Chlamydia trachomatis infection increases the risk of cervical cancer is controversial in the literature, we performed a meta-analysis.As whether C. trachomatis infection and the risk of cervical cancer. The quality of each included study was assessed according to the 9-star Newcastle–Ottawa scale. The strength of association between the C. trachomatis and risk of cervical cancer was estimated by odds ratio (OR) and 95% confidence intervals (CIs). This review was registered at PROSPERO with registration No. CRD42014015672.Based on a comprehensive search of publications in the Medline, Cochrane, and EMBASE databases, we identified and extracted data from all relevant articles examining C. trachomatis was significantly linked to increased cervical cancer risk in prospective studies , as well as in retrospective studies . Additionally, with a multivariate logistic regression analysis adjusted for HPV and age, C. trachomatis infection was identified as an independent predictor of cervical cancer in 11 studies . Coinfection of human papilloma virus and C. trachomatis has a higher risk of cervical cancer . A subgroup analysis based on histological type indicated an elevated risk for both squamous cell carcinoma , and adenocarcinoma , in associated with C. trachomatis. Subgroup analysis by where C. trachomatis infection was detected showed a significantly higher risk of cervical cancer associated with C. trachomatis infection detected in serum , cervical tissue blocks , and cervical secretion , especially in serum with no obvious heterogeneity.A total of 22 studies with 4291 cervical cancer cases and 7628 controls were identified. Overall, C. trachomatis have a higher risk of cervical cancer. Therefore, it is necessary to expand C. trachomatis infection screening and treat women with C. trachomatis promptly, particularly those with human papilloma virus infections. This approach will not only protect against pelvic inflammatory disease and infertility, but may also prevent cervical cancer.In conclusion, our novel data demonstrate that individuals infected with  Behavioral and lifestyle factors and sexually transmitted infections such as bacterial vaginosis, Chlamydia trachomatis (C. trachomatis), herpes simplex virus, and human immunodeficiency virus have been identified as possible cofactors involved in cervical carcinogenesis.3C. trachomatis is one of the most common sexually transmitted pathogens in women. Epidemiological studies have shown a higher rate of C. trachomatis infection in patients with cervical cancer.4 In contrary, other researches have failed to find any association between infection with C. trachomatis and cervical cancer.8 For example, Tungsrithong et al6 in a nested case–control study in North-East Thailand indicated lack of significant effects of C. trachomatis infection on cervical cancer risk. Therefore, the question of whether C. trachomatis infection increases the risk of cervical cancer has so far not been answered and is still a matter of debate. Hence, we conducted a meta-analysis on all eligible case–control studies, cross-sectional studies, and cohort studies to systematically examine the association between C. trachomatis infection and cervical cancer risk. To our knowledge this is the 1st meta-analysis which provides comprehensive and quantitative evidence of the association between C. trachomatis infection and cervical cancer risk.Cervical cancer, the 3rd most frequent cancer and the 4th leading cause of cancer death among women worldwide, accounts for nearly 10% of the total newly diagnosed cancer cases and 8% of the total cancer deaths.Chlamydia trachomatis”) AND . We also checked reference lists and citation histories during the search.In accordance with the PRISMA guidelines, we identified published studies through a systematic review of Medline (via PubMed), Cochrane database, and EMBASE (via Ovid) from the inception to June 31, 2015, with the following search terms:  with 95% confidence intervals (CIs); studies were published in English; and the meta-analysis was restricted to original articles . Conference abstracts and other unpublished articles were also excluded. Studies were excluded if they did not meet all criteria. For multiple publications reporting the same cohort study, the largest or most recent publication was used in the meta-analysis. The approval of the study was obtained from the local research ethics committee. The protocol for this study was published on the International Prospective Register of Systematic Reviews, or PROSPERO. The registration number was CRD42014015672.The following inclusion criteria were used in the meta-analysis: case–control study, cross-sectional study, or cohort study on the association between C. trachomatis, number of cases, and controls, as well as adjusted or crude OR with 95% CI and adjusted variables that entered into the multivariable model as potential confounders. Based on the extracted data, the quality of the included studies was evaluated by the Newcastle–Ottawa scale, a widely used tool for the quality assessment of observational or nonrandomized studies.9The data extraction was performed by 2 investigators independently and conflicts were resolved by consensus. For each study, the following data were extracted: first author's name, year of publication, country of origin, study year (s), study design, age range, duration of follow-up, test method for C. trachomatis and risk of cervical cancer was estimated by OR and 95% CIs. The significance of the pooled OR was determined by Z test, with P < 0.05 was considered significant. Heterogeneity was quantified and evaluated by the Chi-squared-based Q-test and I2 test, with P < 0.10 and I2 > 50% indicating evidence of heterogeneity. When the effects were assumed to be homogenous, the fixed-effects model was used (Mantel–Haenszel method).10 If obvious heterogeneity was present, the random-effects model was used (DerSimonian–Laird method).11 Subgroup analysis was conducted by histological type , source of specimen , and study design . Potential publication bias was assessed by funnel plots.12The strength of association between the P < 0.05 was considered significant.All analyses were conducted using Review Manager 5.3 software with forest plot, whole OR, and 95% CIs . 13 The other analyzed 2 case–control studies in Spain and Colombia.14 The data in each of these 2 articles were extracted as 2 individual studies. Thus, 22 individual studies from 20 publications with a total of 4291 cases and 7628 controls were included in our meta-analysis. Details of the study selection process are presented in Figure The search yielded 514 records, of them, 437 were excluded as irrelevant on the basis of title and abstract. Further assessment for more detailed information identified 77 articles, of which 57 publications were excluded because of improper study design , duplicate reporting (n = 11), not in English (n = 5), and review article (n = 1). Among the remaining 20 articles, 2 studies analyzed 2 distinct cohorts. One is a cross-sectional study involving 2 groups of women .C. trachomatis and the risk of cervical cancers were published between 1981 and 2015. Most of these studies were performed in 1 country, except 3, which involved multiple countries.17 Among those 22 studies, 19 were retrospective, while the other 3 were prospective. All studies included in this meta-analysis were prevalence studies. Most of them were case–control and cross-sectional studies, assessing C. trachomatis infection and cervical cancer prevalence at a given point of time. Only 3 studies had a longitudinal design and assessed prevalence data with a median followed up period of 9 years,15 9.6 years,16 and 9 years,8 respectively.The 22 studies on All of the 22 studies were performed with univariate analysis, in which 11 of them were adopted with multivariate analysis adjusted by age, use of oral contraceptives, history of smoking, and other factors. All of the multivariate analyses were adjusted for HPV and age.C. trachomatis and squamous cell carcinomas (SCC) and 5 studies involved adenocarcinoma in cervix.In addition, eleven studies reported the association between The quality score of the included studies ranged from 6 to 9 stars according to the 9-star Newcastle–Ottawa scale. Their main characteristics are presented in the Table C. trachomatis infection in women with cervical cancer and controls in this study was 41.95% and 26.27%, respectively. Meta-analysis of total eligible studies showed that there was a significant link between C. trachomatis and the risk of cervical cancer in prospective studies    in 11 studies using multivariate logistic regression analysis adjusted for HPV and age   and adenocarcinoma  in the cervix associated with C. trachomatis infection , paraffin embedded cervical tissue , and cervical secretion   imbalance during cervical inflammation induced by C. trachomatis might play a role in cervical carcinogenesis. In the same line of evidence it was shown that infection of mice with C. trachomatis resulted in significantly increased cell proliferation, within the cervix, and in evidence of cervical dysplasia.39In this meta-analysis of 19 retrospective studies and 3 prospective studies , we confirmed that C. trachomatis infection may increase the risk of HPV acquisition as well as HPV persistence.42 Two recent studies have found that the history of C. trachomatis infection appears to increase the probability of persistent HPV infection.44 A recent prospective, population-based cohort study with up to 19 years of follow-up showed that repeated C. trachomatis infection increased the risk of cervical intraepithelial neoplasia 3+ among women with prevalent as well as persistent high-risk HPV infection.42 Similarly, our research indicated that coinfection of HPV and C. trachomatis was related to a higher risk of uterine cervical cancer, further strengthening this relationship. It may be due to 2 mechanisms. First, HPV infection in the basal keratinocytes of the mucosal epithelium requires the presence of microabrasions or altered epithelium. Chlamydial infection could possibly lead to epithelial disruption, thus, facilitating the entry of the virus.46 Second, chlamydial infection might also disturb the immune response necessary to clear the virus.32Infection with HPV is established as a major cause of cervical cancer. A large body of evidence suggests that C. trachomatis are sexually transmitted. They have similar behavioral risk factors, such as younger age and higher numbers of sexual partners. As a result, the 2 infections could occur concurrently, rather than C. trachomatis infection directly affecting HPV acquisition. Epidemiologic evidence have demonstrated a higher risk of cervical cancer for women with antibodies against C. trachomatis, both in analyses that have adjusted for HPV infection and in stratified analyses where only HPV DNA-positive cases and controls have been included.47 In this meta-analysis, multivariate logistic regression analysis was performed in 11 studies and the meta-analysis confirmed a higher risk of developing cervical cancer in patients with C. trachomatis infection, even after adjustment for HPV infection. Consequently, we believe that the C. trachomatis infection is not likely to be a simple comorbidity with HPV infection, but should be an independent predictor for cervical cancer risk.However, the infections both of HPV and C. trachomatis as a carcinogenetic cofactor may be restricted to cervical SCC. Several studies found C. trachomatis infection was a risk factor for invasive cervical SCC, but not for adenocarcinoma.48 Similarly, 2 prospective studies showed the association between C. pneumoniae infection and lung SCC, but not with adenocarcinoma of the lung.50 In this study, it is an interesting result to find that C. trachomatis infection is associated with a higher risk in both SCC and adenocarcinoma of the cervix. Given endocervix (together with the squamocolumnar junction) is the major site of C. trachomatis infection in the lower genital tract, we hypothesize that C. trachomatis infection may play a role in the initiation of malignant transformation of the glandular endocervical epithelium via the above-outlined mechanisms related to HPV coinfection. In addition, C. trachomatis may play a role in the progression of adenocarcinoma by evoking the inflammatory response that damages the mucosal barrier including the basement membrane.51 A further study is recommended in the domain of the effect of C. trachomatis in adenocarcinoma carcinogenesis of cervix.Results of several previous studies suggested the role of C. trachomatis infection in various specimen sources including cervical secretion, serum, and paraffin embedded cervical tissue, especially in serum with no obvious issue of heterogeneity. Therefore, C. trachomatis detection in serum may be a possible method to predict the risk of cervical cancer in clinic. However, 2 studies showed none of the cases was positive for C. trachomatis with polymerase chain reaction assay using DNA extracted from paraffin-embedded cervical tissue specimens of patients with cervical cancer. On the basis of the outcomes in this study, we believe that the polymerase chain reaction assay using paraffin-embedded cervical tissue specimens is not a reliable way to evaluate the infection of C. trachomatis.Elevated risks of cervical cancer were indicated in C. trachomatis and cervical cancers were acquired simultaneously, rather than longitudinally. None of the studies have taken into account the association between the duration of C. trachomatis infection and the risk of cervical cancer. Another limitation is that a meta-analysis is impossible to tackle the problems of confounding factors that could be inherent in the included studies. Inadequate control for confounders may bias the results in overestimation or underestimation of risk estimates. Moreover, heterogeneity may be introduced because of methodological differences among studies, including different specimen sources. Although there was low possibility of bias on visualization of funnel plots in this meta-analysis, the retrieved literature might potentially not be comprehensive enough. Studies with a statistically significant effect are more likely to be published and to be cited by other authors, while the results showed no association between C. trachomatis and cervical cancer may be unpublished.Our study has some limitations. Firstly, most of our quantitative assessment studies were based on case–control studies where data on prevalence of C. trachomatis and cervical cancer risk needs to be confirmed in longitudinal studies. Thus, our study calls for further investigation in more prospective studies to provide more definitive evidence concerning the role of this pathogen as a promoter of HPV-mediated cervical carcinogenesis.The underlying interaction between C. trachomatis could be one of the risk factor of cervical cancer. Individuals infected with C. trachomatis have a heightened risk of developing cervical cancer. Therefore, it is necessary to expand C. trachomatis infection screening and treat women with C. trachomatis infection timely, particularly among women at a higher risk of HPV infections. This approach will not only protect against pelvic inflammatory disease and infertility, but potentially also prevent cervical cancer and reduce the incidence of cervical cancer.In summary, this meta-analysis strengthens the evidence that infection with


The 8q24 polymorphisms have been implicated in various cancers. Three 8q24 polymorphisms  have been extensively investigated for their association with prostate cancer (PCa) susceptibility, yet conclusions are contradictory. We conducted a comprehensive meta-analysis to reevaluate the associations between those polymorphisms and PCa susceptibility, according to the latest meta-analysis guidelines (PRISMA). Eligible publications were searched from MEDLINE, EMBASE and CBM. False positive report possibility analysis was performed. We totally collected 20184 cases and 20439 controls from 20 studies for the rs1447295 C>A, 1850 cases and 2090 controls from 7 studies for the rs16901979 C>A, and 12233 cases and 7582 controls from 17 studies for the rs6983267 T>G. Overall, each of studied 8q24 polymorphisms was significantly associated with PCa risk individually. Significant associations were also observed in stratified analysis by ethnicity, source of control, and quality score. Interestingly, the effect of rs1447295 on PCa risk was observed among Caucasians and Asians, but not Africa-Americans. The effect of rs16901979 was more prominent among Africa-Americans than Asians. Likewise, rs6983267 conferred a higher Pca risk among Caucasians than Asians. Collectively, these 8q24 variant(s) may modulate PCa risk in an ethnic-specific manner. Prostate cancer (PCa) is one of the most common non-cutaneous malignancies among men in the US, with an estimated 240,890 new cases and 33,720 deaths in 20102345P value of 4 × 10−29 , 1 × 10−19, and 1 × 10−11132Chromosomal region 8q24 has emerged recently as bona fide risk locus for multiple cancers782310POU5F1P1, an important gene on 8q24, encodes a weak transcriptional activator that may contribute to carcinogenesisMYC is associated with 8q2442223The mechanisms by which 8q24 influences the course of PCa are not yet fully understood. The 8q24 region has been described as a “gene desert” since the 600-kbp gene-poor region appears to have little or no transcriptional activity. Nevertheless, several lines of evidence has suggested that 8q24 may play an active role in PCa carcinogenesis. First, 8q24 is a highly conserved genomic region. Second, Although PCa carcinogenesis has been found to be associated with hereditary background, increasing molecular epidemiology studies have presented conflicting results on the association between 8q24 SNPs and PCa risk, which may be partially attributable to various sample sizes, different genetic backgrounds, and heterogeneous inclusion criteria among studies. With this in mind, we carried out the current meta-analysis to provide a quality assessment of the association of the most frequently analyzed 8q24 SNPs  with PCa risk.Based on the inclusion criteria, 22 eligible articles consisting of 44 studies were included in this meta-analysis112252627282930313233343536373839P = 0.042), heterozygous , dominant models , and alleles comparison ; intriguingly, the direction of the association was reversed under recessive genetic models  as shown in P = 0.000), 1.31 , or 1.39  for developing prostate cancer, respectively, compared with those with CC genotype. And OR of alleles comparison (C vs. A) for the association was 1.31 . For 8q24 rs6983267 T>G analysis, a total of 17 studies comprising 12233 cases and 7582 controls were incorporated into the meta-analysis. Pooled analysis observed significant associations between increased PCa risk and the variant of interest under homozygous , heterozygous , recessive , and alleles comparison .A total 20 eligible studies were pooled together to evaluate the association between 8q24 rs1447295 C>A and PCa risk, with 20184 cases and 20439 controls. Pooled risk estimates indicated the significant associations of rs1447295 C>A with increased PCa risk under homozygous , P = 0.000; dominant OR= 1.56, 95% CI= 1.24–1.96, P = 0.000; and allele comparison OR= 1.40, 95% CI= 1.21–1.62, P = 0.000. In contrast, Asians with recessive OR= 1.65, 95% CI= 1.13–2.41), P = 0.000; and allele comparison OR= 1.17, 95% CI= 1.00–1.38, P = 0.053) . Moreover, stratified analyses observed significantly increased PCa risk associated with rs6983267 T>G polymorphism among all subgroups defined by ethnicity, source of control, and quality score. Likewise, rs6983267 T>G seemed to confer a higher Pca risk in Caucasians than Asians .As shown in In the current meta-analysis, a high level of heterogeneity was detected in the pooled analysis for rs1447295 C>A. However, the heterogeneity decreased in the stratified analysis by ethnicity, indicating that ethnicity might be a source of heterogeneity. Moreover, the between-study heterogeneity was detected among several subgroups for each of studied SNPs. However, leave-one-out sensitivity analyses suggested that no single study substantially altered the pooled ORs of any SNP of interest (data not shown), suggesting the stability of this meta-analysis. Finally, the FPRP values for all significant findings at different prior probability levels were summarized in Publication bias was examined by Begg’s funnel plots and Egger’s tests across all genetic models for each of the three polymorphisms in the 8q24 region. The shape of funnel plot  was symmTo the best of our knowledge, this is the largest meta-analysis to investigate the association between the selected 8q24 SNPs and PCa risk based on the candidate association studies. Up to now, more than 64 8q24SNPs have been explored for their role in PCa carcinogenesis, among which about 20 SNPs are regarded as PCa-related SNPs. However, those results were often controversial. In this meta-analysis, we evaluated the association of PCa risk with three most frequently investigated SNPs that scatter through the three regions of 8q24, respectively. We found significant associations between each of these 8q24 SNPs and PCa risk under most of the assumed comparisons, either in overall or in stratified analyses by ethnicity, source of control, and quality score. Intriguingly, stratified analyses by ethnicity revealed significant association between rs1447295 C>A and PCa risk among Caucasians and Asians, but not Africa-Americans. The effect of polymorphism rs16901979 C>A on PCa risk was more apparent in Africa-Americans populations when compared with Asian populations. Similarly, rs6983267 conferred a higher Pca risk among Caucasians than Asians. Although it is difficult to explain the ethnic-specific findings, the disparity in different ethnic populations is not completely surprising. Incidence rates of PCa vary internationally by over 25-fold. Developed countries in Oceania, Europe, and North American have the highest rates of PCa, while incidence in Asia is relatively low42http://www.ncbi.nlm.nih.gov/SNP), in which more than 207 variants were reported. Twenty previously reported 8q24SNPs statistically significantly associated with PCa risk show various linkage disequilibrium (LD) with a range from low to high degree  varying from 0.23 to 1.0. Additionally, rs16901979 was found in high LD of 1.0 with some polymorphisms including rs6983561, rs16901966, and rs1551512. None of the variants resides within known genes, of which there are few across the regions of 8q24. It was predicted that those risk-associated variants could affect the regulation or transcription of a causal pseudogene or gene outside the region, including proto-oncogene MYC (located approximately 260 kb telomeric to region 1), FAM84B, TCF7L2, and POU5F121Moreover, although mechanisms by which 8q24 modulates the risk of PCa is poorly understood, mounting evidence from genetic association studies and fine-mapping informatics supports that 8q24 genetic variant may impart susceptibility to PCa in an ethnic-specific manner. 8q24 region is commonly subdivided into three regions on the basis of the local genetic characteristics of 8q24 and the fine-mapping study722h degree . These SFAM84B and MYC genes on the centromeric and telomeric ends, respectively. Although data based on epidemiologic studies have indicated the possible association between 8q24 variants and PCa risk, little is known about the mechanisms. There are significant differences in allele frequency distribution of the three selected SNPs among different ethnic-populations, indicating these 8q24 variant(s) may modulate PCa in an ethnic-specific manner. One study suggested that variants in this region may be a part of the cis-regulatory enhancer element for the MYC gene, with a long-range physical interaction with this gene in PCaTCF7L2), thereby leading to a different physical interaction with MYC8q24 was considered as a gene-free region, flanked by the Up to now, several meta-analyses have investigated the associations between 8q24 polymorphisms and PCa risk4546Finally, some limitations in the meta-analysis should be addressed. First, relatively small samples were included for the assessment, especially for rs16901979 polymorphism. Second, the controls were not uniformly defined, which might result in obscure findings. Third, there was a significant heterogeneity in different ethnic groups; the heterogeneity may be partially attributed to the difference in individuals’ genetic backgrounds or the environment in which subjects live, since these genetic and environmental factors may modify the risk effects of studied SNP on cancer susceptibility. Fourth, due to inadequate information, we failed to control for possible confounders such as age, smoking, obesity, alcohol consumption, and other lifestyle risk factors, and our results were based on unadjusted estimates. Finally, the ethnic-specific effects of the studied SNPs on PCa risk were not adequately discussed due to lack of relevant publications.In summary, this meta-analysis provided evidence of the association between 8q24 polymorphisms  and PCa risk, suggesting that these 8q24 variants may be a low penetrance contributor to PCa. Considering that PCa is one of genetic and geographic related malignancies, more relevant SNPs, variants, SNP-induced gene structural changes, epigenetic changes, and interactions of SNP-SNP, gene-gene, and gene-environment should be addressed in future large multicentric studies, which should lead to better, comprehensive understanding of the association between the 8q24 Polymorphisms and PC risk.P value; and (v) genotype distribution in controls is complied with the Hardy-Weinberg equilibrium . All of the included studies were candidate-based association studies. If participants in studies overlapped, only the study with the largest sample size was included in the meta-analysis. The flow chart of identification the eligible studies was shown in A comprehensive literature search was carried out for publications investigating the association between 8q24 polymorphisms and PCa risk. We searched PubMed, Embase and China Biology Medicine (CBM) databases up to June 2014 using the following keywords, including “8q24”, “variant or polymorphism”, “cancer, carcinoma, or malignancy”, and “prostate disease”. Further limited searching strategy included “English and Chinese language publications” and “human species”. Abstracts alone and unpublished articles were not considered. Moreover, the reference lists of the retrieved articles and reviews were sought manually to find relevant original articles. Eligible Studies for this meta-analysis were required to meet all of the following criteria: (i) studies on associations of at least one of 8q24 polymorphisms  with PCa risk; (ii) enrolled patients had sporadic, primary and histologically confirmed PCa, and controls had no history of cancer or neoplasm; (iii) case-control or nested case-control studies; (iv) availability of genotype data of both case and control group to calculate the odds ratio (OR) with its 95% confidence interval (CI) and The quality of each included investigation was estimated using Extended Quality Score to limit the risk of introducing bias into meta-analyses or systematic reviews. Each article is defined as “high” or “poor” quality according to an extended-quality scale system by evaluating special characteristics of the participant groups and genotyping methods of the studiesP value of HWE test, genotyping methods, genotype counts of case and controls for three studied SNPs, and the clinical/pathological characteristics of cases. For studies involving subjects of different ethnic groups, data were extracted and split by ethnicity.Two reviewers (Qiaoxin Li and Xia Liu) independently appraised and extracted data according to the inclusion criteria listed above. Disagreements were documented and resolved by full discussion with a third reviewer (Jin-Hong Zhu) until a consensus was reached. The following information were extracted from each eligible study: the first author’s surname, year of publication, country in which study was conducted, ethnicity of participants , study design, sample size, source of control, P value less than 0.05 indicating derivation from HWE, and population was regarded as suitable if more than one SNP agreed with HWE. The strength of association between 8q24 polymorphisms and PCa risk was estimated by calculating odds ratios (OR) and the corresponding 95% confidence intervals (CI). For each of studied SNP, we conducted comparison of the frequency of wild (W) and variant (V) alleles between PCa cases and controls (V vs. W). Moreover, pooled ORs were calculated under the following genetic models: homozygous (VV vs. WW), heterozygous (VW vs. WW), dominant (VV + VW vs. WW), and recessive (VV vs. VW + WW) models. Stratification analyses were performed by ethnicity, source of control, and quality score, but not by tumor stage, Gleason score, and PAS levels because of the small size of the eligible studies. For each genetic model, a χ2-based Q-test was performed to check the presence of between-study heterogeneity across all of the comparisons at a level of significance of 0.10I2 statistics, which is independent of the number of studies included in the meta-analysis. I2 lies between 0% and 100% with higher values indicating a greater heterogeneityP values were adopted, and P <0.05 were considered statistically significant without further notification.HWE in the control groups was assessed by the Pearson’s goodness-of-fit chi-square test, with a How to cite this article: li, Q. et al. Association of three 8q24 polymorphisms with prostate cancer susceptibility: evidence from a meta-analysis with 50,854 subjects. Sci. Rep.5, 12069; doi: 10.1038/srep12069 (2015).


AR) could be related to the risk of TC. To evaluate the association between the length of GGN and CAG repeats in AR and TC, a meta-analysis involving 3255 TC cases and 2804 controls was performed. The results suggested that long GGN repeats are associated with an increased risk of TC compared with those < 23 ; similarly, a subgroup analysis revealed that this association occurred in studies with case sizes > 200, and in the mid-latitude, and seminoma subgroups. The subgroup analysis based on populations, high-latitude, and seminomas/non-seminomas suggested that AR CAG repeat polymorphisms with > 25 and < 21 + > 25 repeats might confer a protective effect to the patients with TC . In contrast, an increased risk of TC was observed for AR CAG repeat polymorphisms with > 25 and < 21 + > 25 repeats in the mid-latitude subgroup . In addition, no associations between the remaining subgroups and male infertility were observed. In short, this meta-analysis suggested that AR GGN and CAG repeat polymorphisms may be involved in the etiology of TC.The risk of testicular cancer (TC) is markedly increased in subjects with androgen insensitivity, and previous studies have proposed that GGN and CAG repeats in androgen receptors ( Testicular cancer (TC) is an malignancy, accounting for 1%–2% of all tumors among men worldwide . ClinicaAR gene, located on Xq11-12, has 8 exons and 7 introns, and in exon 1, this gene contains two important polymorphic trinucleotide repeats of polyglutamine and polyglycine tracts . To clarify the potential effect of latitude, sample size, and histological differences, a subgroup analysis of study populations was also conducted, and a significant association was found between GGN repeats and TC in studies with a sample size > 200 and in the mid-latitude and seminoma subgroups .The association between GGN repeats and the risk of TC is summarized in Figure AR and the risk of TC is summarized in Figures vs. 21–25: OR = 0.81, 95% CI = 0.68–0.96, P = 0.017), mid-latitude subgroup , high-latitude subgroup , seminoma subgroup , and non-seminoma subgroup .The association between CAG repeat in vs. ≤ 23, P = 0.840; for CAG repeat < 21 vs. 21–25, P = 0.371; for CAG repeats > 25 vs. 21–25, P = 0.671; for CAG repeats < 21 + > 25 vs. 21–25, P = 0.941).To assess the publication bias of the studies, Begg's funnel plot and Egger's test were performed. The shapes of the funnel plots revealed no evidence of obvious asymmetry. Egger's test was used to provide statistical evidence of funnel plot symmetry  and indiI2 statistics calculated for the overall analysis of the CAG repeats > 25 vs. 21–25 and CAG repeats < 21 + > 25 vs. 21–25 were 73.4% and 56.6%, respectively, indicating that more than 50% of the abnormal CAG repeats may be due to between-study heterogeneity. We then evaluated the source of heterogeneity in these comparisons by sample size, latitude, and histology stratifications, and we observed no heterogeneity in latitude and histology stratifications  studies with a case-control design; (3) studies that provided sufficient information on CAG or GGC/GGN repeat distributions between patients and controls; (4) studies for which the full text was available. Two reviewers assessed the full text of eligible studies from the above databases. Additional studies were identified by manually searching references of original and review articles on this topic.The inclusion criteria were as follows: (1) studies that evaluated the association between Information on the enrolled studies is shown in Tables Data were divided into three categories: CAG repeat length of 21–25, which was used as the reference group, CAG length < 21, and CAG length > 25. The GGN repeat length was divided into 2 categories: GGN repeat length ≤ 23, which was used as the reference group, and GGN length > 23. To obtain specific data from these categories, we thoroughly analyzed and carefully obtained information from all the studies that met the inclusion criteria.AR CAG and GGN repeat polymorphisms to the risk of TC using the Stata software version 11.0. The OR with 95% (CI) was calculated to measure the strength of the associations [Q test and Higgins I2 statistic [I2 > 50% is considered as a measure of significant heterogeneity. If the result of the Q test was P > 0.10, the OR was analyzed using the fixed-effects model (Mantel–Haenszel method). Otherwise, a random-effects model (DerSimonian–Laird method) was used in cases of significant heterogeneity. Sensitivity analysis was performed to estimate the stability of the results by removing each study from the analysis, one at a time. Publication bias was evaluated using Begg's funnel plot. In addition to the visual inspection of the funnel plot, a value of P < 0.05 was considered to indicate the presence of significant publication bias [We predicted the contribution of ciations . A test tatistic . I2 > 50ion bias –37.


Esophageal cancer was the fifth most commonly diagnosed cancer and the fourth leading cause of cancer-related death in China in 2009. Esophageal squamous cell carcinoma (ESCC) accounts for more than 90 percent of esophageal cancers. Genetic factors probably play an important role in the ESCC carcinogenesis.hTERT rs2736098 G>A and TERT-CLPTM1L rs401681 C>T single nucleotide polymorphisms (SNPs) on the risk of ESCC. Six hundred and twenty-nine ESCC cases and 686 controls were recruited. Their genotypes were determined using the ligation detection reaction (LDR) method.We conducted a hospital based case-control study to evaluate functional TERT-CLPTM1L rs401681 CC homozygote genotype was used as the reference group, the CT genotype was associated with a significantly decreased risk of ESCC ; the CT/TT variants were associated with a 26% decreased risk of ESCC . The significantly decreased risk of ESCC associated with the TERT-CLPTM1L rs401681 C>T polymorphism was associated with male sex, young age (<63 years in our study) and alcohol consumption. No association between the hTERT rs2736098 G>A polymorphism and ESCC risk was observed.When the TERT-CLPTM1L rs401681 CT and CT/TT genotypes were associated with decreased risk of ESCC, particularly among men, young patients and those reported to be drinkers. However, our results are preliminary conclusions. Larger studies with more rigorous study designs are required to confirm the current findings. Esophageal cancer was the fifth most commonly diagnosed cancer and the fourth leading cause of cancer-related death in China in 2009 TERT-CLPTM1L), which is located at locus 5p15.33, were associated with the risk of many types of cancer TERT gene and the CLPTM1L gene. The TERT-CLPTM1L SNP, rs401681 , is one of the most extensively studied SNPs. Two variants in 5p15 (rs401681 and rs2736098) are significantly associated with bladder cancer in individuals of European ancestry. These variants are in linkage disequilibrium (LD) with CLPTM1L and TERT, and both variants are also associated with basal cell carcinoma TERT-CLPTM1L rs401681 C allele is also associated with shorter mean telomere length in lymphocytes Recently, several genome-wide association studies (GWAS) reported that common polymorphisms of Telomerase reverse transcriptase-cleft lip and palate transmembrane 1 like, CLPTM1L . We have complied with the World Medical Association Declaration of Helsinki regarding ethical conduct of research involving human subjects and/or animals 629 subjects with esophageal cancer were consecutively recruited from the Affiliated People's Hospital of Jiangsu University and Affiliated Hospital of Jiangsu University  between October 2008 and December 2010. All cases of esophageal cancer were diagnosed as ESCC by pathologic means. The exclusion criteria were patients who previously had: cancer; any metastasized cancer; radiotherapy or chemotherapy. The 686 controls were patients without cancer frequency-matched to the cases with regard to age (±5 years) and sex recruited from the two hospitals mentioned above during the same time period. Most of the controls were admitted to the hospitals for the treatment of trauma.Each subject was personally questioned by trained interviewers using a pre-tested questionnaire to obtain information on demographic data  and related risk factors . After the interview, 2-mL samples of venous blood were collected from each subject. Individuals who smoked one cigarette per day for >1 year were defined as “smokers”. Subjects who consumed ≥3 alcoholic drinks a week for >6 months were considered to be “alcohol drinkers”.Blood samples were collected from patients using Vacutainers and transferred to tubes lined with ethylenediamine tetra-acetic acid (EDTA). Genomic DNA was isolated from whole blood with the QIAamp DNA Blood Mini Kit  http://www.regulomedb.org/andhttp://snpinfo.niehs.nih.gov/snpinfo/snpfunc.htm to predict hTERT rs2736098 G>A and TERT-CLPTM1L rs401681 C>T SNPs function.We used online predictive tool: hTERT rs2736098 G>A and TERT-CLPTM1L rs401681 C>T variants between the cases and controls were evaluated using the χ2 test. The associations between hTERT rs2736098 G>A and TERT-CLPTM1L rs401681 C>T genotypes and risk of ESCC were estimated by computing the ORs and their 95% CIs using logistic regression analyses for crude ORs and adjusted ORs when adjusting for age, sex, smoking and drinking status. The Hardy-Weinberg equilibrium (HWE) was tested by a goodness-of-fit χ2 test to compare the observed genotype frequencies to the expected ones among the control subjects. All statistical analyses were performed with SAS 9.1.3 .Differences in the distributions of demographic characteristics, selected variables, and genotypes of the χ2 tests . As shown in P<0.001), and drinking rate was higher in ESCC patients than in control subjects (P<0.001). The primary information for two genotyped SNPs was in hTERT rs2736098 G>A, the genotyping was successful in 600 (95.39%) ESCC cases and 651 (94.90%) controls in all 1315 samples, and for TERT-CLPTM1L rs401681 C>T, the genotyping was successful in 604 (96.03%) ESCC cases and 664 (96.78%) controls. The concordance rates of repeated analyses were 100%. Minor allele frequency (MAF) in our controls was similar to MAF for Chinese in database for all two SNPs (Characteristics of cases and controls included in the study are summarized in two SNPs . The obstwo SNPs .hTERT rs2736098 G>A and TERT-CLPTM1L rs401681 C>T in the cases and the controls are shown in TERT-CLPTM1L rs401681 C>T were 47.68% (CC), 41.72% (CT), and 10.60% (TT) in the case patients and 40.06% (CC), 47.74% (CT), and 12.20% (TT) in the control subjects, and the difference was statistically significant (P = 0.024). When the TERT-CLPTM1L rs401681 C allele was used as the reference group, the T allele was associated with a significantly decreased risk for ESCC . When the TERT-CLPTM1L rs401681 CC homozygote genotype was used as the reference group, the CT genotype was associated with a significantly decreased risk for ESCC . When the TERT-CLPTM1L rs401681 CC homozygote genotype was used as the reference group, the TT genotype was not associated with the risk for ESCC . In the dominant model, the TERT-CLPTM1L rs401681 CT/TT variants were associated with a 26% decreased risk of ESCC, compared with the TERT-CLPTM1L rs401681 CC genotype . In the recessive model, when the TERT-CLPTM1L rs401681 CC/CT genotypes were used as the reference group, the TT homozygote genotype was not associated with the risk for ESCC  (The genotype distributions of = 0.447) .hTERT rs2736098 G>A was not showed a significant difference in the genotype distributions between cases and controls (P = 0.727). Logistic regression analyses revealed that the hTERT rs2736098 G>A polymorphism was not associated with the risk of ESCC ( of ESCC .http://biostat.mc.vanderbilt.edu/twiki/bin/view/Main/PowerSampleSize) and considering TERT-CLPTM1L rs401681 C>T mutant alleles in the control group, ORs, ESCC samples and control samples, the power of our analysis (α = 0.05) was 0.708 in 604 ESCC cases and 664 controls, with an OR of 0.74.Using Power and Sample Size Calculation , younger patients (<63 years in our study) (CT/TT vs CC: P = 0.049) and patients who were in drinking status   .hTERT rs2736098 G>A and TERT-CLPTM1L rs401681 C>T SNPs with the risk of ESCC in a Chinese population. Multivariate logistic analysis revealed that the TERT-CLPTM1L rs401681 CT and CT/TT genotypes were associated with decreased risk of ESCC, whereas no significant association between the hTERT rs2736098 G>A polymorphism and the risk of ESCC was observed. A significantly decreased risk of ESCC associated with the TERT-CLPTM1L rs401681 C>T polymorphism, particularly among men, young patients and those reported to be drinkers.In this hospital-based case-control study, we investigated the association of the The function of CLPTM1L and its role in tumorigenesis is largely unknown. However, a recent study reported that CLPTM1L was a commonly overexpressed anti-apoptotic factor in lung cancer CLPTM1L gene is upregulated in cisplatin-resistant cell lines, and is linked to cisplatin-induced apoptosis; furthermore, over-expression of CLPTM1L mRNA has been observed in many cancers CLPTM1L at 5p15.33, and it is one of the most studied SNPs. Although little is known about the function of this SNP, our bioinformatics analysis indicated that it might affect transcription regulation and further affect the expression of the gene. To show that these alterations can indeed contribute to cancer properties, invitro validation studies with specific invitro cell lines of ESCC that harbor these genetic alterations are warrented. Such as cell cultures, transient transfections, luciferase assay, electrophoretic mobility shift assays, Western blot analysis, reverse transcriptase PCR, chromatin immunoprecipitation assays and quantitative Real-Time PCR.The CLPTM1L rs401681 polymorphism and cancer have been published, with inconsistent results CLPTM1L T allele was associated with a significantly decreased risk of lung cancer TERT-CLPTM1L rs401681 T allele was associated with decreased risk of lung cancer TERT-CLPTM1L rs401681 T allele is protective but not reach significant  Several studies addressing the association between the TERT-CLPTM1L rs401681 T was 0.361 in 686 control subjects, which is consistent with the values reported in the SNP database for the Chinese Han (0.305) and Japanese populations (0.343); however, the frequency was lower than that of a Sub-Saharan African (0.642) population (http://www.ncbi.nlm.nih.gov/SNP).The frequencies of genetic polymorphisms often vary between ethnic groups. In the present Chinese study, the allele frequency of TERT-CLPTM1L, such as rs402710 and rs2736100 et al. Further studies are needed to clarify the genetic mechanism of esophageal carcinogenesis by fine-mapping the susceptibility region of the variants. Third, the statistical power of our study was limited because of the moderate sample size and absence of a validation cohort. Larger, well-designed studies are warranted to confirm the associations observed in the present study. Finally, we did not obtain detailed information on cancer metastasis and survival, which further restricted the analysis of the roles of the hTERT rs2736098 G>A and TERT-CLPTM1L rs401681 C>T polymorphisms in ESCC progression and prognosis.This case-control study had several limitations. First, the patients and controls were enrolled from hospitals and may therefore not be representative of the general population; the information familial cancer history of the cases and controls was not obtained, this inherent bias may have resulted in spurious findings. Second, the polymorphisms investigated in our study were based on functional considerations and may not provide a comprehensive view of the genetic variability of TERT-CLPTM1L rs401681 C>T polymorphism may contribute to the risk of ESCC. However, the exact functional relevance of the CLPTM1L rs401681 SNP remains unclear. It may be in strong LD with other potential functional or causal SNPs, contributing to the risk of ESCC. Additional, larger studies and in vitro or tissue-specific biological characterization are required to confirm the current preliminary findings.In conclusion, our study provides strong evidence that the functional Table S1Primary information for hTERT rs2736098 G>A and TERT-CLPTM1L rs401681 C>T polymorphisms.(DOCX)Click here for additional data file.Data S1Data of hTERT rs2736098 G>A and TERT-CLPTM1L rs401681 C>T polymorphisms.(SAV)Click here for additional data file.


LBX1) gene polymorphisms and the risk of adolescent idiopathic scoliosis (AIS) are not all the same. As such, we performed a meta-analysis to estimate the association between LBX1 gene polymorphisms and AIS susceptibility.The results of studies investigating the association between the ladybird homeobox 1  and 95 % confidence interval (CI).P < 0.001), Caucasians  and in female . The G allele of rs678741 decreased AIS risk in female , and the G allele of the rs625039 increased AIS susceptibility in Asians .A total number of eight case-control studies including 10,088 cases and 24,538 controls were identified. The results showed that T allele of rs111090870 increased AIS susceptibility in Asians  contains supplementary material, which is available to authorized users. MTNR1B), ladybird homeobox 1 (LBX1), tryptophan hydroxylase 1 (TPH1), arylalkylamine N-acetyltransferase (AA-NAT) and Basonuclin 2 (BNC2) [LBX1 gene is widely investigated.Adolescent idiopathic scoliosis (AIS) is a medical condition which affects 1–4 % of children in the at-risk population of those aged 10–16 years, using a cut-off point of 10° Cobb angle or more . An X-ra2 (BNC2) , and amoLBX1 gene locates on chromosome 10q24.31, and it is a hemeobox transcription factor [LBX1 is a strong biological candidate gene for AIS [LBX1 encodes ladybird homeobox 1, orthologous to Drosophila ladybird-late, which plays a key role in regulation of muscle precursor cell migration and highly functional in central nervous system [LBX1 SNPs polymorphisms and AIS susceptibility have been published in Caucasian subjects [LBX1 gene may act as potential susceptible factors for AIS, such as rs111090870, rs11598564 and rs625039. However, the results are not all the same and with limited statistical power among these studies. In order to overcome the limitation of single studies, we performed this meta-analysis containing one widely studied locus (rs111090870) and three less studied loci , to provide a more comprehensive and precise estimation of LBX1 gene and AIS susceptibility.The n factor , 20. It  for AIS , 22. LBXs system . Large-ss system , 23. In subjects . The resLBX1 gene polymorphisms until 1 November 2015. Searching terms were: “adolescent idiopathic scoliosis” or “AIS”, in combination with “LBX1” or “ladybird homeobox 1” or “HPX6” or “homeobox”, and in combination with: “polymorphism” or “variant” or “genotype” or “allele”. We also checked the reference lists of all included studies to make sure no study was missed.Six databases were electronically searched, including PubMed, EMBASE, ISI web of knowledge, EBSCO, China National Knowledge Infrastructure (CNKI), and Chinese Biological and Medical Database (CBM), to retrieve studies analyzing the association between AIS susceptibility and LBX1 gene polymorphisms and AIS susceptibility; (3) AIS was diagnosed on the basis of clinical and radiologic examinations; (4) Individual genotype frequencies or allele frequencies in cases and controls were available.We first performed initial screening of titles and abstract. A second round screening was based on full-text reviews. Studies were considered eligible if they met the following criteria: (1) It was a case-control study in design; (2) It evaluated the Researches were excluded if they met any one of the following criteria: (1) Data came from reviews or abstracts; (2) Genotype and allele frequencies were both unavailable; (3) Repeatedly published literature.LBX1 gene polymorphisms, and information of Hardy-Weinberg equilibrium (HWE) in control group.Two reviewers independently searched and selected literature, and then, extracted relevant data according to a data extraction form. Disagreements were solved by discussion until consensus was made. The extracted data included: the first author, year of publication, country of origin, ethnicity of the study population, genotyping method, source of control, sample size, the genotype and allele frequencies of the Quality assessment was conducted for each article according to a quality evaluation form base on Critical Appraisal Skills Programme (CASP) for case-control study, which containing eleven questions associated with information provided in single studies . Each quwww.stata.com). Odds ratio (OR) and its corresponding 95 % confidence intervals (95 % CI) were used to evaluate the strength of association between LBX1 gene polymorphisms and AIS susceptibility. Heterogeneity among included studies was tested using chi-square-based Q test and I2 test. Phet < 0.05 and I2 > 50 % were considered as statistically significant for heterogeneity. The Mantel-Haenszel method was used for fix effect model if no heterogeneity was found. Otherwise, the DerSimonian-Laird random effect model was used. Fix effect model considers that across all studies, the genetic factors have similar effects on genetic disorder susceptibility and the observed differences among studies are cause just by chance [LBX1 gene polymorphisms and AIS susceptibility. For instance, for rs1190870 polymorphism, T allele, we assessed the dominant model (TT + CT vs. CC), the recessive model (TT vs. TC + CC), the allele contrast genetic model (T vs. C), the heterozygote comparison (CT vs. CC), and the homozygote comparison (TT vs. CC). HWE was tested for included studies if no relevant information was provided in original research. Sensitivity analyses were conducted by omitting individual studies sequentially. Moreover, we performed subgroup analysis stratified by ethnicity and gender. Publication bias was quantitatively assessed by Egger’s linear regression test [Data analysis was conducted using STATA 11.0 software  and allele contrast genetic model . In mix gender subgroup, allele contrast genetic model also showed a significant increase , but no significant association between rs111090870 and AIS risk was found in male subgroup. In subgroup analyses stratified by ethnicity, significant increasing AIS susceptibility was found for Asians and Caucasians in both genetic models . In the subgroup analysis stratified by gender, significant increasing AIS susceptibility was found for both genders in the dominant model and allele contrast genetic model   Table .LBX1 mutant mice, the morphology and neuronal circuitry of the dorsal horn are aberrant and in mice lacking LBX1, cells types that arise in the ventral alar plate acquire more dorsal identities [LBX1 is essential for sensory pathways developments which relay touch and pain. In 1982, Pincott et al. found that the loss of proprioceptive innervation could result in asymmetrical weakness of the paraspinal muscles, and which may finally cause scoliosis [LBX1 gene may be a target spot in pathogenesis of AIS.Previous clinical and epidemiological studies found that about 27 % female offspring of female AIS patients would also suffer from AIS, but this phenomenon did not exist in male AIS patients, and that the pairwise concordance rate was higher in monozygotic twin pairs comparing with dizygotic twin pairs , 37. So,entities , 38. Thecoliosis . As a reLBX1 gene and AIS susceptibility in 2012 and their results showed statistical significant associations for rs111090870, rs11598564 and rs625039. From 2013 to 2015, several subsequent studies have conducted to investigate the LBX1 polymorphisms in pathogenesis of AIS. However, the results are inconsistent, with some datasets found positive associations, and other find no relevance or even negative association. Several reasons, including different recruitment criteria, subjects’ characteristics, sample size, different ethnic population and gender, may lead to the inconsistency.Case-control study is a useful tool to detect gene and disease susceptibility. GWAS is a kind of case-control cohort study in essential, which is a powerful method to identify genetic association with diseases and has been applied in genetic predisposition studies increasingly. Therefore, GWAS is widely used in AIS susceptibility study, to identity risk genes for this most common and complex musculoskeletal system polygenic disease , 40, 41.P < 0.001), Caucasians  and in female . The G allele of rs678741 decreased AIS risk in female , and the G allele of the rs625039 polymorphism may increase AIS susceptibility in Asians . For the rs11598564 polymorphism, G allele may also increase AIS risk, but in recessive model, no statistical significant association was detected and the result was with heterogeneity. So, the result of rs11598564 should be interpreted with caution.In order to avoid limitations of individual case-control or GWA study, we conducted this meta-analysis to pool the findings of rs111090870, rs678741 rs11598564 and rs625039 polymorphisms in all original studies. As we reported in result part, the eight included studies were of high quality judged by CASP standard. They clearly reported their participants choosing criteria, sample sizes, characteristics of cases and controls and genotyping methods. Moreover, except one dataset cannot be tested for HWE, only one dataset was deviated from HWE in the control group. Gender and ethnicity were matched in case and control group. The results showed that T allele of rs111090870 is significant associated with increased AIS susceptibility in Asians (T vs. C, OR = 1.22, 95 % CI: 1.16–1.29, We should notice the heterogeneity existed in this meta-analysis. For the rs111598564 and rs625039 polymorphisms, no heterogeneity was found among studies. However, in the rs111090870 polymorphism, significant heterogeneity was found in all models except the recessive model, and for the rs11598564 polymorphism, heterogeneity was detected in recessive genetic models. For rs111090870 polymorphism, the heterogeneity detected in four genetic models was effectively decreased in sensitivity analysis when the male dataset in study by Jiang et al.  was omitTwo previous meta-analyses , 43 haveSeveral limitations of this study may affect the results. Firstly, only published English and Chinese studies were included in this meta-analysis and we only included published studies from six databases. Relevant studies in other languages and databases may have been missed. Secondly, in our meta-analysis, all datasets included in rs11598564 and rs625039 were based on Asian subjects. Additional researches in other ethnicities are needed to generalize our finding for rs11598564 and rs625039. For rs678741, all included datasets were based on female subjects, and other researches for males are needed. Because the same polymorphism may act differently in different ethnical backgrounds genders, results from rs678741 cannot extend to male and results from rs11598564, rs625039 cannot extend to Caucasians or other ethnicities. Thirdly, most included studies did not distinguish between the magnitude or phenotype of scoliosis and genotyping results. Therefore, we were unable to provide different pooled ORs according to different magnitude or phenotype of AIS. Finally, the possible ethiology pathogenesis of AIS is complex, but due to insufficiency of included studies, we did not detect the interactions between genetic factors and other factors. Considering that meta analysis is a kind of retrospective research and may easily be affected by methodological deficiencies of included studies, we developed a detailed protocol before conducting this analysis, to ensure the quality of our meta-analysis.LBX1 gene is significant associated with increased AIS susceptibility in Asians, Caucasians and in female. The G allele of rs678741 may decrease AIS risk in female and the G allele of rs625039 polymorphism may increase AIS susceptibility in Asians. More studies with multiple ethnics and different genders are needed to generalize the results.From the combination results of currently included studies, our meta-analysis suggested that the T allele of rs111090870 polymorphism near AA-NAT, arylalkylamine N-acetyltransferase; AIS, adolescent idiopathic scoliosis; BNC2, Basonuclin 2; CASP, Critical Appraisal Skills Programme; CBM, Chinese Biological and Medical Database; CI, confidence interval; CNKI, China National Knowledge Infrastructure; GWAS, Large-scale genome-wide; HWE, Hardy-Weinberg equilibrium; LBX1, ladybird homeobox 1; OR, odds ratios; PCR, Polymorphism chain reaction; SNP, single nucleotide polymorphism; TPH1, tryptophan hydroxylase 1


FTO) gene are related to human obesity. We hypothesize that this gene may also play a role in the risk of immune-related infectious diseases such as tuberculosis.Obesity is known to affect cell-mediated immune responses. Recent studies have revealed that genetic polymorphisms in the fat mass and obesity associated  and 95% confidence intervals (CIs) were calculated using the unconditional logistic regression model.This case-control study included 1625 pulmonary tuberculosis cases and 1570 unaffected controls recruited from the Jiangsu province in China. Single nucleotide polymorphisms (SNPs), rs9939609 and rs8050136, in the We observed a significant association between the genetic polymorphism rs9939609 and tuberculosis risk. Compared with the common genotype TT, individuals carrying AA had a significantly increased risk, with an OR of 3.77 (95% CI: 2.26-6.28). After adjusting for potential confounders, the relationship remains significant. An additive model showed that carriers of an allele A had a 26% increased risk of tuberculosis compared with the T allele . Compared with the common haplotype rs9939609T-rs8050136C, the haplotype rs9939609A-rs8050136C was related to an increased risk of tuberculosis .FTO polymorphism rs9939609 is associated with a risk of pulmonary tuberculosis in the Chinese population.The  Mycobacteria tuberculosis and continues to be a major global health threat, particularly in developing countries. In 2012, an estimated 8.6 million new cases occurred, and approximately 1.3 million people died worldwide due to TB . Malnutrition, tobacco smoking, immunosuppressive treatment, diabetes, indoor air pollution, crowding, migration, aging and poverty have all been recognized as possible risk factors . Th. ThFTO  with pulmonary tuberculosis in a Chinese population.Recent studies have further shown the effects of the diabetes , neural diabetes  and Alzhdiabetes . Althougdiabetes . The impdiabetes . We hypoThis case-control study included 1625 pulmonary tuberculosis cases and 1570 unaffected controls recruited from Jiangsu province in China. All cases and controls were unrelated Han Chinese population. The cases were recruited from local Centers for Disease Control and Prevention and TB dispensaries. All cases were diagnosed by specialized doctors based on clinical signs, chest x-ray examination, sputum smear tests or sputum culture. Controls were recruited through their participation in local community-based health examination programs. Those with a history of tuberculosis or malignancy were excluded. Controls were frequency matched to cases by sex and age. None of the cases and controls had an HIV-positive history. Trained interviewers administered a questionnaire to collect data on their demographic characteristics, tobacco smoking, alcohol consumption and health care-seeking history. A blood sample was collected from each participant for molecular analysis.FTO gene was carried out using TaqMan allelic discrimination assays on the ABI 7900HT Real-Time PCR System  and was ascertained using the SDS software (version 2.3). The sequence specific forward and reverse primers and Taqman MGB probes are listed in Table We extracted genomic DNA from peripheral blood samples by proteinase K digestion and a modified phenol-chloroform protocol. The DNA was frozen at −20°C until genotyping. Genotype determination of rs9939609 and rs8050136 in the 2 test  were used to analyze the differences in demographic variables and potential risk factors between cases and controls. Hardy-Weinberg equilibrium (HWE) was tested using a goodness-of-fit χ2 test by comparing the observed genotype frequencies with the expected ones among the controls to ensure that the alleles were independently segregated. To evaluate the effects of genetic polymorphisms of the FTO gene on the risk of tuberculosis, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) using the unconditional logistic regression model. To avoid potential confounding, we further adjusted by age, sex, tobacco smoking and alcohol consumption. To analyze the effect of SNPs comprehensively, we applied three different genetic models: the additive model, the dominant model and the recessive model. Haplotype analysis on SNP rs9939609 and rs8050136 was performed using the phase 2.1 software.Data were entered with EpiData 3.1 (Denmark) and analyzed using STATA 10.0 . Student's t-test (for continuous variables) and the χThe study was approved by the Institutional Review Board of Nanjing Medical University. Informed consent was obtained for both the interviews and the blood samples.P = 0. 017).The genotype distributions of two SNPs were all in HWE in the controls . The general characteristics of cases and controls are shown in Table P = 0.004] and smear-positive cases . The additive model showed that with each increased number of A alleles, the risk for tuberculosis increased accordingly . Stratified analysis revealed that the effect of AA genotype of rs9939609 on tuberculosis was more evident among men, ever smokers and alcohol drinkers (Tables There was a significant association between rs9939609 (T > A) and the risk of tuberculosis. Compared with the common genotype TT, those carrying the AA genotype had a significantly increased risk, with an OR of 3.77 (95% CI: 2.26-6.28). After adjusting for potential confounders , the association remained significant [adjusted OR: 3.57 (95% CI: 2.13-6.01)]. As shown in Table FTO . A haplotype analysis was carried out, and the rs9939609A-rs8050136C haplotype significantly increased the risk of TB  (Table Linkage disequilibrium (LD) was found between these SNPs of http://snpinfo.niehs.nih.gov/snpinfo/snpfunc.htm) and Regulome DB (http://www.regulomedb.org/). The RegulomeDB showed that rs8050136 was the binding site for the transcription factor (TF) EP300. The RegulomeDB score was 4 (supporting data: TF binding + DNase peak). No data were provided for the functional prediction of rs9939609.To determine the potential functional effect of the SNP, we used the prediction tools SNPinfo  and replicated the association of FTO rs9939609 with the risk of central obesity  . In. InFTO gr system . The firulations . Since Fulations . Li et aulations . The oddulations . Xi et a10-1.50) ,42]. Th. ThFTO gFTO rs9939609 polymorphism was found to be associated with type 2 diabetes in Vietnamese  . Un. UnFTO r06-2.44) . At the In this study, a LD was found between rs9939609 and rs8050136. The haplotype rs9939609A-rs8050136C was related with an increased risk of tuberculosis. Previous studies have revealed that individuals who carry a particular SNP allele at one site often predictably carry specific alleles at other nearby sites. This correlation is known as LD and a particular combination of alleles along a chromosome is termed as the haplotype . The relFTO rs9939609 SNP in the risk of tuberculosis, which supports the hypothesis that genetic polymorphisms of the FTO gene affect the host's susceptibility to infectious diseases. We believe that the effect of FTO-rs9939609 on the risk of tuberculosis may not solely be attributed to its role in the risk of obesity. The altered human immune function related to these genetic variants can explain, at least in part, why some people resist tuberculosis infection more successfully than others . Th. ThFTO rHWE test is commonly used as an initial quality check procedure in genetic association studies. Departure from HWE (DHWE) may suggest a higher risk of genotyping errors . In the FTO variants on obesity. Second, we only selected two SNPs in the FTO gene. Other polymorphisms and their interactions with environmental factors should also be considered [FTO gene and may not be the true causal variant. Based on the RegulomeDB database, we observed a minimal binding evidence of rs8050136, which has a strong LD with rs9939609. We hypothesize that the SNP rs9939609 may be in linkage with the true functional SNP(s). Further work with both knockout and overexpression models of FTO and neighboring genes is likely to provide the most fruitful approach to understand the mechanisms and pathways through which these variants influence the risk of tuberculosis.There are several limitations in this study. First, due to a case-control study design, BMI prior to the diagnosis of tuberculosis was absent, which restricted an in-depth analysis of the ancillary effect of nsidered . Third, FTO rs9939609 genetic polymorphism and the haplotype (rs9939609A-rs8050136C) are involved in the risk of tuberculosis in the Chinese population. Future studies should include a comprehensive sequencing analysis to identify the specific causative sequence variants underlying the observed associations. In future studies, nutritional status and environmental factors will be essential for elucidating gene-environment interactions.Taken together, our results suggest that the YF and JW conceived the idea. YF, FW, HP, SQ, JL, LW, CL and JW were involved in data collection and genotyping. YF and JW participated in the data analysis and drafted the manuscript. All authors read and approved the final manuscript.


Purpose. Effects of a genetic polymorphism in the aldehyde dehydrogenase-2 (ALDH2) on blood pressure (BP) were investigated in a cross-sectional and a longitudinal study over 20 years on Japanese rural residents. Methods. Health examinations were held through 2006 to 2012, and 3,202 participates were recruited for this study. Among these participants, 560 individuals had medical records that were obtained in a health examination 20 years ago. Genomic DNA of participants was extracted from blood and the genotype of a polymorphism in ALDH2 was determined by the TaqMan method. Multivariate regression analyses were performed to examine association between BP and the genetic polymorphism in the ALDH2 gene. Results. Systolic and diastolic BP were higher in the ALDH2∗1/∗1 than the others (ALDH2∗1/∗2 or ALDH2∗2/∗2). Genetic variation of the ALDH2 gene apparently influenced drinking behavior as the number of the drinkers was significantly reduced in the ALDH2∗2/∗2 after 20 years of the observation period. This polymorphism, however, did not confer a risk for BP increase in the longitudinal observation. Conclusion. The present cross-sectional study confirmed a genetic effect of the ALDH2 gene on BP. In contrast, no significant effects on BP were identified in a longitudinal study, which may require a careful consideration. ALDH2: NP_000681.2) [Epidemiological studies have shown a significant relationship between the alcohol consumption and blood pressure (BP) –5. It is ALDH2 activity [ ALDH2∗2, results in the enzymatically inactive form of ALDH2 that fails to convert aldehyde into acetic acid rapidly. Accordingly, the concentration of serum acetaldehyde after alcohol intake reaches much higher levels in individuals with the ALDH2∗2/∗2 and ALDH2∗2/∗1 genotype when compared with homozygote of the wild type allele, ALDH2∗1/∗1  [ ALDH2∗2/∗2 [A nonsynonymous polymorphism, Glu504Lys rs671), is known to have large influence on the1, is knoactivity , 9. The , resp.) , 11. Sin∗2/∗2 , 13. ALDH2 genotype was implicated as a factor modifying the adverse effect of drinking on BP [ ALDH2 gene harbored a strong association with BP [ ALDH2∗2 allele associated with lower BP, which was highly dependent on drinking habit.Considering these observations together, theng on BP –16. In f with BP . In thisAccordingly, in this communication, we attempted to obtain further evidence supporting this result in a longitudinal study as well as in a cross-sectional study using a population in Japan.The study protocol was approved by the ethics committee of Shimane University School of Medicine and written informed consent was obtained from all participants. ALDH2 polymorphism on BP over 20 years. This subgroup was named the “longitudinal cohort.”Participants were recruited at health examinations held in Shimane prefecture from 2006 through 2012. In total, 3,202 participants were recruited. Measurements of height and weight were performed on site. Histories of smoking, alcohol consumption, diabetes mellitus, dyslipidemia, and medication were recorded at on-site interviews. Venous blood was collected after overnight fasting to measure biochemical parameters. Among those subjects, 560 received a health examination in 1986. This subgroup was used in a longitudinal assessment of the genetic effect of theBP was measured in a sitting position at all health examinations. Measurements were performed by certified nurses using an automatic sphygmomanometer, after allowing subjects at least 15-minute sedentary rest. An average of 3 measurements was obtained. Hypertension is defined as either systolic BP (SBP) ≥140 mm Hg and/or diastolic BP (DBP) ≥90 mm Hg, or taking antihypertensive medication.Genomic DNA was isolated from the peripheral blood samples. Genotyping of the Glu504Lys was performed by using the TaqMan method on a GeneAmp PCR 9700 machine  .http://cran.r-project.org/). Differences in demographic data of subjects were analyzed by Student's t-test or χ2 test, whichever was appropriate. Genotype frequencies and the Hardy-Weinberg equilibrium were estimated by the χ2 test. Because the incidence of Lys/Lys was low (about 4.1%), ALDH2∗2/∗2 and ALDH2∗1/∗2 were combined together in the following analyses. Effects of the ALDH2 genotype on BP were assessed by the multiple linear and the logistic regression analysis with adjustment for potential confounding factors including drinking habits.Statistical analyses were performed with the R package  was in agreement with those previously observed in the Japanese [The frequency of theJapanese , 10 and  ALDH2 polymorphism and BP was examined first in a cross-sectional analysis.  ALDH2∗1/∗1 than the other genotypes although the genetic effect of the genotype on BP was attenuated when adjusted with drinking habit .We then examined the effect of ther in DBP ; even an ALDH2 gene had a significant effect on BP under a cross-sectional study design.The present study confirmed that the Glu504Lys polymorphism in theALDH2∗1) showed significantly higher BP than those carrying the A allele (ALDH2∗2). Of note, this association was largely influenced by drinking habit. This was observed also in our cross-sectional study. Habitual alcohol drinking has been demonstrated as a strong risk factor for hypertension [ ALDH2∗1/∗1 are expected to consume more alcohol than those with the other genotypes, most part of the association of the ALDH2 polymorphism with hypertension might be due to difference in alcohol intake. However, our subgroup analysis revealed that the ALDH2 polymorphism was a risk factor for hypertension even in nonhabitual drinkers (see Table S1). This result implies that the ALDH2 genotype has an additional effect on BP independently of the alcohol intake. In addition to the dehydrogenase activity, ALDH shows a wide variety of biological activities, which related to oxidative stress, inflammation, and the serum level of asymmetric dimethylarginine (ADMA) [ ALDH2 gene affect those activities that lead to the difference in blood pressure. Physiological and/or biochemical studies are essential to evaluate effects of the SNP on the metabolic pathway. In addition, a comprehensive genetic analysis in the ALDH2 locus may be necessary to identify polymorphisms responsible for this “alcohol-independent” effect because Glu504Lys may be a “passenger” polymorphism merely linked with the true responsible polymorphisms [A recent result of GWAS indicated that the Glu504Lys (rs671) was associated with BP in Asians including the Japanese . Accordirtension . As indie (ADMA) . Howeverorphisms , 20. ALDH2 genotype and BP was confirmed in a cross-sectional analysis, it was not replicated in a longitudinal study. There are several possible reasons for this discrepancy; first of all, due to a small number of participants in the longitudinal study, the statistical power was not enough to show the effect of the ALDH2 genotype.Although the association between theSecond, age of participants in the longitudinal study was too high at the start of the study. In 1986, the mean age of participants was 51 years which was rather too old to study the development of hypertension longitudinally. Indeed, 319 of 560 individuals (56%) already had hypertension at that time. At this age, many of the participants harbored multiple risk factors for hypertension such as arteriosclerosis, even if they did not develop overt hypertension yet. This might have masked the effects of the genetic risk factors. Supporting this interpretation, age and drinking status, both of which are established risk factors for hypertension, failed to show a significant association with ΔSBP in the present longitudinal study. Further, menopause might be an additional disturbing factor on BP change among women , 22; mos ALDH2 polymorphism.Third, in our study population, one-third of daily drinkers in 1986 quitted drinking during the following 20 years. Change in drinking habit might influence the genetic effect of the ALDH2 gene on BP in a cross-sectional study, though we failed to show the association in a longitudinal analysis. Further studies using a large number of younger individuals are essential to obtain a conclusive result on the effect of the ALDH2 genotype on a longitudinal change of BP.In conclusion, we confirmed the effect of the Glu504Lys polymorphism in theTable S1. The risk of the ALDH2 gene polymorphism on hypertension was examined separately by drinking status. These analyses revealed that the ALDH2 polymorphism was a risk factor for hypertension even in non-habitual drinkers. Table S2. Multivariate linear regression analysis on factors influencing ΔSBP in the longitudinal study showed that that only ΔBMI in men showed a significant association with ΔSBP.


Respiratory syncytial virus (RSV) is the most common pathogen identified in young children with acute lower respiratory infection (ALRI) as well as an important cause of hospital admission. The high incidence of RSV infection and its potential severe outcome make it important to identify and prioritise children who are at higher risk of developing RSV–associated ALRI. We aimed to identify risk factors for RSV–associated ALRI in young children.We carried out a systematic literature review across 4 databases and obtained unpublished studies from RSV Global Epidemiology Network (RSV GEN) collaborators. Quality of all eligible studies was assessed according to modified GRADE criteria. We conducted meta–analyses to estimate odds ratios with 95% confidence intervals (CI) for individual risk factors.We identified 20 studies (3 were unpublished data) with “good quality” that investigated 18 risk factors for RSV–associated ALRI in children younger than five years old. Among them, 8 risk factors were significantly associated with RSV–associated ALRI. The meta–estimates of their odds ratio (ORs) with corresponding 95% confidence intervals (CI) are prematurity 1.96 (95% CI 1.44–2.67), low birth weight 1.91 (95% CI 1.45–2.53), being male 1.23 (95% CI 1.13–1.33), having siblings 1.60 (95% CI 1.32–1.95), maternal smoking 1.36 (95% CI 1.24–1.50), history of atopy 1.47 (95% CI 1.16–1.87), no breastfeeding 2.24 (95% CI 1.56–3.20) and crowding 1.94 (95% CI 1.29–2.93). Although there were insufficient studies available to generate a meta–estimate for HIV, all articles  reported significant associations between HIV and RSV–associated ALRI.This study presents a comprehensive report of the strength of association between various socio–demographic risk factors and RSV–associated ALRI in young children. Some of these amenable risk factors are similar to those that have been identified for  ALRI and thus, in addition to the future impact of novel RSV vaccines, national action against ALRI risk factors as part of national control programmes can be expected to reduce burden of disease from RSV. Further research which identifies, accesses and analyses additional unpublished RSV data sets could further improve the precision of these estimates. Acute lower respiratory infection (ALRI), including pneumonia and bronchiolitis, remains the leading cause of childhood hospitalisation and mortality , primariGlobally, respiratory syncytial virus (RSV) is the most common pathogen identified in young children with ALRI, as well as an important cause of hospital admissions . It is eRSV is known to be more likely to have a severe outcome in children with certain pre–existing chronic medical conditions, resulting in higher rate of hospitalisation and higher risk of death. A case-control study in southwest Alaska indicated that underlying medical conditions, such as prematurity, chronic lung disease and heart disease, were associated with an increased risk of RSV hospitalisation . AnotherTo date, there has been only one systematic review published over a decade ago that assessed the strength of association between various risk factors and RSV–associated ALRI . There hOnline Supplementary Document(Online Supplementary Document). We further hand searched the reference lists of relevant papers for eligible articles. All searches were limited to between January 1995 and July 2015, and there were no publication status or language restrictions applied. Eligible studies were observational studies or randomized controlled trials that assessed the relationship between RSV–associated ALRI and risk factors of interest. We conducted a systematic review according to the PRISMA guidelines. The search was conducted across the following electronic databases: Medline, Embase, Global Health and LILACS. The search terms used are detailed in Appendix S1 in Two investigators (TS and EB) conducted independent literature searches and extracted data using standardised data extraction template. Any discordance or uncertainties regarding relevance or inclusion were arbitrated by HN.Data from unpublished studies provided by RSV Global Epidemiology Network (RSV GEN) collaborators were reviewed (by TS) for quality and inconsistencies. RSV GEN is a working group established to collect unpublished data in order to evaluate the disease burden of RSV worldwide.The protocol of this review was published in PROSPERO database (No. CRD42015017923).We used RSV–associated ALRI as the outcome of interest, which includes clinical pneumonia and bronchiolitis. This was to recognize these common manifestations in young children with viral ALRI , and theOnline Supplementary Document(Online Supplementary Document)). Where there were several slightly different definitions (which may result in differing strengths of association between risk factor and outcome), we pooled the studies into one meta–analysis (where possible) and then conducted a sensitivity analysis. The definitions of risk factors included in the following meta–analysis were listed in .We recognized that the definitions for some risk factors used in the included studies varied substantially (Appendix S2 in Online Supplementary Document(Online Supplementary Document)). We calculated the overall score for each study after assessing each criterion as listed above. Studies with cumulative score ≤ lower quartile (25th percentile) of all scores were considered to have “low quality” and they were excluded in the final estimate. Also a sensitivity analysis was run to show whether the results differ when we included these “low–quality” studies.The quality of each study was assessed by using a modified GRADE scoring system  focusingIn included articles or unpublished studies, data about risk summary measure (odds ratio and relative risk) with 95% CI for risk factors of interest were extracted as provided . If such summary data were not reported, we calculated the same (where feasible) using data reported in the paper.I2>80%, P < 0.05) [Using STATA  we conducted a meta–analysis of risk factor specific odds ratios and reported pooled estimates with corresponding 95% CIs based on random effects model (DerSimonian–Laird method) since significant heterogeneity was found ( < 0.05) . We deciOnline Supplementary Document(Online Supplementary Document). Online Supplementary Document(Online Supplementary Document)). There were 7 studies which had scores ≤6.25 [Online Supplementary Document(Online Supplementary Document). Those “low–quality” studies were also included in a sensitivity analysis (Appendix S7 in Online Supplementary Document(Online Supplementary Document)).We identified 2694 articles through literature search, of which only 23 studies -35 fulfies ≤6.25 ,32,34,35Prematurity has been defined variously in the included studies. One of the studies  used gesThis risk factor was considered as a subgroup (more severe) of children with gestational age <37 weeks. Three hospital–based studies ,21,25 frThe six included studies used birth weight <2.5 kg to define low birth weight. One study  from DenFive hospital–based studies ,23,25,28Six hospital–based studies ,24,28,29Four hospital–based studies ,18,21,28One hospital–based study  from DenDefinitions of low parental education varied among the included studies. Four studies ,19,23  and RSV–associated ALRI using multivariable analysis with the meta–estimate 1.40 95% CI 0.65–3.00) ,30  were observed to be significantly associated with RSV–associated ALRI. Ten additional risk factors  were also observed to have an association with RSV–associated ALRI in 1–3 studies. However, for some of these risk factors , meta–analysis could not be performed to generate odds ratio meta–estimate as case definitions were substantially different or sufficient studies were not available . Therefore, the associations between these risk factors and RSV–ALRI require further study.There was considerable variation among the 27 included studies . Nine ,23,25,29z–score at first vaccination [There were substantial differences with regards to the number of confounders adjusted in each study. Seven studies ,25,27,28cination , or popucination . One stucination . Four stcination ,29,32,33Online Supplementary Document(Online Supplementary Document)). However, this quality assessment tool did not address all aspects related to study quality since we only looked into seven of these: study design, quality of control group, sample size, analysis method, bias, confounding factors and geographical spread of studies. More detailed and appropriate quality assessment tools should be applied and studies with higher quality would be needed to generate more reliable results.The quality score of each study obtained from modified GRADE scoring system varied from 2.5 to 11 with a mean of 7.6. There were 7 studies with “low quality” . Most of them were not designed as case–control studies, did not consider biases within the research, did not take into account of potential confounders or reported estimates using multivariable analysis. A sensitivity analysis was carried out to include these “low–quality” studies. The meta–estimate OR from sensitivity analysis did not differ substantially from the analysis where only studies with quality scores >6.25 were included  to 835 060 . This isAnother limitation is that we did not have access to individual patient data on risk factors for RSV–associated ALRI. Further research should focus on obtaining individual patient data from previous studies or ongoing studies, such as multi–center Pneumonia Etiology Research for Child Health (PERCH) project. With these patient level data, we could have a better understanding about the role of each risk factor in RSV–associated ALRI (particularly with regard to prematurity) and adjust for possible confounders in a pooled analysis.Online Supplementary Document(Online Supplementary Document) shows the comparison of strength of association of risk factors identified in both reviews. The strength of association between risk factors and severe ALRI was generally slightly stronger than the corresponding ones in RSV–associated ALRI. Several risk factors were only investigated for severe ALRI, such as incomplete immunization, vitamin D deficiency, anemia, zinc deficiency, birth interval, birth order, and vitamin A deficiency, while some risk factors were only explored for RSV–associated ALRI .The definitions of some risk factors were similar or the same as those reported in a review  investigCompared to the previous review  conducteFurther research on this topic should identify, seek access to and analyze additional unpublished RSV data sets to further improve the precision of these estimates. This should include, where possible, investigation of possible association with risk factors which have been reported to show association with  ALRI: incomplete immunization, vitamin D deficiency, anemia, zinc deficiency, birth interval, birth order, and vitamin A deficiency.RSV is a major cause of hospital admission and mortality among young children, especially in developing countries . Our stu


Fibroblast growth factor receptor (FGFR) gene amplification has been reported in different types of cancer. We performed an up-to-date meta-analysis to further characterize the prognostic value of FGFR gene amplification in patients with cancer.A search of several databases, including MEDLINE (PubMed), EMBASE, Web of Science, and China National Knowledge Infrastructure, was conducted to identify studies examining the association between FGFR gene amplification and cancer. A total of 24 studies met the inclusion criteria, and overall incidence rates, hazard risk (HR), overall survival, disease-free survival, and 95% confidence intervals (CIs) were calculated employing fixed- or random-effects models depending on the heterogeneity of the included studies.FGFR1: 0.11 (95% CI: 0.08–0.13) and FGFR2: 0.04 (95% CI: 0.02–0.06). Overall survival was significantly worse among patients with FGFR gene amplification: FGFR1  and FGFR2 .In the meta-analysis of 24 studies, the prevalence of FGFR gene amplification was Current evidence supports the conclusion that the outcomes of patients with FGFR gene amplified cancers is worse than for those with non-FGFR gene amplified cancers. FGFR1-FGFR4) and encodes membrane tyrosine kinase receptors involved in signaling by interacting with fibroblast growth factors etc. In contrast to the activation of FGFR3 and FGFR4 by mutation FGFR3 and FGFR4 has been described only rarely in cancer and no data related to prognosis could be obtained. As a result, we mainly discuss FGFR1 and FGFR2 amplification in our present study.The fibroblast growth factor receptor (FGFR) family comprises four main members  studied FGFR gene amplification in any type of human cancers; (ii) measured FGFR gene amplification in human samples; and (iii) reported data necessary to calculate the incidence of FGFR gene amplification and/or HR on survival outcomes. Studies were excluded if they were: (i) reviews, case-only studies, or familial studies; (ii) lacking sufficient data for calculation of incidence and/or HR with 95% CIs; and (iii) duplication of previous publications or replicated samples.Data extraction was carried out by two reviewers independently, using a predefined form. Disagreements were resolved by discussion with a third reviewer. From each study, the following information was extracted: country of origin of the study, first author's name, year of publication, study population, FGFR gene amplification assessment methods, cut-off definition, and incidence of FGFR gene amplification with 95% CIs, HR for OS, and/or DFS with corresponding 95% CIs. In the studies that included cohorts of different ethnic populations, the data were collected separately and the data sets were recognized as independent studies. If the HRs and CIs were not reported, the total observed death events and the numbers of patients in each group were extracted to calculate HR and its variance indirectly Study quality was assessed independently by the two reviewers using the following factors: (i) clear definition of the study population and the type of carcinoma; (ii) clear definition of the measurement method and the cut-off value of FGFR gene amplification; (iii) sample size larger than 10; and (iv) clear definition of the outcome assessment (if applicable). Any studies lacking any of these points were excluded from the final analysis.p≥0.10) p values were two-sided, with p<0.05 considered statistically significant except for the Q-test. Statistical analyses were conducted using STATA version 11.0  and Review Manager Version 5.1 .For the incidence of FGFR gene amplification, the incidences and 95% CIs were combined. For the survival analyses, HRs with 95% CIs were used to combine the pooled data. Heterogeneity was assessed by a Q-test. A fixed-effect model was used when there was no heterogeneity  on FGFR2 amplification.In this analysis, 4394 cases from 17 studies FGFR1/CEN8 greater than 2 FGFR2/CEP10 greater than 2 Single-nucleotide polymorphism (SNP) array, quantitative polymerase chain reaction (qPCR), assay comparative genomic hybridization (aCGH), fluorescence in situ hybridization (FISH), chromogenic in situ hybridization (CISH) and silver in situ hybridization (SISH) FGFR1 amplification in these studies ranged from 0 to 30.9%, partly reflecting the heterogeneity in the criteria for gene amplification. In the meta-analysis of 17 studies, the prevalence of FGFR1 amplification was 0.11 [95% confidence interval (CI): 0.08–0.13] and large heterogeneity existed . In addition, we checked the public Cancer Genome Atlas (http://cancergenome.nih.gov) for the prevalence of FGFR gene amplification. The results showed that FGFR1 amplification occurred in 3.4% of 10,648 patients and FGFR2 amplification occurred in 0.9% of 8352 patients. Consistent with our results, the amplifications were most commonly found in lung cancer (16.9%), breast cancer (13.4%), and gastric cancer (5.1%).The prevalence of assessed  and the FGFR1 amplification and 1344 patients in 3 studies for FGFR2 amplification were included. Notably, the patients in the analysis of FGFR2 amplification were all gastric cancer patients. The results showed that the pooled hazard risks (HRs) were significant for both FGFR1  and FGFR2 ,natural logarithm of HR. SE, standard error.(DOCX)Click here for additional data file.Table S1FGFR gene amplification: characteristics of included studies.FGFR1: fibroblast growth factor receptor 1; FGFR2: fibroblast growth factor receptor 2; NSCLC: non-small-cell lung cancer; SQLC: squamous cell lung cancer; OTSCC: oral tongue squamous cell carcinoma; FISH: fluorescence in situ hybridization; CISH: chromogenic in situ hybridization; SISH: silver in situ hybridization; qPCR: quantitative polymerase chain reaction; aCGH: assay comparative genomic hybridization; SNP: single-nucleotide polymorphism; N/A: not applicable.(DOCX)Click here for additional data file.Table S2Overall and subgroup analysis of FGFR gene amplification prevalence.FGFR1: fibroblast growth factor receptor 1; FGFR2: fibroblast growth factor receptor 2; NSCLC: non-small-cell lung cancer; SQLC: squamous cell lung cancer; OSCC: oral squamous cell carcinoma; OTSCC: oral tongue squamous cell carcinoma; FISH: fluorescence in situ hybridization; CISH: chromogenic in situ hybridization; SISH: silver in situ hybridization; PCR: polymerase chain reaction; aCGH: assay comparative genomic hybridization; SNP: single-nucleotide polymorphism; N/A: not applicable; PDAC: Pancreatic ductal adenocarcinoma.(DOCX)Click here for additional data file.Checklist S1PRISMA statement.(DOC)Click here for additional data file.