P<0.001). A significant association of AA+AG genotype of the TNF −308 A/G polymorphism with susceptibility to silicosis was also found . After stratification by ethnicity, significant associations were detected under the genetic models  for TNF −308A/G polymorphisms in the Asian population (P<0.05). Similarly, meta-analysis of the TNF −238A/G polymorphism revealed the same pattern as that shown by meta-analysis of TNF −308A/G. The meta-analysis suggests that the TNF −308A/G and −238A/G polymorphisms are associated with susceptibility to silicosis, especially in Asians.Studies investigating association between tumor necrosis factor (TNF) gene polymorphisms and silicosis susceptibility report conflicting results. The aim of this meta-analysis was to assess association between TNF gene polymorphisms and silicosis susceptibility. A systematic literature search was conducted to find relevant studies. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the strength of association. Finally, a total of 12 articles, involving 1990 silicosis patients and 1898 healthy controls were included in the meta-analysis. Overall, meta-analysis revealed a significant association between the TNF −308A allele and silicosis (OR = 1.348, 95%CI = 1.156–1.570,  Silicosis is an interstitial lung disease prevalent among miners, sand blasters, and quarry workers, manifested as a chronic inflammatory response leading to severe pulmonary fibrotic changes . It is cSilicotic inflammation and fibrosis are developed when alveolar phagocytes contact or ingest silica particles. Cytokines and fibrogenic mediators were released into the local tissues and triggered an inflammatory response, followed by fibroblast proliferation and collagenization . In thisMeta-analysis is a statistical method for combining the results of several studies to produce a single estimate of the major effect with enhanced precision. It is considered a powerful tool for pooling inconsistent results from different studies . Li et aA systematic literature search in PubMed database, Elsevier Science Direct, the China National Knowledge Infrastructure database (CNKI), the Chinese Biomedical database (CBM), Wanfang Database, and VIP Chinese journal database was performed to identify articles. The text words were as followings: “silicosis” and “tumor necrosis factor or tumor necrosis factor gene or TNF-α or TNF alpha” combined with “gene polymorphism or polymorphisms or mutation or variant or gene.” The languages were limited to English and Chinese. The last search was updated on July 1, 2018. References in the identified studies were reviewed to find additional studies regarding the association between TNF gene polymorphisms and silicosis susceptibility.The inclusion criteria were defined as: (1) the design was a case–control; (2) the studies evaluated the association between TNF gene polymorphisms (−308A/G and −238A/G) and susceptibility to silicosis; and (3) the studies provided sufficient data to calculate the odds ratio (OR). Studies were excluded if one of the followings existed: (1) the studies contained overlapping data; (2) studies included family members who had been studied because of analysis based on linkage considerations.The Newcastle–Ottawa scale (NOS) was adopted to assess the quality of eligible studies from three aspects: (1) selection: 0–4 points; (2) comparability: 0–2 points; and (3) outcome: 0–3 points . Total sP values of Hardy–Weinberg equilibrium (HWE) for controls and NOS score. The study populations comprise American, South African, Iranian, Indonesian, and Chinese. The Asian subgroup included Chinese and Indonesian populations. American and Iranian populations were classified in the Caucasian subgroup, South African in the African subgroup.Data were collected by two independent investigators. If these two investigators could not reach a consensus, disagreements were discussed and resolved by a third investigator. The characteristics of the selected articles are shown in Allele frequencies at the TNF gene polymorphisms from the individual study were determined by the counting method. The association between TNF (–308 A/G and –238 A/G) polymorphism and the risk of silicosis was estimated by calculating a pooled OR and 95%CI under an allele model (A vs. G), a recessive model (AA vs. AG+GG), a dominant model (AA+AG vs. GG), a homozygote model (AA vs. GG) and a heterozygote model (AG vs. GG).χ2 test-based Q statistic was used to examine the heterogeneity of between-studies [I2 statistic measures the degree of inconsistency in the studies by computing what percentage of the total variation across studies was due to heterogeneity rather than by chance. A high I2 value indicated a higher probability of the existence of heterogeneity . If the P value of the heterogeneity Q statistic was less than 0.10, the random effects model was selected. Otherwise, a fixed effects model was adopted. Publication bias was estimated using Egger’s linear regression test and a funnel plot. If the P value was less than 0.05, statistically significant publication bias might exist [The -studies . The I2 ht exist .P value <0.05 was regarded as statistically significant.All the statistical analyses for the meta-analysis were performed with STATA statistical software . A two-sided The process for selecting the studies is shown in Heterogeneity of the included studies regarding each polymorphism is presented in Evidence of publication bias was observed for the meta-analysis of the TNF −308A/G  and −238A/G (recessive model and homozygote model) in all study subjects. Thus, the “trim and fill” method was used to adjust for publication bias. The adjusted results using the “trim and fill” technique remained unchanged, suggesting that these results might not be affected by publication bias .A summary of the meta-analysis of the relationship between TNF gene polymorphisms and silicosis is listed in P = 0.000, P = 0.000 and OR = 1.472, 95%CI = 1.222–1.772, P = 0.000, respectively). Stratification by ethnicity indicated that −308A/G polymorphism was significantly associated with silicosis risk in the Asian population .Eleven studies determined the relationship between the −308A/G polymorphism and silicosis. The total sample size for patients with silicosis and healthy controls was 1591 and 1422, respectively. Meta-analysis revealed a significant association between −308A allele and silicosis in the overall population  in the A vs. G allele was 2.092 . Meta-analysis found a significant association between the AA+AG genotype and silicosis in all study subjects . Meta-analysis of heterozygote model also revealed a significant association between −238A/G and silicosis risk in all study subjects . Ethnicity-specific analysis indicated an association between −238A allele and silicosis in the Asian group . In addition, significant association were identified in the dominant and heterozygote models for the Asian silicosis population . The forest plot is shown in Eight case–control studies including 1191 cases and 1101 controls identified an association between the TNF −238A/G polymorphism and silicosis risk. The pooled OR  of both TNF −308 A/G and −238A/G was not significantly related to silicosis in all populations. These findings show that TNF −308A/G and −238A/G polymorphisms might help to explain the individual differences in the susceptibility to silicosis. Considering the effect of genetic background on the results, subgroup analyses by ethnicity were performed for these polymorphisms. The present meta-analysis showed that TNF −308A/G polymorphism was related to silicosis in Asians. Dominant model of TNF −238A/G polymorphisms (AA+AG vs. GG) showed significantly increased silicosis risk for Caucasian population, but it might not be reliable because only one published article in Caucasian population was included. In addition, single nucleotide polymorphisms (SNPs) have geographical and ethnic differences [The findings of the present study seem to contradict with some individual studies, by which those studies did not find significant correlation between TNF (−308A/G and −238A/G) polymorphisms and risk of silicosis. Reasons may be that, first, even though results of some individual studies explored correlation between TNF gene polymorphisms and risk of silicosis are not significant, the ORs (95%CIs) of the individual studies ,23,27 drCompared with the previous meta-analysis , the preSeveral limitations of the present study should be considered. First, the present study could not analyze the potential gene–environment interactions and gene susceptibility haplotypes owing to lack of relevant data. Second, our literature search was dependent on English and Chinese, language bias might be considered. Third, meta-analysis remains a retrospective research, which is subject to the methodological deficiencies of the included studies.In summary, this updated meta-analysis suggests that TNF −308A/G and −238A/G polymorphisms are associated with susceptibility to silicosis. However, large sample size studies including more ethnic groups should be considered in future association studies to confirm the results of our meta-analysis.


CVD) in the general population, its relevance as a biomarker among populations at high CVD risk is less clear.Osteoprotegerin is a cytokine involved in bone metabolism as well as vascular calcification and atherogenesis. Although circulating osteoprotegerin levels are robustly associated with incident cardiovascular disease , kidney disease (7 studies), preexisting heart disease (5 studies), or recent acute coronary syndromes (5 studies) at baseline. Over a mean follow‐up of 4.2 years, 4066 CVD events were recorded. In a random‐effects meta‐analysis, the pooled risk ratio for CVD events comparing people in the top versus the bottom tertile of osteoprotegerin concentration was 1.30 . There was evidence for presence of publication bias . Correction for publication bias using the trim‐and‐fill method reduced the risk ratio to 1.21 . The risk ratios did not vary significantly by population type, geographical region, statistical adjustment, sample or assay type, age, sex, or length of follow‐up.Three independent reviewers systematically searched PubMed, CVD risk, elevated circulating osteoprotegerin levels are associated with a higher risk for future CVD events. The magnitude of association appears weaker than in the general population.In populations at high  In the present report, we systematically reviewed and combined the published evidence on the relevance of circulating osteoprotegerin concentration to cardiovascular events in high‐risk populations.Our meta‐analysis demonstrated a significant positive association between osteoprotegerin concentration and cardiovascular disease risk.The magnitude of association was similar in various clinically significant subgroups, including those defined by age and sex.This work highlights the potential of osteoprotegerin as a biomarker for cardiovascular disease risk.Osteoprotegerin is a member of the tumor necrosis factor (TNF) receptor superfamily and is involved in bone homeostasis.In addition to its role in bone homeostasis, osteoprotegerin has been implicated in the development of cardiovascular diseases (CVDs).The principal aim of this report is to review comprehensively the available literature and to perform a meta‐analysis of reported associations between osteoprotegerin and risk for future CVD in high‐risk populations . Secondary analyses will assess associations with coronary heart disease (CHD) events and stroke separately and will clarify whether the magnitude of association differs according to study‐level characteristics.The database of published results from studies included in the meta‐analysis is made available to other researchers for purposes of reproducing the results or replicating the procedure.We systematically sought PubMed, Web of Science, and EMBASE for prospective studies published between January 1970 and April 2017 that reported on associations of osteoprotegerin concentration with CVD outcomes . We also scanned reference lists of articles (including reviews) and corresponded with several study investigators. Table For each eligible study, 3 reviewers  independently extracted the following pieces of information: type of baseline disease, study location, year of baseline, duration of follow‐up, mean or median age at baseline, proportion of male participants, osteoprotegerin assay type (ELISAs versus immunofluorometric assays), osteoprotegerin assay manufacturers, and sample types (plasma versus serum). In addition, we extracted information on the statistical adjustment used, categorizing adjustments as “unadjusted” if no adjustment was employed; “+” for adjustment for age and sex; “++” for adjustment for age, sex, and non–blood‐based risk factors, such as smoking, blood pressure, and diabetes mellitus; and “+++” for further adjustments for blood‐based risk factors . If a study reported different adjustment models, the most adjusted model was used to minimize the scope for confounding. If information about the same study was published twice or more often, we used the most recent publication. Study quality was evaluated using the Newcastle‐Ottawa scale for cohort studies.2 statistic was used to assess heterogeneity across studies.P<0.05 was deemed as statistically significant. Data were analyzed using the statistical software Stata, version 14.1 (StataCorp). Because our analysis relied entirely on data available in the published literature, approval by the institutional review board of the project was not required.We conducted analyses according to a predefined statistical analysis plan. The primary outcome was CVD events (as defined above); secondary outcomes were CHD events and stroke events. Because studies reported effect estimates on different scales , we converted risk ratios and 95% confidence intervals (CIs) to reflect a comparison of the top versus bottom tertiles of baseline osteoprotegerin distribution using methods described elsewhere.Of 2602 records retrieved from PubMed, Web of Science, and EMBASE, we excluded 1001 duplicates and 1318 records after review of titles and abstracts  for a comparison of individuals in the top versus the bottom tertile of baseline osteoprotegerin concentration. There was a high degree of between‐study heterogeneity . In comparison, a fixed‐effect meta‐analysis yielded a pooled risk ratio of 1.15 .Figure P=0.013). Using the trim‐and‐fill method, 5 additional artificial studies were included into the meta‐analysis to generate a symmetric funnel plot . Reestimated pooled risk ratios by omitting each study in turn remained significant for all omissions  for CHD and 1.21  for stroke  and low for stroke . Corresponding risk ratios using fixed‐effect meta‐analysis were 1.14  for CHD and 1.21  for stroke.A subset of studies had published risk ratios separately on the secondary outcomes CHD and stroke. When comparing the top versus the bottom tertile of baseline osteoprotegerin concentration, the risk ratio was 1.24 . Furthermore, there was no evidence that the strength of association differed according to mean age, sex distribution, or length of follow‐up of the study population .Figure 2=68.3%). Although studies varied in terms of population type, geographical region, level of adjustment, sample type, assay type, proportion of men, mean age, and length of follow‐up, none of these characteristics significantly influenced the strength of association of osteoprotegerin with future CVD risk. However, our analysis identified significant publication bias resulting from predominantly strong positive results in small studies. After correcting for publication bias, the relative risk was reduced to 1.21, but remained significant, with a 95% CI ranging from 1.03 to 1.42. In addition, we confirmed with the leave‐one‐out cross‐validation method that our overall result was not driven by a single study, highlighting the robustness of our finding.In this literature‐based meta‐analysis, we analyzed 19 high‐risk population studies involving a total of 27 450 participants recruited between 1996 and 2013. Our analysis identified positive associations between osteoprotegerin concentrations and cardiovascular risk. Individuals with a high osteoprotegerin concentration  had a relative risk of 1.30  for CVD events when compared with individuals with osteoprotegerin levels in the bottom tertile. This relative risk remained stable under multivariable adjustment and across various study‐level characteristics. The between‐study heterogeneity was high drug treatment. It has been demonstrated that in vivo treatment with antidiabetic medication,The pathophysiological role of osteoprotegerin in CVD development is multifaceted and not completely understood. It is considered to reflect the overall activity of the osteoprotegerin/RANK/RANKL signaling pathway and regulate calcification in both the bone and the vasculature.Although our meta‐analysis shows positive associations of baseline osteoprotegerin concentration and CVD risk, its incorporation in clinical routine entails some analytical issues. First, available commercial kits for osteoprotegerin measurement use different reference standards of different molecular weight and may, therefore, produce different absolute osteoprotegerin values for the same sample.Strengths of the current review include the systematic and comprehensive search of the literature and the standardization of different reported parameters. We rescaled the reported relative risks to reflect a uniform scale (top versus bottom tertile), thereby enabling a direct comparison between the study estimates.In conclusion, osteoprotegerin is associated with the risk of future CVD in high‐risk populations. The magnitude of association appears weaker than in general population studies.Tschiderer, Klingenschmid, and P. Willeit conducted the systematic literature search, analyzed data, and wrote the article. Nagrani, J. Willeit, Schett, Kiechl, and Laukkanen contributed to writing the discussion and reviewing the article. P. Willeit is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.This work was supported by a K‐project grant from the Austrian Research Promotion Agency .None.Table S1. Search Terms Used to Identify Relevant ArticlesTable S2. Detailed Baseline Conditions of Contributing StudiesFigure S1. Funnel plot including artificial studies generated with the “trim and fill” method.Figure S2. Comparison of combined relative risk for cardiovascular events in the top vs the bottom tertile of osteoprotegerin concentration of high‐risk populations and general population results.Click here for additional data file.


ATM rs1801516 polymorphism and different types of cancer, but their results are inconsistent. To further evaluate the effect of ATM rs1801516 polymorphism on cancer risk, we conducted this meta-analysis.Ataxia telangiectasia mutated (ATM) gene plays a key role in response to DNA lesions and is related to the invasion and metastasis of malignancy. Epidemiological studies have indicated associations between ORs) and corresponding 95% confidence intervals (CIs) under recessive, dominant, codominant, and overdominant models of inheritance were calculated to estimate the association between rs1801516 polymorphism and cancer risk.Studies were identified according to specific inclusion criteria by searching PubMed, Web of Science, and Embase databases. Pooled odds ratios . However, after subgroup analyses by region-specified population, significant associations were found in European , South American , and Asian . Subgroup analyses also revealed that compared with subjects carrying a GG genotype, those carrying a homozygote AA had a decreased risk for breast cancer , and the homozygote AA was associated with decreased cancer risk in subjects with family history .A total of 37 studies with 12,879 cases and 18,054 controls were included in our study. No significant association was found between rs1801516 polymorphism and cancer risk in overall comparisons  contains supplementary material, which is available to authorized users. Cancer is a worldwide public health problem, and considerable parts of death are due to cancer every year. It is reported that one fourth deaths in the United States is caused by cancer . AccordiATM leads to the human autosomal recessive disorder, ataxia-telangiectasia (A-T), resulting in high cellular radiosensitivity, chromosomal instability, immunodeficiency, and cancer predisposition [Pathogenesis of cancer has been studied worldwide for a long time, generating different theories, such as the gene mutation, oxidative stress, and ionization radiation theories. Single nucleotide polymorphisms (SNPs) on different genes have been detected for finding specific biomarkers in different cancers. Ataxia telangiectasia-mutated (ATM) gene is one of the most frequently studied genes in cancer occurrence and progression. Mutation on position , 5. Lympposition , 7. ATM position . ATM is position .ATM polymorphism loci have been studied in different types of cancer, including rs1801516, which is a common nonsynonymous variant on this gene. Genome-wide association studies (GWAS) have identified rs1801516 as a susceptibility locus for melanoma [ATM rs1801516 polymorphism and cancer predisposition, but the results are inconsistent [Several melanoma . Large-snsistent –14.We performed this meta-analysis to further identify the association between rs1801516 polymorphism and cancer risk using larger sample size than ever before, and using the trial sequential analysis (TSA) to give more comprehensive conclusions.We conducted this meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines .Systematic search of publications was performed in PubMed, Web of Science, and Embase datasets . Because of different nomenclatures for SNP, we took all the names that might be used in different studies of this SNP into consideration in our searching terms: “(rs1801516 or G5557A or 5557G>A or 5557 G/A or Asp1853Asn or D1853N or G1853A) and ”.ATM rs1801516 polymorphism and cancer risk; (3) Using a case-control study design; (4) Using healthy subjects without malignant diseases as controls; (5) Genotype data is sufficient for odds ratio (OR) and 95% confidence interval (CI) estimation. In addition, we screened the reference lists of all the relevant studies, including eligible studies, reviews and meta-analyses, and only original articles published in English were included.Studies included in this meta-analysis met the following criteria: (1) A human study with full text available; (2) A study on For each included study, the following information was extracted: the first author, year of publication, country, region-specified population, cancer type, source of controls, matching criteria of controls, family history, genotyping method, Hardy-Weinberg equilibrium (HWE) in controls, minor allele frequency (MAF) in cases and controls, sample size, and numbers of cases and controls with different genotype. Region-specified population in our meta-analysis was defined geographically as European, North American, South American, Asian, and Oceanian. Population-based controls (PBC) and hospital-based controls (HBC) were classified in our meta-analysis: blood donors and controls recruited from birth cohort, general population, and community are defined as PBC; and controls recruited from hospitals, clinics, research institutions, and biorepository were defined as HBC.Two authors (YG and JS) assessed the quality of each study independently according to the Newcastle-Ottawa Scale (NOS) for case-control studies . A studyOR and corresponding 95% CI calculated from logistic regression. For each analysis, stratified or pooled, five comparisons were conducted, including dominant model (GA/AA vs GG), codominant model (GA vs GG and AA vs GG), recessive (AA vs GG/GA), and overdominant model (GA vs GG/AA). For studies of Sommer SS et al. [Q test and I2 statistics. Fixed effect model (Mantel-Haenszel method) was used to calculate OR and 95% CI when P value of Q test was more than 0.10 or I2 value was less than 50%; otherwise, random effect model (DerSimonian-Laird method) was used. When the meta-analysis included 10 studies or more, publication bias was estimated using the visualizing Begg’s funnel plot, in which the log(OR) and its standard error of each study were indicated as Y- and X- axes respectively. An asymmetric funnel plot implied a possible publication bias. Furthermore, Egger’s linear regression test was utilized to determine the significance of asymmetry (P < 0.05 was considered to represent significant publication bias). Sensitivity analysis was performed with one study omitted at each time.Allele and genotype frequencies in controls were calculated for each study to evaluate the HWE using chi-square test. Association between rs1801516 polymorphism and cancer risk was assessed by S et al. , GonzaleS et al. , and CalS et al. , no AA gS et al. , BretskyS et al. , and HirS et al. , frequenS et al. , frequenP value less than 0.05 was considered statistically significant unless otherwise specified.All analyses were performed using Stata 12.0, and two-sided tests with Z-score, and red lines sloping inwards indicating trial sequential monitoring boundaries using adjusted P values.Because of sparse data and repeated significance testing, meta-analyses may lead to type I error for the presence of systematic errors (bias) or random errors (play of chance) –27. To aAfter strict screening, 34 eligible studies with 12,879 cases and 18,054 controls were identified in our meta-analysis . In subgroup analyses by region-specified population, significant associations were found in European , South American , and Asian . In subgroup analyses by cancer types, significant decreased risk of breast cancer was found for those carrying AA genotype . In subgroup analyses by family history, AA carriers had a significant decreased risk compared with GG carriers in those with family history , and a borderline significance was found for AA vs GG + GA .The pooled and subgroup meta-analyses of associations between rs1801516 polymorphism and cancer susceptibility are shown in Table Q test and I2 statistics to evaluate the heterogeneity of our meta-analysis. Our results showed significant heterogeneity among studies for AA+GA vs GG , GA vs GG , and GG + AA vs GA  models  and GA vs GG , suggesting that family history may explain the among-studies’ heterogeneity under these two models. However, no factor was detected as a source of heterogeneity for GG + AA vs GA .Begg’s funnel plot and Egger’s linear regression test were used to assess the publication bias of studies in our meta-analysis. The shape of the funnel plots under four models seemed symmetrical Fig. , and theORs and 95% CIs. The results showed that the pooled ORs and 95% CIs under any model of inheritance were not substantially altered after omitting any individual study , suggesting there is no significant association between rs1801516 polymorphism and cancer risk. Moreover, sample sizes in our overall meta-analyses were all more than the required information sizes , suggesting that the results of our meta-analyses are reliable.The results of TSA under four models (five comparisons) are shown in Fig. Studies of rs1801516 polymorphism on cancer risk have been performed for more than ten cancers in previous studies, and breast cancer and thyroid cancer are the two most studied ones. So far, three meta-analyses have been performed on association between rs1801516 polymorphism and breast cancer risk , 12, 14,In subgroup analyses by region-specified population, cancer types, and family history, significant associations were found for European, South American, Asian, breast cancer, and those with family history. Firstly, results of subgroup analysis by region-specified population were interesting. In European and Asian, reversed results were observed for AA vs GG + GA and AA vs GG. The homozygote AA showed a protective effect against cancer in European, but it presented a susceptible effect for cancer in Asian. Therefore, rs1801516 polymorphism may exert inversed effect on European and Asian. In South American, the other three models  were significant. Susceptible effect for cancer was observed for AA+GA vs GG and GA vs GG, and protective effect against cancer was observed for GG + AA vs GA. We infer that the results in South American may be attributed to the heterozygote GA, which may be a risk genotype of cancer in South American. Populations from different region may be ethnically different, and this difference may in turn have an influence on cancer susceptibility. Studies have revealed cancer trends differed from ethnicity –58, and In this present meta-analysis, heterogeneity was observed in models of AA+GA vs GG, GA vs GG, and GG + AA vs GA. To find the source of among-studies’ heterogeneity, we performed meta-regression analysis by region-specified population, cancer type, source of controls, matched controls or not, family history, sample size, and HWE in controls. As a result, family history was a source of heterogeneity for AA+GA vs GG and GA vs GG models. However, for GG + AA vs GA, none of the analyzed factors was detected as a source of heterogeneity. Lifestyle may be the source of heterogeneity. Lifestyle of the subjects, including smoking and alcohol consumption, influences on their susceptibility to cancer –66. HoweATM rs1801516 polymorphism on cancer risk, we performed TSA to reduce the risk of type I error and to estimate whether further studies are required by calculating the required information size. Sample size in our meta-analysis was more than the required information size, indicating that the results of our meta-analyses are reliable and sufficient to draw a conclusion.Meta-analysis may report false positive results for the risk of type I error, and such results are commonly attributed to publication bias, heterogeneity among studies, and low quality of the studies. However, a limited number of trials may not give enough information size, thereby leading to a false estimation . In ordeWe must admit that there are some limitations in our meta-analysis. Firstly, because of the difference in data presentation of age between studies , we didn’t assess the risk stratified by age. Secondly, environmental factors and life style information were not available for all studies, thus effects of these variables were not taken into consideration. Thirdly, year of data collection may also have an effect on heterogeneity, but not all studies in our meta-analysis provide this information, thus year of data collection was not analyzed in our meta-analysis. Fourthly, 12 types of cancer were included in our meta-analysis. However, only one or two studies were performed on the cancers except breast cancer, thyroid cancer, and cervical cancer, and this may potentially make the result biased.ATM rs1801516 polymorphism is not associated with overall cancer risk in total population. However, for subgroup analyses, rs1801516 polymorphism is especially associated with breast cancer risk; in addition, this polymorphism is associated with overall cancer risk in Europeans, South Americans, Asians, and those with family history. Owing to the limitations mentioned above, our results should be interpreted with caution.In summary, Additional file 1:Table S1. Matching criteria and genotyping method of the eligible studies included in the meta-analysis. (DOCX 24 kb)


MTHFR), transcobalaminII (TCN2) and ring finger protein 213 (RNF213) are related to homocysteine (Hcy) level and are of great significance for hypertension. We aimed to evaluate the associations of MTHFR , TCN2 (rs117353193) and RNF213 (rs9916351) with hypertension and blood pressure (BP). A total of 953 patients with hypertension and 1103 controls were enrolled. Genotyping was performed by Taqman. Logistic regression analysis indicated that A allele of TCN2 rs117353193 under the dominant model had a significantly protective effect (P=0.045) after adjustment, which showed that AA+GA genotype has a lower risk than GG. Additionally, the average diastolic BP (DBP) (P=0.044) and mean arterial pressure (MAP) (P=0.035) levels were significantly different between genotypes of RNF213 rs9916351. Further pairwise comparison showed that the average systolic BP (SBP) level of the TT genotype carriers were significantly higher than in CC (P=0.024), and the average DBP and MAP levels of the TT genotype carriers were higher than in CT  and CC . In the recessive model, the average SBP (P=0.043), DBP (P=0.018) and MAP (P=0.017) levels with the TT genotype carriers were significantly higher than in CT+CC. Multiple linear regression analysis suggested that RNF213 rs9916351 in the recessive model had significant effects on SBP (P=0.025), DBP (P=0.017) and MAP (P=0.010) as a risk factor. However, no associations were observed between MTHFR and hypertension. TCN2 rs117353193 might serve as a protective factor in hypertension, and RNF213 rs9916351 might be a risk factor that is linked to increase BP level in Northeast Chinese population.Methylenetetrahydrofolate reductase gene ( Hypertension is a multifactorial disease and is a major life-threatening health concern throughout the world. Approximately 2 million people in China die of diseases directly associated with hypertension each year, and its the prevalence rate is still on the rise. Especially in the middle-aged and old population, high blood pressure (BP) has become the main cause of coronary heart disease, stroke and many other cardiovascular diseases (CVDs). The results of an 8-year follow-up with 170000 people over 40 years old in China showed that coronary heart disease was the first cause factor of death, while hypertension was the first risk factor for total mortality, and the relative risk ratio (RR) was 1.48 .A number of previous studies have suggested that genetic alterations in the genes controlling homocysteine (Hcy) and folate metabolism were linked to onset of CVDs ,5. HyperMTHFR), which catalyzes the conversion of 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate, is a crucial enzyme in the metabolism of Hcy and folate which both have associated with methylation of genomic DNA , and the AA+GA genotype carriers had 0.56-times higher risk than the GG genotype carriers. Additionally, a borderline significant association was observed under the additive model (GA vs GG) after adjustment . However, in the adjusted analysis, the effects of waistline and BMI still exist.The results of binary regression analysis of environmental factors, including gender, age, weight, waistline, BMI, smoking frequency, FBG, TC and TG, are shown in MTHFR gene are represented in P>0.05). These findings suggest that the haplotypes of the MTHFR gene are not associated with susceptibility of hypertension in our subjects.Haplotype analysis of rs1801131, rs1801133 and rs9651118 polymorphisms of P=0.044) and MAP (P=0.035) levels of RNF213 rs9916351 were significantly different under the additive model, and the average SBP level had a borderline significant difference (P=0.077). Further pairwise comparison showed that the average SBP level with the homozygous TT genotype carriers were significantly higher than in CC genotype carriers (P=0.024), the average DBP and MAP levels with the homozygous TT genotype carriers were significantly higher than in CT  and CC  genotypes carriers. In the recessive model, the average SBP, DBP and MAP levels of RNF213 rs9916351 with the homozygous TT genotype carriers were significantly higher than in CT+CC genotype carriers . However, there were no significant differences in BP levels of rs1801131, rs1801133, rs9651118 and rs117353193 under the three genetic models.As shown in RNF213 rs9916351 had significant effects on SBP (P=0.025), DBP (P=0.017) and MAP (P=0.010) as a risk factor. However, there were no significant associations of rs1801131, rs1801133, rs9651118 and rs117353193 on BP.The results of multiple linear regression analysis of baseline covariates and genetic component on BP are shown in MTHFR , TCN2 (rs117353193) and RNF213 (rs9916351) gene variants with the susceptibility of hypertension and BP among the population of northeast in China.Hypertension is a complex disease that comes about as a result of the interaction between genetic and environmental factors. Recently, numerous gene polymorphisms have been found to be associated with hypertension. The present study was designed to investigate the association of MTHFR gene polymorphisms were not significantly associated with hypertension. Many genetic studies have shown that genetic variants in the MTHFR gene have been linked to CVDs, such as coronary heart disease [MTHFR rs1801133 and rs1801131 alleles and the co-occurrence of rs1801133 CT/rs1801131 CC genotypes were linked to increased risk of hypertension in the Indian population. Koupepidou et al. [MTHFR rs1801133 is an independent factor for hypertension in different ethnic groups [12 and folate are also involved in the metabolism of Hcy as nutritional factors. The former acts as a coenzyme in the catalytic synthesis of methionine with Hcy. TCN2 is recognized as a specific plasma transporter to facilitate the cellular uptake of vitamin B12 by its receptor-mediated endocytosis [TCN2 gene polymorphisms have been considered as another genetic trait which may affect Hcy metabolism by modulating the bioavailability of vitamin B12 [TCN2 rs117353193 genotype frequency was significant difference between patients with normal Hcy levels and hyperhomocysteine [MTHFR rs9651118 as well. In our study, we found that the risk of GG genotype carriers of rs117353193 is lower than that of GA+AA genotypes carriers after adjusting for confounding factors, which suggested that it may be a protective factor for hypertension. However, waistline and BMI also play important roles, so our results may be more influenced by environmental and genetic interactions. In addition, the mutant AA genotype carries are too few to compare with other genotypes carries. The relevant studies are so few and there is need for it to be further explored.In our study, we found that three  disease ,29, type disease ,31, isch disease ,33 and h disease ,35, but  disease  reportedu et al.  also sugu et al. , but no c groups . A meta-c groups . A numbec groups . Increasc groups . Our stuc groups  found noc groups . In addiocytosis . Thus, Tamin B12 . A genomcysteine , and thiRNF213, it has been proved to be a susceptible gene to MMD [RNF213 polymorphisms with SBP [MTHFR rs9651118, TCN2 rs117353193 and RNF213 rs9916351 were recently revealed as the novel susceptibility loci for MMD by a genome-wide association study, no studies were conducted concerning the link to hypertension, and more evidences are needed to support our results.Regarding e to MMD , but it e to MMD . One stuwith SBP . Our pre12 and folate levels. Second, the differences in results in different studies of different countries may also attribute to the ethnic differences. Furthermore, hypertension is a complex disease and is affected by both environmental and genetic factors. Some important characteristics were significantly different between the patients and the controls in our study, such as BMI, smoking, FBG and so on. Smoking is particularly known to exacerbate hypertension [Some limitations of our study should be mentioned. First, we did not get some of the relevant data in subjects, such as serum Hcy, vitamin Brtension , we specTCN2 rs117353193 gene polymorphism might serve as protective factor in hypertension, and the RNF213 rs9916351 gene polymorphism might be an important risk factor that is linked to increase the level of BP among the population of northeast in China. Considering our relatively small sample size and narrow coverage, further studies are needed to confirm our results in the future.In summary, our study suggests that the


However, the results of previous studies were conflicting. In the present study, we assessed whether smad family member 3 gene rs12901499 polymorphism was associated with the risk of osteoarthritis by the meta-analysis. We searched in the databases of PubMed, Embase, and CNKI. Pooled odds ratios and 95% confidence intervals were calculated. Seven papers involving 11 studies (5344 cases and 9080 controls) analyzed the association between smad family member 3 gene rs12901499 polymorphism and osteoarthritis risk. This meta-analysis confirmed that smad family member 3 gene rs12901499 polymorphism increased the risk of osteoarthritis. Stratification analysis of ethnicity found that rs12901499 polymorphism increased the risk of osteoarthritis among both Asians and Caucasians . In addition, subgroup analysis by type of osteoarthritis revealed that smad family member 3 gene rs12901499 polymorphism was correlated with the increased risk of hip osteoarthritis, but not associated with knee osteoarthritis. Sensitivity analysis did not draw different findings. In conclusion, this meta-analysis indicates that smad family member 3 gene rs12901499 polymorphism increased the risk of osteoarthritis.A growing body of evidence suggested that  Osteoarthritis (OA), a complex and multifactorial disease, is the most common degenerative arthritis characterized by the degeneration of articular cartilage with joint space narrowing, osteophyte formation, and subcondral sclerosis resulting in pain and joint stiffness ,2. AccumSMAD3 may be a candidate gene for OA susceptibility.Smad family member 3 (SMAD3) locates on chromosomes 15q21-22. SMAD3 is a key intracellular messenger of the transforming growth factor-β (TGF-β) signaling pathway, which is an important growth factor to the integrity of articular cartilage ,7. TGF-βSMAD3 gene rs12901499 polymorphism and OA risk [SMAD3 gene rs12901499 polymorphism in the development of OA, we performed a comprehensive meta-analysis to clarify the association between this single nucleotide polymorphism (SNP) and OA risk.Recently, several studies explored the relationship between  OA risk . HoweverSMAD3 gene rs12901499 polymorphism and OA risk. Additional usable data were obtained by hand searching the bibliographies of genetic association studies on the subject in this analysis. We used no restrictions on the number of samples and language to minimize publications bias. All studies were carefully selected and were up to date as of March 1, 2018. The inclusion criteria for studies were as follows: (1) studies that evaluated the association between SMAD3 gene rs12901499 polymorphism and OA, (2) studied on human beings, and (3) contained genotype data for the calculation of odds ratios (ORs) and 95% confidence intervals (CIs). The following information was extracted from each study: author, year of publication, ethnicity based on the continent of origin of the study population, type of OA, source of controls (SOC), numbers of cases and controls, and the genotype methods.We performed a comprehensive literature search throughout PubMed, Embase, and CNKI databases to retrieve the genetic association studies of OA. The following terms were used in our searching strategies: “Smad family member 3”, “SMAD3”, “SNP”, “polymorphism”, “variant”, “osteoarthritis”, “OA” to identify the publications reporting on SMAD3 gene rs12901499 polymorphism and OA risk. Stratification analyses were carried out by ethnicity, SOC, type of OA, Hardy–Weinberg equilibrium (HWE), genotype methods, and study quality. P<0.05 was considered statistically significant. Multivariate ORs and corresponding 95% CIs between extreme levels of annualized case volume (highest vs lowest) were pooled using a random-effects model, accounting for clinical heterogeneity. Heterogeneity across studies was assessed by using the Q statistic with its P value and I2 statistic [http://ihg.gsf.de/cgi-bin/hw/hwa1.pl). The data analyses were conducted with Stata 11.0 software . Potential publication bias was assessed by Begg’s and Egger’s linear regression test [P<0.05 was considered to indicate statistically significant. We performed sensitivity analysis by omitting each study in turn to determine the effect on the test of heterogeneity and evaluated the stability of the overall results.ORs and 95%CIs were used to evaluate the strength of correlation between tatistic ,19. Pooltatistic . Two revtatistic . All dision test . P<0.05 SMAD3 gene; two citations did not provide detailed genotyping data and four were not case–control study. Eventually, we identified seven eligible citations (5344 cases and 9080 controls) containing eleven studies [A total of 127 citations were derived after incipient search. Forty-one citations were removed due to duplication. Of the 86 remaining citations, 70 were excluded after reading titles and abstracts. Sixteen citations were selected for further full-text review. Three investigated other SNPs of  studies . SelectiSMAD3 gene rs12901499 polymorphism increased OA risk , P<0.001; GG vs AA: OR and 95%CI, 1.39, P=0.001; GG + GA vs AA: OR and 95%CI, 1.34, P=0.010; GG vs GA+AA: OR and 95%CI, 1.32, P=0.001 P=0.012; Caucasians, OR and 95%CI, 1.21, P<0.001, In the general analysis, we found that SMAD3 gene rs12901499. The pooled ORs for the effects of the SNP on the risk for OA indicated that our data were stable and trustworthy. Both Egger’s and Begg’s tests were used to evaluated the publication bias of this meta-analysis. Our data revealed that there was no obvious publication bias for SMAD3 gene rs12901499 (We assessed sensitivity analysis by omitting each study once at a time in every genetic model for 12901499 .SMAD3 gene rs12901499 and OA susceptibility. TGF-β has anabolic effects on chondrocytes especially via the SMAD3 genes signaling which promote the development and progression of OA [SMAD3 gene rs12901499 polymorphism and risk of OA, but the results were inconsistent [SMAD3 gene rs12901499 polymorphism increased OA risk. Stratification analyses of ethnicity, SOC, type of OA, HWE, genotype methods, and study quality revealed that SMAD3 gene rs12901499 polymorphism was also correlated with the increased risk of OA.To our best knowledge, the present study is the first systematical meta-analysis regarding the association between on of OA . Previouon of OA . In the on of OA . Severalnsistent . This meSMAD3 gene rs12901499 polymorphism and knee OA in an Indian population. Xiao et al. [SMAD3 gene rs12901499 polymorphism is involved in increased risk of both hip and knee OA in European populations. Zhong et al. [SMAD3 SNP rs12901499 GA genotype and G variant may increase the risk of hip OA in Chinese Han patients. Zhang et al. [SMAD3 gene plays a protective role in the pathology of knee OA in a Chinese population. However, Su et al. [SMAD3 gene rs12901499 polymorphism and knee OA from a Chinese population. It is worthy of note that Valdes et al. [SMAD3 gene rs12901499 polymorphism with OA risk.A single study could be underpowered because of sample size, diversity inheritance of the heterogeneous and complex OA etiology, different ethnicities, clinical heterogeneity, and so on. For instance, Sharma et al.  reportedo et al.  found tho et al.  indicateg et al.  found thg et al.  confirmes et al.  conducteSMAD3 gene rs12901499 polymorphisms are susceptibility loci of other types of OA, highlighting the necessity for the further investigation of more types of OA.Large sample and unbiased epidemiological studies of predisposition gene polymorphisms could provide insight into the association between candidate genes and diseases. When we dropped the study  which isSMAD3 gene rs12901499 polymorphism increased OA risk. Stratification analysis of ethnicity found that rs12901499 polymorphism increased the risk of osteoarthritis among both Asians and Caucasians, subgroup analysis by type of osteoarthritis revealed that smad family member 3 gene rs12901499 polymorphism was correlated with the increased risk of hip osteoarthritis, but not associated with knee osteoarthritis. Further, studies with large sample size and multiple OA type are necessary to validate whether SMAD3 gene rs12901499 polymorphism contribute to OA susceptibility.In conclusion, this meta-analysis confirms that


LEP gene with the risk of cancer have yielded inconsistent results. In this study, we have carried out a case‐control study [1063 esophagogastric junction adenocarcinoma (EGJA) cases and 1677 controls] in a Chinese population. Furthermore, we carried out a pooled‐analysis of 13 studies involving 8059 cancer patients and 11 930 controls to assess whether the LEP G19A locus was associated with overall cancer susceptibility. Odds ratios (ORs) with the corresponding 95% confidence intervals (CIs) were harnessed to evaluate the potential association. In our case‐control study, we found an association between the carriers of LEP 19A allele and EGJA risk. In addition, the results of meta‐analysis also suggested significant associations with cancer risk . Upon conducting a stratified analysis, we found that LEP 19A allele might decrease the susceptibility of non‐Hodgkin lymphoma (NHL) and colorectal cancer (CRC). In a stratified‐by‐ethnicity analysis, significant associations were also found in Asians, Caucasians, and mixed populations. We can conclude that the LEP G19A polymorphism constitutes a decreased risk of cancer.Accumulating evidence has suggested that leptin (LEP) is very important for the development of cancer. Recently, a number of case‐control studies about the relationship of the rs2167270 G > A (G19A) variants in the  LEP, a 16 kDa glycol‐protein, is predominantly made >95%) by fat cells.5% by fatLEP rs2167270 G > A (G19A) locus is correlated with LEP levels and may also give a fascinating insight into the potential correlations with the development of cancer.LEP 19A allele might have a lower tendency for cancer risk.LEP G19A polymorphism and cancer risk have been performed in Asians with relatively large samples.It is found that the LEP G19A polymorphism with the susceptibility of developing esophagogastric junction adenocarcinoma (EGJA). And then, we performed a meta‐analysis to estimate the relationship of this polymorphism with overall cancer risk.In this study, to acquire an understanding of the relationship between LEP polymorphism and risk of cancer, we first studied 22.1LEP G19A polymorphism was detected by SNPscan genotyping assay  according to conditions described by Chen et al.A total of 1063 unrelated EGJA cases were diagnosed and selected at Fujian Medical University Union Hospital, Fujian Medical University Cancer Hospital and Affiliated People’s Hospital of Jiangsu University. In addition, 1677 noncancer subjects were included in a control group. Both groups belonged to the Chinese Han populations from eastern China. The patients included 759 males and 304 females; the average age was 64.19 ± 8.63 years. Of them, 625 patients had lymph node metastases. There were 305 stage I/II and 758 stage III/IV EGJA patients included in the case group.2.2We performed an extensive literature search in PubMed and EMBASE databases, covering all medical publications until 24 August 2018, with the following key words: LEP gene (e.g.: ‘LEP’ or ‘leptin’), cancer , and polymorphism . In addition, we also carried out a manual search of the listed references of the included publications and related reviews.LEP G19A polymorphism with risk of cancer; (c) genotypes data listing in the publications. The major exclusion criteria of studies were as follows: (a) reviews; (b) duplicated reports; (c) not case‐control study designs; (c) lack of data for genotype frequencies.The criteria of literature selection were as follows: (a) investigation designed as a case–control study; (b) focusing on the association of Two authors (J. Yang and Z. Zhong) extracted data from the included publications independently. The following information was collected: (a) first author; (b) publication year; (c) number of cases and controls; (d) country; (e) ethnicity; (f) source of controls; (g) cancer type; (h) genotyping method; and (I) genotype frequency. Ethnicities were defined as mixed, Asians, and Caucasians. For the source of controls, the publications were categorized as hospital‐based and population‐based studies.https://ihg.gsf.de/cgi-bin/hw/hwa1.pl). The strength of the correlation between LEP G19A locus and cancer risk was determined by calculating crude odds ratios (ORs) with their 95% confidence intervals (95% CIs). The following four models were calculated: homozygote comparison (AA vs GG), dominant model (AA/GA vs GG), recessive model (AA vs GG/GA), and allele model (A vs G). If I2 > 50% or P < 0.1, it suggested that there was significant heterogeneity. Considering the heterogeneity among the included studies, a different model was used to pool the data. When no significant heterogeneity was identified, the Mantel‐Haenszel method (fixed effects model) was usedP < 0.1 was defined as representative of significant bias. The Newcastle‐Ottawa Quality Assessment Scale was used to assess the quality of the enrolled literatures. If scores ≥ 6 stars, the publication was considered as related high‐quality. In this study, all P values for statistics were calculated with two‐sided. STATA 12.0 software  was used to analyze the data.In this study, we analyzed Hardy‐Weinberg equilibrium (HWE) using a goodness‐of‐fit test using an online software  were included in this case‐control study. Table LEP G19A polymorphism. In the analysis of LEP G19A polymorphism, differences in the distribution of LEP G19A genotypes between EGJA patients and controls were found . The results of multivariate linear regression analysis also showed that LEP G19A polymorphism was correlated with a decreased risk of EGJA .Table 3.2We have summarized the meta‐analysis process in Figure LEP 5′‐UTR region with a decreased risk of overall cancer in four genetic models .As demonstrated in Table LEP 19 A allele might have a lower susceptibility of NHL in three models . In addition, we also found that the G19A polymorphism in LEP gene was correlated with a decreased susceptibility of CRC in homozygote comparison  and recessive model .When an analysis stratified by cancer type was conducted, we found that individuals carrying P = 0.005), Caucasians for three models , and mixed population .In an analysis stratified by ethnicities, significant associations were found also in Asians , gene‐environment interaction could not be carried out. Third, in this study, only LEP 5′‐UTR region is associated with a decreased risk of EGJA. In addition, the subsequent meta‐analysis also indicates that this SNP decreases the risk of overall cancer. To confirm or refute our findings, large scale case‐control studies are needed.In conclusion, it is highlighted that the G19A polymorphism in the The authors declare that they have no conflicts of interest.


Inconsistent results according to numerous studies that had investigated the association between serum zinc levels and lung cancer risk were reported. The aim of this study was to explore whether serum zinc levels were lower in lung cancer patients than that in controls.We systematically retrieved the databases of PubMed, Wanfang, Cochrane, ScienceDirect website, CNKI, and SinoMed databases for comprehensive relevant studies published before December 2018 and conducted a meta-analysis. Standard mean differences (SMD) were pooled using a random effects model.Thirty-two articles were eligible to investigate the correlation between serum zinc levels and lung cancer risk, involving 2894 cases and 9419 controls. The pooled results showed sufficient evidence approving the association between serum zinc levels and lung cancer risk. And the serum zinc levels in lung cancer were significantly lower than that in controls  = − 0.94, − 0.82). Meanwhile, consistent results were obtained both in European populations and Asian populations. No publication bias was detected in our analysis.The present meta-analysis suggested that serum zinc levels were significantly lower in lung cancer patients than that in controls. Cancer is a crucial health problem on a global scale that has become one of the primary causes of death. The increasing trend in cancer globally could be slowed and reversed if preventive measures could provide the feasible approach . As we aThis meta-analysis was designed and performed according to the guidelines of the preferred reporting items for systematic reviews and meta-analyses (PRISMA compliant) statement .A comprehensive, computerized literature search regarding the association between serum zinc levels and lung cancer risk was conducted in six databases , from their inception to December 2018. Combinations of the following keywords were used for the search: “zinc levels” OR “zinc concentration” OR “zinc” OR “trace element” in combination with “lung cancer” OR “lung tumor”. Moreover, we also scrutinized the references of retrieved publications to identify any studies that were potentially missed.To be eligible for our analysis, the studies had to meet the following criteria: (1) epidemiological studies; (2) the aim was to evaluate the associations between serum zinc levels and lung cancer risk; (3) the numbers, mean, and standard deviation (SD) of serum zinc levels for cases and control are available. It is noted that duplicated results may be published in more than one paper, so we selected the most recent or most informative paper in our analysis.Two of the authors extracted all data independently, complying with the selection criteria above. A standardized data collection protocol was as follows: the last name of the first author, publication year, study design, the location of the study conducted in, subject in cases and control, gender, range or mean age of cases, method of measurement for serum zinc, and mean and SD of serum zinc levels for cases and control.Q test and I2 (inconsistency index) statistic [P values were two-sided and less than 0.05 was considered statistically significant.The strength of the association between serum zinc levels and lung cancer risk was measured by standard mean differences (SMD) and 95% confident interval (CI) by adopting random effects models that taking into account both within-study and between-study variations . The anatatistic . Subgroutatistic . Furthertatistic  and Eggetatistic  to evalun = 13), not reported mean or SD (n = 7), reported dietary factors (n = 5), and letter to the editor (n = 2). Ultimately, 32 articles [The specific step of searching and selecting relevant articles was summarized in Fig. articles –47 met tZ value = 28.32, P for Z test < 0.001). Extreme heterogeneity was present among the pooled results . Based on Egger’s test (P = 0.548) and the Begg’s funnel plot  and Asian populations . Thirty-one of the 32 studies were case-control studies, and the result was consistent with the overall result .Subgroup analyses by study design and geographic location were conducted to further examine serum zinc levels and lung cancer risk. We found lower serum zinc levels in lung cancer patients than that in controls both in European populations (summary SMD = − 0.65, 95% CI = − 0.89, − 0.41, Meta-regression analysis was evaluated in this article, indicating that no source of heterogeneity was observed in the association between serum zinc levels and lung cancer risk.Sensitivity analysis indicated that no evidence of overall result changing was observed when removed each study from the analysis, one at a time.The meta-analysis was conducted to investigate the association between serum zinc levels and lung cancer. Findings from our report suggested that serum zinc levels in lung cancer cases were significantly lower than that in controls. Consistent results were found both in European populations and Asian populations.Some previous studies had been published to explore serum element levels and lung cancer risk. Chen et al. performed a meta-analysis with 13 publications to assess the association between serum iron levels and lung cancer risk . The autPrevious studies had significantly revealed that serum zinc had a protective effect on some cancers. Xie et al. conducted a meta-analysis about serum zinc levels and cervical cancer, indicating that serum zinc levels were lower in cervical cancer patients than controls . In addiHowever, there are some limitations and potential bias that must be acknowledged in our meta-analysis. First, we only included papers published in English or Chinese, which may omit some other language paper. Furthermore, we only searched published articles, which may omit some unpublished articles or some meeting articles. These factors may yield between-study heterogeneity and publications bias in the overall pooled results. Second, although most method of measurement for serum zinc was using atomic absorption spectrophotometer, different methods of measurement as well as a different instrument could also cause between-study heterogeneity. Third, evidence of high heterogeneity was found, both in overall and subgroup analysis, in our analysis. However, we could not find the source of heterogeneity due to stratified analysis and meta->regression analysis concerning the relationship between serum zinc levels and lung cancer risk. Fourth, our meta-analysis included three articles from Europe and 29 articles from Asia, thus, further epidemiological studies are warranted in the future to assess the association between serum zinc levels and lung cancer risk.In summary, our meta-analysis, which included a large number of subjects of 32 articles, manifested that serum zinc levels were significantly lower in lung cancer patients than that in controls.


I2 = 8.98%), 0.76 , 3.17 , 0.31 , and 10.26 , respectively. The area under the receiver operating characteristic curve was 0.78 (95% CI: 0.74–0.81). The study confirmed the use of circRNAs in diagnosing lung cancer in a Chinese population.Circular RNA (circRNA) is a class of recently discovered noncoding RNA. circRNAs can be used as a potent noninvasive biological marker of cancer owing to their varying expression levels among different cancers. This meta-analysis was performed to assess the accuracy of circRNAs in diagnosing lung cancer. A total of eight studies identified through searching the PubMed, Web of Science, Cochrane Library, and Embase from inception to March 20, 2019 were eligible for this meta-analysis. The pooled sensitivity, specificity, positive likelihood ratios, negative likelihood ratios, and diagnostic odds ratio were 0.77 : 0.73–0.80;  Circular RNA (circRNA) is a circular single-strand RNA first discovered in plants , 2 and aExperiments proved that circRNAs were associated with proliferation, apoptosis, invasion, and migration of tumor cells, and the expression varied with tumor cells, thus helping in diagnosing and predicting the prognosis of tumors. Li et al.  found thLung cancer accounts for 25% of cancer-related deaths worldwide, which is much higher compared with other cancers such as breast carcinoma, prostatic carcinoma, and colorectal carcinoma. The survival rate of patients with lung cancer is relatively low, possibly due to the lack of early testing methods . The rolElectronic databases, including PubMed, Web of Science, Cochrane Library, and Embase, were systematically searched from inception to March 20, 2019. The following search terms were used: circRNA, circular RNA, lung cancer, lung neoplasm, lung adenocarcinoma, non-small-cell lung cancer, NSCLC, pulmonary cancer, and pulmonary neoplasm. In addition, the reference lists of eligible studies were manually searched to guarantee the comprehensiveness of the literature.The inclusion criteria were as follows: (1) studies analyzing the relationship between circRNAs and lung cancer, (2) studies providing data on the sensitivity and specificity, and (3) studies involving ≥30 patients and controls. The exclusion criteria were as follows: (1) repetitive research; (2) letters, editorials, commentaries, or abstracts; (3) studies involving ineligible patients or controls; (4) studies lacking data; or (5) studies in a non-English language. If the results came from the overlapping population, only the first study or the most complete study was included.Two reviewers (Xuexin Zhong and Zhihao Xiao) extracted data. The discrepancies were resolved by the third reviewer (Xiaodan Lu) if needed. The following information was extracted from each study: first author name, year of publication, country, sample size, sample type, sensitivity, specificity, area under the receiver operating characteristic (ROC) curve (AUC), testing methods, tumor staging, reference gene, and differential expression of circRNAs.P < 0.05. The heterogeneity induced by the threshold effect of included studies was tested using the Spearman correlation analysis. Cochran's Q and I2 tests were used to assess the heterogeneity of data. I2 > 50% indicated significant heterogeneity. A subgroup analysis was performed based on sample type, cancer type, reference gene type, and differential expression of circRNAs. The potential source of heterogeneity by the nonthreshold effect was analyzed by regression analysis. A Fagan nomogram was used to calculate the posttest probabilities. Finally, publication bias was assessed.Stata 12.0 software and Meta-DiSc 1.4 were used for statistical analysis. The sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), 95% confidential intervals (95% CI), summary ROC (SROC) curve, and AUC were calculated for quality assessment. The significance level was set as The flowchart of the study selection process is shown in P = 0.829), suggesting no threshold effect.The threshold effect was evaluated with the Spearman rank correlation. The Spearman correlation coefficient was 0.079 (I2 > 50%). For the value of circRNAs in diagnosing lung cancer, the pooled sensitivity, specificity, PLR, NLR, and DOR were 0.77 , 0.76 , 3.17 , 0.31 , and 10.26 , respectively. AUC was 0.78 (95% CI: 0.74–0.81). Forest plots and SROC are shown in Figures Significant heterogeneity was assessed using the random-effects model I > 50%. FI2 value was 96.84%, suggesting significant heterogeneity. The sample type, cancer type, reference gene type, and differential expression of circRNAs were taken as potential causes of heterogeneity, and a metaregression analysis was performed. No significant causes for heterogeneity were found. The results are shown in The β-actin as the reference gene. The results are shown in A subgroup analysis was performed based on the sample type, sample size, cancer type, reference gene type, and differential expression of circRNAs. Although the sample size did not contribute to heterogeneity, the sensitivity, specificity, and DOR of blood samples were 0.72, 0.78, and 9.32, while the corresponding values of tissue samples were 0.80, 0.75, and 11.67, respectively. These findings suggested that tissue circRNAs were slightly superior to blood circRNAs in diagnosis. The sensitivity, specificity, and DOR of the non-small-cell carcinoma subgroup were 0.78, 0.70, and 9.66, while the corresponding values of the lung adenocarcinoma subgroup were 0.75, 0.80, and 12.54, respectively, suggesting the superiority of circRNAs in lung adenocarcinoma over those in non-small-cell carcinoma. The subgroup analysis of the reference gene was not conducted because only one study considered P < 0.05) suggested the publication bias. The funnel plot was constructed with the Stata 12.0 software (P = 0.24).The publication bias of the included studies was tested using Deeks' funnel plot, and significant differences in the slope rate , 0.76 (95% CI: 0.69–0.82), and 10.26 (95% CI: 6.87–15.31). The findings suggested the diagnostic value of circRNAs for lung cancer. The included studies involved only a preliminary analysis of the role of one or two circRNAs in diagnosing lung cancer, with small sample size and sensitivity varying from 0.511 to 0.884 (lower than pooled sensitivity in six studies), specificity from 0.575 to 0.933 (lower than pooled specificity in six studies), and AUC from 0.643 to 0.897 . The sensitivity, specificity, and AUC fluctuated largely among these studies, possibly due to the involvement of one or two circRNAs and small sample size.P = 0.829), suggesting that the threshold effect was not the cause of heterogeneity. In addition, the regression analysis of sample type, lung cancer type, reference type, and differential expression of circRNAs showed that these factors did not cause heterogeneity. The causes of heterogeneity could not be directly found using the studies included in this analysis. Neither study was a randomized controlled study, possibly leading to heterogeneity. However, this hypothesis should be further verified. Additionally, the present meta-analysis included 8 studies and systematically reviewed the value of 10 different circRNAs in diagnosing lung cancer. The analysis revealed that the expression levels of these circRNAs were different, which might be one of the sources of heterogeneity and also a common problem in this type of analysis.The Spearman correlation coefficient was calculated to test the threshold effect and was 0.79 (In conclusion, this systematic review of data extracted from eight studies showed the value of circRNAs in diagnosing lung cancer. These studies were primarily based on the testing of lung cancer tissues. Blood and exocrine secretions were less used, and clinical data were limited. Therefore, the relationship of circRNAs in the blood or exocrine secretions with lung cancer needs further investigation, and the finding might help in the development of molecular markers of diagnosis and prognosis. Further, the recent studies explored the role of a single circRNA in diagnosing and treating cancer using a small sample size; no multicenter and large-sample studies were reported. Hence, the diagnostic accuracy and stability of circRNAs need further elucidation.


Multiple independent cancer susceptibility loci at chromosome 8q24 have been identified by GWAS (Genome-wide association studies). Forty six articles including 60,293 cases and 62,971 controls were collected to conduct a meta-analysis to evaluate the associations between 21 variants in 8q24 and prostate cancer risk. Of the 21 variants located in 8q2\5 were significantly associated with the risk of prostate cancer. In particular, both homozygous AA and heterozygous CA genotypes of rs16901979, as well as the AA and CA genotypes of rs1447295, were associated with the risk of prostate cancer. Our study showed that variants in the 8q24 region are associated with prostate cancer risk in this large-scale research synopsis and meta-analysis. Further studies are needed to explore the role of the 8q24 variants involved in the etiology of prostate cancer. Prostate cancer (PCa) is the commonest non-cutaneous malignancy in men all over the world. Based on epidemiological and biological data, there is growing evidence that many influencing factors, including geography, ethnicity, genetic factors, and so onRebbeck, , are assMultiple risk loci for prostate cancer have been identified by GWAS. In 2007, a two-stage GWAS from 1,854 prostate cancer patients and 1,894 population-screened controls was conducted. In this study, common loci at 8q24 were identified to be associated with prostate cancer  independently assessed the eligibility of each study. All studies included in this meta-analysis must meet all the following inclusion criteria: (i) evaluating the associations of the 8q24 variants with prostate cancer risk; (ii) providing sufficient data or multivariate-adjusted risk estimates  to calculate these estimates. The exclusion criteria were as follows: (i) insufficient data; (ii) they were published as letters to editors or conference abstracts; (iii) they were studies about cancer mortality.Guidelines recommended were used to report meta-analyses of observational studies by an investigator (Yu Tong and Tao Yu) to extract data. Extracted data efrom each eligible study included name of first author, study design, publication date, source population, ethnicity, sample size, variants, alleles, and genotype counts, Hardy-Weinberg equilibrium (HWE) among controls. Ethnicity was classified as Caucasian, African, Asian, or others such as Latinos and Hawaiians. In this meta-analysis, 46 eligible publications are available with sufficient data.I2 statistic h. I2-values < 25%, 25–50%, and > 50% represent no or little heterogeneity, moderate heterogeneity, and large heterogeneity, respectively. Sensitivity analyses were conducted to examine if exclusion of first published study deviated from HWE in controls influence the significant association. Harbord's test was performed to evaluate publication bias. Small study bias was calculated by egger's test. All analyses were conducted using Stata, version 14.0 , with the metan, metabias commands.For each study, the odds ratio (OR) was used as the metric of choice. Pooled odds ratios were computed by the fixed effects model and the random effects model based on heterogeneity estimates, according to Prof. Michael Borenstein's suggestion .p = 1.08 × 10−12, random effect OR = 1.48, 95% CI: 1.33, 1.65; Q = 141.34, p = 0.00, I2 = 83.7%, Figure p = 1.26 × 10−26, random effect OR = 1.33, 95% CI: 1.26, 1.40; Q = 2.76, p = 0.949, I2 = 0.0%), Asians  and Caucasians . No publication bias was found in the eligible studies  and Caucasians . However, no significant association was found for Africans , No publication bias was found in the eligible studies  and Caucasians . No publication bias was found in the eligible studies  and Caucasians . No publication bias was found in the eligible studies  and Caucasians . No significant association was found for Africans . No publication bias was found in the eligible studies . No publication bias was found in the eligible studies . No publication bias was found in the eligible studies . No publication bias was found in the eligible studies . No publication bias was found in the eligible studies . No publication bias was found in the eligible studies . No publication bias was found in the eligible studies . No publication bias was found in the eligible studies  and CA vs. CC (OR2) were calculated. Multivariate meta-analysis was conducted to estimate the pooled risk  and heterozygous CA genotype  have increased risk of prostate cancer.Of the 24 studies, nine reported genotype information. The effects of genotype for AA vs. CC (OR1) and CA vs. CC (OR2) were calculated for each study  and heterozygous CA genotype  have increased risk of prostate cancer.Of the 38 studies, 19 reported genotype information. The effects of genotype for AA vs. CC  and AC vs. AA (OR2) were calculated for each study . However, no significant association was found among individuals with the homozygous CC genotype.Of the 11 studies, five reported genotype information. The genotype effects for CC vs. AA  and CT vs. CC (OR2) were calculated for each study  have an increased risk of prostate cancer. However, no significant association was found among individuals with the homozygous TT genotype.Of the 9 studies, four reported genotype information. The effects of genotype for TT vs. CC , rs1447295 , rs6983561 , rs7000448 , rs6983267 , rs13254738 , rs7017300 , rs7837688 , rs1016343 , rs7008482 , rs4242384 , rs620861 , rs10086908 , DG8S737 Allele-8 , rs10090154  were significantly associated with PCa risk. In particular, both homozygous AA  and heterozygous CA  genotypes of rs16901979, as well as the AA  and CA  genotypes of rs1447295, were associated with PCa risk. Heterozygous AC genotype  of rs6983561, CT genotype  of rs10090154 were also found to be associated with the risk of PCa. Our findings were robust in regard to study design and sensitivity analyses according to several gene-variants-association studies and thousands of participants. No evidence of small study bias or publication bias was found.Of the 21 variants located in 8q24, 15 were associated with prostate cancer risk significantly. Our primary analysis shows that, the rs16901979  associated with risk for prostate, colorectal, breast cancer, et al. There are about five separated different cancer susceptibility loci specific for different cancers within the 8q24 “desert” (Huppi et al., Our study provides summary evidence that common 15 variants in the 8q24 region are associated with PCa risk. To explore the exact mechanisms of 8q24 variants involved in parthenogenesis of prostate cancer needs further functional studies.Data were extracted by YT and TY. SL, FZ, and JY analyzed the data. YQ and DM wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Background: Urotensin-II (UII) rs228648 polymorphism has been reported to be associated with the risk of diabetes mellitus (DM) with inconsistent results. The present study sought to reassess the relationship between this polymorphism and susceptibility to DM by meta-analysis.Methods: Relevant eligible studies and whole genome association study (GWAS) data electronically searched were pooled to evaluate the strength of the association with odds ratios (ORs) and 95% confidence intervals (CIs).Results: Seven case–control studies involving 894 cases and 1186 controls were finally included in the meta-analysis. Overall analyses indicated that UII gene rs228648 variant was significantly associated with reduced risk of DM . In subgroup analyses based on ethnicity, the results showed a significant association of rs228648 polymorphism with decreased risk of DM in Chinese population under all five genetic models as well as in non-Chinese population under heterozygote and recessive models. Stratified analyses by specific type of DM also presented a significant association for common diabetes mellitus (CDM) under allele and homozygote as well as gestational diabetes mellitus (GDM) under all genetic models except for homozygote model. However, the synthetic analysis with GWAS data suggested an increased risk of DM with rs228648 effect allele in European population .Conclusion: The present meta-analysis preliminarily suggested a potentially opposite role of rs228648 polymorphism associated with DM risk in the Chinese and European population. Further studies are in great request to verify the results. Diabetes mellitus (DM) posting one of the most common chronic diseases develops generally in individuals with insulin resistance in insulin target tissues and impaired insulin secretion from pancreatic β-cells in the presence of appropriate genetic and environmental factors ,2. RecenUII initially isolated from the urophysis of teleost fish is a somatostatin-like cyclic undecapeptide and known as the most potent mammalian vasoconstrictor specified as yet ,5, exertConsidering the potential influence of genetic alteration on the expression or activity of corresponding genes which may result in altered risk of diseases, a number of studies have investigated the role of polymorphic variations in UII gene in the susceptibility to DM to date. Expectedly, a previously identified single nucleotide polymorphism 143G>A  mapped on the exon 1 of UII gene has been reportedly linked to DM , howeverPotential eligible studies evaluating the association between UII gene rs228648 polymorphism and susceptibility to DM were electronically searched in Pubmed, Embase, Cochrane Library, Wanfang, China National Knowledge Infrastructure, and the Chinese Biomedicine Databases up to July 2018 using the following limits: Humans, and article in English or Chinese. We developed a search strategy using the following query in various combinations: [‘Urotensin II’ or ‘Urotensin-II’ or ‘UII’ or ‘U-II’] and [‘SNP’ or ‘variant’ or ‘polymorphisms’ or ‘polymorphism’]. Additionally, all the relevant references of the identified studies were further reviewed for additional eligible studies. If necessary, we contacted authors for additional data. In case of duplication, only the study with large sample size and complete information was selected.Studies would be considered eligible if they met the following criteria: (1) Studies assessing the association of UII gene rs228648polymorphism with the risk of DM, including GDM. (2) Studies with case–control design. (3) Studies containing available genotype frequency in cases and controls. (4) Studies providing sufficient information to estimate an odds ratio (OR) with 95% confidence interval (CI). The major reasons for exclusion were as follows: (1) Studies reporting duplicate data. (2) Studies without control design. (3) Studies lack of sufficient data to extract the genotype frequency or estimate the concerned ORs and 95%CIs. Information extracted from each individual study was collected by two independent reviewers using a uniform tabulation and any discrepancy was resolved by discussion or a consultation with a third reviewer to reach a consensus. The information was extracted as follows: first author, year of publication, country, ethnicity, types of DM, distribution of genotype or allele in cases and controls, source of control, genotype method, and evidence of Hardy–Weinberg equilibrium (HWE).http://www.type2diabetesgenetics.org/). The ORs with 95%CIs of individual studies were extracted and synthesized to evaluate the association of rs228648 polymorphism effect allele with DM risk by Stata 12.0 software .Considering the limited sample size and population representation of the original case–control study, the additional synthetic analysis with whole genome association study (GWAS) study was also performed. GWAS data were retrieved with the T2D Knowledge Portal database (http://www.cochrane.org/software/revman.htm). The significance of the pooled OR was determined by the Z-test and P<0.05 was considered significant [Q-test and the I2-test (P<0.10 and I2 > 50% indicated evidence of heterogeneity) [P>0.05 indicated no evidence of publication bias [Individual or pooled ORs with 95% CIs were calculated to assess the strength of associations between the UII gene rs228648 polymorphism and the risk of DM using Review Manager version 5.2 software  . In the geneity) ,25. Sension bias ,27.The flow chart summarizing study selection is shown in As shown in In the subgroup analyses based on ethnicity, we also found a significant association in Chinese population  as well as in non-Chinese population , however only one single study for the non-Chinese population was included. The stratified analyses by specific type of DM indicated a significant association of rs228648 polymorphism with decreased risk of CDM . Likewise, such association was also observed for GDM .P=0.958>0.05). For the sensitivity analyses by sequential omission of individual studies, no substantial alteration for the pooled ORs was observed under the allele, homozygote and recessive models; however, the significance of pooled ORs was excessively affected by excluding the study by Zhu et al. [As shown in u et al.  and Zhouu et al.  under dou et al.  under heAs shown in The study is the first to reliably quantify the association between UII gene rs228648 polymorphism and susceptibility to DM. Our meta-analysis implied a potentially opposite role of rs228648 polymorphism in different populations, suggesting that the UII rs228648 variant seemed to be associated with a reduced risk of DM in the Chinese population while an increased risk in European population.Over decades, numerous polymorphic regions in UII gene encoding for UII peptide, including rs228648 polymorphism, have been identified and correlated to many diseases, such as DM, diabetic retinopathy , breast Overall, the present meta-analysis involving 894 cases and 1186 controls from seven case–control studies suggested a significant effect of UII gene rs228648 variant on the decreased risk of DM. In the subgroup analysis based on ethnicity, we found a significant association between UII gene rs228648 polymorphism and reduced risk of DM in Chinese population under all five genetic models with relatively less heterogeneity but only under heterozygote and recessive models, suggesting that this association may be comparatively evident in Chinese population. However, only few studies were included in the analysis regarding non-Chinese population, more necessity is required for validation of this association in other populations. In addition, the stratification analysis by specific types of DM indicated an association of UII gene rs228648 polymorphism with CDM as well as GDM, suggesting a possibility that the UII gene rs228648 polymorphism may causally and partially contribute to the pathogenesis of CDM and GDM on the basis of similar hereditary context ,21. HoweDespite an appropriate approach applied for the present study, some limitations should be acknowledged yet. First, most of the included individual studies were retrieved from Chinese population, however, the rs228648 polymorphism is most predominant in the South Asian and European populations compared with East Asians. No population from South Asian, American, and fewer population from other East Asian countries were represented in the present study, thus our results may be primarily applicable to limited populations. Second, limited studies conducted in the Chinese population were enrolled in the meta-analysis in spite of no evident publication bias indicated, which would limit our confidence in drawing conclusions especially in the subgroup analysis regarding the specific forms of DM and ethnicity. Third, our estimates were based on unadjusted data, some important compounding factors such as BMI, gender, age, etc., were not taken into consideration due to the lack of original information. Fourth, as DM is multifactor-affected disease, potential environment–gene, gene–gene interactions including haplotype effects may be of importance for the observed disease-effect unconformity , but we In conclusion, the present meta-analysis suggested that UII gene rs228648 polymorphism may be associated with a decreased risk of DM in Chinese population but an increased risk in European population. In light of the limitations existed, additional larger studies allowing stratification analyses for environment–gene interaction, haplotype effects, type and ethnicity specifications are greatly suggested to further clarify the possible role of the concerned genetic variant in the etiology of DM in future work.