Cadmium (Cd) is a widespread environmental pollutant and has been a recognized carcinogen for several decades. Many observational studies reported Cd exposure might be one cause of renal cancer. However, these findings are inconsistent. We conducted a meta-analysis to evaluate the relationship between cadmium exposure and renal cancer risk. A comprehensive PubMed and Embase search was conducted to retrieve observational studies meeting our meta-analysis criteria. A combined odds ratio (OR) and corresponding 95% confidence interval (CI) were applied to assess the association between Cd exposure and renal cancer risk. The meta-analysis showed that a high Cd exposure significantly increased renal cancer 1.47 times . The significant association remained consistent when stratified by geographic region and gender, however mixed results were produced when stratified by sample size, study design, NOS score, adjustment for covariates, effects measure, and exposure type. Our results indicated that a high Cd exposure was associated with increased renal cancer risk and the association was higher for occupational exposure compared with non-occupational exposure. This meta-analysis suggests that a high Cd exposure may be a risk factor for renal cancer in occupational population. In 2015, a total of 61,560 new cases of renal cancer were diagnosed with 14,080 deaths in the USA alone, making renal cancer the sixth leading cause of cancer deathsCadmium (Cd) is a toxic heavy metal harmful to human health found naturally at low levels in rocks and soil. Cd is accumulated in the kidney cortex and is one cause of end-stage renal disease4567891112Following development of our search strategy, 332 records were initially identified. Thirty-six duplicate studies were excluded; 296 were subsequently screened, and 139 were excluded because titles and abstracts indicated the studies did not fit our criteria. Nineteen full-text articles were reviewed for further assessment. Five articles were excluded because Cd content in kidney tissues was measured15161718202123The descriptive data for all articles included in the study are summarized in 6710581156781098910111256567891012The Newcastle-Ottawa Scale (NOS) was used to assess the quality of studies included in the meta-analysis . The medP = 0.000) with low heterogeneity . Two estimates from the same study were shown; the study provided separate analyses for two case-control studies, which were depicted separately in the figure  to 1.51 ; in addition, low heterogeneity was observed. Subgroup analysis was also performed , Table 3P = 0.759) and funnel plot symmetry was observed in the meta-analysis , suggesting stable results.)Evidence of publication bias was not detected using Egger’s test  causing rare health events, this design has inherent limitations, such as selective and recall or memory bias. Second, confounding factors, including co-exposure to other toxic chemicals and lifestyle factors  are difficult to control in a meta-analysis. Third, the small number of studies included in a meta-analysis limits the ability to draw robust conclusions, particularly in the subgroup analysis. Finally, the included studies were only distributed in Europe and North America. Therefore, further study should investigate the association between Cd exposure and renal cancer susceptibility among Caucasian, African, and Asian populations or additional ethnicities on other continents.The following factors should be considered for further studies. First, in the meta-analysis, we found only one study validated Cd exposure levels. It is vital to estimate Cd exposure levels in urine and blood, proportional to the body’s tolerance, which reflect long-term Cd exposure levels. The precision of observational Cd related renal cancer hypothesis studies could be greatly improved by incorporating Cd exposure biomarkers. Therefore, future studies should examine Cd levels in urine and blood as a method to assess long-term Cd exposure. Second, most studies we examined investigated the association between Cd occupational exposure and renal cancer risk. Therefore, the results of our meta-analysis should only be used to infer Cd under occupational conditions leading to increased renal cancer risk. Compared with the general population, Cd levels are typically higher in certain industries as a component of an occupational population where Cd is present . However, Cd exposure levels in the general population are usually low. Therefore, further studies are needed to confirm the association among the non-occupational (Cd-exposed) population. Finally, studies we analyzed in the meta-analysis did not examine whether an association between Cd exposure and renal cancer risk differed among anatomical or histological sub-sites within the body.In summary, the meta-analysis suggests that a high cadium exposure may be a risk factor for renal cancer in occupational population. Further study should be conducted to determine whether a low level Cd exposure in general population was associated with increased risk of renal cancer.A comprehensive search was performed using PubMed and EMBASE databases to retrieve all potentially related studies up to June 2015. We employed the following search strategies  without limitations: “renal cancer” or “kidney cancer” or “renal cell cancer” or “renal cell carcinoma” combined with “cadmium”. The search was limited to human subjects. The previous review and related article references were manually screened to identify other potentially eligible studies.Studies were considered eligible for inclusion in the meta-analysis if they met the following criteria: (1) Cd was the heavy metal of human exposure; (2) the outcome was renal cancer risk; (3) the study design was cohort, case control, or cross-sectional; and (4) the relative risk (RR), odds ratio (OR), or hazard risk (HR) with corresponding 95% confidence interval (CI) were reported or provided sufficient data to estimate crude OR, RR, or HR with corresponding 95% CI. If the included population was duplicated in more than one study, only data from the study with the most comprehensive information was included.Two authors (JKS and XHY) independently extracted data from the selected studies. The following key points were collected: first author; publication year; study design; country; total number of cases and subjects; sex; Cd exposure type; and adjusted variables. Adjusted OR was extracted as a preference to non-adjusted OR; however, unadjusted OR and CI were calculated when OR was not provided. When more than one adjusted OR was reported, the ratio with the most number of adjusted variables was selected. Disagreements between authors (JKS and XHY) were resolved through discussion and consensus.The Newcastle-Ottawa Scale (NOS) was employed to evaluate the methodological quality of each studyI2 statistic, which measured quantitative inconsistency in heterogeneity levels across studies. Studies with I2values from 25% to 50% exhibited low heterogeneity, 50% to 75% showed moderate heterogeneity, and studies with results >75% exhibited high heterogeneity. An I2 value >50% and Pheterogeneity<0.10 indicated significant heterogeneity. Sensitivity analysis was conducted to evaluate data robustness and stability by sequentially omitting one study on each turn. Studies were sequentially omitted if the data did not meet the restrictions. In addition, subgroup analysis was stratified by study design, effects measure, geographic region, sample size, exposure type, adjustment for variates, and NOS quality.We used OR with 95% CI as the common measure across all studies. Cd caused renal cancer was considered a rare event, the RR and HR in the cohort study was considered approximations of OR. Two articles did not report overall risk estimates, but instead separately presented results for men and women. Therefore, we combined the results using fixed effects and included the pooled risk estimates in the primary analysis85a priori P < 0.1 indicating a significant publicationWe evaluated potential publication bias using a funnel plot and Egger’s tests, with How to cite this article: Song, J. et al. Association between cadmium exposure and renal cancer risk: a meta-analysis of observational studies. Sci. Rep.5, 17976; doi: 10.1038/srep17976 (2015).


Coronary artery disease (CAD) is a disease which has become a leading cause of death worldwide. The polymorphisms in Interleukin-17 (IL-17A), including rs2275913, rs3819024, rs3819025, rs3748067, rs8193037, rs4711998, and rs8193036, have been found to be probably associated with the risk of CAD. However, the results were inconsistent and inconclusive. The present study performed a meta-analysis to get a more precise and comprehensive estimation of the association between the IL-17A polymorphisms and CAD risk. The Pubmed, Embase, Cochrane Central Register of Controlled Trials, Chinese National Knowledge Infrastructure, and Chinese Biomedical Literature Databases were searched for related studies. A total of six studies, including 3542 cases and 3212 controls, were identified for the meta-analysis. The main findings of the present meta-analysis show that the TT genotype of IL-17A rs3748067 is associated with a significant lower risk of CAD in the homozygous model odds ratio (OR) (OR = 0.37) in Asians. No significant association was found for rs2275913, rs3819024, rs3819025, rs8193037, rs4711998, and rs8193036 with CAD susceptibility in the overall analysis. However, subgroup analysis indicated a significant decreased risk of CAD for the GG genotype and G allele of rs2275913 in a small sample size group, and a higher risk of CAD for the GG genotype and G allele of rs8193037 in a heterozygous model (OR = 1.56), dominant model (OR = 1.54), and allelic model (OR = 1.47) in Asians. In conclusion, the current meta-analysis suggests a significant relationship between rs3748067, rs8193037, and CAD in Asians, while for rs2275913, rs3819024, rs3819025, rs4711998, rs8193036, no such relations were found. Thus, IL-17A rs3748067 and rs8193037 might be recommended as a predictor for susceptibility of CAD for Asians. However, the results of this meta-analysis are hypothesis-generating results which should be interpreted with caution because of the heterogeneity and publication bias among study designs. It is well known that atherosclerosis is a chronic inflammatory disease, which has become the major cause of cardiovascular diseases (CVDs), including coronary artery disease (CAD), ischemic stroke, cerebral stroke, and peripheral vascular disease . Among tInterleukin-17 (IL-17) is a novel family cytokine that consists of six protein members (from IL-17A to IL-17F), which plays an important role in many chronic inflammatory diseases ,3. It haWe systematically searched the published studies in the following electronic databases: Pubmed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Chinese National Knowledge Infrastructure (CNKI), and Chinese Biomedical Literature Database (CBM). The searched terms were , (“interleukin-17A” or “IL-17a”), and (“polymorphism” or “mutation” or “SNP” or “single nucleotide polymorphism”), without restrictions on language. The deadline for publication was 30 April 2016. All of the results from the databases were screened. Firstly, we screened the title. If the titles fulfilled our criteria, we then screened the abstract. We retrieved the full text if the abstract matched our interest. The references of all eligible studies were retrieved manually for other potentially relevant studies. We contacted the authors for related data that were unavailable in the original publications.Inclusion criteria: (a) case-control design; (b) the association of interleukin-17A polymorphisms and CAD risks should be evaluated; (c) the data in the publication were sufficient for the present estimation. Studies were excluded if any of the following applies: (1) repeat publications, abstracts, letters or reviews; (2) studies not meeting all of the inclusion criteria.We extracted information from each eligible publication manually by two investigators independently. For each study, the extracted information included: first authors’ name, publishing year, country, ethnicity, genotyping method, the source of controls, sex and age match, and genotype numbers of cases and controls. If we met discrepancies during the data extraction, they would be resolved by a consensus achieved by the third author.The quality of the included studies was evaluated according to the predefined scale for quality assessment . The scoχ2-test was used to evaluate the HWE of the control group polymorphism. If p < 0.05, it was considered to be deviated from HWE. To evaluate the association between IL-17A polymorphisms and CAD risk, the crude odds ratio (OR) with 95% confidence interval (CI) was used. The pooled ORs were calculated using homozygous, heterozygous, dominant, and allelic genetic model. The statistical significance was determined by the Z-test, and the p-value was adjusted using Bonferroni’s correction. p < 0.05 was considered to be statistically significant. Subgroup analysis was conducted by the sample size and ethnicity. Total samples minor than 1000 will be treated as small, and large, otherwise.I-square statistical test, which was not dependent on the number of studies in the meta-analysis [I2 > 50%), the random-effects model (the DerSimonian and Laird method) was used for the meta-analysis [p < 0.05 was considered to be statistically significant [The statistical heterogeneity between studies was evaluated by an analysis . If theranalysis . Otherwianalysis . Sensitinificant . All staA total of 68 studies were obtained from the literature search after duplicates were removed. Among them, 57 studies were excluded for irrelevance, three were master’s degree theses, two for predicting IL-17A polymorphisms and ischemic stroke. Finally, six studies met the criteria, including 3542 cases and 3212 controls ,10,11,17The results of the meta-analysis for the associations between IL-17A rs2275913, rs3819024, rs3819025, rs8193037, rs3748067, rs4711998, rs8193036, and CAD risks were shown in adjp < 0.0001; GG vs. GA/AA, OR = 0.76, 95% CI = 0.64–0.90, adjp = 0.007; G vs. A, OR = 0.77, 95% CI = 0.68–0.87, adjp < 0.0001). In the subgroup analysis by ethnicity, we did not find any remarkable differences between Asians and Caucasians after Bonferroni’s adjustment of p-value.Five studies, with 3022 cases and 2732 controls, were included in this analysis. No significant associations were found between rs2275913 and CAD susceptibility in the overall analysis for all genetic models. However, when we conducted a subgroup analysis by sample size, significant decreases in risk of CAD for the GG genotype and G allele in a small sample size group in all genetic models was found , dominant model , and allelic model  in Asians.Three studies, with 2449 cases and 2082 controls, were included in this analysis. No significant associations were found in the overall analysis for all genetic models. In the subgroup analysis by ethnicity, a significant increase in CAD susceptibility was found for the GG genotype and G allele in a heterozygous model . No significant associations were found between these SNPs and CAD risk in other genetic models.Two studies, with 788 cases and 820 controls, were included in this analysis. A significant decrease in CAD risk was found in the homozygous model . No significant relationship was found between these SNPs and CAD risk in all genetic models .One study with 1031 cases and 935 controls was included in the analysis for rs4711998 and CAD; other study with 895 cases and 664 controls, was included in the analysis for rs8193036. No significant associations were found between these SNPs and CAD susceptibility in the overall analysis.Since a significant heterogeneity was found for IL-17A rs2275913, we performed a subgroup analysis by sample size and ethnicity to explore the source of heterogeneity. The results indicate that the sample size was the source of heterogeneity for rs2275913 in all genetic models. Ethnicity also took the responsibility in heterogeneity and dominant models. For IL-17A rs8193037, ethnicity is the source of the heterogeneity in all genetic models.The influence of each study on the pooled ORs and 95% CIs was evaluated by excluding one single study at a time using STATA 12.0 software. No significant altered pooled ORs were found in all genetic models for IL-17A rs2275913 (data not shown).p values for Begg’s and Egger’s tests are shown in We performed the Begg’s funnel plot and Egger’s test to evaluate the publication bias. The The main findings of the present meta-analysis show that the TT genotype of IL-17A rs3748067 was associated with a significant lower risk of CAD in a homozygous model (OR = 0.37) in Asians. No significant association was found for rs2275913, rs3819024, rs3819025, rs8193037, rs4711998, and rs8193036 with CAD susceptibility in overall analysis. However, a subgroup analysis indicated a significantly decreased risk of CAD for the GG genotype and G allele of rs2275913 in small sample size groups. A higher risk of CAD for the GG genotype and G allele of rs8193037 was observed in a heterozygous model (OR = 1.56), dominant model (OR = 1.54), and allelic model (OR = 1.47) in Asians.Previous studies have reported the importance of inflammation in the risk of atherosclerosis . IL-17 iRecently, several SNPs in IL-17A have been studied to investigate their relations with CAD risk. rs2275913 has gained the greatest attention in these involved studies, some of which found a significant association between rs2275913 and CAD , while op < 0.05) was found for both of the two included studies. Furthermore, the two studies were all conducted among Asians. Therefore, further studies with larger sample sizes are required to confirm the results.In Asians, we also observed a higher risk of CAD for the GG genotype and G allele of rs8193037. However, only one study was included for the evaluation in Caucasians. Further studies are still needed to confirm the associations in other ethnicities. We also found a significant association between rs3748067 and CAD, but significant deviation from HWE , the cause for the asymmetry in funnel plots includes selection bias , small-sample effects, true heterogeneity, artifacts, and chance. In the present meta-analysis, most of the included studies were of small size. After a comprehensive literature search, all published studies were included in the present study. No large consortia or GWAS data are available yet. Therefore, the small-sample effects might be one reason for this bias. Furthermore, we have assessed the quality of all included studies, and they are all of high quality. However, only studies in English or Chinese have been searched and included. There might be studies in other languages which are not included in the present analysis. Based on the Cochrane Handbook, tests for funnel plot asymmetry should be used only when there are at least 10 studies included, because when there are fewer studies the power of the test is too low to distinguish chance from real asymmetry. In the present test, only five studies are included, which might be another reason for the asymmetry.We found an obvious asymmetry in funnel plots, and a significant We included six studies in our present meta-analysis, while only one study was conducted in Caucasians, which estimated the associations between rs2275913, rs8193037, and rs3819024 with risk of CAD. However, no obvious relationships were found in all of these SNPs. The positive results in our meta-analysis are all related with Asians. Thus, the conclusion drawn in the present meta-analysis might be only of generalizability for Asians.The results of the present meta-analysis should be interpreted carefully because of the following limitations. Firstly, the number of patients was relatively small, and may influence the outcomes. After a very comprehensive literature search from several different databases, only six studies including 3542 cases and 3212 controls were included in the present meta-analysis, and for rs8193037, rs3748067, rs3819025, and rs3819024, even fewer studies, each less than three were included. Secondly, the clinicopathological characteristics or disease subtypes are limited in most of these studies. Thirdly, the ethnicity of the subjects is predominantly Asiatic. Only one study, with 898 cases and 667 controls, was committed in Caucasians, and the last limitation is that CAD is a multi-factorial disease influenced by both genetic and environmental factors. The gene-gene and gene-environment interactions may play important roles in the functions of these polymorphisms, but most studies lack the information on environmental exposure and multiple SNPs in haplotypes.In conclusion, the current meta-analysis suggests a lower risk of CAD for the TT genotype of IL-17A rs3748067 in Asians, and a higher risk of CAD for the GG genotype and G allele of rs8193037 in Asians. A decreased risk of CAD for the GG genotype and G allele of rs2275913 were observed in a small sample size group, while rs3819024, rs3819025, and rs4711998 are not associated with the risk of CAD. Thus, IL-17A rs3748067 and rs8193037 might be recommended as predictors for susceptibility of CAD in Asians. However, the results of this meta-analysis are hypothesis-generating results which should be interpreted with caution because of the heterogeneity and publication bias among study designs. Further study is needed to evaluate the association between these SNPs and CAD, especially in a large sample size, in Caucasians, and with clinicopathological characteristics.


The pooled analysis also revealed that NTD-affected mothers had significantly lower levels of folate , vitamin B12  and red blood cell folate . Therefore, altered plasma levels of biomarkers related to one-carbon metabolism are associated with NTD-affected pregnancies.Periconceptional supplementation with folic acid reduces the occurrence of neural tube defects (NTDs). The association between maternal abnormalities in homocysteine metabolism  and the risk of NTDs-affected pregnancies has been widely evaluated in recent years, although the results are conflicting. To investigate this inconsistency, we performed a meta-analysis of 32 studies, involving 1,890 NTD-affected mothers and 3,995 control mothers, to develop an understanding of the relationship between maternal biomarkers related to one-carbon metabolism and NTD. A random-effects model was used to calculate the ratio of means (RoM) between the cases and controls, along with the 95% confidence intervals (CIs). A significant increase in homocysteine levels was observed in NTD-affected mothers compared with controls (RoM: 1.16, 95% CI: 1.09–1.23, P = 1.8 × 10 Neural tube defects (NTDs) are thought to be one of the most common congenital defects234Numerous studies have demonstrated that periconceptional supplementation with folic acid reduces the occurrence and recurrence risk of NTDs by 50–75%81213Over the past decades, a considerable amount of research has investigated the relationship between disturbed maternal metabolism of folate and homocysteine and NTDs, hoping to identify biomarkers that could facilitate non-invasive prenatal diagnosis and prevent congenital defects. However, the maternal metabolic profile for the relevant components of the metabolic pathway are not currently known, due to the complexity of the metabolism and the lack of effective methods. Furthermore, existing studies have reported inconsistent results regarding the relationship between a disturbed maternal metabolic profile and risk of NTDs. This inconsistency may be due to insufficient power of their limited sample size, false-positive results, phenotypic heterogeneity and/or publication biases. The interpretation of these studies has also been complicated by their use of different ethnic populations, or bias in the study design. Therefore, we performed a meta-analysis of the published studies to clarify this inconsistency, and to develop an understanding of the relationship between maternal biomarkers of one-carbon metabolism and NTDs.The search generated 1,348 publications that were available on electronic bibliographic databases . Of thes891315161718192021222324252627282930313233343536373839404142−6). Ethnic subgroup analysis revealed that the pooled RoM for Asian mothers was 1.27 , 1.05 for Caucasian mothers  and 1.32 for the other ethnic populations . When analysed according to study design, a significant increase in maternal homocysteine was observed among prospective studies , with a marginally significant effect among retrospective studies  (−4) and study design (P < 10−4) were significantly correlated with the magnitude of the effect, although age (P = 0.59), number of cases (P = 0.05) and number of controls (P = 0.44) were not.In the primary analysis of 26 studies, NTD-affected mothers had significantly higher mean total homocysteine levels compared to control mothers  . In addi = 0.04) . To evalWe also conducted sensitivity analysis, and the results confirmed the significant difference between maternal homocysteine levels for NTD-affected cases and controls, with RoMs and 95% CIs ranging from 1.13 (95% CI: 1.07–1.20) to 1.17 (95% CI: 1.09–1.27) . Funnel −4). To determine the potential sources of this heterogeneity, we conducted subgroup analyses according to ethnicity and study design. When stratified by ethnicity, a significant decrease in maternal folate levels was observed among Asian and Caucasian mothers, with RoMs of 0.88  and 0.93  respectively. However, no significant difference was detected among the other ethnic populations   and statulations . When anulations . EthniciSensitivity analysis indicated that no single study qualitatively influenced the pooled RoM, which suggests that the results of this meta-analysis were statistically robust . The sha−5) (−4). When analysed according to study design, the effects were significant for both prospective and retrospective studies, with RoMs of 0.90  and 0.86 , respectively. In the meta-regression analysis, ethnicity (P = 0.07), age (P = 0.25), study design (P = 0.13), number of cases (P = 0.31) and number of controls (P = 0.13) explained the minimal level of heterogeneity.The meta-analysis detected a significant decrease in maternal vitamin B12 levels among NTD-affected mothers, with an overall RoM of 0.89  . When stOne-way sensitivity analyses confirmed that no single study qualitatively influenced the pooled RoM . The shaUsing the random effect model, a marginally significant decrease in maternal RBC folate levels was observed among NTD-affected mothers  . When stSensitivity analysis indicated that the results of this meta-analysis were stable, with RoMs and 95% CIs ranging from 0.903  to 0.934  . No publThis meta-analysis of 32 association studies, involving 1,890 NTD-affected mothers and 3,995 control mothers, provides the first comprehensive assessment of the relationship between disturbed maternal folate and homocysteine metabolism and the risk of NTDs. Our results indicate that NTD-affected mothers have higher levels of homocysteine, and lower levels of folate, vitamin B12 and RBC folate, compared to mothers with unaffected offspring.To identify and evaluate potential sources of heterogeneity, we performed several subgroup analyses according to ethnicity and study design. As we detected significant heterogeneity between the studies included in our meta-analysis, the results must be interpreted with caution. However, the high degree of inter-study heterogeneity may be complicated by several factors. First, heterogeneity may exist in the NTD groups, as the phenotypic severity varies with the type and level of the lesion. Second, variations in vitamin supplement content and use by the studied populations may contribute to these different results. Furthermore, the nutritional habits and dietary folic acid intake may have varied across different study populations. Third, differences in sample collection protocols  may also have affected the results. The optimal period for blood sampling is in the first several weeks of pregnancy, before or soon after the failed closure of the neural tube, as nutritional changes may occur after delivery. Finally, differences in the sensitivity and/or specificity of the analytical techniques, or sample degradation during storage, may also have affected the results.Among the prospective studies, we observed a significant increase in homocysteine metabolism in NTD-affected women. If congenital susceptibility to NTDs is partially mediated by metabolic derangement, it is possible that exposure to high levels of homocysteine may affect the closure of the neural tube at its rostral pole . Although most blood samples in the prospective studies were collected during pregnancy, they were generally collected several weeks after closure of the neural tube. Therefore, if the resulting measurement error biased our results, it likely resulted in an underestimation of the measured effects.in ovoSeveral studies have previously implied that excess homocysteine, regardless of the source of its elevation, might play an independent role in the development of NTDs9When we stratified our analysis by study design, significantly lower levels of folate and vitamin B12 were observed in NTD-affected mothers (vs. controls) from the prospective studies. Maternal folic acid intake substantially reduces the probability of occurrence or recurrence of NTDs2As a retrospective study, the current meta-analysis is subject to the methodological deficiencies of the included studies, and several specific details merit consideration. First, heterogeneity is a potential factor must be considered when interpreting our results. Although we failed to identify the main sources of the heterogeneity in effect size, a meta-analysis of reported data has little capacity to do so. Ideally, we would prefer to pool individual-level data to allow for efficient assessment of the sources of heterogeneity, although this would be impractical for the present study. Second, populations from geographically distinct countries were pooled according to ethnicity in the subgroup meta-analyses, which may have generated a fluctuation effect. Third, our results were based on unadjusted estimates. If each individual's raw data were available, a more precise analysis could be conducted, which could be adjusted for other co-variants, such as age, obesity, folate supplementation and other lifestyle factors.Despite these limitations, the findings of the present study indicate that altered plasma levels of biomarkers related to one-carbon metabolism are associated with NTD-affected pregnancies. To confirm these findings, future studies should involve a prospective design, strict selection of cases and larger studies of diverse ethnic populations.Given the limited evidence available regarding other metabolism biomarkers, the present meta-analysis was restricted to studies that evaluated maternal total homocysteine, folate, vitamin B12 and red blood cell (RBC) folate. We used computer-based searches to identify epidemiologic association studies published before September 2014, which investigating at least one of the four metabolism biomarkers in NTD-affected pregnancies. The databases we searched included PubMed, ISI Web of Science, EMBASE, EBSCO, the Cochrane Library databases, and the Chinese National Knowledge Infrastructure. No language restrictions were imposed on our search.The search included keywords relating to NTDs  in combination with words related to the maternal biomarkers . The titles and abstracts from retrieved articles were screened to determine their relevance, and irrelevant studies were excluded without further evaluation. For the remaining articles, the full texts were evaluated to determine whether they contained data of interest. The reference lists from all relevant publications were also hand-searched for additional eligible reports.For inclusion, studies were required to meet all of the following criteria: (1) investigated maternal one-carbon metabolism and the risk of NTDs (2) original human studies with independent data; (3) followed a case-control or cohort study design; (4) maternal biomarkers were measured separately for cases and controls using a reliable assay; (5) described the assessment methods, equipment and protocols, or provided reference to them; (6) the results were expressed as, or could be estimated into, mean and standard deviation (SD). Major exclusion criteria were: (1) case-only studies and (2) overlapping data. Case reports, editorials, and review articles were also excluded. If more than one paper was published studying the same sample series, only the study with the largest sample size and the most detailed information was included. Studies with different ethnic groups were considered as individual studies for our analyses.NTD-affected pregnancies were defined as women whose children had NTDs, including live births, stillbirths, and prenatally diagnosed foetuses. Control subjects were defined as healthy women with unaffected pregnancies, or those who had a normal child-bearing history without any history of congenital malformation.The two authors independently extracted the following information from each study according to a fixed protocol: first author, year of publication, ethnicity of the study population, clinical characteristics, matching criteria, study design, quantified method of biochemical analyses, diagnostic criteria for NTDs, number of cases and controls, collection strategy for maternal biological specimens and the mean and SD values for metabolites from the cases and controls. When only median and range were reported in the text, a conversion formula2 testAs metabolite concentrations were measured using different methods and reported in various units across different studies, we therefore used a ratio method to meta-analyse continuous values for each metabolite5253Sources of heterogeneity were investigated by stratified meta-analyses based on ethnicity and study design (prospective vs. retrospective study). A prospective study was defined as a study where the maternal blood sample was collected before delivery, and a retrospective study was defined as a study where the maternal blood sample was collected postpartum. Ethnic groups were defined as Asian , Caucasian  or other ethnic populations. In addition, ethnicity, sample size and study design were analysed as covariates in a meta-regression. To assess the stability of the results, sensitivity analysis was performed by removing each individual study in turn from the total, and re-analysing the remaining studies. Funnel plots and Egger's linear regression test were used to evaluate potential publication biasConceived and designed the study: K.F.T.; Performed the experiments: K.F.T., Y.L.L. and H.Y.W.; Contributed material/analysis tools: K.F.T. and Y.L.L.; Statistical analyses and paper writing, revising: K.F.T. and H.Y.W.Supplementary information


To evaluate the association of insulin-like growth factor 1 gene rs12423791 and rs6214 polymorphisms with high myopia.An electronic search was conducted on PubMed, Embase, the Cochrane Library and the Chinese Biological Abstract Database for articles published prior to May 6, 2014. A meta-analysis was performed using Revman 5.1 and Stata 12.0, and the odds ratios with 95% confidence intervals were calculated in fixed or random effects models based on the results of the Q test. The subgroup analysis was conducted on the basis of the various regions, the sensitivity analysis was also performed to evaluate the stability of the results, and the publication bias was evaluated by a funnel plot and Egger’s linear regression analysis.This comprehensive meta-analysis included 2808 high myopia patients and 2778 controls from five unrelated studies. The results demonstrated that the significant association was not present in any genetic models between IGF-1 rs12423791 or rs6214 and high myopia. However, subgroup analysis indicated that rs12423791 polymorphism was associated with high myopia in the Chinese populations in the allelic contrast model , the dominant model , and the codominant model . Additionally, none of the individual studies significantly affected the association between IGF-1 rs12423791 and high myopia, according to sensitivity analysis.This meta-analysis shows that IGF-1 rs12423791 or rs6214 gene polymorphism is not associated with high myopia. Myopia is a complex disease caused by multiple genetic and environmental factors and potentially the interaction of those two factors.  It affecPrevious studies have demonstrated that environmental exposure is a risk factor for myopia; for example, outdoor activities have been increasingly recognized as protective factors for myopia. ,12 WhileInsulin-like growth factor-1 (IGF-1) is a member of the human growth hormone-insulin-like growth factor pathway that plays a key role in growth and metabolism. It can also regulate scleral proteoglycan production,  potentiaTo assess the complete evidence of an association between the IGF-1 gene and high myopia, we performed the present comprehensive meta-analysis of published studies. An electronic search was conducted on PubMed, Embase, the Cochrane library and the Chinese Biological Abstract Database for articles published prior to May 6, 2014. The search strategy was based on a combination of ‘ and  and ’ without language restrictions. The references of the retrieved articles were also screened.Inclusion and exclusion criteria: all the studies that were included satisfied all of the following criteria: 1. the studies evaluated the rs12423791 and rs6214 polymorphisms in the insulin-like growth factor 1 gene and high myopia; 2. the studies including normal individuals with spherical refraction ranged from -1.5 to 1.5 D and free from any complications as control subjects, and high myopia was defined as the axial length of 26 mm or higher and/or a refractive error of -8.0 D or less; 3. the studies contained sufficient published data to estimate an odds ratio (OR) and a 95% confidence interval (CI); 4. the studies provided genotype or allele distributions in both the case and control groups; 5. the studies were independent studies; 6. the studies presenting non-original data, such as reviews, editorials, opinion papers, or letters to the editor, were excluded; 7. the studies using nonhuman subjects or specimens were excluded; and 8. the studies with no extractable numerical data were excluded.Two researchers independently applied the inclusion criteria to all identified studies and made decisions on which studies to include. Differences were resolved by discussion and consultation with a third author. The following data were extracted from each study: the first author, year of publication, study design, study population, definition of high myopia, number or frequency by different genotypes, number of cases and controls, minor allele frequency (MAF) of cases and controls, mean age, mean spherical equivalent and mean axial length of high myopia participants.This study was approved by the ethics committee of the School of Public Health of Sun Yat-sen University. Then the researches were allowed to read and analyze the data.P<0.05 considered statistically significant. We calculated the Q statistic to estimate the heterogeneity, and a P≤0.10 was considered statistically significant for the Q-statistic test. The I2 statistic was used to quantify heterogeneity, and an I2-value of 0% indicated no observed heterogeneity with larger values showing increased heterogeneity. [P<0.05 was considered statistically significant in this test. Because the potential cause of heterogeneity among studies was geographic region, the subgroup analysis was conducted on the basis of the various regions. To test the stability of the association, we performed a one-way sensitivity analysis by excluding each study in the meta-analysis in turn. The possibility of publication bias was assessed by visual inspection of a funnel plot in which the standard error of the log (OR) of each study was plotted against its corresponding log (OR); an asymmetric plot indicates possible publication bias. Additionally, Egger’s linear regression test was used to evaluate asymmetry, and a P<0.05 was set as significant. All statistical analyses were performed using RevMan 5.1  and Stata 12.0 .The odds ratios (ORs) with 95% confidence intervals (CIs) were computed to assess the strength of the association between IGF-1 gene polymorphisms and high myopia risk. The significance of the pooled ORs was determined by the Z-test, with a geneity.  If hetergeneity.  In additA total of thirteen potentially relevant studies were retrieved. Of these, five studies were excluded because they were animal studies, which were determined by reading the title and abstract. After a more detailed full-text review, three studies were excluded because two used a family-based design and the other failed to extract sufficient data. Some IGF-1 gene SNPs, such as rs10860861 and rs5742632, were described in only one or two studies. To ensure the validity of the results, any IGF-1 gene polymorphisms reported in fewer than four studies were not included. Thus, only rs12423791 and rs6214 were analyzed in our meta-analysis. Finally, five studies including rs12423791 and rs6214 were included in this meta-analysis. A detailed flow chart of the study selection is shown in 2 = 74%, P = 0.004), the dominant model , and the codominant model , then the random-effect models were used to calculate the pooled ORs in these models. The fixed-effect models were used in the codominant model  and recessive model . The results demonstrated that no significant associations between IGF-1 rs12423791 and high myopia were present in the allelic model , the codominant model , the dominant model , and the recessive model . . Further subgroup analysis by study population indicated that rs12423791 polymorphism was associated with high myopia in the Chinese population in the allelic contrast model , the dominant model , the codominantmodel . P>0.10). The fixed-effects models were used to calculate the pooled ORs, and the results suggested that there were not significant associations in the allelic contrast model , the codominant model , the dominant model , and the recessive model . .  Further  model). A sensitivity analysis was conducted to explore the source of this heterogeneity. In our study, we only performed sensitivity analyses to assess the influence of each study on the IGF-1 gene allelic contrast model (C vs. G), dominant model (CC+CG vs. GG), and codominant model (CG vs. GG), because there was not significant heterogeneity in the IGF-1 gene rs12423791 recessive model (CC vs. CG+GG), codominant model (CC vs. GG), and all rs6215 comparison models.  By the sPrs12423791 = 0.36, Prs6214 = 0.94), the dominant model , the recessive model , the codominant model of rs12423791 (Prs12423791 = 0.45 for CC vs. GG and Prs12423791 = 0.29 for CG vs. GG), and the codominant model of rs6214 (Prs6214 = 0.95 for AA vs. GG and Prs6214 = 0.54 for AG vs. GG). . High myopia is associated with various ocular complications,  and it iHowever, our subgroup analysis by study population showed that Chinese populations with the rs12423791 variants may have somewhat higher risks of developing high myopia. Prior researches in China also illustrated that IGF-1 rs12423791 was significantly associated with high myopia in Chinese populations. ,36,37 AsTo our knowledge, heterogeneity may restrict the interpretation of pooled estimates; therefore, sensitivity meta-analyses were performed in this meta-analysis. We found that none of the individual studies significantly affected the pooled ORs by excluding each study in turn in every comparison, and the association between IGF-1 rs12423791 and high myopia did not change in any genetic models, suggesting the high stability of the meta-analysis. Furthermore, we performed publication bias analyses to validate the reliability of the meta-analysis. In this study, we used a funnel plot and Egger’s linear regression analysis to evaluate for publication bias, and the results showed that there was no evidence of publication bias among the included studies. Therefore, our results suggest that the IGF-1 rs12423791 or rs6214 gene polymorphism was not associated with high myopia susceptibility.To the best of our knowledge, this is the first meta-analysis to assess the association between rs12423791 and rs6214 of the IGF-1 gene and high myopia. This meta-analysis increases the power to detect and quantify an effect and provides a control for publication differences. Additionally, it must be stressed that there are several limitations to this meta-analysis. First, the study populations were mainly from China and Japan, and study populations from other countries were rare or did not exist. Thus, more studies should be conducted in other ethnic groups to increase the statistical power. Second, the IGF-1 gene is just one of a host of genetic risk factors for high myopia; other genes, such as transforming growth factor β1, may also participate in the pathogenesis of high myopia. Third, our results were based on unadjusted estimates; a more precise analysis should be conducted if individual data are available to allow for adjustment by other covariates, such as age, gender, environmental factors and so on. Finally, this meta-analysis only used the single-marker analysis but not the haplotype analysis for the available data. Despite these limitations, this study also has some merits. First, we did not use the language limitation opinion when searching the literature database to minimize the bias within our research. Additionally, the sensitivity analysis indicated the results of the meta-analysis were stable, and we found no evidence of publication bias among the included studies.In summary, this meta-analysis provides evidence that IGF-1 rs12423791 or rs6214 gene polymorphism is not associated with high myopia. Therefore, in view of the fact that myopia is a polygenetic disease, IGF-1 would not play independently important roles in the development of high myopia. Moreover, gene-gene and gene-environment interactions should be considered.S1 ChecklistMeta-analysis on Genetic Association Studies Checklist.(DOCX)Click here for additional data file.S2 ChecklistThe PRISMA Checklist for our meta-analysis.(DOC)Click here for additional data file.


TLR3) gene polymorphisms with the risk of developing various types of cancer have reported conflicting results. Clarifying this association could advance our knowledge of the influence of TLR3 single nucleotide polymorphisms (SNPs) on cancer risk.Recent studies examining the association of Toll-like receptor 3 .We systematically reviewed studies that focused on a collection of 12 SNPs located in the TLR3 genotype rs5743312  was significantly associated with an increased cancer risk as compared with the wild-type allele . No such association was observed with other TLR3 SNPs. In the stratified analysis, the rs3775290  variant genotype was found to be significantly associated with an increased cancer risk in Asian populations. Additionally, the rs3775291  variant genotype was significantly associated with an increased cancer risk in Asians, subgroup with hospital-based controls, and subgroup with a small sample size.The variant TLR3 rs5743312 polymorphism may contribute to an increased cancer risk.After data integration, our findings suggest that the  Toll-like receptors (TLRs) are members of a membrane receptor protein family that recognize the antigenic determinants of viruses, bacteria, protozoa, and fungi, and are thus associated with immunity. There are two pathways associated with the immune deficiencies that lead to disease: the MyD88-IRAK4 pathway, involving all TLR family proteins except TLR3, and the TLR3-Unc93b-TRIF-TRAF3 pathway , 2. TherTLR3 single nucleotide polymorphisms (SNPs) could possibly affect cancer susceptibility and could therefore serve as potential biomarkers to evaluate cancer risk  > 1), four studies testing this conclusion did not reach statistical significance (P > 0.05) [P < 0.05) [TLR3 SNPs and cancer risk is needed. In addition, no systematic review or meta-analysis for the TLR3 gene polymorphisms has been performed.e et al.  in 2007. > 0.05)  and only < 0.05) . Thus, aTLR3 SNPs and cancer risk. We also contacted the authors of these studies to obtain any data that was omitted from published articles so as to enhance our comprehension of the details surrounding these SNPs. We included a meta-analysis for hotspot SNPs  that have been described in at least three published studies to enhance the comprehensiveness of our assessment into the association between TLR3 SNPs and cancer risk.Here, we systematically reviewed published data and comprehensively analyzed and integrated all published studies on the relationship between TLR3 rs3775290, rs3775291, rs3775292, rs5743312 polymorphisms and cancer risk. Our final search concluded with literature published on or before October 5th, 2014. Two independent researchers (Ben-Gang Wang and De-Hui Yi) searched the PubMed, Chinese National Knowledge Infrastructure (CNKI), and Web of Science databases for the following keywords: “TLR3,” “cancer/carcinoma/tumor/neoplasm,” and “polymorphism”. The inclusion criteria were as follows: (1) case-control studies, (2) studies evaluating the association between TLR3 polymorphisms and cancer risk, and (3) the SNP was reported in at least 3 publications. The major exclusion criteria were as follows: (1) studies that presented duplicate data, (2) studies that included only cancer patients , and (3) studies that investigated benign diseases compared with controls.A systematic literature search was performed on the association between the Two independent researchers (Ben-Gang Wang and De-Hui Yi) each extracted all data that were considered to be relevant, and in cases of inconsistent selection, a third author (Yong-Feng Liu) participated in data selection. In this way, a consensus was reached on which studies should be included for analysis. For each study, the following items were collected: first author’s name, publication year, country of origin, ethnicity, cancer type, source of control groups , genotyping method, total numbers of cases and controls, and genotype distributions in cases and controls. When we considered the published data to be insufficient for our analyses, we contacted the authors to obtain the original data. Thus, the data included in this review were obtained from both published and unpublished studies.TLR3 polymorphisms; a result of P < 0.05 was considered to indicate significant disequilibrium. The strength of the association between TLR3 polymorphisms and cancer risk was calculated using odds ratios (ORs) with 95 % confidence intervals (CIs). The heterogeneity between different studies was calculated using the Cochran’s Q test and quantified by the I2 (a significance level of P < 0.10). When heterogeneity did not exist, a fixed-effect model based on the Mantel-Haenszel method was used to assess the pooled OR of each study [1 and OR2 were calculated for the genotypes aa vs. AA (M2) and Aa vs. AA (M1), and were used to determine the most appropriate genetic model. According to the reference [1 ≠ 1 and OR2 = 1, whereas a dominant model is suggested for cases in which OR1 = OR2 ≠ 1, and a codominant model is indicated if OR1 > OR2 > 1 or OR1 < OR2 < 1.The Chi-square test was used to determine the Hardy-Weinberg equilibrium (HWE) for the genotype frequencies of different ch study . Five coeference , a recesP < 0.10 was considered statistically significant. All analyses were performed using STATA software, version 11.0 .For studies with sufficient patients, we also performed stratification analyses on cancer type, ethnicity (Asian or Caucasian), sources of controls , and sample size . The Begg’s rank correlation and the Egger’s linear regression tests were used to evaluate publication bias , 14. A vTLR3 gene polymorphisms, and 24 were not relevant to cancer). Thus, a total of 14 case-control studies that met our inclusion criteria were included in our systematic review and final meta-analysis, which consisted of 7997 cancer patients and 8699 cancer-free controls [Searches of the PubMed, CNKI, and Web of Science databases using different combinations of our keywords yielded a total of 155 records (after duplicates were removed). We excluded 50 studies based on the information presented in the title or abstract  and 91 studies based on the information presented in the text , quantitative polymerase chain reaction , Chip (1 study), multiplexed bead array (1 study), two multiplex PCR (1 study), the KASPar SNP genotyping system (1 study), SNP Stream (2 studies), and sequencing (1 study). Eight studies checked genotypes for quality control –18, 21. TLR3 SNPs and cancer risk. In summary, there are 10 types of cancer that have been evaluated in relation to TLR3 SNPs. The majority of the 12 SNPs located within an intronic region of the TLR3 gene, except for 2 that were found in the 3′ and 5′ regions of the gene and another 2 that located within exons. Only 4 SNPs  were reported in at least 3 studies. For this reason, we defined them as hotspot SNPs which covered all 10 cancer types included in this study   and 1.02 (P = 0.832), respectively. Thus, a codominant model (M2) was the most appropriate choice for rs5743312. Regardless of the genetic model, no other TLR3 SNPs  were found to be associated with cancer risks.The variant T allele of the rs5743312 SNP was significantly associated with an increased risk of cancer when compared with the wild C allele , M2 , and M3 models   (Table P = 0.048)   . Variations in ethnic backgrounds play an important role in genetic susceptibility, and genetic differences between Asians and Caucasians may be the reason that these different ethnic populations follow different life styles and are thus exposed to different environmental factors [rs3775290 is located in exon 4 of the  factors . Populat factors . The C t factors .Fig. 2ThTLR3. In the stratified analysis, TLR3 rs3775291 was also found to be associated with cancer risk in Asians in a heterozygote model (Table et al. [et al. [et al. [TLR3 SNPs with cancer risk. Differences in patients’ genetic or environmental backgrounds might certainly be a common mechanism behind the conclusions of our stratification analysis. Differences in how studies were controlled or documented might also provide an explanation for these conclusions. For example, the studies conducted by Li et al. [et al. [To date, the rs3775291 polymorphism has been the most investigated SNP in  [et al. , and Mou [et al.  indicate [et al.  were welSimilar to rs5743312, rs3775292 is an intronic polymorphism that has also been investigated in detail, as its location in intron 3 is near rs3775290 and rs3775291. Thus, this polymorphism might be associated with variability in alternative splicing and further associated with the linkage disequilibrium between rs3775290 and rs3775291 . Two of TLR3 polymorphisms and the incidence of various types of cancer. Additionally, we were not always able to obtain original data from the published literature, such as the age and sex of the patients, or the environmental factors that might have affected the hosts. Thus, we used unadjusted information, whereas a more precise analysis could be conducted if detailed information on the original data were available. Therefore, additional studies are required to improve the reliability of these results.Our meta-analysis had several limitations. First, only studies that were published in English or Chinese were included in our analysis, thereby creating potential publication bias. Second, the pooled sample size was relatively limited and therefore could support only preliminary evaluations of the association between various TLR3 rs5743312 is potentially associated with increased cancer risks both in the whole collection of studies and in the large sample size subgroup. In the stratified analysis, the variant genotype of the TLR3 rs3775290 polymorphism was associated with an increased cancer risk in the Asian subgroup. TLR3 rs3775291 was also associated with an increased cancer risk in the Asian, hospital-based source of controls, and small sample size subgroups. No association was found between TLR3 rs3775292 and cancer risk. Additional well-designed, large-scale, and functional studies on TLR3 SNPs are required to confirm our findings.In summary, this meta-analysis indicated that the variant allele of


Therefore, the meta-analysis was performed to provide a quality reevaluation of the association between the COMT Val158Met polymorphism and the risk of lung cancer.The association between the Val158Met polymorphism in the Two major public databases (Pubmed and Embase) and several Chinese databases were searched for eligible studies. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated to estimate the strength of the association.COMT Val158Met polymorphism with lung cancer susceptibility were included in this meta-analysis. Overall, pooled analysis indicated that there was no significant association between COMT Val158Met polymorphism and lung cancer susceptibility under all genetic models. Likewise, no association was observed in the stratified analysis by ethnicity and control source, either. However, Val158Met polymorphism was shown to increase lung cancer risk among women .Five publications, including six individual studies with a total of 4,043 subjects  regarding the association of COMT l58Val/Met polymorphism confer genetic susceptibility to lung cancer among women. However, no evidence was found for the association with lung cancer risk in ethnicity and smoking status.These findings suggested that the http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_192The virtual slide(s) for this article can be found here:  Lung cancer is the most frequently diagnosed cancer and is also considered as one of the most commonly lethal malignancies worldwide . Despitecatechol-O-methyl transferase (COMT) gene is located on the chromosome 22q11.2. The Val158Met  single nucleotide polymorphism (SNP) in COMT gene have been identified in a protein coding region [The g region , which lg region . The DNAg region ,10, and COMT Val158Met polymorphism in the risk of lung cancer. However, the results remain inconclusive and controversial. For example, Zhang et al. [COMT Val158Met was significantly associated with a reduced risk of NSCLC, whereas Lim et al. [COMT Val158Met polymorphism was positively associated with lung cancer in never-smokers. So far, no meta-analysis had been conducted to investigate the association between COMT Val158Met polymorphism and Lung cancer. With this in mind, we performed this meta-analysis with large samples to reevaluate this association.Up to date, a number of molecular epidemiologic case–control studies have shown the potential role of g et al.  had showm et al.  had suggcatechol-O-methyltransferase or COMT”, “Val158Met or rs4680 or G472A”, “polymorphism or variant or variation”, and “lung cancer or lung carcinoma”. Additionally, we identified extra studies by manually searching of the references lists of retrieved studies. All eligible studies included in our meta-analysis were conducted on human subjects, and published in either English or Chinese. If several studies overlapped with each, we only selected the one with the largest sample size or the one published most recently. The included studies have to meet the following criteria: (1) full-text studies were included, (2) designed as nested case–control, case–control, or cohort study, (3) estimated the association between COMT Val158Met variant and lung cancer, (4) odds ratio (OR) and the corresponding 95% confidence interval (CI) were provided, and (5) provided the sufficient genotypic or allelic information to estimate.A comprehensive literature search was conducted in two comprehensive literature search engine , and several Chinese database, such as, Chinese Biomedical database, China National Knowledge Infrastructure (CNKI) and Wan fang (WF) Database until October 20, 2013. The search terms were “Information was extracted carefully from all eligible studies independently by two investigators (X. Tan and MW. Chen). All disagreements were resolved by fully discussing between two investigators until a consensus was reached. The following data were collected from each study: first author’s surname, publication date, country, ethnicity, source of control, genotyping method, and genotype counts  of cases and controls Table .Table 1The Newcastle-Ottawa Scale (NOS) was used to assess the methodological quality of studies included in our meta-analysis. The NOS consists of eight items that are further classified into three categories: selection, comparability, and outcome. A star system was created to Semi-quantitatively weigh up the study quality. The comparability group was granted two stars whereas other each items awarded a maximum of one star in highest quality studies. The range of 1–9 stars in the NOS was adopted for estimation, with more stars indicating a higher quality study . Since sCOMT Val158Met (G > A) polymorphism and lung cancer risk was assessed by the pooled ORs with 95% CIs. The pooled estimates were performed under several genetic models, including allele comparison model (A vs. G), homozygote comparison (AA vs. GG), heterozygote comparison (AG vs. GG), dominant model (AA/AG vs. GG), and recessive model (AA vs. AG/GG).The strength of association between p-value were used to test the statistical heterogeneity between studies. A P >0.10 and I2 < 25% for the Q test indicated that no heterogeneity existed among studies. And 25% < I2 < 50% indicated that there was moderate heterogeneity. If there was no heterogeneity, the fixed-effects model was adopted in Mantel–Haenszel method; if I2 > 50% or p-value < 0.1, the random-effects model was performed using the DerSimonian and Laird method if I2 > 50% or p-value < 0.1 [Chi-square-based Q test and ue < 0.1 .p-value less than 0.05 represented significant deviation from HWE [P < 0.05 indicating that there was a significant publication bias in the study [Hardy–Weinberg equilibrium (HWE) was checked in controls by the chi-square test, and a from HWE . An asymhe study .The false-positive report probability (FPRP) ,17 was cP values were two-sided, and a P value less than 0.05 were considered statistically significant.Moreover, we performed subgroup analyses by the ethnic subgroup (Asian and Caucasian), control source  and smoking status (Never-smokers and Ever-smokers). All statistic except for FPRP analysis, were performed by using the Stata software version11.1 (Stata Corporation. USA). And FPRP was conducted by using SAS software . All COMT Val158Met polymorphism with lung cancer risk were included in this meta-analysis. The study characteristics are summarized in Table According to the previously described search strategy and inclusion criteria, the literature selection process was shown in Figure COMT Val158Met polymorphism and the risk of lung cancer are shown in Table COMT Val158Met was not associated with lung cancer . Similarly, no significant associations were observed under all other genetic models    Figure .Figure 3FPRP analysis indicated that, for a prior probability of 0.1, assuming that the OR for specific genotype was 0.67/1.50 (protection/risk), Val/Met carriers for women were not increased lung cancer risk at the prior probability level of 0.1or 0.01 . However, these finding need further validation with larger sample sizes, because of some possible bias that resulted from small sample size in subgroups.Significant heterogeneity was observed in the overall pooled analysis, whereas, the degree of heterogeneity was decrease in the stratified analysis. In order to assess the stability of the present meta-analysis, sensitivity analysis was performed by deleting one study at each time (data not shown) and recalculating ORs and 95% CIs. Overall, the pooled estimates were not materially altered upon the removal of any of single study, suggesting that the stability of the results.P = 0.851, Egger’s test, p = 0.810; AG versus GG, Begg’s test, P = 0.188, Egger’s test, p = 0.345; dominant model, Begg’s test, P = 0.348, Egger’s test, p = 0.529; recessive model, Begg’s test, P = 0.851, Egger’s test, p = 0.599).Begg’s funnel plot and Egger’s test were conducted to estimate the publication bias. The shape of the funnel plot revealed no evidence of obvious asymmetry in this meta-analysis Figure . LikewisLung cancer is the leading cause of cancer-related mortality worldwide. Lung carcinogenesis is a complicated long multi stage process, involving the interplay of cancer susceptibility genes and specific environmental exposures . For exaNumerous studies have adopted a candidate gene approach to explore the effects of genetic variations on the genetic susceptibility to lung cancer. A large proportion of relevant studies has been focused on SNPs in the genes coding for enzymes involved in tobacco carcinogen metabolism (e.g. CYP1A1 and NQO1) and genes involved in DNA repair (e.g. XRCC1) ,24. MoreCOMT polymorphism has also gained more and more attentions in this field. In addition, COMT is a rate-limiting enzyme that played a role in the detoxification of catechol estrogens. Reduced activity of this enzyme might cause the accumulation of catechol estrogens, which may sequentially lead to oxidative DNA damage [A damage ,27. EstrA damage ,29. TherA damage .COMT Val158Met polymorphism in the risk of lung cancer. Zienolddiny et al. [COMT Val158Met polymorphism and overall lung cancer risk. To the best of our knowledge, this is the first meta-analysis that has evaluated the relationship between the COMT Vall58Met polymorphism and the risk of lung cancer.Several epidemiologic studies have reported the role of y et al.  suggestey et al.  reportedCOMT Vall58Met polymorphism appeared to have no influence on the risk of lung cancer either, when studies were stratified by ethnicity, source of controls and smoking status. There might be due to different genetic backgrounds or some other potentially suspected factors, which influenced our research.Furthermore, COMT Val158Met polymorphism among women. To avoid false positive result from multiple comparison, we performed the FPRP analysis for these significant findings. Nevertheless, Val/Met carriers were not increased lung cancer risk at the prior probability level of 0.1or 0.01. There are several possible explanations for these findings. Some findings in the stratified analysis may be discovered by chance because of multiple comparisons and the limited sample size in the subgroups. Given only a few studies were included in this meta-analysis, it was hard to draw firm conclusions from this current analysis. Particularly, the borderline significant association for women was just based on 2 studies. Therefore, these findings should be interpreted with caution.The stratified analysis by sex observed a borderline significant association of COMT Val158Met polymorphism with the risk of lung cancer in Chinese non-smokers. The limitations of study by Zhang et al. [We used the methods of the Newcastle-Ottawa Scale (NOS) to assess the quality of the studies included in our meta-analysis. As a result, three studies ,18,20 weg et al.  was thatg et al.  includedg et al.  performeCOMT Vall58Met polymorphism and its correlation with lung cancer risk, there were also some limitations to be addressed. Firstly, there were only a few studies investigating relationship between COMT polymorphisms and lung cancer risk, therefore, the sample size of our meta-analysis was relatively small. Moreover, this meta-analysis might be also subjected from population stratification, a systematic difference in allele frequencies between subpopulations. In some cases, positive finding of an association study could result from population stratification, instead of a true association between studies SNP and disease. Secondly, our meta-analysis was based on unadjusted estimates, while a more precise analysis should be performed if individual data such as age, smoking status, lifestyle and environmental factors were available. These factors may be sources of the heterogeneity. Thirdly, only five studies were retrieved from Pubmed, Embase, China National Knowledge Infrastructure, and Medline data base. And unpublished studies and conference abstracts were excluded from the current study. Although Begg’s funnel plot, Begg’s test, and Egger’s test were conducted to estimate the publication bias. Lack of publication bias in this study might be due to the fact that Egger’s test was not very powerful with only a few studies in the meta-analyses, the results must be considered cautious. In spite of these limitations, our research was more powerful than each of single study.Although we took considerable efforts to collect all available data to investigate the association of COMT Vall58Met polymorphism and lung cancer risk in the overall analysis. However, a borderline significant association indicated that COMT Vall58Met polymorphism might increase lung cancer susceptibility. Finally, high-quality case–control studies with large sample sizes will be required to confirm these findings.In conclusion, no significant association was found between


Lung cancer is one of the most common human malignant diseases and the leading cause of cancer death worldwide. The rs931794, a SNP located in 15q25.1, has been suggested to be associated with lung cancer risk. Nevertheless, several genetic association studies yielded controversial results.A hospital-based case-control study involving 611 cases and 1062 controls revealed the variant of rs931794 was related to increased lung cancer risk. Stratified analyses revealed the G allele was significantly associated with lung cancer risk among smokers. Following meta-analysis including 6616 cases and 7697 controls confirmed the relevance of rs931794 variant with increased lung cancer risk once again. Heterogeneity should be taken into account when interpreting the consequences. Stratified analysis found ethnicity, histological type and genotyping method were not the sources of between-study heterogeneity. Further sensitivity analysis revealed that the study “Hsiung et al (2010)” might be the major contributor to heterogeneity. Cumulative meta-analysis showed the trend was increasingly obvious with adding studies, confirming the significant association.Results from our current case-control study and meta-analysis offered insight of association between rs931794 and lung cancer risk, suggesting the variant of rs931794 might be related with increased lung cancer risk. Lung cancer is one of the most common human malignant diseases and the leading cause of cancer-related death in western society. It accounts for 87697 deaths in males and 70389 deaths in females of American in 2009. The incAGPHD1) gene which is involved in the cluster of cholinergic nicotenic receptor subunit genes, has been supposed to be associated with lung cancer risk. A number of epidemiological studies have been conducted to examine the association between rs931794 and lung cancer risk in diverse populations[A study investigated a high-risk lung cancer family and suggested the genes of familial lung cancer were located in 6q23-25. Nonethepulations,14,15,16The study adheres to the STREGA guidelines for the Genomic DNA was isolated from peripheral blood sample using the RelaxGene Blood System DP319-02  according to the manufacturer’s instructions. The TaqMan SNP Genotyping Assay  on a 7900HT Fast Real-Time PCR System  were used to detect the polymorphism of rs931794. For quality control, 5% of duplicated samples were randomly sequenced in order to assess the reproducibility, with a concordance rate of 100%.t test, Fisher exact test, and χ2-test were applied to estimate differences in the distribution of demographic variables, potential influencing factors and genotypes between cases and controls, where appropriate. The association between rs931794 and lung cancer susceptibility was estimated by calculating odds ratio (OR) and 95% confidence interval (CI). The genotypic OR and its 95% CI were calculated after adjusting for age, sex and smoking status under logistic regression model. We defined the early-onset cases as who were < = 50.0 years of age in order to explore the association between the SNP and early-onset of cancer. To avoid the assumptions of genetic models, dominant, recessive and additive model for rs931794 in association with lung cancer were analyzed. Hardy-Weinberg equilibrium was assessed by the goodness-of-fit χ2 test for genotypes in the control group[The rol group. All aboTo further confirm the relevance of rs931974 with lung cancer susceptibility, a meta-analysis including published articles and our current studies was conducted. To ensure the rigour of this current meta-analysis, we designed and reported it according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement  and the Information was carefully extracted from all eligible studies. Data extraction was done independently by two of the authors (Q. Wang and W. Hu). The following data were collected from each study: first author’s name, year of publication, country, ethnicity of the population, genotyping methods, histological type, gender, smoking status, OR observed in the primary studies, HWE (Hardy-Weinberg equilibrium), frequencies of genotypes in cases and controls. Two reviewers (J. Ke and X. Lu) independently performed the quality assessment with the Newcastle-Ottawa Scale (NOS) foχ2 test at first, and p-value < 0.05 was considered as a significant disequilibrium [I2 statistic[P<0.1 of Cochran’s Q-test. The following thresholds were used to quantify I2 metric: I2=0-25%, no heterogeneity; I2 = 25-50%, moderate heterogeneity; I2 = 50–75%, large heterogeneity; I2 =75–100%, extreme heterogeneity. If significant heterogeneity was detected (P<0.1), the random-effects model (the DerSimonian and Laird method)[tau2 was the standard deviation of underlying effects across studies and used to estimate the heterogeneity independent of sample size. The smaller the tau is, the less heterogeneity between studies. In order to explore the sources of between-study heterogeneity, we conducted stratified analysis according to ethnicity, histological type and genotyping method. For the purpose of assessing the impact of a single study on the pooled OR and confirming stability of the results, sensitivity analysis was performed to repeat analyses by sequential removal of individual studies[P values are two-tailed with a significant level at 0.05, except Cochrane’s Q-test for heterogeneity (P<0.1). All the statistical tests used in our meta-analysis were performed with STATA version 10.0  and R 3.1.1 .Hardy-Weinberg equilibrium was firstly estimated in the controls for each study using ilibrium . ORs andilibrium ,24 and Istatistic. Heterogd method) was appll studies. Cumulatl studies,29 were l studies. All P vP = 0.475) and age (P = 0.155) distribution. More smokers were presented among cases compared with controls as expected . Among the cases, 427 (69.9%) were classified as NSCLC and 184 (30.1%) as small cell lung cancer.A total of 611 cases of lung cancer and age- and gender-matched 1062 controls were enrolled from 2009 to 2011. The relevant characteristics of subjects were listed in P = 0.921). However, the genotype distribution was markedly different between cases and controls (P = 0.001). The frequencies of genotypes in the controls conformed to Hardy-Weinberg equilibrium , after removal of the study, the heterogeneity greatly reduced . It could be accounted for different inclusion criteria among the included studies. Since Hsiung enrolled lung cancer cases from never-smoking females with adenocarcinoma, while others recruited patients without such strict criteria. Similar result was seen in additive comparison that no single study changed the pooled OR markedly and Hsiung was the contributor to heterogeneity.Since significant heterogeneity existed in meta-analyses, sensitivity analysis was performed to repeat analyses by sequential removal of individual studies so as to examine the influence of a single study on the pooled estimation and assess stability of the result. The detailed information of sensitivity analysis under dominant model was listed in The cumulative meta-analysis was performed to investigate the trend between rs931794 polymorphism and lung cancer risk with accumulation of studies by published year. As shown in The funnel plot of dominant model showed asymmetric distribution of the included studies, indicating there might be some unpublished articles were not included in the meta-analysis shown in . We inclDue to the inconsistent results of the association between rs931794 and lung cancer risk reported by different researchers, we conducted a case-control study and meta-analysis to clarify the real relationship between the rs931794 genotypes and lung cancer risk. In this study, we found rs931794 was related with lung cancer risk in the case-control study performed in the Chinese population. Further meta-analysis combining data from published articles and our current studies showed this SNP might be related with lung cancer risk. To the best of our knowledge, this meta-analysis was the first study combining published articles to represent the association of rs931794 with lung cancer risk.CHRNA5-CHRNA3-CHRNB4, the nicotenic acetylcholine receptor subunits, encode proteins that form receptors expressed in neurons and other tissues, particularly respiratory epithelium, pulmonary neuroendocrine cells and lung cancer cells[CHRNA5-CHRNA3-CHRNB4 could be able to influence the binding function, thus influence individual lung cancer risk. Besides, Tournier[CHRNA5-CHRNA3-CHRNB4 clusters of neotenic acetylcholine receptor subunit genes could influence individual cancer susceptibility by altering receptor nicotine binding function, normal cell proliferation, cell migration and wound repair. AGPHD1 gene is involved in CHRNA5-CHRNA3-CHRNB4 clusters and supposed to be associated with lung cancer risk. The rs931794, which belongs to AGPHD1 gene, is located at 15q25.1 and has been identified as putative genes involved in susceptibility of lung cancer. The rs931794 is situated in the intronic region of AGPHD1, might play an important role in transcription regulation and thus impact on the AGPHD1 expression. Although the AGPHD1 in vivo function is unknown and no functional report is concerning the rs931794, we propose the hypothesis based on previous studies that the rs931794 might alter activity of certain members of neotenic acetylcholine receptors and thus affect lung cancer incidence. However, several genetic association studies reached separate conclusions for the past few years.cer cells. The reccer cells. SNPs in Tournier found no Tournier found niAGPHD1 rs8034191 was risk-conferring factors for lung cancer. The meta-regression analysis revealed an association of the polymorphism with lung cancer in patients with higher smoking rate. Several studies have revealed that the CHRNA5-CHRNA3-CHRNB4 cluster of neotenic acetylcholine receptor subunit genes also have a role in nicotine dependence[CHRNA5-CHRNA3-CHRNB4 cluster of neotenic acetylcholine receptor subunit genes could affect individual lung cancer susceptibility directly by influencing mucosa repair or indirectly by impacting on smoking behavior. Either way, these SNPs play an important role in exogenous carcinogens-induced carcinogenesis, which takes time to be carried out. This might be why the relation of rs931794 with lung cancer risk was positive among the older group, but not younger group.In this study, we firstly conducted a case-control study of the Chinese population. Logistic regression analysis revealed that the increased risk was in relation with the GG carriers compared with the AA carriers, and the similar results were also found under dominant, recessive, additive and allelic models. Further analysis confined with histologically confirmed NSCLC cases found weaker genetic effect and significant association of rs931794 with lung cancer risk. Stratified analyses according to smoking status, age and gender were conducted. The results showed the G allele was associated with lung cancer risk among smokers. It was strange that the variant allele tended to involve in lung cancer risk in non-smokers although the trend did not reach significant. This result could be accounted for the relative small sample size. However, there were several studies revealed the genetic involvement of rs931794 in lung cancer risk among smokers instead of non-smokers. Schwartz and colleagues found thependence,39,40, aThe following meta-analysis including 6616 cases and 7697 controls combined previously published articles and our current study was conducted for the purpose of estimating the real relation between rs931794 and lung cancer risk. Overall results suggested all the genetic models could confer G allele in relevance of lung cancer risk, except recessive model. The meta-analysis of rs931794 proved the similar relation with lung cancer risk to the current case-control study. However, obvious between-study heterogeneity in the meta-analysis should be considered when explaining results and drawing conclusions. Heterogeneity was not reduced in further stratified analysis according to ethnicity, histological type and genotyping method under homozygous, recessive, additive and allelic model. After stratifying by ethnicity and histological type, heterogeneity was existed, but the variant of rs931794 was related to increased lung cancer as before. In stratified analysis based on genotyping method, heterogeneity was not removed. The stratified analysis suggested that ethnicity, histological type and genotyping method were not the major sources of between-study heterogeneity. Further sensitivity analysis found the main source of heterogeneity in the dominant model was the study conducted by Hsiung[Despite the strength of our study that yielded enough power to implement a comprehensive analysis, that’s a lot of room for improvement. At first, the sample size of the current case-control study was relatively small. So we conducted further meta-analysis. The following meta-analysis came to the same conclusion as our case-control study. Though sensitivity analysis and cumulative analysis showed stability of our results, the funnel plot indicated there might be some unpublished articles were not included in the meta-analysis. In addition, lung cancer is a complex disease, which is resulted from interactions between environmental carcinogens, such as nicotine, and genetic factors. Nevertheless, lacking individual personal data and environmental data limited us to further assess gene-gene and gene-environment interaction in the meta-analysis. Further studies should focus on the mechanism of lung cancer risk, especially gene-gene and gene-environment interactions.In conclusion, the results from our current case-control study in the Chinese population and meta-analysis provided a comprehensive description of association between rs931794 and lung cancer risk, suggesting the variant of rs931794 might be related with increased lung cancer risk. However, more studies should be performed to confirm the authenticity of our conclusion. Since other factors, such as genetic background is also a predisposing factor of lung cancer, the interations between gene-gene and gene-environment should be carried on research for understanding the mechanism of lung cancer. Moreover, fine-mapping of 15q25.1 region or functional analysis should be conducted to identify more possible variants.S1 Appendix(DOCX)Click here for additional data file.S1 Fig(TIF)Click here for additional data file.S2 Fig(TIF)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.


C2 rs547154 polymorphism and polypoidal choroidal vasculopathy (PCV) risk, while the results are controversial and inconsistent. Herein, we perform a meta-analysis to gain a precise estimation of the association using 5 eligible studies involving 4076 subjects, of which 1220 were PCV cases, 1073 were age-related macular degeneration (AMD) cases and 1783 were controls. Allelic frequencies of C2 rs547154 polymorphism between PCV and AMD were also compared. Both crude and adjusted odds ratios (OR) with their 95% confidence interval (CI) were included to assess the strength of the association. The pooled OR in random-effect model for allele T versus G was 0.64 , for genotype TG versus GG was 0.65 , and for genotype TT + TG versus GG was 0.64 . No difference in allelic frequency was observed between PCV and AMD . Sensitivity analysis proved the robustness of our data. No significant ethnic divergence was suggested by subgroup analysis, and no publication bias was detected via Egger's test. In conclusion, our data indicate that C2 rs547154 polymorphism plays a protective role in the development of PCV.Previous studies have indicated the association between  Polypoidal choroidal vasculopathy (PCV) is a hemorrhagic and exudative maculopathy characterized by hyalinization and peripapillary, macular or peripheral sub-retinal pigment epithelium (RPE) polypoidal dilatations of branching choroidal vascular networks in indocyanine green angiography (ICGA) presentations12245618ARMS2; MIM: 611313) rs10490924 and complement factor H  rs800292 polymorphisms, variants implicated in AMD etiology, might also increase PCV risk10C2; MIM: 613927) rs547154 variant is a G to T substitution located on chromosome 6p21, which shows protective effect against AMD1214151617C2 variant and PCV susceptibility.The pathogenesis of PCV remains elusive, while it is widely accepted that both genetic and environmental factors play important roles in the disease course of PCV. Considering the clinical similarities between AMD and PCV, researchers aim to find out whether AMD and PCV share common pathogenic pathways. Previous meta-analyses have reported that age-related maculopathy susceptibility 2  were finally included for the meta-analysis1415161715171517C2 rs547154 variant from each individual study are presented in Table 217Allelic and genotypic distributions for the p < 0.0001) , pooled OR for genotype TG versus GG was 0.65 , pooled OR for genotype TT + TG versus GG was 0.64 , and pooled OR for genotype TT versus TG + GG was 0.46  (p < 0.0001)   , pooled , 0.154) . No sign 0.0001) . No diffp, 0.32) . Subgroup, 0.32) . SensitiC2 rs547154 polymorphism and PCV risk, suggesting the necessity to perform an exhaustive review and quantitative analysis on all evidence to determine the effect. In the present study, to assess the association between C2 rs547154 polymorphism and PCV risk, we reviewed a total of 97 published reports and completed an analysis on 4076 subjects from 5 original studies. Our result suggests that C2 rs547154 has protective effect on PCV in all populations.Inconsistencies exist in the association between C2 locus and the CFB locus are located closely together on chromosome 6pC2 gene showed 39% sequence identity with its functionally analogous complement factor B C2 gene, shows a wide expression in the neural retina, RPE, and choroid. C2 is part of the classical pathway of the complement system. Upon the binding with component C4b, component C2 is cleaved by activated factor component C1 into two fragments, C2b and C2aC2 have been implicated in causing complement component 2 deficiency 22C2 in the etiology of PCV and AMD has not been fully elucidated. Thus, more functional investigations are warranted to give a better insight into the relationship between the C2 variant and PCV.The C2 rs547154 polymorphism and PCV susceptibility has been discussed in a previous report, while they have only included 3 studies and tested the allele model (T versus G)To enhance the reliability of our results, we adopted the quality assessment tool recommended by the Newcastle-Ottawa Scale (NOS) for case-control studies. No language limitation was applied. Only studies published in peer-reviewed journals were included. In addition, we also used adjusted data for better estimation of the association. The association between C2 rs547154 variant shows a protective effect on the development of PCV. No significant difference was detected between the allelic frequencies in the PCV and the AMD groups. More epidemiological and biological studies are needed to ascertain the association, and to help to understand the molecular basis behind this association.In conclusion, our study suggests that the http://endnote.com/).This meta-analysis was performed according to the PRISMA guidelinesC2 rs547154 polymorphism and PCV risk; (2) genome-wide association studies, or studies of case-control, cohort or population-based epidemiologic design; (3) studies using predefined criteria and procedures for PCV and AMD diagnoses; (4) OR have been reported, or present allelic and genotypic distributions of the C2 rs547154 variant in PCV cases and control subjects that enable calculations of the outcomes. Alleles included T and G, and genotypes covered TT, TG and GG. We excluded case reports, reviews, conference proceedings, editorials, reports with incomplete data, and only included those with the latest follow-up information for serial publications from the same research team using overlapped subjects. Our study was approved and reviewed by the institutional ethics committee of The First Affiliated Hospital of Nanjing Medical University and adhered to the tenets of the Declaration of Helsinki.Included studies were: (1) studies evaluating the association between http://www.ncbi.nlm.nih.gov/books/NBK35156/) was applied for evaluation of the risk of biases for included studies.Two investigators (X.C. and X.K.) independently reviewed all retrieved articles based on title, abstracts, and complete document if necessary. They also extracted data from each study separately with a customized datasheet. All data obtained from the two reviewers were compared. Disagreements were resolved through consensus with a senior reviewer (C.Z.). Data collected included: first author, year of publication, country of sample origin, ethnicity, genotyping method, demographics of subjects, average age and gender ratio of each studied group, allelic and genotypic distributions in cases and controls, adjusted OR and adjusted factors. The NOS  and STATA software . Alpha was set to 0.05 for two-sided test.The following five ORs and their 95% CI were calculated using both random-effect (the DerSimonian and Laird method)Study design: X.C., K.Z. and C.Z. Collected the samples and performed the experiments: X.C. and X.K. Data interpretation and analysis: X.C. and X.K. Wrote the manuscript: X.C. and C.Z. All authors have read and approved the final manuscript.Supplementary Table 1