathy. All the patients participated in the study had given informed written consent prior to the study. This study was approved by Sri Ramachandra University Review Committee for Protection of Research Risks to Humans. 3 mL of blood sample was collected into EDTA coated vacutainers from all the participants.The genotypes were determined for each individual by finding the polymorphic combination for the 2 candidate polymorphisms from the ACE and PPARG genes. Genomic DNA was isolated from lymphocytes by standard techniques, and we used published methods to genotype the ACE  and P12A2 analysis. For the computation of percentages, odds ratios (OR) with 95% confidence interval and chi square tests were used. We used the statistical package SPSS 14.0 for the analyses.The genotype distribution for each polymorphism was evaluated for Hardy-Weinberg equilibrium by using HWSIM program . The str2 statistics. The genotype frequencies were in Hardy-Weinberg equilibrium in DN (P = 0.57) and diabetic controls (P = 0.514). The frequency of ID genotype was slightly higher in both diabetic controls than DN cases with an OR (95% CI) of 1.27 (0.52-3.13). The mutant homozygous genotypes were almost similar in both case and control groups, and not associated with DN. Similar trend was observed when analyzed in the dominant model.The genotypic frequency of ACE ID and PPARG P12A in patients with DN and diabetic controls was presented in For PPARG P12A polymorphism, of the 54 patients with DN analyzed, 37 (68.5%) were P12/P12, 17 (31.5%) were P12/A12, and no A12/A12 were found. Among 67 diabetic controls, 36 (53.73%) were P12/P12, 31 (46.26%) were P12/A12, and 0 (0%) were A12/A12. The frequency of A12 allele was 15.7% in DN group, and 23.1% in diabetic controls. Thus the frequency of A12 allele was slightly less in DN than the diabetic controls. The genotype frequencies were in Hardy-Weinberg equilibrium in DN (P = 0.17) but not in diabetic controls (P = 0.014). The frequency of P12/A12 genotype was slightly higher in diabetic controls than the cases with diabetic nephropathy with an OR (95% CI) of 0.53 (0.24-1.20). As there was no A12/A12 mutant homozygous genotypes in both case and control groups the computation of OR (95% CI) was not possible. Also the association between diabetic nephropathy and PPARG P12A was not observed in the dominant model . The syn2 analysis did not show any significant association between these polymorphisms and DN both at allele and genotype level. The mutant genotypes of both polymorphisms exhibited differences in microalbumin, but the difference was not significant. Both serum creatinine and protein-creatinine ratio did not show any significant differences between the mutants of the two polymorphisms studied.Analysis of 67 diabetic controls and 54 patients with DN for PPARG P12A and ACE ID polymorphisms revealed that both are polymorphic in the study subjects. ChiThe ACE gene is one of the important genes in RAS pathway. Although the data from our study failed to confirm an increased risk for development of DN in T2DM, previous studies from Japan, the USA, and Iran showed association between ACE-DD genotype and/or D-allele and the risk for nephropathy in T2DM -18. In cThe present study did not show any significant association between PPARG A12 allele and DN and its clinical parameters. The results of the present study are consistent with the results of the study from Han Chinese , AfricanIn conclusion, the ACE and PPARG genes do not play a key role in conferring risk for diabetic nephropathy. Although the ACE D-allele (38.3 to 56.5%) , 31-33 a