I2=64.3%), and no significance was detected in sub-grouped analyses of this polymorphism. Contrastingly, the -592C allele was significantly associated with reduced PCa risk in both prospective  and population-based  studies (Heterogeneity I2=0.0% and 18.1%). Moreover, carriers of combined -592CA/CC genotypes had a significant higher level of peripheral blood IL-10 than the -592AA genotype carriers . The above comparisons possessed a low probability of publication bias. In sum, our findings suggested that IL-10 gene -592A>C polymorphism may represent a promising candidate locus for the occurrence of PCa, and further signified a contributing role of this polymorphism in prostate carcinogenesis.This study purported to investigate the impact of interleukin-10 (IL-10) gene 4 polymorphisms  on peripheral blood IL-10 variation and prostate cancer (PCa) risk, with a special consideration given to various origins of between-study heterogeneity. 2 researchers independently fulfilled literature retrieval, quality assessment and information collection. Sub-grouped analyses per ethnicity, continent, design type, control source, genotyping procedure, genotype validation, age-matched status, study sample size, quality score and controls’ mean age were conducted, respectively. Total 17 unduplicated studies (patients/controls: 7561/8101) were assessable for PCa risk, and 4 unduplicated studies (1189 subjects) for peripheral blood IL-10 variation. Pooling all assessable studies identified a marginally significant association between the -1082A allele and increased PCa risk (odds ratio (OR)=1.10, 95% confidence interval [CI]: 1.00 to 1.21) (Heterogeneity  The latest statistics from the American Cancer Society have predicted that PCa accounts for 21 per cent of all new cancer cases in men, and for 8 per cent of all male cancer deaths in the United States [Prostate cancer (PCa) is frequently occurring among men, and its mortality is continuing to rise, especially in some Western countries , 2. As rd States . A growid States , 5. As ad States . Interled States . IL-10 iAs we all know, PCa is a malignant cancer, and it exhibits familial aggregation . Some stLiterature retrieval of three public sources using prior key subjects identified a total of 114 articles written in the English language. Therein, 97 articles were debarred due to some precise reasons as elucidated in Figure 8 of 17 studies enrolled Caucasians, 4 studies enrolled Asians, 2 studies enrolled African-Americans and 3 studies enrolled mixed-ethnicity populations of Caucasian and African-American. 11 studies followed retrospective design and 6 studies followed prospective design. 10 studies were population-based studies, and 7 studies were hospital-based studies. IL-10 genotypes were determined by TaqMan in 7 studies, by PCR-related methods in 7 studies and by MassARRAY in 3 studies. Only 11 studies validated the accuracy of genotypes, either internally or externally. Age was reported to be matched in frequency between PCa patients and controls in 11 studies. 9 studies possessed a total sample size of less than 600 , and 8 studies involved more than 600 subjects. Quality score of 17 studies ranged from 6 to 11, and its mean value was 8.47. To be specific, 15, 9, 11 and 3 studies were assessable to respectively investigate the impact of IL-10 gene -1082G>A, -819T>C, -592A>C and 210T>C polymorphisms on PCa risk.I2=64.3% and 63.2%). No hints of significant association and between-study heterogeneity were observed for the other three polymorphisms under investigation. Both Begg's and Egger's tests indicated no statistical evidence of publication bias. The Begg's funnel plots seemed symmetrical for all 4 polymorphisms , heterozygous genotype with wild genotype (termed the hetero-genotype model), homozygote genotype with wild genotype (termed the homo-genotype model) and combined heterozygote/homozygous genotypes with wild genotype (termed the dominant model), respectively. Overall risk prediction is offered in Table As only 3 studies were assessable for 210T>C polymorphism, its association with PCa risk was unlikely to be of use in sub-grouped analyses. For the rest 3 polymorphisms, sub-grouped analyses were undertaken to probe into various origins of heterogeneity, per ethnicity, continent, design type, control source, genotyping procedure, genotype validation, matching status, study sample size, quality score (at the median cut-off point of 9) and controls’ mean age (> 50 years old), respectively . For -592A>C, association of the -592C allele with reduced PCa risk was significant in the studies with mixed-ethnicity populations (Caucasians and African-Americans) , as well as in prospective studies  and population-based studies .I2=0.0%).The characteristics of 4 studies for the association of interleukin-10 gene -592A/C and -819T>C polymorphisms with peripheral blood interleukin-10 variation are presented in After taking age, per cent of smokers, family PCa history and PSA as independent variables, a meta-regression model was constructed. Unfortunately, none of these 4 variables showed a significant impact on the association of IL-10 gene 4 polymorphisms with PCa risk (P>0.05).In the present study, we meta-analytically investigated the impact of IL-10 gene 4 polymorphisms on peripheral blood IL-10 variation and PCa risk. The most important observation was that the mutation of -592A>C polymorphism was significantly associated with reduced PCa risk and increased peripheral blood IL-10 level. Moreover, ethnicity, design type and control source served as the possible origins of heterogeneity. As the -592A>C polymorphism is in IL-10 gene promoter region, it appears reasonable to postulate that this polymorphism may alter an individual's susceptibility to PCa risk by regulating peripheral blood IL-10 level.As indicated by two previous meta-analyses, there were no signs of statistical significance between IL-10 gene 3 widely-studied promoter polymorphisms  and PCa risk under all possible genetic models of inheritance , 19. By in-vitro and in-vivo experimental investigations. On the other hand, we also found that design type and control source were the other two potential contributors interpreting between-study heterogeneity in the present meta-analysis. It is widely accepted that case-control studies are often prone to selection bias that often occurs, if the cases are not representative of all cases within the population and the controls are not representative of the population where the cases are from [Differing from previous meta-analyses, we in this meta-analysis comprehensively probed into potential origins of between-study heterogeneity by both sub-grouped analyses and meta-regression analyses. Our findings suggested that ethnicity might be a potential origin of heterogeneity, in view of discrepant estimates between IL-10 genetic polymorphisms and PCa risk. It is easily understood that linkage pattern in human genomes varies during evolution in populations of different ethnic backgrounds , which, are from , 40. It Several limitations of the present meta-analysis deserved comments. Firstly, the probability of publication bias was always a concern for a meta-analysis , becauseIn sum, our meta-analytical findings suggested that IL-10 gene -592A>C polymorphism may represent a promising candidate locus for the occurrence of PCa, and further signified a contributing role of this polymorphism in prostate carcinogenesis. Further studies covering more genome regions on IL-10 gene and related inflammatory genes are warranted among diverse ethnic groups to gain a deeper insight into the impact of IL-10 genetic alterations on peripheral blood IL-10 variation and PCa risk, which can aid in dissecting the molecular mechanisms of PCa for further therapeutic targeting.This meta-analysis is geared on genetic observational studies. The conduct of this meta-analysis methodologically accords with the chief protocols of the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) statement .Retrieval of published articles was confined to electronic sources of Medline (PubMed), EMBASE (Excerpt Medica Database) and Web of Knowledge. Key subjects for retrieval consisted of (“prostate cancer” or “prostate carcinoma”) in the Title and (“interleukin-10” or “interleukin 10” or “IL-10” or “cytokine” or “inflammatory” or “inflammation”) in the Title/Abstract and  in the Abstract. The last retrieval date was November 14, 2016. Articles written in non-English languages were ignored. Citations of retrieved articles and previous meta-analyses were also inspected. Literature retrieval was fulfilled by 2 researchers (Dan Wang and Fang Liu).nd inclusive criteria, 4 polymorphisms absorbed our attention in the present study, and they were -1082G>A (rs1800896), -819T>C (rs1800871), -592A>C (rs1800872) and 210T>C (rs3024496).As the purport of this meta-analysis was to investigate the impact of IL-10 gene all potential polymorphisms on peripheral blood IL-10 variation and PCa risk, articles were includable if they met the three criteria simultaneously, as follows: (i) study subjects were composed of human adults (aged 18 years old or over); (ii) at least one polymorphism in IL-10 gene was determined by standard methods, and only the polymorphism assessed by three or more independent studies was meta-analyzed; (iii) the genotypes or if unavailable the alleles of assessed polymorphism(s) were delivered between PCa patients and controls or mean peripheral blood IL-10 level along with its standard deviation were delivered across genotypes of the polymorphism under investigation in PCa patients or controls or both. According to the 2Quality of the articles that met above-listed inclusive criteria was justified by producing a quality score based on 7 respects of a genetic association study , as follows: family name of the first author, publishing year, sampling region, ethnicity, design type, control source , genotyping procedure,  genotype validation, age-matched status, study sample size, mean age, per cent of current or ever smokers, family PCa history, prostate specific antigen (PSA), the genotypes of 4 above-listed polymorphisms between PCa patients and controls, mean (standard deviation) of peripheral blood IL-10 level in PCa patients or controls or both. Consistency of data excerpted by the 2 researchers was tested with any disagreement resolved through discussing.I2, the acronym for inconsistency index, which characterized the per cent of variability due to heterogeneity rather than due to chance. Heterogeneity is judged significant if the I2 overpasses 50 per cent [The impact of IL-10 gene 4 polymorphisms on peripheral blood IL-10 variation and PCa risk was respectively signified with weighted mean difference (WMD) and odds ratio (OR), along with 95 per cent confidence interval (95% CI) under either a fixed-effects model in case of non-significant heterogeneity or a random-effects model in otherwise case. Significance of between-study heterogeneity was connoted by the per cent . To prob


Many published studies have estimated the association between the +331G/A (rs10895068) polymorphism in the progesterone receptor (PgR) gene and breast cancer risk. However, the results remain inconsistent and controversial. To address this inconsistency, we systematically interrogated the aforementioned association via a meta-analysis.Through a literature search, we identified 13 case-control studies, including 12,453 cases and 14,056 case-free controls. The strengths of reported associations were evaluated using odds ratios (ORs) with 95% confidence intervals (95%CIs).p = 0.027). Via subgroup analysis, we found no association between +331G/A and breast cancer risk in Caucasians, Asians or mixed racial groups.An association was found between +331G/A polymorphism and +331G/A risk in the dominant model (Through meta-analysis, we were able to gain insight into previously reported associations between +331G/A polymorphism and breast cancer risk. However, further studies are still needed to provide more evidence. The most common malignant neoplasm in women, breast cancer has a higher developed versus developing countries. It is a complex and multi-factorial disease caused by a combination of genetic and environmental factors. Although the exact mechanism of breast cancer carcinogenesis is still not completely elucidated, many factors are known to influence its development including age, nulliparity, early menarche, late menopause, and family history . In addiProgesterone (PR) is known to regulate cell proliferation and differentiation in the female reproduction system . DysreguThe progesterone receptor (PgR) is essential for mediating the effects of progesterone, which is necessary to establish and maintain pregnancy. The PgR gene encodes two iso-forms, PR-A and PR-B. Breast cancers commonly express a predominance of one PR isoform, and the loss of coordinated expression in the ratio between PR-A/PR-B proteins within a cell is likely to result in an aberrant hormonal response . The PgRAmong the variations of PgR gene, the +331G/A variant (rs10895068), locating in the promoter region, has been wildly studied. One case–control study including 990 cases and 1364 controls showed that the +331G > A polymorphism increases PR-B isoform expression, which is reported to increase PR-B-dependent mammary cell proliferation, thereby promoting breast cancer . HoweverWe used four online electronic databases to select studies to include in this meta-analysis . Search terms included “breast cancer” or “breast neoplasm” or “mammary” combined with “progesterone receptor gene” or “PgR” or “+331G/A” or “+331G > A” or “rs10895068” and with “polymorphism” or “variant” or “genotype” or “allele”, without any limitation applied. Referenced lists of all included studies were then manually searched to identify any additional eligible studies. Only the study with the most recent, complete data was included when multiple studies included the same set of subjects.Included studies met the following criteria: (1) case-control design; (2) clinical trial evaluating associations between +331G/A gene polymorphisms and breast cancer susceptibility; (3) pathological confirmation of breast cancer diagnosis was reported for all patients; (4) data regarding sample size and individual genotype frequencies were available for all cases and controls; and (5) at least two comparison groups (cancer group and control group) were included. Exclusion criteria: (1) duplication of prior studies and (2) meta-analysis, letters, reviews, or editorial articles.Two investigators (Xing-ling Qi and Jun Yao) independently extracted data from eligible studies. Inconsistencies were resolved via discussion between the investigators. We recorded the first author’s name, publication year, country of origin, ethnicity studied, sample size, genotypes and allele frequencies for patients with the PgR +331G/A polymorphism, and Hardy-Weinberg equilibrium (HWE) results for controls groups. We recorded studies including more than one ethnicity as mixed ethnicity.p < 0.05 indicating a significant deviation. Pooled frequency analyses were performed using Thakkinstian’s method [p values.We used STATA 12.0 software  to perform all statistical analysis. PRISMA checklists and guidelines were adhered to when performing the meta-analysis . For cons method , 19. The2 test, and describe I2 values as low (25%), moderate (50%), or high (75%) estimates [p value less than 0.05 determined statistical significance. We also explored the effect of included studies on combined ORs via sensitivity analysis employing sequential omission of each study. In addition, we conducted subgroup analyses by ethnicity  as well as by source of control subjects . We generated a funnel plot to reflect any possible publication bias [p < 0.05 indicating significant publication bias.We used five models to evaluate associations the +331G/A and breast cancer risk: allele model, dominant model, recessive model, homozygote comparison model, and heterozygote model. A random effects model was used to pool effect sizes of all included studies for a possible effect size across populations with different genetic backgrounds after considering the heterogeneity among the included studies . We alsostimates . A Z-tesion bias , 24, witp < 0.0001) [We performed the online search of multiple databases for available studies reporting associations between PgR +331G/A polymorphisms and breast cancer risk. We included 13 original articles in this meta-analysis after meeting inclusion criteria. As shown in Table  0.0001) .Table 1Bp = 0.027, 95% CI = 1.015–1.279) , Asian  and mixed race  populations via subgroup analysis. Furthermore, using subgroup analysis by source of controls, there was an association between +331G/A locus and breast cancer risk in hospital-based , but not in population-based controls .We assessed possible publication bias using a Begg’s funnel plot and Egger’s test. As shown in Fig. This meta-analysis included 12,453 breast cancer cases and 14,056 controls, and was used to evaluate reported associations between breast cancer risk and the +331G/A (rs10895068) functional polymorphism in the PgR gene promoter. In the dominant model, when all studies meeting eligibility criteria were pooled, we found an association between +331G/A and breast cancer risk. However, after subgroup analysis, this association disappeared in Caucasians, Asian, and mixed race. Therefore, we could cautiously assert that there is no association of the +331G/A PgR gene polymorphism and breast cancer susceptibility in Caucasian and Asian populations.PgR gene polymorphism and breast cancer risk associations than previous meta-analyses.There have been several prior meta-analysis studies reporting on this particular association, with mixed results. An association between breast cancer risk and PgR +331G/A was reported by Yang, et al. . HoweverThere were several limitations to this study that may have affected our results. Firs, only 13 studies were included in our meta-analysis, which limited subsequent analyses because of a shortage of original studies. Second, there was moderate heterogeneity in the overall meta-analysis and in the subgroup analysis that suggested that ethnicity and source of controls, to some extent, contributed heterogeneity between studies. Third, other factors influencing breast cancer, such as genetic background, environment, and lifestyle factors, should also be considered. Finally, there was only ten studies that specified Caucasians and just one study that compared certain populations (Asian and mixed race) in the ethnicity sub-group analyses. Thus, the discrepancy of association among different ethnic sub-groups should be interpreted carefully.In conclusion, our meta-analysis suggested that the +331G/A polymorphism may not be associated with susceptibility to breast cancer. However, because of the comparatively insufficient number of published studies included, our conclusions require support from additional studies. More evidence from epidemiologic studies is required to validate our results regarding the role of +331G/A (rs10895068) in the genetic susceptibility to breast cancer.


Although deregulation of miR-146a has been reported in type 2 diabetes repeatedly, the direction of deregulation events (up or down) remained to be inconsistent in literatures. Therefore, in this study we performed a meta-analysis on the possible association between miR-146a expression levels and type 2 diabetes. A systematic literature searching of PubMed, ISI Web of Science and Google Scholar was performed up to the end of September 2016. Finally, a total of 12 studies including 344 diabetic patients and 316 controls were selected for meta-analysis. All statistical analysis was performed using the metafor package with R software. Moreover, publication bias was assessed by Egger’s and sensitivity analysis was applied on the meta-analysis. The results are presented as log10 odds ratios (logORs), 95% confidence intervals (CI) with relevant P values. The results revealed that miR-146a was downregulated in type 2 diabetes cases compared with normal subjects . Furthermore, sub-group analysis showed that the association between miR-146a expression levels and type 2 diabetes in whole blood (P<0.001) and PBMCs (P<0.001) samples were significant. However, this association was not significant in the serum (P=0.67) and plasma (P=0.90) samples. Our finding suggests that miR-146a downregulation could be associated with type 2 diabetes susceptibility. Further investigations with larger sample size are required to evaluate this association in the type 2 diabetes pathogenesis. Type 2 diabetes (T2D) is the most common form of diabetes resulting from interactionof genetic and environmental factors . This meSince the discovery in 1993, there has been a steady increase in the number of studies investigating the role of circulatory microRNAs (miRNAs) as highly stable and non-invasive biomarkers , 7. MiRNTo date, several studies have provided important evidence about the role of circulating miRNAs as biomarkers for T2D -14. The Search strategyA Systematic literature search using PubMed, ISI Web of Science and Google Scholar were performed for relevant articles from 1993 to September 2016 and the language was restricted to English. To find eligible articles, a combination of the following key words was used: “miR-146a”, “expression”, “profiling”, “type 2 diabetes”, “circulating”, “plasma”, “serum”, and “blood”. In additon, to identify additional eligible studies, we scanned the reference lists of reviews and publications selected for inclusion in this paper.Selection criteria and publication quality assessmentStudies were eligible if they met the following criteria: (1) had miRNAs expression profiling design, (2) compared patients with diabetes and healthy controls, (3) with information on cut-off criteria  for differentially expressed genes, (4) studied human circulatory miRNAs , and (5) reported total number of samples in both patient and control groups. We excluded review articles and studies that determined miRNAs expression profiling on human tissues.Data extraction and quality assessmentThe required data were retrieved by two independent investigators from the full- text eligible articles and supplementary materials. Any disagreement was resolved by a team discussion. For each study, the following information and characteristics were collected and recorded: the first author’s name, year of publication, paper DOI number, study population, miRNAs expression profiling technique, number of cases and controls, number of studied miRNAs, type of sample, cut-off value and type of dysregulation (upregulation or downregulation). With regardto the technique used in a given study, microarray platform or qPCR, quality assessment of data was performed according to the Minimum Information About a Microarray Experiment (MIAME) guidelines version 2 and Minimum Information for Publication of Quantitative Real-time PCR Experiments (MIQE).Statistical analysis2 statistics, respectively. If a difference in statistical heterogeneity was detected (PQ<0.10 or I2≥50%), a random-effects model (fitted by restricted maximum-likelihood estimator) was applied to the pooled logORs. Otherwise, the ﬁxed-effects model was used. To assess the stability of acquired P-values, leave-one-out  was applied on the meta-analysis. Additionally, since the sample sources  were different, a sub-group analysis was performed. Also, publication bias was examined by a funnel plot and funnel plot asymmetry was assessed by Egger’s linear regression test. The significance of the intercept was determined by the t test, as proposed by Egger, with P<0.10 considered indicative of statistically significant publication bias. Otherwise, the study was considered to have no publication bias.All analyses were performed using the metafor package with R statistical software 3.1. Meta-analysis was performed as described elsewhere . To asseThe characteristics of included studiesAfter titles and abstracts initial screening, 10 related articles were obtained by literature search from PubMed, ISI Web of Science and Google Scholar databases. Further, we added our work as unpublished study (consisted of two sub-studies). Finally, a total of 12 studies/sub-studies including 344 T2D patients and 316 normal samples were selected for meta-analysis .Meta-analysis of miR-146a expression in T2D2  was as 90.15%. Overall, meta-analysis revealed that miR-14a was downregulated in T2D cases compared with controls   . As a fu, -1.11) . Subsequ, -1.11) . Indeed,, -1.11)  and Rong, -1.11)  studies Finally, to evaluate the sample type effects on the meta-analysis, we performed sub-group analysis . Our anaT2D is a silent slow progressive killer disease resulting from chronic metabolic disorder in the body which is characterized by hyperglycemia, insulin resistance and finally pancreatic β-cell dysfunction . There iIRAK1)/TNF receptor-associated factor 6 (TRAF6), thus attenuating the inflammatory cytokines production in macrophages (Our results revealed that miR-146a was downregulated in T2D samples compared with controls. The miR-146a is one of the most important miRNAs that its deregulation has been implicated in diabetes. Accumulating evidence has reported that miR-146a regulates the genes involved in the pathogenesis of T2D and its related complications. It has been suggested that chronic inflammation is an important determinant in insulin resistance and also microvascular complications of T2D including nephropathy, neuropathy and retinopathy (rophages , 27. It rophages , 21. yetrophages , 14.Further, the subgroup analysis by sample type showed that the association between miR-146a expression level and T2D was significant in PBMCs and whole blood samples, whereas it was not significant for serum and plasma samples. As a result, determination of miR-146a expression level as molecular marker for T2D can be more useful in PBMCs than in serum and plasma. One possible reason for this finding may be due to the fact that miRNAs expressions are cell and tissue specific . It has Importantly, there is a report which performed a meta-analysis on miR-146a expression in different tissues in human and model organisms . AlthougEven though we tried to perform a well-designed and robust meta-analysis, the present study may suffer from some limitations. First, the existing bias in publishing of reports has significant result. Second, in the subgroup analysis using sample types, the number of studies in each group was relatively small. Third, methodological limitation in miRNAs expression meta-analysis analyzed all studies with non-significant results. Four, because our meta-analysis did not estimate the contribution of other risk factors related to T2D and also the stage of disease, these variables may have influenced the result of our study and partially explain the discrepancies in the involved case-control studies.In conclusion, our finding suggest that miR-146a downregulation could be associated with T2D susceptibility. Furthermore, this result suggests that miR-146a can be considered as a potent marker to predict the clinical outcome of diabetes. This association needs to be confirmed through more clinical investigations with larger sample size and well characterized study populations.


TGFB1) and hepatocellular carcinoma by choosing TGFB1 gene C-509T polymorphism as an instrument in a Mendelian randomization (MR) meta-analysis. Ten English articles were identified for analysis. Two authors independently assessed each article and abstracted relevant data. Odds ratio (OR) and weighted mean difference (WMD) with 95% confidence interval (CI) were synthesized under a random-effects model. Overall, the association of C-509T polymorphism with hepatocellular carcinoma was negative, but its association with circulating TGF-β1 was statistically significant, with a higher concentration observed in carriers of the -509TT genotype  and -509TT/-509TC genotypes . In subgroup analysis, C-509T polymorphism was significantly associated with hepatocellular carcinoma in population-based studies under homozygous-genotype  and dominant  models. Further MR analysis indicated that per unit increase in circulating TGF-β1 was significantly associated with a 38% (95% CI: 1.03–4.65) and 49% (95% CI: 1.01–6.06) increased risk of hepatocellular carcinoma under homozygous-genotype and dominant models, respectively. Conclusively, based on a MR meta-analysis, our findings suggest that enhanced circulating TGF-β1 is causally associated with an increased risk of hepatocellular carcinoma.The aim of this study was to test the causal association between circulating transforming growth factor beta 1 (protein: TGF-β1 and coding gene:  Transforming growth factor beta 1 (TGF-β1) is a polypeptide cytokine that belongs to the transforming growth factor beta super-family –4. EpideTGFB1 gene (Gene ID: 7040) that is mapped on chromosome 19q13.1 and contains 7 exons. Experimental evidence lends support to the observation that TGFB1 gene is frequently up-regulated in tumor cells and the loss of TGF-β signaling is proposed as a hallmark of carcinogenesis [TGFB1 gene is polymorphic in genomic sequences and it incorporates approximate 1700 validated bi-allelic polymorphisms. One of the most widely-evaluated polymorphisms is C-509T (rs1800469) in the promoter region of TGFB1 gene and this polymorphism was reported to be associated with the significant changes of circulating TGF-β1 by many investigators [TGFB1 gene differed significantly between the -509C allele and the -509T allele, and this difference may be caused by selective activator protein 1 (AP1) recruitment to its promoter [TGFB1 gene C-509T polymorphism as an instrument and conducted a meta-analysis of available published studies under the principles of MR method.In theory, MR means the usage of a genetic alteration as an instrument to dissect a causal effect of an intermediate phenotype on a disease and importantly this effect is not subject to reverse causation and confounding that often confuse the interpretation of observational findings , 10. An ogenesis . TGFB1 gtigators , 17. WhaC-509T rs00469 in TGFB1 gene C-509T polymorphism with hepatocellular carcinoma, involving 2809 patients with hepatocellular carcinoma and 4802 cancer-free controls. The basic characteristics of the 12 qualified studies are shown in Table Using the predefined inclusion criteria, 10 out of 86 retrieved articles were qualified for analysis , 19–25 aAll qualified articles were published from the year 2003 to 2015 and total sample size ranged from 188 to 1624. Of 12 studies, 8 were performed in China (5 in southern China and 3 in northern China), 1 separately in Japan, South Korea, Italy and Egypt. Seven studies collected cancer-free controls from hospitals and five from general populations. The C-509T genotypes were determined by restricted fragment length polymorphism (RFLP) method in 7 studies and by chip-related methods in 5 studies. Eight studies had a total sample size of at least 500 and four studies of less than 500.I2 > 50%). However, it was unlikely for the existence of publication bias as revealed by Egger's tests and filled funnel plots , homozygous-genotype  and dominant  models, with significant statistical heterogeneity. Additionally, in studies with a total sample size of less than 500, carriers of the -509TT genotype vis-à-vis the -509CC genotype were 2.07-times more likely to develop hepatocellular carcinoma  and heterogeneity was improved (I2 = 42.8%).To identify possible sources of clinical heterogeneity, subgroups by country, source of controls, genotype method and sample size were conducted and effect-size estimates are presented in Table P > 0.05).After modeling age, gender and the percentages of hepatitis B and C virus infection in meta-regression analysis, we failed to detect any significance of these confounding factors under four genetic models , the -509TC genotype  and the -509TT/-509TC genotypes  had significant higher concentrations of circulating TGF-β1 in a random-effects model  and 49%  increased risk of having hepatocellular carcinoma under homozygous-genotype and dominant models, respectively.TGFB1 gene C-509T polymorphism as an instrument under the principles of MR method. Our findings provided evidence for the significant association of TGFB1 gene C-509T polymorphism with hepatocellular carcinoma in population-based studies and circulating TGF-β1 changes, and importantly enhanced circulating TGF-β1 was suggested to be causally associated with an increased risk of hepatocellular carcinoma. To the best of our knowledge, this is the first report that has explored the cause-and-effect relationship between circulating TGF-β1 and hepatocellular carcinoma.This meta-analysis was designed to explore the causal association between circulating TGF-β1 and hepatocellular carcinoma by choosing TGFB1 gene is one of promising candidates [TGFB1 gene in hepatocellular carcinoma; however, there is little published knowledge revolving the genetic determinants of circulating TGF-β1 and their possible relationship with this disease. To fill this gap in knowledge, we introduced the concept of MR in this meta-analysis and produced convincing estimates for the possible causal involvement of circulating TGF-β1 in hepatocellular carcinogenesis by means of a well-defined promoter polymorphism in TGFB1 gene as an instrument.Hepatocellular carcinoma is the most common type of liver cancer and its incidence is soaring to endemic proportions, especially in Asian and African countries . The incndidates , 30. CurTGFB1 gene C-509T polymorphism and hepatocellular carcinoma, our subgroup analysis demonstrated that carriers of the -509TT genotype or the -509T allele vis-à-vis the -509CC genotype who had higher concentrations of circulating TGF-β1 were at a significantly increased risk in studies with population-based controls. Under the principles of MR, we propose for the first time the causal involvement of circulating TGF-β1 in the development of hepatocellular carcinoma. This involvement may be biologically plausible. Generally, there are two possible mechanisms for the involvement of TGF-β signaling in hepatocellular carcinoma, via intrinsically acting as an autocrine or paracrine growth factors and via extrinsically altering cancer-related microenvironments [Although overall analysis failed to show any significance between ronments , 32. A pronments . A more ronments . In addironments . Howeverronments , 32. Theronments . ExploriTGFB1 gene C-509T polymorphism is well defined, as this polymorphism is reported to account for a nearly twofold difference in circulating TGF-β1, which might be due to transcriptional suppression by the binding of activator protein 1 to this locus [Despite the promising results of this study, we must draw special attention to the MR method adopted in this meta-analysis. It is widely believed that testing for a cause-and-effect of a phenotype on a disease by testing an association between a genetic locus and the disease is reasonable and straightforward pending three key assumptions for a genetic locus quantified as an instrument variable, that is, the locus (i) should be robustly associated the phenotype, (ii) should not be associated with confounding factors that may bias the association between the phenotype and the disease and (iii) should exert its impact on the clinical outcome through the specific phenotype . For theis locus . In addiis locus .TGFB1 gene was selected as an instrument and it is encouraging to see whether this polymorphism in combination with another functional locus will enhance risk prediction for hepatocellular carcinoma.Finally, when interpreting these finding, several potential limitations of this MR meta-analysis should be considered. The first limitation was the retrieval of only English-language articles, which might result in a selection bias. However, this bias is unlikely to affect the validity of our findings because our Egger's tests and filled funnel plots suggested a low probability of publication bias. The second limitation might be inadequate study power in view of limited qualified studies and small sample sizes involved and this limitation became more obvious in some subgroup analyses. The third limitation was that although statistical heterogeneity was improved in some subgroups, other sources of clinical heterogeneity remained to be resolved. The fourth limitation lied in the incapability to justify some prerequisites of the MR method due to the unavailability of original data from each qualified study. The fifth limitation was that only one promoter polymorphism in TGFB1 gene C-509T polymorphism with hepatocellular carcinoma in population-based studies and circulating TGF-β1 changes, and importantly enhanced circulating TGF-β1 was suggested to be causally associated with an increased risk of hepatocellular carcinoma by choosing TGFB1 gene C-509T polymorphism as an instrument, the association warranting further validation in large, independent studies. Considering the ubiquity of genetic heterogeneity and in view of sample sizes involved, our findings should be viewed to be preliminary until further confirmation in future larger, well-designed studies.In conclusion, our findings provide evidence for the significant association of http://www.ncbi.nlm.nih.gov/pubmed/) and Embase (http://store.elsevier.com/embase) were searched to identify articles that examined the association of TGFB1 gene C-509T polymorphism with hepatocellular carcinoma and/or TGF-β1 changes in circulation before July 2016. Key terms included (“hepatocellular carcinoma” or “hepatocellular cancer” or “liver cancer” in title) and (“transforming growth factor beta” or “TGFB” or “TGFbeta” or “TGF-beta” in abstract) and . All retrieved articles were managed by the EndNote X7 software (Thomson Reuters EndNote). For major reviews, meta-analyses and original investigations, we also checked the bibliographies to avoid possible missing articles. The implementation of this meta-analysis abides by the guidelines in the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement [The Medline (tatement .TGFB1 gene C-509T polymorphism with hepatocellular carcinoma and/or TGF-β1 changes in circulation were included pending sufficient information to deduct odds ratio (OR) and weighted mean difference (WMD), as well as their 95% confidence interval (95% CI). Moreover, only articles published in English language were taken into account. Additionally, source of study participants must be described clearly in each study.Articles that examined the association of TGFB1 gene C-509T polymorphism or/and the mean and standard deviation values of circulating TGF-β1 across C-509T three genotypes and if available age, gender composition and the percentages of hepatitis B and C virus infection.From each article, necessary data were collected and typed into a standard form separately by two authors (Wei-Qun LU and Ji-Liang QIU) and after cross-checking, disagreements were resolved by consensus. Necessary data incorporated the first author's surname name, year of publication, country, source of controls, genotyping platform, matching status, sample size, the genotype counts of TGFB1 gene C-509T polymorphism for hepatocellular carcinoma was measured by the ORs with 95% CIs in a random-effects model using the DerSimonian/Laird method [The risk prediction of d method . The meaI2). The I2 represents the percentage of observed diversity resulting from heterogeneity rather than from chance. Higgins et al suggested an I2 of 50% or over as significant heterogeneity [Statistical heterogeneity between studies was measured by inconsistency index .


Objective: The rs2479106 and rs10818854 polymorphisms in the DENND1A gene have been reported to be extensively associated with risk of polycystic ovary syndrome (PCOS). However, the results from these studies remained inconclusive and conflicting. To detect a true association of rs2479106 and rs10818854 polymorphisms with PCOS risk, a single study may be underpowered, particularly for those studies with inadequate sample size. Therefore, we performed a meta-analysis of all available studies to explore this association.Methods: All studies published up to March 2015 on the association were identified by searching electronic databases PubMed, EMBASE, Web of Science, and China National Knowledge Infrastructure. Studies containing available genotype frequencies of those 2 polymorphisms were chosen, and the odds ratios and associated 95% confidence intervals were calculated using fixed- or random- effects models.Results: A total of 8 studies about s2479106 polymorphism (8185 cases and 28675 controls) and 5 studies about rs10818854 polymorphism (6638 cases and 27443 controls) met the inclusion criteria for the meta-analysis. Overall, significant increase of PCOS risk was found between DENND1A-rs10818854 and PCOS susceptibility. In addition, we also found an increased risk of PCOS in rs2479106 allele model, heterozygote variant genetic model, and dominant genetic model.Conclusion: This meta-analysis suggested that rs2479106 and rs10818854 polymorphisms in the DENND1A gene were associated with increased risk of PCOS. To validate the association between these polymorphisms and PCOS susceptibility, further large and well-designed studies are needed. The rs2479106 and rs10818854 polymorphisms in the DENND1A gene have been reported to be extensively associated with risk of polycystic ovary syndrome (PCOS). However, the results from these studies remained inconclusive and conflicting.This meta-analysis suggested that the DENND1A gene s2479106 and rs10818854 polymorphisms were associated with increased risk of PCOS.Polycystic ovary syndrome (PCOS), known as the most common endocrinopathy in women of reproductive age, is a hyperandrogenic and ovulatory disorder . It affeDENND1A, or connecdenn1, encodes a protein containing domains differentially expressed in normal and neoplastic cells (DENN). The DENND1A protein involves in endosomal membrane trafficking and acts as a guanine exchange factor and interacts with members of the Rab family of small GTPases Rab35 ,6. DENNDOver the last two decades, a number of studies have been conducted to investigate the potential association between DENND1A genomic region and PCOS risk in humans. Among the many polymorphisms of DENND1A genes, rs2479106 and rs10818854 polymorphisms have received much attention. Several studies have previously suggested that the rs2479106 and rs10818854 polymorphisms were associated with an increased risk of PCOS , presumaSearch Strategy and Selection CriteriaWe conducted a PubMed search, a Google Scholar search, an EMBASE search, and a China National Knowledge Infrastructure (CNKI) search using the keywords “DENND1A”, “polycystic ovary syndrome”, “rs2479106”, “rs10818854”, and “polymorphism” for the articles. We also supplemented this search by reviewing the reference lists of all retrieved publications. If more than one article was published by the same author using the same case series, we selected the latest research. The relevant search was finished in March 15, 2015. Data on sample characteristics were extracted by 2 independent reviewers who reached a consensus regarding inclusion or exclusion of the article. For the meta-analysis, the following inclusion criteria were considered: 1) Unrelated case-control studies; 2) about rs2479106, rs10818854 polymorphisms and risk of polycystic ovary syndrome; 3) describing useful genotype frequencies; 4) sufficient genotypes data were presented to calculate the odds ratios (ORs); 5) conforming to Hardy-Weinberg (H-W) equilibrium ; 6) pathological diagnoses and the sources of cases and controls should be clearly described. The exclusion criteria were: 1) Incomplete data; 2) non-case-control studies; 3) duplicated publications; 4) unbalanced matching in patient populations; and 5) lack of approval of local ethics committees.Data ExtractionTwo separate investigators reviewed and extracted data from all of the eligible publications independently according to the inclusion and exclusion criteria listed above. The following information will be collected: Characteristics of the methodological research project, the first author’s name, year of publication, country of origin, ethnicity, source of controls, number of cases and controls, PCOS confirmation criteria, genotyping method, genotype frequency for cases and controls, and HWE of controls.Statistical AnalysisThe meta-analysis evaluated the overall association between the DENND1A polymorphism and the risk of PCOS using ORs with the corresponding 95% confidence interval (CI) for each study. The significance of the pooled OR was determined by Z test and a p-value of less than 0.05 was considered significant. Different ORs were calculated using the following models: the allele model (A vs. a), the additive genetic model (AA vs. Aa/Aa vs. aa), the dominant genetic mode (AA+Aa vs. aa), the recessive genetic model (AA vs. Aa+aa), heterozygote variant genetic model (Aa vs. aa), and homozygous variant genetic model (AA vs. aa). The heterogeneity of these studies was tested by the χ2 based Q test and I2 statistics . We considered the result of PQ<0.1 or I2≥50% as indicative of heterogeneity according to Cochrane Handbook, a random-effects (REs) model (the DerSimonian and Laird method) was used to estimate the summary ORs (14); Otherwise, PQ≥0.1 or I2<50%, indicating the absence of heterogeneity, the fixed-effects the (Mantel-Haenszel method model) was used (15). If heterogeneity was presented in this meta-analysis, meta-regression and subgroup analyses were conducted by grouping studies that showed similar characteristics, such as ethnicity, control sources, and genotyping methodology. We also performed meta-analysis using REs models as a sensitivity analysis to examine the robustness of our findings to alternative methods of pooling. If potential publication bias was found in the meta-analyses, contour-enhanced funnel plots and Egger’s test were performed to explore the probable source of publication bias. All statistical analyses were performed using Stata 8.0  and RevMan 4.2 .Characteristics of StudiesA total of 64 articles relevant to search keywords were identified based on the search criteria. After removing 27 duplications, 37 articles remained for which the full-text article was retrieved. By reading the titles and abstracts, we excluded 11 articles, including non-relevant studies, reviews, and meta-analysis. After retrieving the full text of the remaining 26 articles, we excluded 16 articles because of the following reasons: non-case-control studies, incomplete data, unbalanced matching in patients, and not relevant to rs2479106 and rs10818854 polymorphisms. Of these 10 articles, the Han Chinese samples (828 participants) in the Zhao et al  study, aOverall, a total of 8 case-control studies about rs2479106 with 8185 cases and 28675 controls were included. Simultaneously, 5 studies about rs10818854 with 6638 cases and 27443 controls were analyzed. The main characteristics of these studies are summarized in Meta-analysis ResultsThe determined association between rs2479106 polymorphism and the risk of PCOS are shown in The meta-analysis findings of the correlation between rs10818854 and PCOS risk are summarized in Tests of HeterogeneityWe reckoned the heterogeneity between each of the studies using the Q-test. For rs2479106-related PCOS risk , signifiSensitivity AnalysisSince significant heterogeneity across studies was observed for some models, we performed a sensitivity analysis to assess the influence of each individual study on the pooled OR by sequentially removing the individual study . The results suggested that no single study dramatically change the pooled ORs, indicating that our results were robust and reliable Figures .Publication BiasThe results of Egger’s test did not show any evidence of publication bias in any comparison model (p>0.05).The DENND1A gene has been mapped to chromosome 9q22.32 and consists of 22 exons extending over 500,000 bases . Rs24791To date, a number of epidemiological studies have evaluated the association between DENND1A rs2479106 and rs10818854 polymorphisms and PCOS risk, but the results remain inconclusive. Meta-analysis can comprehensively evaluate and quantitatively analyze multiple research results from a critical and objective perspective, thereby improving the efficiency of statistical analysis and tests.In this study, we found a significant association between the variant rs10818854 and increased risk of PCOS. Nevertheless, the results were conflicting in previous studies. Shi et al  found a Reviewing the past studies about DENND1A-rs2479106 polymorphism and the risk of PCOS, Shi et al  found anHeterogeneity is a potential problem when interpreting the results of a meta-analysis, and the obvious evidence of between-study heterogeneity in this meta-analysis should be issued. In the present meta-analysis, there were modest heterogeneities in some comparisons for DENND1A-rs2479106 polymorphism and PCOS risk. After stratifying by ethnicity, the subgroup did not show heterogeneity anymore, reflecting that ethnicity might influence the heterogeneities. Nevertheless, for rs10818854-related PCOS risk, there were still notable heterogeneities in Asians in subgroup analyses, which may be caused by the different ethnicities, study quality, genotyping methods, and experimental designs.There are several limitations in the present study. First, the sample size of our case-control study was relatively small. Some non-English articles, unpublished reports were not included in our meta-analysis, which may bias our results. Second, our meta-analysis was based on unadjusted estimates, whereas a more precise analysis of the various groups should be conducted according to potentially confounding factors, such as age, gender, obesity, drinking and smoking status, menopausal status, use of contraceptives, environment factors, and so on.In summary, this meta-analysis suggests that the rs10818854 polymorphism may be associated with increased risk of PCOS in the allele model and additive model. In addition, increased risk of PCOS was found in rs2479106 allele mode, the heterozygote variant genetic model, and dominant genetic model. Our findings comprehensively evaluate the association between DENND1A SNPs and PCOS risk and provide the basis for subsequent research of molecular mechanisms underlying the identified association. Further large sample size and well-designed studies in different ethnic populations are needed to verify our observations.EthicsEthics Committee Approval: Human Research Committee of Hainan Provincial People’s Hospital for Approval of Research Involving Human Subjects, Informed Consent: Each participant gave written informed consent.Peer-review: External and Internal peer-reviewed.Surgical and Medical Practices: Shan Bao, Jun-Hong Cai, Concept: Shan Bao, Jun-Hong Cai, Shu-Ying Yang, Design: Tianbo Jin, Zhuo-Ri Li, Data Collection or Processing: Yongchao Ren, Tian Feng, Analysis or Interpretation: Yongchao Ren, Tian Feng, Literature Search: Yongchao Ren, Tianbo Jin, Writing: Yongchao Ren.Financial Disclosure: This work was supported by social development of Hainan province special fund of science and technology (SF201302).


Purpose. The aim of this meta-analysis was to clarify the association between the plasma endothelin-1 level and the risks of normal tension glaucoma (NTG) and primary open-angle glaucoma (POAG). Methods. Relevant publications were collected from three databases including PubMed, EMBASE, and the Web of Science through December 31, 2015. In this study, the terms “(endothelin OR ET) AND glaucoma” were searched. Review Manager 5.2 was used to process the data. Results. Seven studies  were included for the NTG analysis. The mean plasma endothelin-1 level in the NTG subjects was 0.60 pg/mL  higher than that of the healthy controls. Six studies  were included for the POAG analysis, and the endothelin-1 level was 0.63 pg/mL  higher in the POAG subjects than in the healthy controls. Additionally, two studies influenced the meta-analysis results regarding the association of plasma endothelin-1 with POAG by sensitivity analysis, and the probability of publication bias was low. Conclusions. The observation that NTG and POAG subjects showed significantly elevated endothelin-1 plasma concentrations suggests that a higher plasma level of endothelin-1 might increase the risk of NTG and POAG development. Glaucoma is a group of heterogeneous diseases characterized by the following features: optic nerve head cupping, glaucomatous visual field defects, and elevated intraocular pressure (IOP) . Open-anAlthough many publications evaluated the plasma ET-1 level in NTG and POAG, the association between plasma ET-1 and glaucoma still remained controversial. Several studies showed that plasma ET-1 level is significantly elevated in NTG –16 and PThe studies were obtained from PubMed, EMBASE, and the Web of Science. The search terms “(endothelin-1 OR ET-1) AND glaucoma” were used to retrieve the relevant studies. The reference lists of all the relevant articles were searched to identify other studies. We searched for relevant studies from the beginning of indexing for each database to August 31, 2015.the study evaluated the association between glaucoma and ET-1;the report was a case-control study of the disease;healthy subjects were collected as the control group;the plasma ET-1 concentrations in the case subjects and control subjects were measured;it was possible to obtain the full article. A chart of the article search process is presented in The studies were included in the meta-analysis if the following criteria were met:The articles were reviewed independently by two investigators (Shengjie Li and Aiping Zhang), who searched all the items in the articles. The following characteristics were extracted from each study: (1) name of the first author, (2) publication year, (3) country, (4) ages of the cases and controls, (5) number of cases and controls, and (6) the ET-1 concentration data of the cases and controls.I2 statistic. The significance of the pooled effect size was determined with the Z test. The relative risk was observed using inverse-variance weighted random effects models. The pooled standardized mean difference (SMD) and 95% confidence interval (CI) for ET-1 were calculated for each study. A funnel plot analysis was performed to assess the potential publication bias. We performed a sensitivity analysis to evaluate the stability of the results through a leave-one-out strategy. This method uses sequential omission of individual studies in every comparison to determine whether there is a significant alteration of the combined values. A p value of <0.05 was considered statistically significant.The statistical analyses were performed using Review Manager 5.2 . The heterogeneity of the pooled mean differences was estimated using the From the initial search strategy, 182 articles were identified, and 172 articles were subsequently excluded . Thus, 1p = 0.007, 95% CI = 0.17–1.04]; however, there was significant heterogeneity across the 7 studies   .p = 0.02, 95% CI = 0.12–1.15]; however, there was significant heterogeneity across the 6 studies   .In the meta-analysis of the association between plasma ET-1 and NTG, the sensitivity analysis revealed that one study had a slight influence on the result. Two studies influenced the meta-analysis results regarding the association between plasma ET-1 and POAG . The funp = 0.007, 95% CI = 0.17–1.04). Similarly, the plasma ET-1 level was significantly elevated in the POAG group compared with the control group . The results of this meta-analysis indicate that a higher ET-1 plasma level is associated with a significantly increased risk of NTG and POAG.Because the relationship of the plasma ET-1 level and the presentation of NTG or POAG remained uncertain, we performed this meta-analysis to clarify the relationship. To the best of our knowledge, this is the first meta-analysis examining the relationship between ET-1 and glaucoma. We found that the ET-1 plasma level was higher in the NTG group than in the control group (ET-1 is supposed by some to have association with NTG –16. Lee Moreover, Chen et al.  and CellIt is of the most interest that in addition to an important role of ET-1 in the pathogenesis of systemic vascular disease, it also may be significant that the plasma level of ET-1 was higher in glaucoma patients. The fact that both NTG and POAG patients have a similarly high ET-1 level might indicate that ET-1 functions in the pathogenesis of both POAG and NTG. Several major population studies and clinical trials have reported the association of cardiovascular disease or hypertension with OAG and have indicated that cardiovascular disease and hypertension increase the risk of OAG –24. The In this meta-analysis, the increased plasma ET-1 level in POAG and NTG were observed while the heterogeneity should also be considered. A sensitivity analysis was performed by a leave-one-out strategy to further evaluate the stability of the data in the individual studies. A total of three studies , 16, 20 Although a standard search strategy and a thorough computerized search method were applied, certain limitations of our meta-analysis should be considered. First, our meta-analysis included only studies with accessible full-text articles in English. Second, the studies differed widely in the study population characteristics and the measurement techniques. Third, the definitions of NTG across the studies we analyzed were different. Last, only ten eligible studies could be used for the meta-analysis while the number of cases/controls in each study was relatively limited.In this meta-analysis, we confirmed that NTG and POAG patients have a higher plasma level of ET-1. Consequently, the possible involvement of vascular dysfunction in the pathogenesis of glaucoma and the potential utility of ET-1 as a predictive biomarker might be considered.


Objective: Previous studies have reported that Ile462Val polymorphism in the gene Cytochrome P450 1A1 (CYP1A1) is associated with the risk of cervical cancer, but inconsistent results have emerged. Hence, we performed this updated and cumulative meta-analysis to ascertain a more accurate association between CYP1A1 Ile462Val polymorphism and risk of cervical cancer.Methods: Studies involving the CYP1A1 Ile462Val polymorphism associated with cervical cancer risk were searched from the databases of PubMed, Scopus, ScienceDirect, and Chinese National Knowledge Infrastructure (CNKI). The strength of correlation was evaluated through calculating summary odds ratios (ORs) with the corresponding 95% confidence intervals (95% CIs). Subgroup analyses according to ethnicity, source of control and HWE were completed to further explore specific association between the polymorphism and the cancer risk.Results: Altogether, 11 eligible case-control studies were ultimately encompassed into the current meta-analysis, with 1,932 patients and 2,039 healthy controls. The total analysis revealed a borderline relationship between CYP1A1 Ile462Val polymorphism and cervical cancer risk in general population. Interestingly, after subgroup analyses based on ethnicity and source of control, the polymorphism increased the susceptibility of cervical cancer in Caucasian  and population-based  groups.Conclusion: The CYP1A1 Ile462Val polymorphism may enhance the susceptibility to cervical cancer in Caucasian females. Cervical cancer is followed by breast cancer, which is the first common cancer among women all over the world . There are five published meta-analyses directly or indirectly investigated the association between CYP1A1 Ile462Val polymorphism and risk of cervical cancer  gene family and susceptibility to many cancers has been the most widely studied  as a cohort or case-control design; (3) both cases and controls were clearly diagnosed and all controls were healthy subjects or tissues; (4) included information that allowed for calculation of the odds ratios (ORs) and 95% confidence intervals (CIs). The study investigated the cervical dysplasia, cervical intraepithelial neoplasia (CIN), or cervical squamous intraepithelial lesions (CSIL) was excluded. If any publication involved the same subjects, we compared them according to the population, exposure, control, and study period and chosen the more comprehensive one.Any study was considered eligible if it met all of the following criteria: (1) contain information investigated the association between CYP1A1, cytochrome P-450, cytochrome P450, polymorphism, Ile462Val, A2455G, and rs1048943. Moreover, we also searched through the references which were cited in the included studies to obtain additional relevant studies. Two independent authors searched and evaluated the eligibility of all studies and any disagreements were resolved by discussion.The PubMed, Scopus, ScienceDirect, and Chinese National Knowledge Infrastructure (CNKI) databases were searched for relevant studies that were published up to January 10, 2017. The search strategy included usage of the following key words: cervical, cervix, cancer, carcinoma, P < 0.05 according to the genotype distribution in control. Disagreements were resolved by discussion.Two authors extracted the following data independently from all included studies: the last name of first author, year of publication, country of origin, ethnicity, sources of controls, sample sizes of cases and controls, genotype distribution in cases and controls, Hardy-Weinberg Equilibrium (HWE) for controls, and genotyping methods. If the HWE was not reported, we assessed it by the chi-square test and significance was set at I2 test and Cochran Q test, both I2 < 50% and P > 0.1 was considered acceptance heterogeneity and the fixed-effect model was chosen to pool single study; otherwise, the random-effect model was used. Subgroup analyses according to ethnicity, source of control, and HWE were conducted. Five genetic models were used for overall and subgroup analyses: G vs. A, GG vs. AA, GA vs. AA, (GA+GG) vs. AA, and GG vs. (AA+GA). The odds ratio (OR) and its 95% confidence interval (95%CI) were used to evaluate the pooled effect size. Sensitivity analysis was performed to investigate the influence of a single study on overall analysis, and to test the robustness of overall results. Cumulative meta-analysis was carried out to observe the change when with sample sizes were enlarged . After stratified analysis by source of controls, significant results were found in population-based controls . No significant association existed in the studies conforming to HWE or deviating from HWE under all five genetic models .As shown in Figure Cervical cancer is the second most common cancer among women worldwide, frequently occurring in developing countries in particular  is a member of the CYP1 family and participates in the metabolic activation of structurally diverse xenobiotics and endobiotics , COMT (rs4680), and CYP2E1 (rs3813867) polymorphisms. Importantly, a significant association between the MspI polymorphism and elevated cervical cancer risk was observed , or cervical squamous intraepithelial lesions (CSIL) were excluded. Thus, the study by Taskiran et al. was not included in this meta-analysis (Taskiran et al., Despite certain advantages, there still were some limitations to be addressed. To begin with, the sample sizes of subgroup analyses were relatively small, which might affect the final results. Second, since meta-analysis is a secondary analysis (Zeng et al., CYP1A1 Ile462Val polymorphism and cervical cancer risk in general population, and this polymorphism significantly increase the risk in Caucasian females. It provides an important theoretical basis to reveal the CYP1A1 Ile462Val polymorphism and the biological mechanism of developing cervical cancer, which may be helpful to predict the occurrence of cervical cancer in Caucasian females. Importantly, special attention should be paid upon the design of future studies, such as selection of subjects and adjustment of interfering factors so as to uncover any underlying mechanisms and distinct patterns. In view of the above mentioned restrictions, these results should be applied with prudence and further verified by large-scale and well-designed studies with various ethnic groups.In summary, our meta-analysis outcomes revealed a borderline relationship between L-NW and X-QR designed this study; FW and Y-HJ searched databases and collected full-text papers; JL and CF extracted and analyzed data; L-NW, FW, and JL wrote the manuscript, X-QR reviewed 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.


Reports on the relationship between the lncRNA H19 rs217727 polymorphism and the risk of cancer in the Chinese population have been inconsistent. Therefore, we performed a meta-analysis to evaluate this association, by searching the Embase, PubMed, Web of Science, Wanfang, and CNKI databases. Four case-control studies with 3,157 cases and 3,564 controls were selected for this meta-analysis. The odds ratios with 95% confidence intervals were examined using the random effect model. Allelic (A vs. G), dominant (AA + GA vs. GG), recessive (AA vs. GA + GG), and additive (AA vs. GG) genetic models were used to determine the association. Overall, no significant association was observed between the rs217727 polymorphism and cancer susceptibility in any of the four genetic models. Sensitivity analysis revealed that the results were stable in the allelic and dominant genetic models, but those from the recessive and additive models were unstable, which should be treated with caution. Our meta-analysis suggests that the lncRNA H19 rs217727 polymorphism might not be associated with overall cancer risk. However, well-designed, large-scale studies with different ethnic populations need to be conducted in the future to elucidate the potential association. Various long non-coding RNAs (lncRNAs) have been known to play a role in various diseases, including cancer, via transcriptional and post-transcriptional regulation of the expression of oncogenes or tumor suppressors . The lncTherefore, to achieve a more accurate evaluation of the association between the lncRNA H19 rs217727 polymorphism and overall cancer risk in the Chinese population, we performed this meta-analysis with an aim to explore the role of rs217727 in cancer carcinogenesis and to explain the possible reasons for the inconsistent results reported so far in previous studies.The study selection process was as shown in Figure P = 0.490; AA + GA vs. GG, OR: 0.970, 95% CI: 0.802, 1.174, P = 0.755; AA vs. GA + GG, OR: 1.232; 95% CI: 0.968, 1.568, P = 0.090; AA vs. GG, OR: 1.156, 95% CI: 0.868, 1.541, P = 0.321]. Stratified analysis based on the genotyping method also showed similar results in the Taqman-method subgroup , sample size (> 2000 vs. ≤ 2000), and genotyping method (Taqman vs. RFLP) as possible covariates; however, the meta-regression analysis did not reveal any covariate significantly contributing to the heterogeneity in any genetic model (data not shown).P < 0.001; additive, OR: 1.301, 95% CI: 1.053, 1.608, P = 0.015). These data suggest that our meta-analysis results were not stable in the recessive and additive genetic models, but remained stable in the allelic and dominant genetic models.Sensitivity analysis showed that the pooled ORs were not materially influenced by any single study in the allelic and dominant genetic models, indicating that our results were statistically robust in the allelic and dominant genetic models Table . In the Begg's and Egger's tests were performed to assess the publication bias of the studies, and no significant publication bias was found Table , which iLncRNA H19, as an imprinted gene, servers as an oncogene and was aberrantly increased in several cancers, and it might promote carcinogenesis via acting as competitive endogenous RNAs (ceRNA) or precursors of microRNAs. Liu L et al., reported that lncRNA H19 promoted thyroid carcinogenesis by competitively binding miR-17-5p to regulate its target YES1 expression, functioning as ceRNA . LncRNA In the current meta-analysis, we comprehensively analyzed all literatures studying the association between the lncRNA H19 rs217727 polymorphism and cancer risk in the Chinese population; however, we did not find any significant association in any genetic model in the overall Chinese population and in our stratification analysis based on the genotyping method Figure . Meta-reDifferent cancer types might contribute to the overall result of our meta-analysis. In our meta-analysis, bladder cancer, colorectal cancer, breast cancer, and gastric cancer were included, but each type of cancer only included one study, thus making stratification impossible. Furthermore, different cancers may also be affected by gender, smoking habits, and other subgroup populations, suggesting that studies on a larger scale including different cancers need to be conducted in the future. Different sex ratios may also affect the overall result In the study on breast cancer by Xia et al., due to the special characteristics, only women were included . In the Our current meta-analysis had some limitations that will need to be addressed in future studies. First, only the Chinese population was analyzed, as only one study with a Caucasian population was found. We also performed an overall meta-analysis including both Caucasian and Chinese populations, and the result was similar to that found when only the Chinese population was considered . Second,Nevertheless, our study showed that the lncRNA H19 rs217727 polymorphism might not be associated with cancer rick in the Chinese population. However, further case-control studies with larger sample sizes in different ethnic populations will be needed to achieve more definitive results.Eligible studies were systematically searched in Embase, PubMed, Web of Science, Wanfang, and CNKI databases up to July 6, 2016, with keywords including “long Noncoding RNA H19 OR lncRNA H19 OR long non-coding RNA H19” and “polymorphism OR variation OR rs217727” and “cancer OR carcinoma OR tumor”. We also manually examined reference lists for relevant publications.Eligible studies should meet the following criteria: a) studies evaluating the association between lncRNA H19 rs217727 polymorphism and the risk of cancer in Chinese population, b) case-control designed studies, c) studies with sufficient genotype data for calculation of the odds ratio (OR) with 95% confidence intervals (95% CIs). Exclusion criteria were as follows: a) reviews, b) studies lacked detailed genotype information, c) studies included overlapping subjects, d) studies on other population rather than Chinese population, e) studies not on human, f) studies not on lncRNA H19 rs217727. In cases where overlapping subjects were included, the study with the larger sample size was selected.P value for Hardy-Weinberg equilibrium (HWE). Disparities, if any, were resolved via discussion.Two investigators  independently extracted the following data from each article with a standardized protocol: first author name, publication year, Country, ethnicity, age, genotyping method, sample size, genotype, allele frequency, source of control, minor allele frequence (MAF), The quality of the studies was independently evaluated by two reviewers  according to quality assessment scale Table . Total s2 test in the controls. Cochran Q test and I2 statistic were used to assess heterogeneity. If P value for Q test>0.1 or I2<50%, fixed effect model was used; otherwise, random effect model was chosen. The significance of the pooled OR was determined with Z test, and P<0.05 was considered to be statistically significant. Sensitivity analysis was conducted by sequentially omiting one single study at a time and recounting ORs and 95% CIs. Egger's and Begg's tests were applied to detect the potential publication bias. Meta regression analysis was performed to estimate the main source of heterogeneity. All statistical tests were analyzed by STATA 11.0 .The crude ORs and 95% CIs were calculated to measure the association between lncRNA H19 rs217727 polymorphism and cancer risk. Four genetic models were used: allelic (A vs. G), dominant (AA + GA vs. GG), recessive (AA vs. GA + GG), and additive (AA vs. GG) genetic models. HWE was examined by χ


P=0.009). By further stratified analysis, we found that rs4919510 SNP had some relationship with decreased cancer risk in both homozygote model  and dominant model  in Caucasians but no relationship in any genetic model in Asians. These results indicated that miR-608 rs4919510 polymorphism may contribute to the decreased cancer susceptibility and could be a promising target to forecast cancer risk for clinical practice. However, to further confirm these results, well-designed large scale case–control studies are needed in the future.Single nucleotide polymorphisms (SNPs) in MicroRNAs (miRNAs) are involved in the mechanism of carcinogenesis. Several studies have evaluated the association of rs4919510 SNP in miR-608 with cancer susceptibility in different types of cancer, with inconclusive outcomes. To obtain a more precise estimation, we carried out this meta-analysis through systematic retrieval from the PubMed and Embase database. A total of 10 case-control studies were analyzed with 6,000 cases and 7,664 controls. The results showed that 4919510 SNP in miR-608 was significantly associated with decreased cancer risk only in recessive model (CC vs. GG+GC: OR=0.89, 95% CI: 0.82-0.97,  MicroRNAs (miRNAs) are small , evolutionarily conserved, noncoding RNA molecules which participate in post-transcriptional gene regulation by binding to the complementary sequences in 3’ untranslated region (3’ UTR) of target messenger RNAs (mRNAs) , 5. StudSingle nucleotide polymorphisms (SNPs), the most common genetic variation, have been demonstrated to influence the expression or target site selection of miRNAs and thus are involved in a series of biological processes by interfering interaction between miRNAs and target mRNAs , 9. SNPsG) polymorphism showed a consistent association with nasopharyngeal carcinoma susceptibility in south area of China [Recently, rs4919510 SNP in miR-608 has been reported to be a predictor of clinical outcomes for patients with renal cell carcinoma , colorecof China . Other sof China . By systG) in the controls were in agreement with HWE. A variety of genotyping methods were applied including Taqman, RT-PCR, MassArray, SNaPshot, and SNPstream. Genomic DNA was isolated from blood samples in all included studies except one (using both blood and tissue) [A total of 51 literatures based on our searching strategy were selected out from PubMed and EMBASE database. After screening the title and abstract, 25 studies uncorrelated with cancer risk and SNPs were excluded and 26 literatures were then evaluated in detail. Finally ten case-control studies –26 meeti tissue) .P=0.009)  Figure . In otheP=0.034) and dominant model  , heterozygote model , dominant model  and recessive model . Sensitivity analysis through evaluating the influence of each study on overall ORs showed that the omission of any study made no significant difference Figure . We alsoGenetic mutations are responsible for cancer occurrence . SNPs asin vitro and in vivo by eliminating NAA10 mRNA which participate as a key molecule in the process of carcinogenesis [In this meta-analysis, we demonstrated that individuals carrying CC genotype in rs4919510 have a decreased cancer risk. Moreover, Yang and colleagues reported that miR-608 suppressed the carcinogenesis of colon cancer cells ogenesis . Taken tBy subgroup analysis, we found that in Caucasians miR-608 rs4919510 polymorphism had some relationship with decreased cancer risk in homozygote model and dominant model while in Asians there exist no relationship in any genotype model. These differences may be a result of various genetic backgrounds in different races and various mechanisms of carcinogenesis in different areas.Nevertheless, some limitations in this meta-analysis should be paid attention to. First, included studies are still so limited that we cannot perform subgroup analysis for different cancer types although it is well known that one microRNA may play different functions in different types of cancer. Second, there exists a certain degree of heterogeneity between studies. After subgroup analysis stratified by races, it could be found that heterogeneity of Caucasians reduced significantly. Thus, it could be presumed that the heterogeneity partly resulted from differences in races. Simultaneously, the selection of subjects may become another source of heterogeneity. Third, only three studies were included in subgroup analysis for Caucasians and the results could be inaccurate and dubious. Fourth, only published articles were included, the unpublished and ongoing studies could convert our result. Last, we did not take sex, age, sex, family history and environmental factors into consideration and further detailed meta-analysis remain needed.G) polymorphism in miR-608 was significantly associated with decreased cancer risk and could become a promising target to forecast cancer risk for clinical practice. However, these results should be treated with caution due to the limitations above. For further verifying the results, well-designed large scale case–control studies are needed in the future.In conclusion, the results of meta-analysis indicated that rs4919510 were searched without language, publication, or date restrictions using the following search terms: (“microRNA 608” OR “microRNA-608” OR “miR-608” OR “rs4919510”) AND (“polymorphism” OR “SNP” OR “variation” OR “locus” OR “mutation”) AND . The included papers should meet criteria listed below: (1) Assessment of the relationship between miR-608 rs4919510 polymorphism and cancer risk; (2) a case-control design; (3) histologically confirmed for malignant tumors; (4) sufficient published data for further calculating odds ratios (ORs) and their 95% confidence intervals (95%CIs); (5) Meeting Hardy-Weinberg equilibrium (HWE) in the control group (P>0.05). Two reviewers (HQ Liu and BY Wang) in our group screened out the data independently and had reached a consensus on each term. All extracted data consisted of author (year), country, ethnicity, cancer type, genotyping method, source of controls, characteristics of cases and controls and P value for Hardy–Weinberg equilibrium (HWE) was exhibited in Table 2 test and considered P value>0.05 as fulfilling Hardy-Weinberg equilibrium [G) SNP and the risk of cancer was measured by odds ratios (ORs) with 95% confidence intervals (CIs) based on different genetic models such as homozygote model (CC vs. GG), heterozygote model (CG vs. GG), dominant model (CG+ CC vs. GG) and recessive model (CC vs. GG+GC) respectively. Hierarchical analysis was conducted by Ethnicity (Asian and Caucasian). The statistical significance of the pooled OR was evaluated by Z test, and P value of <0.05 was regarded as significant. Heterogeneity assumption was tested among studies using a Chi-square-based Q-test. We considered P value of > 0.10 for Q-test as a lack of heterogeneity which indicate fixed-effects model should be used to perform the meta-analysis [We calculated P value of HWE in control group by Xilibrium . The assanalysis . If signanalysis . To evalanalysis . The inf


Findings from this meta-analysis indicate that obesity is associated with a higher risk of liver cancer incidence in men, especially in non-Asian men, which might partially contribute to the male dominance of liver cancer incidence.Excess body weight has a positive association with risk of liver cancer, but the gender difference in the relationship between body mass index and liver cancer risk remains uncertainty. In this work, we performed meta-analysis for excess body weight and risk of liver cancer incidence to identify the gender difference. We searched the English-languages database and the Chinese literature databases to May 12, 2017. Overall, a total of 17 studies were included. Relative risks (RRs) with 95% confidence intervals was used to evaluate the strength of these associations. The RRs of liver cancer incidence for obese men and women were 2.04 (1.70–2.44) and 1.56 (1.37–1.78). The former one was significantly higher than the later one (P for interaction = 0.02). Notably, the RR of liver cancer incidence in non-Asian obese men was even higher than their counter part (2.31(1.85–2.91) vs. 1.56 (1.31–1.86), P for interaction = 0.01). Similar gender difference was observed in the dose-response curve. As example, at the point of BMI = 32 kg/m Liver cancer is the sixth most prevalent neoplasm , an estiOne universal epidemiologic characteristic of liver cancer is the prominent male dominance . It is tObesity is growing globally, the worldwide prevalence of obesity has doubled from 1980 to 2008 . There wAs shown in Figure Compared to the reference category , a positive association was observed between high BMI and liver cancer incidence (overweight: 1.16 (1.08–1.25); obesity: 1.83 (1.60–2.09)) .P for interaction = 0.47)  Table .P for interaction = 0.00, Table The prevalence of obesity is markedly different between in Western countries and in Asian countries . Thus weP for interaction = 0.88).Furthermore, the RRs of liver cancer incidence for men and women were calculated and compared in non-Asia countries and Asia countries separately. As shown in Figure There were no differences between HCC and overall liver cancer, study design, disease type, duration of follow-up, study size, adjustment factors Table .P = 0.000) relationship between BMI and the risk of liver cancer incidence. This meta-analysis showed an increased liver cancer incidence of 4% for each 1 kg/m2 increment in BMI as shown in Figure 2, the RRs for men and women were 1.61 (1.45–1.79) and 1.41 (1.02–1.94) respectively  meta-analysis was found in non-Asian studies, which showed an increased risk of 7% for each 1 kg/m2 increment in BMI as shown in Figure Furthermore, we assessed the dose-response relationship between BMI and liver cancer incidence with 8 studies , 33–35. y Figure . SimilarI2 = 8.3%, Asia: I2 = 48.5%). Study location of Sweden could explain heterogeneity in obesity group . The heterogeneities decreased significantly when these Sweden studies were stratified in the group  (P = 0.900) (p = 0.877) and obesity (p = 0.794)    . However= 0.900) , as well= 0.794) . Similar) Figure  as well We will conduct a formal trial sequential analysis (TSA)  by usingPower analysis were conducted and the power value Table  was 97.1Men develop liver cancer more often than women. However, the causes for the gender difference still need to be explored. In this meta-analysis, the liver cancer incidence risk in obesity was found to be higher in non-Asian men than in non-Asian women. Further dose-response analysis showed that a tendency towards higher liver cancer incidence was also seen in men.The association between BMI of liver cancer incidence is well documented –17. InstIn our meta-analysis, 17 studies were included and we applied TSA to reduce the risk of type I error and testify whether the evidence of our results was reliable. These results indicated that conclusive evidence was established and that further trials were not required. In addition, the power analysis suggests that the meta-analysis have high statistical power. Based on these solid risk data, interaction statistics between men and women have been further analyzed. In addition, a dose-response meta-analysis is firstly conducted for BMI and liver cancer incidence in our work. And thus the gender difference revealed in our meta-analysis is informative.As countries move towards higher economic level, the prevalence of obesity shift from the female to the male population . HoweverNotably, it was reported that higher free estrogen in women may promote the cell proliferation and growth in breast cancer , 45, kidOf note, overweight/obesity and its related morbidities are a growing health problem claiming 2.8 million lives annually , the obeThere were several potential limitations in our study that should be considered. First, although the studies had been adjusted for important risk factors, unmeasured factors related to BMI may still have influenced results of individual studies. Second, the relatively small number of studies limited conclusions from further subgroup analyses. Third, some important confounders had not been measured with sufficient precision. Only some article had considered alcohol consumption, cigarette smoking, hepatitis infection status, dietary factors and physical activity. Lack of adjustment for these important risk factors limited the ability to generalize between obesity and liver cancer.In conclusion, the association of BMI with risk of liver cancer varies by gender. The obese men had significant higher liver cancer incidence than obese women, especially in non-Asian countries. Even stricter body weight control is strongly suggested for liver cancer prevention, especially for men in non-Asian countries.We searched English-language databases (PUBMED and EMBASE) and Chinese literature databases (CNKI and WanFang) to January 12, 2017 for studies on the relationship between BMI and liver cancer risk. Our research consisted of terms related to ‘body mass index’, ‘BMI’, or ‘obesity’ or ‘excess body weight’ or ‘overweight’; ‘liver cancer’ or ‘hepatocellular carcinoma’ or ‘HCC’; ‘risk’ or ‘incidence’ to identify eligible studies. No language limits were set. In addition, the reference lists of selected research papers were manually reviewed to find additional articles.Studies were included in the meta-analysis if they fulfilled the following criteria: (1) published as an original article; (2) Cohort or case–control studies study in which liver cancer incidence or mortality was an outcome; (3) having clear description of normal weight, overweight and obesity defined by BMI; (4) the studies reporting risk estimates with the corresponding 95% confidence intervals (95% CI) or sufficient information to calculate them; (5) the RR and corresponding 95% CI were at least adjusted for age; (6) reported outcomes of men and women separately. When the same population was shared by multiple studies, only the study with most detailed information or the largest sample size was included.Three authors  separately screened the title and abstract of the retrieved studies and then reviewed the full texts to extract studies that met the inclusion criteria of this meta-analysis Figure . NO studThe Newcastle-Ottawa Scale (NOS) procedure was used to assess the quality of the study. Three parameters of quality including selection, comparability, and outcome (cohort studies) or exposure (case-control studies) were included –56. The A high-quality study was defined as a study with ≥ 7 points .2), normal weight (18.5 to 24.9 kg/m2), overweight (25.0 to 29.9 kg/m2) and obesity (≥ 30.0 kg/m2) were applied on defining BMI-categories primarily. When non-standard BMI categories were provided, the category closing to the WHO definition was selected. Data were analyzed using a random-effects model [P value of < 0.05 was considered a criterion for statistical significance [http://link.springer.com/article/10.3758/BRM.41.1.35 Statistical analyses were performed by Stata 12.0  and P values of two-sided less than 0.05 were considered statistically significant. Heterogeneity among studies was assessed using I2 statistics, which test total variation across studies [We followed the WHO international classification and defined body mass categories as follows: underweight (< 18.5 kg/mts model , 57. Dosts model . Influents model . Interacificance , Power cificance . We baseificance , 63 and  studies , 64, 65.In meta-analyses, it is important to minimize the risk of reaching a false-positive or false-negative conclusion. However, repeated significance tests of sparse and accumulated data are prone to yielding random errors, which increase the risk of type I errors . In orde