IFN-γ +874T/A gene polymorphism and hepatitis virus-related diseases is heterogeneous.Interferon gamma (IFN-γ) is a key regulatory cytokine, which plays an important role in antiviral defense of an infected host. However, the association between the Based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement, a comprehensive literature search of eligible studies in Embase, Pubmed, and the Cochrane Library was undertaken through November 2014. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were used to measure the strength of the models.IFN-γ +874T/A polymorphism and hepatitis virus—related diseases in a recessive gene model , especially in Asians  and hepatitis B virus (HBV)–related disease .Seventeen case-control articles, including 24 studies with 5503 individuals, met the inclusion criteria. The results indicated a statistically significant association between the IFN-γ +874T/A polymorphism increases the risk of hepatitis virus—related diseases, especially in Asians and HBV—related diseases. Further studies on this topic in different ethnicities, especially genome-wide association studies, should be conducted to strengthen our results.The evidence suggests that the  Liver disease can have various causes, including infection with viruses, such as the hepatitis B virus (HBV) and the hepatitis C virus (HCV), especially in developing countries . InterfeIFN-γ gene on chromosome 12q24 spans approximately 5.4 kb and is composed of four exons, with three intervening regions; many single nucleotide polymorphisms (SNPs) are located in this region [IFN-γ gene. The TT genotype is associated with increased IFN production when the immune system responds to stimuli [Genetic susceptibility is an important factor in the development of diseases. The IFN-γ +874T/A polymorphism and virus-related disease risk, especially liver diseases, such as CH, LC, and HCC, which are caused by persistent hepatitis virus infection. However, the literature on the impact of the IFN-γ gene polymorphism on the risk of hepatitis virus—related diseases has provided contradictory results [IFN-γ +874T/A polymorphism is strongly associated with circulating IFN-γ concentrations, it is assumed that this polymorphism might be closely related to the risk of the hepatitis virus—related diseases. Our aim was to examine the association between the IFN-γ +874T/A polymorphism and the risk of hepatitis virus-related diseases in published studies using a meta-analysis.Many studies have mainly focused on the  results –16. SincThis meta-analysis was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement, including the search strategy, selection criteria,data extraction and data analysis .We used the following terms to search for articles published in Embase, PubMed, and the Cochrane Library up to November 30, 2014: “interferon,” “IFN” “polymorphism,” “polymorphisms,” “mutation,” “variant,” “hepatitis,” “cirrhosis,” and “hepatocellular carcinoma.” Two investigators (Yifan Sun and Yu Lu) conducted an extensive independent literature search. Articles in reference lists were hand-searched. Only English-language articles and human studies were searched.The following criteria were used to select suitable studies: (1) case-control or cohort design studies; (2) contained data that could be extracted to calculate the odds ratio (OR), 95% confidence intervals (CIs), and Hardy—Weinberg equilibrium (HWE); (3) stated the DNA genotyping method and source of cases and controls. The following were excluded: review articles, letters, case reports, editorials, conference abstracts, and family-based studies.Two investigators (Yifan Sun and Yu Lu) independently extracted data from the included studies. The data included the first author’s name, publication date, country, ethnicity, total sample size, virus type and liver disease type, genotyping method, genotype frequencies of cases and controls, source of the case group and control group, age and sex ratio, source of specimens used to determine the genotypes, and the estimated HWE. If the literature did not provide sufficient data, the investigators tried to contact the author to get the original data by email.In the subgroup analysis, ethnicities from Europe, West Asia, North Africa, and the Americas were categorized as Caucasian and those from East or Southeast Asia as Asian. The hepatitis virus type and liver disease type were also categorized. If the data in the study were related to various liver diseases, the study was treated as a separate study in the meta-analysis. To determine the accuracy of the extracted information, the data extracted by the two investigators were expected to be the same. In cases of a dispute, they checked their data again. If they could not reach an agreement, the dispute was resolved by a third reviewer (Xue Qin).Two investigators (Yifan Sun and Shan Li) assessed the quality of the selected studies independently, following the criteria predefined by Thakkinstian et al.  and usedIFN-γ +874T/A polymorphism and hepatitis virus-related diseases was assessed with various comparison models, including an allelic model (A vs. T), a co-dominant model (TA vs. TT and AA vs. TT), a dominant model (TA+AA vs. TT), and a recessive model (AA vs. TA+TT). Because the studies lacked details of the environmental factors, unadjusted ORs and the corresponding 95% CIs were used to measure the strength of the models.The association between the PQ<0.1 or I2≥50%, the heterogeneity was considered significant. The random-effects model used the DerSimonian and Laird method. Otherwise, the summary OR and the corresponding 95% CI were calculated with a fixed-effects model (the Mantel—Haenszel method). We also conducted a subgroup analysis by ethnicity, genotyping method, source of controls, hepatitis virus type, liver disease type, and quality assessment score. A meta-regression that included the following covariates was performed: ethnicity, genotyping method, source of controls, and quality scores. Covariates with values of P<0.05 were considered the main sources of heterogeneity. Galbraith plot analysis was performed for further exploration of the heterogeneity. Sensitivity analysis was conducted to examine such influence by removing studies one by one and recalculating the pooled OR and 95% CI.In common with previous studies , 21, hetP<0.05 indicated that the result was statistically significant.A Begg’s funnel plot and an Egger’s test were used to investigate publication bias in the meta-analysis. All tests in this meta-analysis were conducted with STATA software .Based on the search terms, 17 articles, which included 24 case-control studies containing 2,607 cases and 2,896 controls, were identified as suitable for a meta-analysis , 22–30 . The priIFN-γ +874T/A loci A allele had a higher representation in the controls of the Asian group than in the Caucasian group . On average, the frequency of AA, TA, and TT as a proportion of 1 was 0.38, 0.41, and 0.21 respectively in the Asian population controls and 0.32, 0.48, and 0.20 in the Caucasian population; a significant difference was observed between the two ethnicities , as well as in the cases . The allele frequencies in the African group were not analyzed because of the sample size was too small.Allele frequencies in different ethnicities were calculated according to the original data of the studies. The IFN-γ +874T/A polymorphism and hepatitis virus—related disease risk are listed in P = 0.004, I2% = 54.3, and PQ = 0.001 for heterogeneity; see The results of the meta-analysis of the IFN-γ +874T/A polymorphism significantly increased the risk of hepatitis virus-related disease in Asians , SSP-PCR method group , and hospital-based population .For the recessive model, the results of the subgroup analysis showed that the IFN-γ +874T/A polymorphism significantly increased the risk of hepatitis virus—related disease in the HBV-related diseases group . Similar results were observed for the CHB patient group  and the hospital-based population .For the allelic model , the IFN-γ +874T/A polymorphism and hepatitis virus—related disease risk . A Galbraith plot analysis confirmed that the studies by Korachi et al. (HBV), Gao et al. (HCV), Bouzgarrou et al. (HCV), and Mishra et al. (HEV) were responsible for the heterogeneity in the recessive model. After these four studies were excluded, the summary OR value did not change significantly . In the allelic model, the studies by Korachi et al. (HBV) [I2 values were lower than 50%, and the PQ value was larger than 0.10 (data not shown).All the models revealed statistical heterogeneity for the l. (HBV)  and SaxeIFN-γ (+874T/A) polymorphism. Further sensitivity analysis was performed by excluding the studies by Karatayli et al. [The control groups in the studies by Teixeira et al. , Gao et i et al.  and Mishi et al. , in whicIFN-γ +84T/A polyi et al. , 27. FinPEgger’s test = 1.840; P = 0.08).A Begg’s funnel plot and an Egger’s test were used to investigate the publication bias in the meta-analysis . No signIFN-γ +874T/A polymorphism and the risk of hepatitis virus—related diseases has been studied extensively because of the importance of IFN-γ in immune responses [IFN-γ +874T/A polymorphism and risk of hepatitis virus—related disease in the pooled analysis in the recessive model, with the +874 AA genotype associated with a 1.350-fold increased risk of hepatitis virus related—disease, especially in Asian and HBV—related diseasesVarious environmental and dietary factors are responsible for liver diseases, but hepatitis infection is the main cause of CH, LC, and HCC . The assesponses , 25, 29.IFN-γ +874T/A polymorphism may play an important role in hepatitis virus—related disease. The following pathways are considered the main way in which the IFN-γ +874T/A polymorphism affects the development of hepatitis virus infection. First, the IFN-γ +874T/A genotype TT, which produces a high level of IFN-γ, aids the host’s antiviral defense system. In contrast, the AA and TA genotypes result in low IFN-γ production, potentially increasing the risk of hepatitis virus infection [IFN-γ +874T/A polymorphism leads to dysfunction of IFN-γR, potentially increasing the risk of liver diseases [κB) transcription factor. If the NF-κB pathway is affected, it may lead to oxidative damage, which can also increase the risk of LC and HCC [IFN-γ polymorphism increase in hepatitis virus—related diseases risk is shown in The results indicate that the nfection . Second,diseases . In addi and HCC . The posIFN-γ +874T/A polymorphism influenced the risk of hepatitis virus-related diseases in Asians but not in Caucasians. Many factors may contribute to this finding. First, hepatitis virus related—disease is a complex entity, with multiple determinants other than virus infection, such as diet and the environment. Some studies noted significant gene—gene and gene—environmental interactions in patients with hepatitis virus related—diseases [IFN-γ +874T/A polymorphism varies in ethnicities [The stratified analysis by ethnicity in the present study suggested that the diseases –35. Seconicities , 37, andIFN-γ +874 was seen to play a functional role in relation to viral load, consistent with its known role inhibiting and replicating of HBV-infected cells [The subgroup analysis showed that the significant results are mainly reflected in the HBV—related group. Evidence suggests that IFN-γ can suppress viral replication/clear HBV without causing liver injury, the non-cytolytic HBV suppression effect of IFN-γ is believed to have an important role in the control of HBV viral activity in patients with CHB . Regardied cells . IFN-γ ced cells , and a ged cells .IFN-γ +874T/A TT genotype produces a high level of IFN-γ, and the AA and TA genotypes result in low IFN-γ production. Thus we can suppose that the AA+TA vs. TT model may have significant association in the analysis. However, the ORs of AA vs. TT+TA and AA+TA vs. TT are opposite in our meta-analysis. These confusing results suggested that the T allele is a protective gene in liver disease; moreover, this allele has more power than the A allele, therefore, only the population with the AA genotype has higher risk of hepatitis virus-related liver disease. Indeed, similar results happened in the association between the IFN-γ +874T/A polymorphism and cervical cancer with human papillomavirus (HPV) infection [Mycobacterium leprae[IFN-γ showed a protective significant association with tuberculosis susceptibility [As we now known, the nfection  and leprum leprae. A meta-tibility .IFN-γ gene in the response to drug treatment in cancer [IFN-γ gene, which is also the specific binding site for NF-κB similar to the +874 locus, influenced HCV therapy. Moreover, Oxenkrug et al. [IFN-γ gene were a risk factor in depressed patients with HCV who were treated with IFN-alpha. The IFN-γ gene polymorphism may further affect the development of HCC and the response to cancer drugs by increasing the risk of hepatitis virus-related diseases, although we did not observe a significant association between the (+874T/A) polymorphism and HCC risk in this study, which is worthy of further investigation in the future.Studies have also reported the role of the n cancer . Sarvarin cancer  indicateg et al.  found thWe noticed that the meta-analysis by Ge et al. also sugP>0.05) showed no publication bias. Therefore, we consider that the results are credible, although there are some confounding factors in the articles.Heterogeneity is the most common problem when explaining the results of a meta-analysis. In the current meta-analysis, we assessed heterogeneity using various statistical methods, including subgroup analysis, meta-regression, and Galbraith plot analysis. Finally, we concluded that the heterogeneity in the meta-analysis was due to the genotyping method, mixed infection, and various virus types. Sensitivity analysis was performed by excluding the studies not in HWE. The studies of HDV infection and HEV infection and those that used different genotyping methods, especially the DNA sequencing method, were also excluded one by one. The corresponding pooled OR value did not differ significantly from that of the overall meta-analysis. However, a Begg’s funnel plot and an Egger’s test Click here for additional data file.S2 Table(DOC)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.


Purpose. While individual participant data (IPD) meta-analyses are considered the gold standard for meta-analysis, the feasibility of obtaining IPD may be problematic. Methods. Using data from a previous meta-analysis of 29 studies on exercise in adults with arthritis and other rheumatic diseases, the percentage of studies in which useable IPD was provided was calculated. Results. Eight of 29 authors  provided IPD. Using logistic regression, neither year of publication  nor country  was significantly associated with the obtainment of IPD. Conclusions. The retrieval of IPD for exercise meta-analyses may not be worth the time and effort. However, further research is needed before any final recommendations can be made. The number of meta-analyses focused on exercise has also increased dramatically over the same time period. Using the keywords “exercise AND meta-analysis”, the number of meta-analyses has increased from 7 in 1990 to 472 in 2014 (Supplementary File 2). While aggregate data (AD) meta-analysis, an approach in which summary statistics from eligible studies are pooled, is still the most common type of meta-analysis, individual participant data (IPD) meta-analysis, an approach that pools the results from different studies based on data from each participant, is considered the gold standard [ brief report was to contribute to the scant exercise literature by providing up-to-date information regarding the retrieval of IPD, including potential covariates, for a specific meta-analysis.The prevalence of meta-analyses has increased dramatically over approximately the past 25 years. For example, recent PubMed searches by the first author on December 4, 2015, using the keyword “meta-analysis” found that the number of citations increased from 331 in 1990 to 14,329 in 2014 , deidentified IPD was requested by having the second author contact the corresponding author of each eligible study via electronic mail asking if they would be interested in providing IPD. A response was requested within two weeks, regardless of interest, with the authors being informed that they would be listed in the acknowledgements section of each published study derived from the project if they provided their IPD. If no response was received within two weeks, up to two additional requests were sent via electronic mail. For those who responded but chose not to contribute, reasons given for not participating, if any, were recorded. For those authors who expressed interest in providing IPD, a second electronic mail was sent that included an attachment consisting of a predefined list of IPD requested (see Supplementary File 4). Investigators were asked to provide IPD in a format that was convenient for them within four weeks. If IPD was not received within four weeks, as many as two additional reminders were sent via electronic mail. The dates of all communications were recorded.Descriptive statistics were used to describe the number of responses to initial electronic mail requests for IPD, number of days to respond to initial electronic mail requests, number of authors who provided useable IPD, and number of days from initial requests to receipt of IPD. Reasons for not providing IPD from authors who were willing to supply such information were also recorded. Furthermore, descriptive statistics were calculated for the two potential predictors included in the regression model.χ2) was used to examine the overall model. The alpha level for statistical significance was set at p ≤ 0.05.Because of the small sample size, exact logistic regression was used to examine potential predictors with respect to whether or not IPD was received . Based on = 4) and time (n = 1). Another author said that they would supply IPD if a consortium was formed and in which they were included as a coauthor. Year of publication ranged from 1989 to 2011. Thirteen studies  were conducted in the United States while the remaining 16  were conducted in countries other than the United States.The authors from 20 of 29 studies  responded to initial electronic mail requests for IPD while 9  never responded despite multiple requests. The response time to initial requests varied widely from 1 to 181 days  and neither year of publication nor country was a significant predictor for the receipt of IPD (p > 0.05 for both).Results for exact logistic regression are shown in The current study resulted in a low obtainment of IPD for this exercise meta-analysis, with less than one-third of eligible studies providing IPD. The response rates observed are either similar to , 42, lowThe study reinforces the importance of considering the feasibility of obtaining IPD when deciding whether to conduct an AD or IPD exercise meta-analysis. In addition, the increased costs associated with an IPD meta-analysis need to be considered. For example, Steinberg et al. estimated that the costs associated with conducting a meta-analysis of 12 ovarian cancer studies were more than 5 times greater using the IPD versus AD approach .This study provides important up-to-date information regarding the retrieval of IPD for an exercise meta-analysis. This is noteworthy given that this is only the second study that has examined the feasibility of retrieving IPD for an exercise meta-analysis, the first being conducted by the authors back in 2002 . In addiThe retrieval of IPD for exercise meta-analyses may not be worth the time and effort. However, further research is needed before any final recommendations can be made.Supplementary File 1: This file provides details regarding a PubMed search conducted on December 4, 2015 for citations indexed between the years 1990 and 2014 using the key term “meta-analysis”.Supplementary File 2: This file provides details regarding a PubMed search conducted on December 4, 2015 for citations indexed between the years 1990 and 2014 using the key terms “exercise and meta-analysis”.Supplementary File 3: This file is an example of the initial letter that was sent to authors requesting de-identified individual participant data for their previously published study.Supplementary File 4: This file is an example of the follow-up letter that was sent to eligible investigators describing what de-identified individual participant data was needed from their previously published study.


AA: OR = 1.64, 95% CI = 1.32–2.05, P < 0.01, I2 = 55.6%; GG vs. AA: OR = 2.24, 95% CI = 1.69–2.97, P < 0.01, I2 = 38.5%; AG + GG vs. AA: OR = 1.70, 95% CI = 1.36−2.14, P = 0.02, I2 = 61.8%; GG vs. AA + AG: OR = 1.89, 95% CI = 1.23−2.90, P = 0.01, I2 = 46.3%) in the total population, as well as in subgroup analysis. Moreover, increased HNC risks were also associated with the IL-10 −819T > C polymorphism and the GCC haplotype. In conclusion, our meta-analyses suggest that IL-10 polymorphisms, specifically the −1082A > G polymorphism, may be associated with increased risk of HNC development.Molecular epidemiological research suggests that interleukin-10 (IL-10) polymorphisms may be associated with an increased risk of head and neck cancer (HNC), but results remain controversial. To derive a more precise evaluation, we performed a meta-analysis focused on genetic polymorphisms of IL-10. PubMed, Embase, CNKI and Wanfang databases were searched for studies that examined the relationship between IL-10 polymorphisms or haplotypes and HNC risk. The odds ratio (OR) and 95% confidence interval (CI) were applied to assess the relationship strength. Publication bias, sensitivity and cumulative analyses were conducted to measure the robustness of our findings. Overall, nine related studies involving 2,258 patients and 2,887 control samples were analyzed. Significant associations between the IL-10-1082A > G polymorphism and HNC risk were observed (G vs. A: OR = 1.56, 95% CI = 1.27–1.92, P < 0.01, I Head and neck cancer (HNC) is one of the most common malignancies and derives from the malignant transformation of the epithelial cells that line the upper respiratory tract and digestive system156789Interestingly, these factors do not explain the variation in susceptibility observed within different populations. Over the past decade, many studies have suggested that leukocytes and their relevant cytokines may play a central role in inflammatory infiltration and malignant transformation1112et al.IL-10 is an important inflammatory cytokine with anti-inflammatory properties. The IL-10 gene is located on chromosome 1 at q31-32, contains five exons and four introns that span a length of 4.8 kb and encode a 178-amino-acid protein1718202123This meta-analysis was designed according to the guidelines described in the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA Compliant) statementThe Pubmed, Embase CNKI and Wanfang databases were searched to identify studies that examined the association between HNC and IL-10 polymorphisms, using the following search terms: “head and neck cancer”, “oral cancer”, “nasopharyngeal cancer”, “pharynx cancer”, “larynx cancer”, “Interleukin-10”, “IL-10”, “polymorphism”, and “variant”.All selected studies met the following criteria: 1) the research design was a case-control study; 2) the study focused on the association between the IL-10 polymorphisms and HNC susceptibility; 3) the study included sufficient genotype distribution data to calculate odds ratios (ORs) and 95% confidence intervals (CIs); 4) the study was published in either Chinese or English. The largest sample size or most recent publication was preferentially selected in cases of overlapping data or duplicate publications.The following information was extracted from all qualified studies by two independent researchers (Niu and Cai): first author, publication year, country, racial descent (categorized as either Asian or Caucasian), source of controls, number of cases and controls with different genotypes, genotyping method, Hardy-Weinberg equilibrium (HWE) for controls, cancer location and study quality assessment.Two independent authors (Niu and Du) assessed the quality of the included studies using quality scoring criteria modified from previous meta-analyses , co-dominant model , dominant model (GA + GG vs. AA), and recessive model (GG vs. AA + GA). These similar genetic models were also used to assess the IL-10 −819T > C and −592A > C polymorphisms. Subgroup analyses were performed based on cancer location, HWE status of controls, ethnicity, and study design. ORs were calculated using the random-effects model (DerSimonian and Laird method) when the P-value was less than 0.10 or IA systematic review of the literature identified 111 relevant studies. 2937383940414243293738394041424329373942432938373941424329412 = 69.4%; AG vs. AA: OR = 1.64, 95% CI = 1.32–2.05, P < 0.01, I2 = 55.6%; GG vs. AA: OR = 2.24, 95% CI = 1.69–2.97, P < 0.01, I2 = 38.5%; AG + GG vs. AA: OR = 1.70, 95% CI = 1.36–2.14, P = 0.02, I2 = 61.8%, 2 = 46.3%; 2 = 55.2%; AG vs. AA: OR = 1.71, 95% CI = 1.15–2.54, P = 0.01, I2 = 71.1%; GG vs. AA: OR = 3.13, 95% CI = 2.06–4.77, P < 0.01, I2 = 0%; AG + GG vs. AA: OR = 1.83, 95% CI = 1.26–2.66, P < 0.01, I2 = 70.1%; GG vs. AA + AG: OR = 2.69, 95% CI = 1.77–4.09, P < 0.01, I2 = 0%) and nasopharyngeal cancer  and HWE deviation responsible for other models . Importantly, heterogeneity was relieved in the subgroup analysis.Heterogeneity was observed in the following four models: G vs. A, AG vs. AA, AG + GG vs. AA and GG vs. AA + AG. Meta-regression analyses highlighted ethnicity as a major driver of heterogeneity in the G vs. A model , as well as among Asian populations  and recessive model . Moreover, these results were consistent with subgroup analysis of the population control group  revealed increased risk of HNC in the population control group. Further subgroup analysis of ethnicity and cancer type was conducted, and no significant association was identified. The pooled ORs did not exhibit any change with sensitivity and cumulative analysis, and no publication bias was observed .Association between the IL-10 −592A > C polymorphism and HNC risk Six studies consisting of 1,676 cases and 2,230 controls were included in the analysis to determine whether the IL-10–592A > C polymorphism was associated with HNC risk. Overall, no significant association was observed in all five models . Only tw2 = 52.6%; Association between the IL-10 haplotype and HNC risk Of the selected studies, only four described the association between the IL-10 −1082A > G, −819T > C and −592A > C haplotype and HNC risk . QuantitGenetic factors have been shown to influence the susceptibility of patients to various diseases and have attracted increasing attention454748et al. reported that the AG and GG genotypes were associated with a significant increase in HNC risk compared with the AA genotype in a Chinese population (95% CI = 1.37–3.48 and 1.33–10.84)3940422938To date, numerous molecular epidemiological studies have been conducted to evaluate the association between polymorphisms of IL-10 and the risk of HNC development, but results have remained conflicting. Regarding the IL-10 −1082A > G polymorphism, Wei In 2014, a meta-analysis that included four studies focused on nasopharyngeal cancer was published and reported an increased risk with the IL-10 −1082A > G polymorphismIn the current analysis, we found that the frequency of GCC haplotype was higher in the HNC patients than in controls and was associated with a significant increased HNC risk. The GCC haplotype of the IL-10 promoter may result in increased transcription and IL-10 expression. These effects down-regulate the expression of Th1 cytokines, thus allowing tumor cells to escape immune surveillanceStratified analysis was successfully used to relieve moderate heterogeneity bias in the IL-10–1082A > G polymorphism analysis within the Asian population and the oral cancer group, suggesting that ethnicity and cancer location may influence heterogeneity. Moreover, we did not observe any publication bias in the three polymorphisms, demonstrating that the results of this meta-analysis are stable.It is important to note the limitations of our meta-analysis. First, all of our results may be influenced by casualness due to the small number of studies included and the limited sample size of each study. Larger sample sizes are necessary to accurately clarify the association between the IL-10 polymorphisms and HNC risk. Second, only articles published in English or Chinese were selected, potentially causing a language bias. Third, HNC is a multi-factorial malignant tumor that likely arises from complex interactions between genetic mutations, environmental changes, lifestyle, diet, age and gender. Meta-analysis is a retrospective approachDespite these limitations, our results suggest that the IL-10 −1082A > G polymorphism is a risk factor for HNC, especially in Asian populations. Our findings also indicate that the IL-10 −819T > C polymorphism also plays an important role in HNC development. No significant association was detected between the IL-10 −592A > C polymorphism and HNC risk. Moreover, the GCC haplotype was associated with an increased risk of HNC. In the future, additional studies with larger sample sizes are needed to identify the precise pathogenesis of IL-10 polymorphisms in HNC.How to cite this article: Niu, Y.-M. et al. Increased risks between Interleukin-10 gene polymorphisms and haplotype and head and neck cancer: a meta-analysis. Sci. Rep.5, 17149; doi: 10.1038/srep17149 (2015).


SPP1 polymorphisms with human cancers in Chinese population, but the results remain inconsistent. The aim of this meta-analysis is to clarify the associations between SPP1 polymorphisms and cancer susceptibility.Several studies have been conducted to examine the associations between osteopontin (OPN) promoter gene All eligible case-control studies published up to March 2015 were identified by searching PubMed, Web of Science, Embase, and Cochrane Library without language restrictions. Pooled odds ratio (OR) and 95% confidence interval (95% CI) were calculated using fixed- or random-effect model.A total of 11 case-control studies were included; of those, there were eleven studies (3130 cases and 3828 controls) for -443T>C polymorphism, ten studies (3019 cases and 3615 controls) for -156G>GG polymorphism, eight studies (2258 cases and 2846 controls) for -66T>G polymorphism. Overall, no evidence indicated that the -443 T>C polymorphism was associated with cancer risk . While, a significantly increase risk was found for -156 G>GG polymorphism . For -66T>G polymorphism, we found a decrease risk of cancer , but this result changed  when we excluded a study.SPP1 might be a risk factor for human cancers, while -443T>C mutation is not associated with cancer risk. For -66T>G polymorphism, it may be a protective factor for human cancers.This meta-analysis suggests that in Chinese population the -156G>GG polymorphism of  SPP1 have been searched.Cancers contribute a greatest deal to death worldwide , as a reSPP1 (mapped to chromosome 4q24-q25), which is predominantly a transcriptionally regulated gene with highly conserved promoter  AND [-443C>T or rs11730582 or -156G>GG or rs17524488 or -66T>G or rs28357094] AND [variant or genetic polymorphism or polymorphism or mutation]. Additional studies were identified by screening references in the retrieved articles and preceding reviews on the topic.A literature research was conducted using PubMed, Web of Science, Embase, and Cochrane Library up to March 2015 without language restrictions. Relevant studies were searched using the terms  ] .P = 0.09); recessive model ; GGG vs GG model ; GGGG vs GG model ] ] . We eval= 0.03)] .P = 0.15), but no significant association was found under other three models . For -156G>GG polymorphism, significant heterogeneity between studies was observed in overall comparisons under GG/GG versus GG model . And for -66T>G polymorphism, significant heterogeneity between studies was found in overall comparisons under recessive model and TG versus TT model . . . Then, sP = 0.818, -156G>GG: P = 0.418, -66T>G: P = 0.842).Begg’s funnel plot and Egger’s test were performed to address potential publication bias in the available literature. The shape of funnel plots did not indicate any evidence of funnel plot asymmetry . Egger’sSPP1, may potentially alter the expression of OPN and then modulate the risk for cancer. In recent years, SNPs have been identified as a powerful tool for predicting some complex diseases. However, previous genetic epidemiological studies about the associations between OPN gene polymorphisms and the risk of human cancer are limited, and the results were inconclusive. To our knowledge, this is the first meta-analysis which investigated the possible correlations of rs11730582 (-443 T>C), rs17524488 (-156G>GG), and rs28357094 (-66T>G) polymorphisms in the SPP1 gene with cancer susceptibility.Osteopontin is a member of small intrgrin-binding ligand N-linked glycoproteins (SIBLINGs) family. There are many pieces of evidences indicating that osteopontin profoundly regulate the development and progression of various tumors. Additionally, OPN expression was significantly higher in human cancers tissues than in matched normal tissues and it was significantly associated with nodal metastasis and more advanced clinical stage. Therefore, numerous publications have tested OPN as a biomarker for cancer invasiveness –34. HoweOur results revealed that -443T>C polymorphism might have no relation with pathogenesis of cancer. And we found that different studies had inconsistent results about this polymorphism even for the same cancer. For example, Chen JX  said thaFor -156G>GG, our study found that GG allele was at significant high risk for cancer under all four genetic models, and this result was confirmed among studies in HWE. When we exclude the study of Mu GY  which maThe meta-analysis of -66T>G include eight studies, however, two studies ,29 that SPP1 polymorphisms. Mu GY [SPP1 polymorphisms affected the tumor OPN expression level, but not the serum OPN level; (2) the association is indeed related and further studies are just needed; (3) SPP1 polymorphisms make no difference in OPN level.High OPN expression in the primary tumors is associated with cancer risk, metastasis and poor clinical outcome –39. The s. Mu GY  and Zhans. Mu GY  observeds. Mu GY  found ths. Mu GY  thought SPP1 gene and the increased susceptibility to human cancers in Chinese population systematically. One the other hand, the exhaustive inclusion criteria and articles on wide range of cancers enhanced the power and persuasion of our conclusion. Furthermore, all literatures included had acceptable quality scores (scored at least 6). Meanwhile, we were also aware of several limitations of our study. First, all eligible studies come from China and the patients are Chinese population. Second, the number of the studies, especially for -66T>G polymorphism, was not sufficiently large, Third, for -443T>C polymorphism, the heterogeneity was big, the comprehensive analysis should be explain with caution.Some advantage could be highlighted in this meta-analysis. On one hand, this research shed lights on the relationship of genetic polymorphisms in SPP1 may increase the susceptibility of human cancers, while -443T>C mutation is not associated with cancer risk. For -66T>G polymorphism, it may be a protective factor for human cancers. Accordingly, large and well-designed studies are warranted to validate our findings. The populations in this study only came from China. Thus, populations of other ethnicities should be involved in future studies.This meta-analysis indicated that in Chinese population the -156G>GG polymorphism of S1 Checklist(DOCX)Click here for additional data file.S1 Checklist(DOC)Click here for additional data file.


We investigated the associations between lung function and current residential exposure to a range of air pollutants  in London children. Moreover, we placed the results for NO2 in context with a meta-analysis of published estimates of the association.There is widespread concern about the possible health effects of traffic-related air pollution. Nitrogen dioxide  expected under different scenarios of NO2 exposure. In CHASE, there were non-significant inverse associations between all pollutants except ozone and both FEV1 and FVC. In the meta-analysis, a 10 μg/m3 increase in NO2 was associated with an 8 ml lower FEV1 . The observed effect was not modified by a reported asthma diagnosis. On the basis of these results, a 10 μg/m3 increase in NO2 level would translate into a 7% (95% CI: 4% to 12%) increase of the prevalence of children with abnormal lung function.Associations between primary traffic pollutants and lung function were investigated in 4884 children aged 9–10 years who participated in the Child Heart and Health Study in England (CHASE). A systematic literature search identified 13 studies eligible for inclusion in a meta-analysis. We combined results from the meta-analysis with the distribution of the values of FEVExposure to traffic pollution may cause a small overall reduction in lung function and increase the prevalence of children with clinically relevant declines in lung function. Ambient concentrations of urban air pollution comprise a variety of particulate and gaseous pollutants emanating from different sources. Of particular concern in modern cities is pollution from traffic sources, and its possible effects on respiratory health in children –3. Reduc2), previously considered to be merely an indicator of more toxic correlated pollutants, may also have a direct toxic effect on lung tissue [2 is one of the most commonly reported markers of traffic-related air pollution in epidemiological studies [2 can be useful to evaluate the health effects of traffic pollution and possible abatement strategies [Arising from a common source, primary traffic pollutants tend to be highly correlated which makes it difficult to separate the effects of individual pollutants. Until recently, the pollutant of most concern has been particulate matter, itself comprising a complex physicochemical mixture but there is now concern that nitrogen dioxide  project comprises a collaborative investigation into the effects of air pollution and noise on health outcomes ranging across the whole life-span in the London population. Exposure was estimated using fine scale (20x20m) spatial dispersion models of annual average concentrations of both primary traffic pollutants (pollutants which are directly emitted by traffic) and regional/urban background pollutants . Here we report on an investigation linking air pollution exposures with lung function in a large cross-sectional study of lung function in 9–10 year-old children living in London, The Child Heart and Health Study in England (CHASE). The primary hypothesis concerns the effects of near-traffic primary pollutants. We place the results in context by conducting a systematic review and meta-analysis of the published reports on the association between NO1) and other indices were automatically recorded for the “best” test as defined by the American Thoracic Society [1 and FVC. Where the variation between FEV1 and FVC was >5%, a fourth manoeuvre was performed.Full details of CHASE design have been reported elsewhere . Ethical Society , based oParents or guardians living with the child provided information on their home address and postcode and on their occupation(s). Information on parental occupation was coded using the National Statistics Socioeconomic Classification (NS-SEC) , as prev10 and PM2.5  total, exhaust (tailpipe emissions) and non-exhaust (brake and tyre wearing and resuspension), coarse fraction , nitric oxide (NO), nitrogen dioxide (NO2), nitric oxides (NOx), ozone (O3) and total oxidants (Ox), obtained by adding NO2 to O3. The KCLurban model is based on the Atmospheric Dispersion Modelling System (ADMS) v.4 and road source model v.2.3, measured hourly meteorological data, empirically derived NO, NO2, O3 and PM relationships and source emissions from the London Atmospheric Emissions Inventory [Annual average concentrations of air pollutants for all locations in London were estimated at a 20x20m resolution using the KCLurban dispersion model, developed as part of the TRAFFIC project . The modnventory . For linLinear mixed effect models fitting school as a random effect were used to take into account the natural clustering of children within schools. Lung function metrics were included as dependent variables in the different models without transformation. All analyses were adjusted for age, sex, ethnicity, observer, trunk length, indoor room temperature, and month. Secondary analyses were conducted adjusting the estimates also for potential confounding factors including salivary cotinine levels, IMD score, NS-SEC group, sum of skin folds, fat mass index, and having a pet at home.2 and lung function among children or adolescents. The search string is reported in A systematic literature search was conducted in Medline to identify eligible studies published between 1990 and 2015 reporting cross-sectional associations between NOStudy participants were children or adolescents (age 0–18 years).2 levels and FEV1, the most commonly reported lung function parameter in the epidemiological literature [2 and FEF25-75 because too few studies reported estimates for this association. Results from longitudinal studies reporting changes in growth of lung function over time were excluded.The study reported cross-sectional estimates of the association between outdoor NOterature . We chos1 as dependent variable and NO2 levels as a continuous independent variable.The study reported linear regression analyses with either untransformed or natural log (ln)–transformed FEV2 exposure was available at the individual level or, in the case of aggregated data, the analysis was based on measurements on at least three communities.Information on NO2. For this reason, only studies based on an exposure period of at least one year were included.The reported estimates reflected the effect of long term exposures to NO3 increment of NO2. NO2 levels reported in ppb were converted to μg/m3 using the conversion factor adopted by European Commission (1 ppb = 1.91 μg/m3) [Relevant details were extracted from the selected papers. Quantitative estimates and their 95% confidence intervals were standardized to a 10 μg/m1 μg/m3) . Studies1 μg/m3) . The rep1 μg/m3) .2 statistic [We calculated summary effects estimates using random effects models , and hettatistic . Publicatatistic  and throtatistic ,24.x but not for NO2 [2, as previously proposed by Anderson and colleagues [We carried out sensitivity analyses to evaluate the robustness of our estimates. Analyses were replicated excluding the studies pooled in the ESCAPE project. We also conducted the analysis stratifying by method of exposure assessment used (land use regression and dispersion models versus fixed monitoring stations) and asthma status. The ESCAPE project reported only the pooled estimate of effects stratified by asthma status . For thi for NO2 . For thilleagues . We calc2 exposure, as previously reported [2 (40 μg/m3). Then we shifted the distribution of FEV1 in the population, assuming a 10 μg/m3 increase in the levels of NO2 and applying the corresponding effect on FEV1 as estimated by the log-linear model in our meta-analysis. Finally, we calculated the proportion of subjects that would have abnormal values of FEV1 under this second scenario, and we compared the two proportions.A change in the mean values of lung function in the population is not straightforward to interpret in a public health perspective. Indeed, a small reduction in mean physiological measures such as lung function at the population level can translate in a substantial increase in the proportion of subjects with abnormally low lung function ,28. For Analyses were performed with the software Stata 12 . Statistical significance was defined as p < 0.05 for all analyses.Among 7806 London children invited to participate, 4884 (63%) participated in the study, did not change address during the study period and had valid lung function measurements and complete data on covariates. Participants and non-participants were similar in age, but girls and South Asian ethnicity had higher prevalences among participants than non-participants (by 2% and 3% respectively).The participants included similar numbers of boys and girls (2396 and 2488 respectively); their mean age was 9.9 (SD 0.4) years . The stuVariations in exposure to the different pollutants in the study participants are reported in The estimated associations between residential exposure to different pollutants and lung function in CHASE are presented in 2 on lung function was observed  (2 = 32%), principally driven by the study of Lee and colleagues [2 on FEV1 was very small (I2<1%). In a random effects meta-analysis, a 10 μg/m3 increase in NO2 was associated with a small decrease in FEV1  (The search yielded 461 papers . Among tobserved . Among t= 0.016) . There w016) 2 = %, princi= 0.001) . In all 3 increase in NO2 in subjects without a diagnosis of asthma was associated with an 14 ml lower FEV1 . No association was observed for subjects with asthma . A similar pattern was also observed in studies using log-linear models .Several sensitivity analyses were conducted to further evaluate the robustness of the main results. We conducted the analysis stratifying by exposure assessment method (land use regression and dispersion models versus fixed monitoring stations) to evaluate possible heterogeneity of the results. Among studies using linear models, there was no evidence of heterogeneity between the studies using different methods of exposure assessment (p = 0.66). No such analysis could be conducted among the studies using log-linear models, as only one study was based on fixed monitoring stations. However, the exclusion of this study from the meta-analysis did not change the results appreciably. We also did not find evidence of heterogeneity between the studies that were previously included in the ESCAPE project and the other studies (p = 0.30). When we reran the analysis excluding studies from ESCAPE, the estimates were similar to those from the main analysis . Results did not change substantially when we conducted the analysis separately in subjects with and without a diagnosis of asthma. Among studies using linear models, a 10 μg/m1 less than the 80% of the predicted value. According to the results of the meta-analysis, a 10 μg/m3 increase in the levels of NO2 would be associated with a 0.7% decrease of FEV1 in children. The consequent shift in the distribution of the FEV1 values would translate in a 7% increase of the prevalence of children with abnormal lung function, from 4.0% to 12%. In absolute terms, this in turn translates in a difference of 507 children per 100,000.We observed that in the CHASE population, 7.0% children had a FEV2 and FEV1.In the present study, we used data from a large cross-sectional study and from a meta-analysis of published studies to evaluate the association between air pollution and lung function in children. Using CHASE data we found consistent, albeit not statistically significant, inverse associations between levels of primary traffic pollutants and lung function in children. When the results of CHASE were included in a meta-analysis of published studies, we found a statistically significant inverse association between NO2 on lung function. Gotschi and colleagues in their 2008 review of ambient air pollution and lung function reported that the methods of published studies on air pollution and lung function were too varied to allow meta-analysis [2 levels and FEV1, using similar statistical approaches.The analysis based on CHASE data has several strengths. This is one of the largest individual studies conducted so far to investigate the long-term effects of air pollution on lung function in children. An individual level exposure assessment was used to evaluate the role of a number of air pollutants and traffic proximity metrics at residential level. Moreover, data on several possible confounders at the individual and contextual level were available. In particular, exposure to passive smoking and socio-economic status were assessed very accurately in CHASE. In addition to information from questionnaire, passive smoking exposure was assessed measuring cotinine levels among the participants. Socio-economic status was thoroughly assessed both at the individual level, using information on the parental socio-economic position, and at the contextual level, using an index of multiple deprivation of the neighbourhood where the participant lived. However, estimates of the association between the different air pollutants and lung function did not change appreciably after this adjustment . Informaanalysis . Howeveranalysis ; the rem2 was evaluated at the individual level in most of the included studies.The outcome was measured in the studies according to standardized methods . ExposurIt is not possible to exclude that the results of our meta-analysis are due to unmeasured confounding at the level of the individual studies. However we note that, with the exception of the study by Peters and colleagues , all the2 with lung function too small in size to be consistently detected by the individual studies so far conducted. Recent reviews of evidence provide support for an association between NO2 and several respiratory health effects [2 and asthma prevalence in within -community spatial studies [2 can be also associated with subclinical respiratory effects in the population. In this respect, it is noteworthy that in our meta-analysis we found a statistically significant association between NO2 and FEV1 when we restricted the analysis to children without a diagnosis of asthma. Moreover, the association between NO2 and FEV1 among subjects with asthma tended to be weaker rather than stronger. This suggests that the observed effect is not limited to a subgroup of susceptible individuals, but affects the whole population.Our results suggest an association of NO effects . This is studies ,26. Our 2 levels and lung function estimated in our meta-analysis is comparable to that reported for environmental tobacco smoke. Cook and colleagues reported a 1.4% reduction in FEV1 among children exposed to passive smoking at home [3 increase of NO2 would be associated with a similar reduction in lung function. As the entire population is exposed to outdoor air pollution, the potential health impact of air pollution on lung function can be substantial. According to our calculations, a 10 μg/m3 increase of NO2 levels would translate into a 7% increase of the prevalence of children with abnormal lung function. Longitudinal studies following children into adulthood are warranted to evaluate whether these deficits in lung function are compensated by a prolonged growth phase, or whether these individuals maintain a reduced lung function during the whole life [The magnitude of the association between NO at home . Accordiole life .2 per se. Unfortunately, too few studies reported multi-pollutant models to be included in a meta-analysis. This is due to the fact that levels of exposure to the different pollutants are usually very highly correlated, as was also the case in CHASE, and thus multi-pollutant models produce unstable effect estimates. On the other side, if NO2 is considered a proxy of traffic pollution, a single pollutant model can be appropriate. Future integration of the epidemiological evidence with chamber studies and toxicological evidence will help to evaluate whether the observed effect is due to NO2 rather than to other traffic pollutants [One of the main limitations of our meta-analysis is that we used estimates based on single pollutants models. This made impossible to evaluate the effects of NOllutants .Exposure to traffic pollution may cause an overall reduction in lung function. This reduction is expected to increase the prevalence of children with clinically relevant declines in lung function.S1 Appendix(DOCX)Click here for additional data file.S2 Appendix(PDF)Click here for additional data file.S3 Appendix(DOCX)Click here for additional data file.S1 Dataset(TXT)Click here for additional data file.S1 PRISMA Checklist(DOC)Click here for additional data file.S1 STROBE Checklist(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S5 Table(DOCX)Click here for additional data file.S6 Table(DOCX)Click here for additional data file.


ACE) and plasminogen activator inhibitor-1 (PAI-1) gene polymorphisms with diabetic retinopathy (DR) and its sub-clinical classes in Pakistani type 2 diabetic patients. A total of 353 diabetic subjects including 160 DR and 193 diabetic non retinopathy (DNR) as well as 198 healthy controls were genotyped by allele specific polymerase chain reaction (PCR) for ACE Insertion/Deletion (ID) polymorphism, rs4646994 in intron 16 and PAI-1 4G/5G (deletion/insertion) polymorphism, rs1799768 in promoter region of the gene. To statistically assess the genotype-phenotype association, multivariate logistic regression analysis was applied to the genotype data of DR, DNR and control individuals as well as the subtypes of DR. The ACE genotype ID was found to be significantly associated with DR  1.870 [95% confidence interval (CI) = 1.04–3.36]) and its sub-clinical class non-proliferative DR (NPDR) , while PAI polymorphism did not show any association with DR in the current cohort. In conclusion in Pakistani population the ACE ID polymorphism was observed to be significantly associated with DR and NPDR, but not with the severe form of the disease i.e. proliferative DR (PDR).In the present study we determined the association of angiotensin converting enzyme ( Diabetic Retinopathy (DR) is one of the most damaging microvascular complication of diabetes mellitus and remains a major cause of visual morbidity among the developed and under developed countries , 2. BeinPAI-1 was associated with high risk of development of retinopathy, as elevated serum levels of PAI-1 result in dysfunctioning of the endothelium, which could lead to thickening of blood vessels [Angiotensin converting enzyme (ACE), which is a component of the renin-angiotensin system (RAS) plays an important role in the regulation of systemic and renal circulation by converting angiotensin I into vasoconstrictor molecule angiotensin II . A numbe vessels .ACE and PAI-1 polymorphisms in the onset of DR in Pakistani type 2 diabetics, which resulted in the identification of a significant association of a studied polymorphism with the disease.Despite a number of studies the evidence of association of these genes in the development of different multifactorial diseases including diabetes-induced retinopathy remains inconsistent, not only because of the involvement of multifactorial pathways in the pathogenesis of diabetes but also due to genetic diversity among different populations worldwide. Therefore, the present case control association study was conducted to investigate the role of The cases were clinically diagnosed and sampled from Shifa International Hospital (Islamabad), Railway Hospital , Armed Forces Institute of Ophthalmology  and Mayo Hospital (Lahore). The current study was approved by the Department of Biosciences Ethics Review Board, COMSATS Institute of Information Technology, Islamabad, Pakistan. Before taking the blood samples, each participant was informed about the purpose of the study and a written consent in accordance with the guidelines of the Helsinki Declaration was taken. All the patients who participated in the present study belonged to the same ethnic group therefore there was no ethnicity bias in the data. The controls were sampled from the general population to which the cases belonged.The current study was a case-control association analysis. All cases were initially diagnosed for T2DM by a qualified endocrinologist and had T2DM for more than 10 years. Patients were subjected to detailed eye examination  to assess retinopathy. The patients who were negative and positive for retinopathy were classified as DNR and DR, respectively. The inclusion criteria for the patients suffering from T2DM was according to the American Diabetes Association: age 18–75 years, fasting plasma glucose level ≥ 126mg/dl, random plasma glucose concentration ≥ 200mg/dl, serum creatinine concentration ≤ 2.0 mg/dl and glycated hemoglobin 6.5% or higher [Blood samples of patients and controls were collected in 8.5 ml BD vacutainer tubes  containing ethylene diamaine tetra-acetic acid (EDTA) as an anti coagulant. DNA extraction from the lymphocytes was carried out using standard organic phenol-chloroform method .ACE Insertion/Deletion (ID) polymorphism rs4646994 in intron 16 and PAI-1 4G/5G (deletion/insertion) polymorphism rs1799768 in promoter region were genotyped as described previously by Anderson et al. [The n et al.  and Ahmen et al. , respectACE (ID) and PAI-1 (4G/5G) polymorphism were analyzed statistically. The genotype and allele frequencies were compared among cases and controls by using z-test. To assess the association of disease with genotype, logistic regression analysis was performed, while adjusting for age, gender and sub-clinical classes including NPDR and PDR. The analyses were performed using R software (R Core Team (2012). R: A language and environment for statistical computing . Statistically significant p-values obtained from logistic regression analysis were corrected for multiplicity using simultaneous inference. A p-value of ≤0.05 was taken as statistically significant.The genotyped data for both ACE polymorphism rs4646994 was significantly different between DR, DNR and healthy controls. Among the sub-clinical classes the ID frequency was higher in NPDR than PDR. The multivariate-gender adjusted logistic regression analysis resulted in significant association of ID genotype with the development of DR  and the sub-clinical class NPDR , which remained significant even after the correction of the data by simultaneous inference  of the risk allele 4G with the development of DR or any of its sub-clinical types in the studied cohort  and Plasminogen Activator System (PAS), respectively, we observed significant association of ACE polymorphism with DR and NPDR. Worldwide different ACE and PAI-1 SNP based case-control association studies have implicated ethnicity as an important disease susceptibility risk factor [ACE genotype association was found with the onset of DR in Pakistan. These results are contradictory to some of the other studies in which no significant association of ID polymorphism was found with the development and progression of retinopathy in subjects with T1DM and T2DM [ACE ID polymorphism in the Caucasian population when the genotypes of healthy non-diabetic controls were compared with TIDM and T2DM patients suffering from retinopathy including NPDR and PDR [In the current study of Pakistani T2DM subjects genetic association was studied of single nucleotide polymorphisms (SNPs) of k factor , not onlk factor , schizopk factor , cardiovk factor , dental k factor , etc. ACk factor , but patand T2DM , 18. Nagand T2DM  also did and PDR . In addi and PDR  did not ACE ID polymorphism was also found to be significantly associated with NPDR, while no significant association was observed in the case of PDR. This is in contrast to the previously reported significant association of ID polymorphism in Chinese [ACE in the development of the disease at early stages of retinopathy (NPDR), which is in contrast to the other studies, where significant association was found with advanced stages of retinopathy i.e. PDR. A reason for not finding an association of RAS with advanced stages of DR in the current study could be inadequate number of patients in the PDR group or ethnic variations between Pakistani and other populations, in addition there might be other pathophysiological mechanisms along with environmental factors that are also possibly involved in disease pathogenesis. Clinical and experimental studies on the pathophysiological role of RAS in DR underscores vasoconstriction, inflammation, oxidative stress, ischemia, angiogenesis, cell proliferation and fibrosis to be the major tissue responses of retinal microvasculature under hyperglycemic conditions that lead to retinal dysfunction in DR patients [ACE ID polymorphism is involved in the development of retinopathy but probably other factors such as angiogenic pathway e.g. VEGF etc. are involved in disease progression to the more severe form i.e. PDR. This would indicate that retinopathy is not a simple process but probably involves a pathway in which the patient first develops the less severe form of retinopathy NPDR and only develops the more severe proliferative form PDR when other factors like angiotensin II start playing their role in disease progression.However, in the current study because of the significantly higher frequency of heterozygous ID genotype in DR cases as compared to DNR and control, the ID genotype was found to be associated with the susceptibility of development of retinopathy in the Pakistani diabetics. As opposed to this Nikzamir et al.  found th Chinese  T2DM subpatients . The RASpatients . Though patients  and direpatients . VEGF ispatients . Thus itPAI-1 locus influence PAI-1 levels in the serum [PAI-1 was found with the development and progression of retinopathy in subjects with T2DM. Although, the “4G” polymorphism has been previously shown to be associated with higher risk of DR in the Pima Indians [PAS consists of characteristic serine protease activator Tissue Plasminogen Activator (t-PA) and its inhibitor PAI-1, where t-PA is involved in the conversion of plasminogen to plasmin causing degradation of metalloproteinase matrix . PAI-1 ihe serum , 29. In  Indians , but in  Indians , Chinese Indians , Euro-Br Indians , Tunisia Indians , Whites  Indians  and Slov Indians  sufferinACE and PAI-1 from RAS and PAS pathways in the present study indicated possible association of only ACE with DR and NPDR susceptibility but not with PDR.In conclusion, this is the second report of DR genetic association from Pakistan after our first report on PPARγ association with PDR , the scr


Studies on associations between ataxia telangiectasia-mutated (ATM) polymorphisms and late radiotherapy-induced adverse events vary in clinical settings, and the results are inconsistent.We conducted the first meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to investigate the role of the ATM polymorphism rs1801516 in the development of radiotherapy-induced late fibrosis.We searched PubMed, Embase, Web of Science, and Chinese National Knowledge Infrastructure databases to identify studies that investigated the effect of the ATM polymorphism rs1801516 on radiotherapy-induced late fibrosis before September 8, 2015. Summary odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were used to assess the association between late fibrosis and the rs1801516 polymorphism. Subgroup analyses were conducted to evaluate the influence of clinical features on the genetic association. Tests of interaction were used to compare differences in the effect estimates between subgroups.2 = 66.6%, P = 0.002). In subgroup analyses, we identified that the incidence of late fibrosis was a major source of heterogeneity across studies. The OR for patients with a high incidence of late fibrosis was 3.19 , in contrast to 1.09  for those with a low incidence. There was a significant difference in the effect estimates between the 2 subgroups .The overall meta-analysis of 2000 patients from 9 studies showed that the minor allele of the rs1801516 polymorphism was associated with a significantly increased risk of developing late fibrosis , with high between-study heterogeneity (IThis meta-analysis supported previously reported effect of the ATM polymorphism rs1801516 on radiotherapy-induced late fibrosis. This finding encouraged further researches to identify more genetic polymorphisms that were predictive for radiotherapy-induced adverse events. In addition, we showed that the inconsistency of the associations seen in these studies might be related to variations in the incidence of late fibrosis in the patients. This suggested that future studies should consider the incidence of radiotherapy-induced adverse events when investigating radiosensitivity signature genes. For patients treated with radiotherapy, the incidence of late adverse events increases as the radiation dose increases and as the follow-up time increases.4 The first gene that has received significant attention is the ataxia telangiectasia-mutated (ATM) gene.5 The product encoded by the ATM gene functions primarily as a protein kinase involved in cellular stress responses, cell cycle checkpoint control, and DNA repair.6 The ATM protein plays a central role in mediating the cellular response to radiation induced DNA damage such as double-stranded breaks.7 Patients with the disease of ataxia telangiectasia suffer from severe and devastating responses to ionizing radiotherapy.5A substantial amount of work has been performed over the past decade in an effort to identify SNPs that are associated with the development of normal tissue injuries after radiotherapy.8 also known as G5557A. rs1801516, a substitution of asparagine for aspartic acid at amino acid position 1853, is located in ATM exon 39.5 The functional impact of this polymorphism is unclear.5 A recent meta-analysis9 showed no significant association between the rs1801516 polymorphism and radiotherapy-induced adverse events in general. However, the studied adverse events included a variety of different clinical endpoints, involving a variety of different pathological mechanisms. In addition, this meta-analysis showed high unexplained between-study heterogeneity. Therefore, we had a concern about the rationale for combining all clinical endpoints. Another concern for this meta-analysis was an incomplete coverage of studies, including some large studies with appropriate statistical power.11 It is thus unclear whether there is a role of the rs1801516 polymorphism in the development of radiotherapy-induced adverse events. We have found that late fibrosis was the most frequently studied late adverse events (data unpublished). To address this issue, we conducted a meta-analysis of the rs1801516 polymorphism with a single clinical endpoint—late subcutaneous fibrosis.Our previous study indicated that the SNP most frequently studied in the ATM gene was rs1801516,12This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.Ethical approval was not necessary because this study was a systematic review and meta-analysis.Radiotherapy-induced late adverse events included a variety of different clinical endpoints, leading to potential heterogeneity in the analysis of the association between genetic polymorphisms and radiotherapy-induced late adverse events. We had found that late fibrosis was the most frequently studied late adverse events . References from the relevant articles or reviews were also searched for additional studies. In addition, we searched the Internet (www.google.com) for unpublished data. To avoid the use of different names for the same polymorphism, we included all surrogates of the rs1801516 polymorphism in this meta-analysis, including rs17503060, rs52821794, rs60879649 (http://www.ncbi.nlm.nih.gov/snp/), and rs4988023.10A systematic literature search before September 8, 2015 was conducted in Electronic databases . The following search terms were used: (radiation OR radiotherapy) AND (ATM OR ataxia-telangiectasia mutated) AND  in patients, sample size, incidence of late fibrosis, cancer site, length of follow-up, study type (cohort and case–control), number of genotyped cases and controls, and results on the association between the rs1801516 polymorphism and late fibrosis. Data on treatment- and injury-related factors were also collected from each study. Treatment-related factors included surgery and radiotherapy . Injury-related factors included clinical endpoint and diagnosis criterion. Study authors were contacted when there was insufficient information to determine the relationship between the rs1801516 polymorphism and late fibrosis. Disagreement was resolved by discussion between authors.13 It should be noted that deviation from HWE in patients might not point to a sampling bias or mistyping of genotypes, but could be an evidence of association between the genotype and the disease.14 Two authors independently evaluated the quality of each study, with discrepancies resolved during a consensus meeting. Because a summary quality score can lead to bias in the results of a meta-analysis,17 it was not used to weigh the contribution of each study to the meta-analysis. Instead, the study quality was used as a stratification factor in the subgroup analysis to evaluate its influence on the effect size.18Study quality was assessed on the basis of HWE in patients (yes/no), and sample size , adhering to the established criteria.A single primary meta-analysis was performed on all datasets. Subgroup meta-analyses were conducted based on prespecified clinical features, including sample size, ethnicity, HWE in patients, cancer site, incidence of late fibrosis, and period of follow-up. We aimed at determining whether the result of the primary meta-analysis was stable or dependent on the clinical features of the included studies. Sensitivity analysis was conducted by excluding 1 study at a time and analyzing the remaining ones to explore whether the result was influenced by a particular study.2 test to assess deviation from HWE. Because homozygotes and heterozygotes of the rs1801516 polymorphism were grouped together (dominant model) in most included studies, we conducted meta-analyses only under the dominant model. Odds ratios (ORs) and the 95% confidence intervals (CIs) were used to assess the strength of the association between the rs1801516 polymorphism and late fibrosis. The statistical significance of the ORs was evaluated by using the Z test. Between-study heterogeneity was evaluated by using the Cochrane Q test and the I2 statistic. The random-effects model (DerSimonian and Laird method)19 was used to calculate ORs when the P value of the Cochrane Q test was <0.10 or the I2 value was >50%21; otherwise, we used the fixed-effects model. We used the test of interaction proposed by Altman et al22 to compare differences in effect estimates between subgroups. The above statistical analyses were performed by using Stata, version 12, software  with 2-sided P values. Statistical significance was defined as a P value of <0.05.We performed the appropriate goodness-of-fit χ27 were identified to meet the inclusion criteria. In addition, 1 study28 was identified from the references of a review article.29 Our search on Chinese National Knowledge Infrastructure database identified no study that met the inclusion criteria .31 No unpublished data were identified using Internet search (www.google.com). As a result, a total of 9 studies were eligible for this meta-analysis  yielded 1373 studies dated until September 8, 2015. Of these, 1308 studies were irrelevant by title or abstract reading. After full text reading, 39 studies were found to investigate the association between ATM polymorphisms and radiation-induced adverse events. We then excluded studies that reported acute adverse events (n = 3), mixed data on acute and late adverse events (n = 3), combined data on multiple polymorphisms (n = 2), polymorphisms other than rs1801516 (n = 11), and duplicate samples (n = 2). 18 studies were identified to investigate the rs1801516 polymorphism and the risk of developing late adverse events. After further exclusion of studies with nonextractable data (n = 2) and studies on late adverse events other than fibrosis (n = 8), 8 published studies28 2 in United Kingdom,11 1 in Switzerland,25 1 in Saudi Arabia,26 1 in Brazil,27 and 1 in Germany.23 None of these studies stated the ethnicity of the participants . For each study, the endpoint was selected which was judged to reflect late fibrosis most closely. The cut-off to differentiate cases from controls was grade 2 in 5 studies,27 and grade 3 in 2 studies.25 The number of patients within each grade was given in 2 studies.28 Therefore, a grade 2 cut-off was set for differentiating cases from controls in this meta-analysis.These studies were published between 2005 and 2013. 3 out of 9 studies were conducted in the United States,P = 0.026), with high between-study heterogeneity  27 for the minor allele carriers. Notably, the study by Zschenker et al23 had the longest median follow-up of 12 years compared with a median follow-up of no more than 5.2 years in the other studies.28 The subgroup of long-term follow-up (n = 69), including only the study by Zschenker et al,23 had an OR of 0.21 . The genetic effect for studies with short-term follow-up (n = 1931) was significant . The effect sizes were significantly different . Due to the small sample size of the subgroup of long-term follow-up, the result of the interaction test should be considered as exploratory only.Overall, 9 studies with 2000 patients was included in the primary meta-analysis. There was a significant association between the rs1801516 polymorphism and late fibrosis . Similarly, for the incidence of late fibrosis, the cut-off for differentiating high from low incidence was also based on the median of the incidences across all included studies (21%). When subgroup analyses were conducted based on cancer site, sample size, definition of cases, and HWE in participants, high between-study heterogeneity was observed  compared versus the participants with a low incidence . The effect sizes were significantly different .Because the Zschenker et al studyOur meta-analysis of 2000 patients from 9 studies provided evidence of an association between the ATM polymorphism rs1801516 and the risk of developing late fibrosis in cancer patients after radiotherapy. The inconsistent association between late fibrosis and the rs1801516 polymorphism observed in some studies was probably attributable to variations in the follow-up period and the incidence of late fibrosis in the patients.32 In addition, there is a possible existence of gene–survival interactions, which in turn may influence the genetic association. Therefore, for a reliable assessment, patient-to-patient variability due to genetic factors in late tissue injuries has to be evaluated in a small time span.32 In this meta-analysis, the included studies differed significantly in the length of follow-up, which was highly likely to generate heterogeneities. Indeed, the rs1801516 polymorphism was shown to be associated with an increased risk of late fibrosis in the subgroup of short-term follow-up, but with a trend in the opposite direction in the subgroup of long-term follow-up. The result of interaction tests supported a genuine difference in the effect sizes between the 2 groups. However, due to the relatively small number of studies included in the subgroup of long-term follow-up, and this finding should be treated with caution.Our meta-analysis suggested that the length of follow-up might be a factor influencing the observed genetic effect of the rs1801516 polymorphism on late fibrosis in the patients. Late normal tissue injuries typically manifest years after radiotherapy, and this latency–response relationship may be fairly steep in clinical range, which means a small difference in latency can produce divergent outcomes.33 Despite the variability, the association between the rs1801516 polymorphism and an increased risk (significant or nonsignificant) of late fibrosis was also consistently seen across different patient subgroups  of late fibrosis was consistently shown for the minor allele carriers of the rs1801516 genotype across all studies with short-term follow-up Figure . Howeverps Table . The ext8 Late injuries show a dose–effect relationship, which may be steep in clinical range. As a result, a small dose difference can cause a substantial interpatient variability in late injuries.29 It was therefore crucial to determine whether radiation dose was a source of heterogeneity across these studies. However, the radiation dose received by a normal tissue is not straightforward. For a meta-analysis, obtaining complete dose information in individual patients is generally not possible. Because there is a strong correlation between radiation dose and the incidence of late injuries,36 the incidence of late injuries can be used to estimate the radiation dose received by the normal tissue in the patients. Previous studies also demonstrated that an ideal population to identify genetic factors affecting radiosensitivity was patients with a high incidence of radiation injuries.37 Consistently, the results from both our subgroup analyses and interaction tests showed that the incidence of late fibrosis was the major source of heterogeneity across these studies.The genetic effect of the rs1801516 polymorphism on the development of late fibrosis was modified by the incidence of late fibrosis in the patients. This result was in agreement with a recent meta-analysis on the association between the rs1801516 polymorphism and acute radiotherapy-induced adverse events.38 However, meta-anlayses based on summary data are often consistent with those based on IPD,39 and should not be viewed as “inferior.”40 Clearly, further analyses using IPD should be conducted to assess main genetic effects as well as interactions between covariates and genetic effects. The publication bias was not tested by the funnel plot due to heterogeneity observed in this meta-analysis, for tests to assess publication bias is unreliable when there is heterogeneity in the meta-analysis.41 However, small studies did not show significantly larger effects than large studies. In addition, according to the Venice criteria that had been developed to assess cumulative evidence of genetic associations, a small OR (OR < 1.15) might be vulnerable to biases .43 Our primary meta-analysis showed an OR of 1.78, indicating that this genetic effect was not so vulnerable to biases. Except for the dominant model, other genetic models  were not examined because of the limited information in the included studies. Therefore, the most appropriate genetic model for the genetic association could not be determined. None of the included studies reported subgroups based on tumor stage or tumor subtype, so sources of between-study heterogeneity were not able to be investigated by stratifying analyses accordingly. However, the results of our subgroup analyses showed that majority of the heterogeneity was explainable by the incidence of late fibrosis in the patients.There were a number of possible weaknesses in this meta-analysis. The sample size was small for some subgroup analyses , and the interpretation of these results should be taken carefully. This meta-analysis was based on summary data and not on individual patient data (IPD). An IPD-based meta-analysis is able to give an effect estimate that is adjusted for covariates.After a decade of extensive research on this issue, this meta-analysis found strong evidence of an association between the ATM polymorphism rs1801516 and late fibrosis in patients after radiotherapy. This finding may be an important step toward personalized radiotherapy. Next, we will make an effort to obtain more genetic indicators, and our ultimate aim is to integrate genetic information to optimize radiotherapy. In addition, we found that the observed genetic effect of the rs1801516 polymorphism might be modified by the incidence of late fibrosis in patients. This suggested that future studies should consider incidence of radiotherapy-induced adverse events as a key factor when assessing radiosensitivity signature genes.


Evidence has shown that single nucleotide polymorphism located in pre-miRNA or mature microRNA may modify various biological processes and affect the processing of carcinogenesis. Published results about the association between miR-146a rs2910164 G/C polymorphism and human gastric cancer susceptibility are inconclusive. The aim of this study was to acquire a more precise effect of the association between the miR-146a rs2910164 polymorphism and gastric risk by meta-analysis.Eligible genetic association studies were searched from PubMed, Web of Knowledge and Chinese Biomedicine Database on human subject. Quantitative data synthesis was conducted for the associations of miR-146a rs2910164 G/C polymorphism with susceptibility to gastric cancer.Nine eligible studies that included a total of 3,885 gastric cancer patients and 5,396 controls were identified in the present meta-analysis. The overall OR indicated a potential association between rs2910164 polymorphism and GC but the effect was not statistically significant . When stratifying for population, the result showed that miR-146a rs2910164 GG genotype was associated with increased gastric cancer risk among Chinese in recessive model . Besides, no significant difference was found in gender, smoking, location, metastasis of lymph node and Laurèn’s classification.The present meta-analysis suggests an increased risk between miR-146a rs2910164 GG genotype and gastric cancer susceptibility in Chinese based on published literatures. Gastric cancer (GC) is still one of the most common causes of cancer-related death worldwide despite an overall decrease in incidence over the past 10 years . It is gMicroRNAs (miRNAs/miR) are endogenous 18–24 nucleotide noncoding RNAs that could regulate gene expression and sequentially regulate various biological processes ,4. FunctStudies have shown that the polymorphisms in pre-miRNA or mature microRNA may modify various biological processes by influencing the expression and/or target selection of microRNAs ,9. Over A number of studies were published to describe the association between miR-146a rs2910164 G/C polymorphism and cancer risk in recent years. A meta-analysis reported by Lian et al. . A HuGE However, published data on the association between miR-146a rs2910164 G/C polymorphism and human gastric cancer susceptibility are inconsistent and inconclusive. Therefore, we performed the present meta-analysis to quantitatively estimate the association of miR-146a G/C SNP with gastric cancer risks.Electronic databases including PubMed, Web of Knowledge and Chinese Biomedicine Database (CBM) were searched for relevant studies conducted on human subject until July 2014. The following search keywords were used: “gastric” or “stomach”, “neoplasm” OR “carcinoma” OR “cancer” OR “tumor” OR “adenocarcinoma” and “miR-146a OR “miRNA-146a” OR “microRNA-146a” OR “has-miR-146a”. To further identify potentially relevant studies, the reference lists of articles identified in the initial search were also scanned manually. We directly contacted authors for related data that were unavailable in the original publications.Studies were considered eligible if they met all of the following criteria: (1) explore the association between miR-146a polymorphism and human GC risk, (2) design as case–control studies, (3) identification of gastric cancer cases was confirmed histologically or pathologically. Studies were excluded based on any of the following reasons: (1) no sufficient data reported, (2) articles of letters, reviews, case reports, conference abstracts, editorials or expert opinion. If serial studies of the same population from the same research group were published, only the largest series were selected.The final set of articles was assessed independently by two reviewers (Zhong Xu and Lingling Zhang) according to the inclusion criteria listed above. Disagreements were resolved by discussion. The following information was retrieved from each report: first author, publication year, study population, ethnicity, number of GC cases and controls, frequency of genotypes, and genotyping method.2 test in each study (P <0.05 was considered as significant disequilibrium in the control group). The strength of the association between GC and the miR-146a rs2910164 polymorphism was assessed by calculating odds ratio (OR) with 95% confidence interval (CI). The pooled ORs were obtained from combination of single studies by homozygote comparison (GG vs. CC), heterozygote comparison (CG vs. CC), dominant and recessive models , allele comparison (G vs. C), respectively. The analysis of heterogeneity between studies was determined by using the Cochrane’s Q test and I2-test  [P <0.05 was considered representative of statistically significant publication bias) [Hardy–Weinberg equilibrium (HWE) status was examined by Pearson’s goodness-of-fit χgeneity) . When thon bias) ,22. StatA total of 288 articles were identified from the PubMed, ISI and CBM database. The flow chart summarizes the literature review process as shown in Figure PQ-test <0.1, I2 > 50%). The pooled OR estimates of the meta-analyses were often greater than 1.00, indicating a potential association of rs2910164 polymorphism and GC although this effect was not statistically significant. For recessive model, as PQ-test <0.1 by heterogeneity analysis, also the random-effects model was used for analysis. As shown in Figure The summary of this meta-analysis for the association between miR-146a rs2910164 G/C polymorphism and the susceptibility of gastric cancer were shown in Table However, as shown in Table We use one-way sensitivity analysis to evaluate the stability of the result in China . In receP = 1.000 and 0.355, respectively). The funnel plots showed some asymmetry, which is probably due to the limited number of studies.Begg’s funnel plot Figure  and EggeMiR-146a has been shown to play an important role in cell proliferation, differentiation, apoptosis and tumorigenesis -37. StudStill why we performed this meta-analysis concerning the miR-146a polymorphism in gastric cancer susceptibility? Firstly, as shown in Table Focused on rs2910164 SNP and gastric cancer, the present meta-analysis showed that the miR-146a GG genotype was associated with increased risk of gastric cancer in China subgroup in recessive model (pooled OR = 1.193). There were no significant differences in gender, smoking, location, metastasis of lymph node and Laurèn’s classification across genotypes.Of the nine studies included, studies by Zeng et al.  and ZhouThe results should be interpreted with carefulness because of several limitations. First, the limited patient numbers may have influence the outcomes. Although we conducted comprehensive literature research from multiple databases with no restriction in publication languages, dates, ethnicities and other factors, there were only a total of nine studies involving 3,885 gastric cancer cases and 5,396 controls for the present meta-analysis. The overall OR indicated a potential association between rs2910164 polymorphism and GC but the effect was not statistically significant. It is still hard to make a firm conclusion about the accuracy of association between miR-146a rs2910164 G > C polymorphism and gastric cancer susceptibility. Second, we use one-way sensitivity analysis to evaluate the stability of the meta-analysis and the result altered when omitting the study with the largest samples. Third, only a few included researches reported data of interactions between miR-146a polymorphism and clinicopathological characters in gastric cancer, and all of the pooled analysis of interactions was limited by small sample size and deficit of data.In conclusion, the present meta-analysis suggests an increased risk between miR-146a rs2910164 GG genotype and gastric cancer susceptibility in Chinese based on published literatures. Further studies on a large scale may be needed to confirm the genetic susceptibility of miR-146a rs2910164 in gastric cancer.