Studies suggest that the 9p21-3 locus may influence susceptibility to myocardial infarction. We performed a systematic review and meta-analysis to assess whether this locus is associated with severity of coronary atherosclerosis and adverse clinical outcomes in those with known coronary disease.Multiple electronic databases were searched from inception through August 2012. Studies examining 9p21-3 genotype in patients with known coronary artery disease were included. We extracted the association of the 9p21-3 locus with measures of severity of coronary atherosclerosis , angiographic outcomes [change in minimum lumen diameter (∆MLD) and number of new lesions at follow-up], and key clinical outcomes . Relative risks (RR) and weighted mean difference (WMD) were pooled using the random effects models.23 cohorts enrolling 16,860 participants were analyzed. There was no significant difference between HR and LR genotypes in terms of all-cause mortality, recurrent myocardial infarction or the frequency of coronary revascularization. HR genotype was associated with increased risk of triple vessel disease  and increased baseline Gensini Score . However there was no association with DPI . HR genotype did not predict ∆MLD or number of new lesions at follow-up.Patients of coronary atherosclerosis who carry the high risk genotype of the 9p21-3 allele may be more likely to have multi-vessel CAD. However the effect of this allele on CAD progression and disease specific clinical outcomes are not observed possibly due to diminishing genetic risk following dietary modification and therapy. Coronary artery disease (CAD) remains a worldwide leading cause of mortality. Modification of major environmental risks such as smoking and high cholesterol reduces CAD mortality by 20% to 30%. The preGenome wide association studies (GWAS) have identified over 30 risk variants for CAD. Of thesWe therefore conducted a systematic review and meta-analysis of the published literature investigating the association of the 9p21-3 locus with angiographic CAD severity, progression, and key clinical outcomes.The reporting of this systematic review complies with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.Eligible studies were comparative studies of human subjects, provided genotyping was done at the 9p21-3 locus in a population with known coronary artery disease . Applicable study designs included observational studies  where an association between the 9p21-3 allele and poor outcome or prognostic marker was reported. Only studies written in English were included due to feasibility.We searched Ovid MEDLINE from 1948 until August 2012 and Ovid EMBASE, Web of Science and SCOPUS, from inception to August 2012. Subject headings  were used: Chromosomes, Pair 9, Coronary artery disease, alleles and atherosclerosis. Keywords (9p21*) were used in Web of Science and Scopus. The detailed search strategy is attached in Additional fileA team of two trained reviewers independently screened all articles identified in the literature search. Discrepancies between the reviewers were resolved through discussions and consensus.Markers of atherosclerotic severity included number of diseased vessels, Gensini Score and Duke CAD Prognostic Index (DPI). Markers of atherosclerotic severity and coronary disease progression are defined elsewhere. We alsoRecurrent MI was defined any acute coronary syndrome associated with troponin elevation and/or ST segment elevation on electrocardiography (ECG). Need for coronary re-vascularization included surgical and percutaneous procedures performed either at target or non-target coronary vessels.We extracted details on sample size, mean age, race, the identification (rs number) of the particular SNP genotyped, and outcomes of interest. SNPs previously reported in GWAS studies or in strong linkage disequilibrium with them were considered in the analysis.In keeping with our goal to determine locus-outcome association we did not limit our analysis to a single SNP but instead tested for all available SNPs published in reports chosen for the meta-analysis. In studies reporting > 1 SNP-outcome association, we chose the SNP not elsewhere tested in other data sets. This allows us to capture all known markers in the locus and test as many markers as possible.We used the Newcastle-Ottawa Quality Assessment to assess the risk of bias of the included studies. The folGenotypes were classified as either homozygous low risk (LR) heterozygous intermediate risk (IR) or homozygous high risk (HR). Study results were variedly reported using recessive [LR vs. (IR + HR)], dominant [(LR + IR) vs. HR)] and additive models [LR vs. IR vs. HR]. For the purpose of this manuscript we included additive models. For dichotomized outcomes, we extracted or calculated relative risk (RR) and its 95% confidence intervals (CI). We then pooled RR across the studies using the DerSimonian and Laird random effects methods with the heterogeneity from the Mantel–Haenszel method. For conWe assessed the optimal information size (OIS), similar to power calculation in clinical trials, to evaluate the minimum sample size required in the literature to reach reliable conclusions.I2 statistic, where I2 > 50% suggests a high level of heterogeneity[We assessed the consistency of the outcomes by testing heterogeneity using the ogeneity. All staThe literature search yielded 229 studies of which 21 (describing 23 distinct cohorts) met criteria for inclusion. Study selection process is described in  . Table Likewise, no significant association emerged in the meta-analysis of 9p21-3 with recurrent MI in patients with known CAD in the additive model .Four cohorts from 3 studies reported need for re-vascularization. No significant association was identified between 9p21-3 and re-vascularization after development of CAD .The meta-analysis supported an association between 9p21-3 and triple vessel disease. Homozygotes (HR) for the risk allele had significantly greater risk . However the DPI which also quantifies CAD severity was not significant in the combined analysis of the two studies reporting it .Three studies reported severity of CAD as measured by Gensini score at baseline. Combined analysis of these studies showed 5.30 higher mean Gensini score in the LR group vs. the HR group. This difference was significant  and new lesions at follow up was 0.03 .Combined analysis of two studies testing for association of angiographic progression as measured by Δ MLD and number of new lesions at follow-up revealed no association with the 9p21-3 allele. The combined WMD for Δ MLD was 0.07 (95% CI −0.02-0.15; p = 0.15; IIn this meta-analysis of studies investigating angiographic severity and clinical outcomes in patients with CAD, we found an association of 9p21-3 allele with increased risk of triple vessel disease and greater quantitative severity of atherosclerosis as measured with the Gensini score at baseline. The meta-analysis did not support an association of the allele with angiographic outcomes at follow up or clinical outcomes.Our findings are consistent with the results of Chan et al. who repoWe found no association between the 9p21-3 allele and angiographic outcomes. This was also unexpected as the process underlying de-novo atherogenesis would remain unchanged over the course of time. One likely explanation can be index event bias. ConceivWe found no association between genotypic risk and all-cause mortality among CAD patients. This negative finding is supportive of existing evidence published by Ganna et al. which shMost GWAS showing locus-disease association, have shown positive results in conditions which are observed to be heritable. Given that there is no published study reporting heritability of the risk of re-infarction, the genetic risk of recurrent events among survivors of ACS remains less probable; an observation noted in our meta-analysis. Likewise in the case of TLR, which could result either from progression of atherosclerosis or recurrent acute ischemic events, we anticipated no association given the absence of increased risk of disease progression and re-infarction among 9p21-3 carriers.Our study suffers some important limitations. First, we cannot rule out that our findings may be due to chance as multiple testing had been conducted. However, there is no consensus when this problem should be taken into account and which statistical method should be used in meta-analysis,39. SecoPatients of CAD who carry the high risk genotype of the 9p21-3 allele may be more likely to have multi-vessel CAD. However the effect of this allele on CAD progression and disease specific clinical outcomes are not observed possibly due to diminishing genetic risk following dietary modification and therapy.CAD: Coronary artery disease; GWAS: Genome wide association studies; MI: Myocardial infarction; PRISMA: The preferred reporting items for systematic reviews and meta-analyses statement; DPI: Duke CAD prognostic index; ∆ MLD: Change in minimum lumen diameter; ECG: Electrocardiography; LR: Homozygous low risk; IR: Heterozygous intermediate risk; HR: Homozygous high risk; WMD: Weighted mean difference; RR: Relative risk.The authors declare that they have no competing interests.MM and ZW contributed equally to this study. MM carried out study design, study screening, data extraction, and drafted the manuscript. ZW carried out study design, quality appraisal, data analysis, and drafted the manuscript. FA participated in quality appraisal and critically revised the manuscript. MS conducted data extraction, drafted and critically revised the manuscript. PE designed the search strategy and revised the manuscript. IK carried out study design, advised on all methodological issues, drafted and critically revised the manuscript. MHM participated in study design, advised on all methodological issues, drafted and critically revised the manuscript. All authors approved the final version of this manuscript and agreed to be accountable for all aspects of the workThe pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2350/15/66/prepubSearch Strategy.Click here for file


Upon reviewing our recently published review , we discPlease replace:P = 0.01).A separate analysis using only CBT-based interventions yielded a significant SMD of 0.12 .(Page 5: Results. Overview of search results and included studies)Please add the following text at the end of the second paragraph:However, upon closer inspection two studies ,3 were fPlease replace:Figure 2 presents the SMDs at post-test and the pooled mean effect size using the random effects model (REM), for the nine studies included in the meta-analysis. The overall mean difference between the intervention and control groups was 0.16 , with effect sizes varying from small negative effects (d = −0.01) to moderate positive effects (d = 0.61). No heterogeneity was detected . As noted above, more than half of the included studies (n = 5) examined the impact of interventions based on CBT. A separate meta-analysis including only CBT-based intervention studies was conducted, the results of which are presented in Figure 3. The overall mean difference between CBT-based interventions and the control groups was 0.12 , indicating a positive effect for CBT-based interventions. There was no evidence of heterogeneity in this analysis .With the amended text:Figure 2 presents the SMDs at post-test and the pooled mean effect size using the random effects model (REM), for the eight studies included in the meta-analysis. The overall mean difference between the intervention and control groups was 0.17 , with effect sizes varying from small negative effects (d = −0.01) to moderate positive effects (d = 0.61). No heterogeneity was detected . As noted above, more than half of the included studies (n = 5) examined the impact of interventions based on CBT. A separate meta-analysis including only CBT-based intervention studies was conducted, the results of which are presented in Figure 3. The overall mean difference between CBT-based interventions and the control groups was 0.12 , indicating a small effect, of borderline statistical significance, for CBT-based interventions. There was no evidence of heterogeneity in this analysis .Please delete:When analyzed separately universally delivered CBT-based interventions significantly reduced levels of depressive symptoms among workers.(Page 10: Conclusions)Please replace:Specifically, workplace CBT-based interventions are effective at universal symptom reduction for depression.With amended text:There is emerging evidence that workplace CBT-based interventions are likely to be effective at universal symptom reduction for depression.


Seventeen articles were included in the systematic review and thirteen studies were taken into account in the meta-analysis. Combined estimated were calculated separately according to whether the exposure metric was continuous or categorical. Only one significant combination was; NO2 concentrations were significantly associated with coarctation of the aorta ). This finding could stem from strong heterogeneity in study designs. Improved exposure assessment methods, in particular more accurate spatial measurements or modeling, standardized definition of cases and of better control of confounders are highly recommended for future congenital anomalies research in this area.Congenital anomalies are the main causes of preterm and neonatal mortality and morbidity. We investigated the association between congenital anomalies and mothers’ exposure to air pollution during pregnancy by combining risk estimates for a variety of air pollutants (SO Due to industrial emissions, urbanization and transport of goods and people by fuel-engine motor vehicles, air pollution affects everyone in developed and developing countries. Common pollutants such as nitrogen oxide  for sulfur dioxide (SO2), 10 μg/m3 for particulate matter with diameter less than 10 μm (PM10) and to an increase of 1 part per million (ppm) for carbon oxide (CO), and 5 part per billion (ppb) for ozone (O3) and 10 ppb nitrogen dioxide (NO2). Key features and definitions of exposure of each study are detailed in The methodology adopted has been described in detail in the previous published review . Meta-antegories . OtherwiA literature search was conducted in the PUBMED database in order to select articles published between January 2011 and January 2014. The search strategy followed the PRISMA guidelines . The keyWe selected measures from the adjusted models presented in each study. Odds ratios and similar metrics relating outcomes and pollutants were extracted. For cohort studies, we used risk ratios since the two ratios give equivalent results when the outcome is rare. In addition, the period of exposure during the pregnancy has been taken into account since the pregnancy weeks 3–8 constitute the critical window of exposure for embryogenesis; later exposures may not contribute to the etiology of major congenital anomalies .p-value higher than 0.1. In contrast, random effects models were used for p-values lower than 0.1. Following Higgins et al. [2 between 25%–50%, moderate between 50%–75%, and high for >75%, where I2 is defined as the percentage of variation attributable to heterogeneity. Forest plots were generated to illustrate the combined risk estimates. Statistical analysis was performed using STATA 11 .Heterogeneity was assessed for pollutant-congenital anomaly outcomes by using the Cochrane Q-test. Fixed effect models were used when the result of the Q-test gave a heterogeneity s et al. , a low hn = 14); it was not included in the meta analysis [Seventeen articles met the inclusion criteria for the systematic review, and the characteristics of each study are shown in analysis .Most studies used a population-based case-control design, selecting cases from clinical or autopsy reports. Controls were randomly selected from birth registries. Cases included live birth, stillbirth or termination of pregnancy after a congenital anomaly diagnosis. One study collected only newborns with diagnosis of congenital anomalies . Two stui.e., SO2, NO2, PM10, PM2.5, CO and O3 in most studies. Total suspended particulate (TSP), NO, NOx and black smoke were assessed in a small number of studies. Pollutant concentration distributions are shown in Mother residence concentration estimates from air quality monitoring networks were frequently used for exposure assessment. Average concentrations of pollutants during the first or the first two months of pregnancy were calculated from the nearest monitors. The distance from monitors to maternal residence varied among studies, from 10 km to a maximum of 50 km. Classical air pollutants were measured, 2, for which random effects models were applied. Heterogeneity varied between 0% and 93.4%, which indicated that the measurement methods, sample property and characteristics varied among and within different congenital groups.We conducted the meta-analysis for 21 combinations of air pollutants and congenital anomalies when at least four studies were available for the same combination. Heterogeneity tests (the Q-test) indicated four combinations with high values of I2 and the risk of coarctation of aorta ), which is in accord with the previous meta-analysis [Regarding cardiovascular anomalies, 16 combinations of pollutants-cardiac anomalies could be included in the meta-analysis . In all,2 whose result is presented in For oro-facial clefts, seven articles were included in the meta-analysis, with one study exhibiting a statistically significant association : the OR 2 ). Our meta-analysis did not reveal any other significant association for cardiac anomalies and oral-facial defects, which is in coherence with the previous meta-analysis published in 2010 by Vrijheid et al. [Congenital anomalies are the leading cause of neonatal mortality. The prevalence in France reported by the national health surveillance institute is equal to 3.3% . In thisd et al. .2, SO2 and the tetralogy of fallot ; and OR per 1 ppb SO2 = 1.04, 95% CI (1.00–1.08), respectively) and coarctation of aorta ; OR per 1 ppb SO2= 1.04; 95% CI (1.00–1.08)). We did not undertake the meta-analysis for these combinations because the number of studies was small. In the present work, we chose to realize two-separate meta-analyses according to the type  of the exposure variable, not to introduce too much heterogeneity in the meta-estimates, whereas Vrijheid et al. converted all continuous to categorical variables in order to increase their statistical power.However, these authors revealed a significantly increased risk between exposure to NOThe present meta-analysis has several limitations. The first one deals with the sample size. Most of the combined effects were computed with about five studies; we did not try to compute combined effects for less than four studies. There was, however, a large total number of cases included in the meta-analysis , that provided enough statistical power to reveal significant associations. The numbers of cases and controls of each study are reported in Secondly, we found differences in the methodologies adopted in the 17 individual studies included in the present review, which make difficult the comparisons and assessment of the combined effects. Certain studies relied on measurement of air quality at the birth residence ,32,33,36et al. study [et al. [Different classifications of congenital anomalies also yield some heterogeneity. Specific definition of defects could ease detection of significant associations. Ventricular septal defects are the most common congenital subgroups that were studied and a variety of classifications were found. For example, ventricular septal defects were classified into three subgroups  in the Padula l. study , accordi [et al. , whereas [et al.  or only  [et al. ,29,32,36 [et al. ,32,36; wConfounding factors included in the individual studies are an additional problem. Few confounders, such as smoking , parentaet al. [The different methods used in the studies, such as case and control definition, exposure assessment and confounding factors as all mentioned earlier, could damage the quality level of each study included in the meta-analysis and consequently the quality of the combined estimates. Assessing the quality of studies is important to understand properly each study to be used in meta analysis. It would be interesting to use the Newcastle-Ottawa Scale (NOS)  followedet al.  in orderLanguage selection may also bias the data basis. Non-English publications of relevant articles may have been ignored. Moreover, the risk of publication bias is inherent in systematic literature review. Unpublished results  may distort the meta-analysis findings. So far, the two meta-analyses (the one published in 2010 and the present one) tend to suggest an adverse effect of air pollution on at least one type of birth defects, and this call for further studies in order to confirm the finding. We failed to assess publication bias by using funnel plots. According to the recommendations from Cochrane Handbook for Systematic Reviews of Interventions , there sAir pollutants could directly exert adverse effects as pro-oxidants binding to lipid and proteins, therefore promoting oxidative stress and the production of free radicals, a process that may elicit a variety of diseases or defects . This oxAir pollution is a universal issue. Therefore, a small increase in risks may lead to serious public health problems. Congenital anomalies are the main causes of preterm and neonatal mortality and morbidity. Meta-analysis is an appropriate tool to enhance statistical power in the analysis of weak associations. It might shed new light on the association between air pollution and congenital anomalies insofar as new studies are conducted that overcome the limitations discussed in the present literature review. Improved exposure assessment methods, in particular more accurate spatial measurements or modeling, standardized definition of cases and accommodation of known or putative confounders are highly recommended for future congenital anomalies research on the effect of air pollution.


Background. The associations between the Fractalkine receptor (CX3CR1) gene T280M (rs3732378) and V249I (rs3732379) polymorphisms and atherosclerosis (AS) risk are conflicting. The aim of this meta-analysis was undertaken to assess their associations. Methods. PubMed, Embase, Web of Science, Medline, Cochrane database, and CNKI were searched to get the genetic association studies. All statistical analyses were done with Stata 11.0. Results. Twenty-five articles involving 49 studies were included in the final meta-analysis. The analysis showed that the 280M allele carriers of the CX3CR1 T280M polymorphism decreased the risk of AS and coronary artery disease (CAD) in the heterozygous state but increased the risk of ischemic cerebrovascular disease (ICVD) in the homozygote state. The 249I allele carriers of the CX3CR1 V249I polymorphism decreased the risk of AS and CAD in the heterozygous state. The V249I-T280M combined genotype VITM and IITM also decreased the risk of AS. Conclusions. The present meta-analysis suggests that the CX3CR1 T280M and V249I polymorphisms are associated with the susceptibility to AS. However, the results should be interpreted with caution because of the high heterogeneity in the meta-analysis. Atherosclerosis (AS) is a multifactorial, progressive disease and a major global cause of morbidity and mortality. Atherosclerosis-related cardiovascular diseases, such as coronary artery disease (CAD), acute myocardial infarction (AMI), and ischemic cerebrovascular disease (ICVD), are the causes of death in almost 50% of cases in developed countries . The exa CX3CR1 in the inflammatory process, the mutations in the CX3CR1 may also play a significant role in the development of atherosclerotic diseases. Recently, a number of molecular epidemiological studies have been done to evaluate the associations between the CX3CR1 gene polymorphisms (T280M and V249I) and the risk of atherosclerotic diseases [ CX3CR1 T280M and V249I polymorphisms and CAD and demonstrated that the CX3CR1 280M allele was associated with a reduced risk of CAD in the heterozygous state and 249I-280M haplotype had a atheroprotective effect on CAD. However, they just studied the 280M allele and 249I-280M haplotype of CX3CR1 in Caucasians. Considering the meta-analysis only focused on the association of the CX3CR1 polymorphism with the single atherosclerotic disease, we, therefore, performed this meta-analysis of all the studies available now to get a more precise estimation of the associations between the CX3CR1 T280 M (rs3732378) and V249I (rs3732379) polymorphisms and overall AS risk.It has recently been accepted that AS is predominantly an inflammatory process , 33 and diseases –31. Howediseases  performeThis meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) criteria . Eligibl CX3CR1 T280M and V249I polymorphisms and AS risk; (2) published studies with full text articles; (3) sufficient published data for calculating odds ratios (ORs) with their 95% confidence intervals (CIs); (4) study population being adults; (5) the diagnosis of ischemic heart disease (CAD and AMI) being accorded with the result of coronary angiography, criteria of World Health Organization (WHO), criteria of European Society of Cardiology (ESC), or criteria of American College of Cardiology/American Heart Association (ACC/AHA); the diagnosis of ICVD is accorded with result of computed tomography (CT) or magnetic resonance imaging (MRI); the diagnosis of carotid atherosclerosis (CAA) was assessed by ultrasound color Doppler (USCD), and peripheral arterial disease (PAD) was diagnosed by the following criteria: clinical symptoms of PAD  accompanied by an ankle-brachial-index and significant stenosis of leg arteries confirmed by FCDS and/or angiography.To be included in the present meta-analysis, the studies had to comply with the following major criteria: (1) case-control or cohort studies evaluating the associations between theStudies were excluded if they were (1) review or meta-analysis; (2) not conducted in humans; (3) duplicate studies.Data, including name of the first author, year of publication, study population , study type (case-control and cohort study), type of atherosclerotic disease, source of controls , sample size , and number of genotypes in cases and controls, were extracted from each study by two reviewers independently (JW and QZL) according to the prespecified inclusion criteria. Studies that reported a comparison of two case samples, such as different age groups, were included in the meta-analysis as independent studies. Decisions were compared and disagreements about study selection were resolved by consensus or by involving a third reviewer (RXY).The quality of the individual studies was evaluated and scored by two reviewers independently based on the Newcastle-Ottawa Scale (NOS) . Each stGRADE  approach was adopted to grade quality of evidence for each association . The GRAP < 0.05 was considered significant deviation from HWE). We performed a haplotype analysis based on the genotype data, the haplotype frequencies were calculated by CubeX analysis software for each study separately and for the whole sample [ CX3CR1 T280M and V249I polymorphisms and AS risk was assessed by ORs with 95% CIs. The pooled ORs were performed for dominant model , recessive model , codominant model , additive model , and allelic model . Bonferroni correction was used to control for the multiple testing in view of five genetic models under investigation (significance was set at 0.05/5 = 0.01), then another statistical significance was set as P < 0.05.For the controls of each study, Hardy-Weinberg equilibrium (HWE) was assessed using the chi-square test (e sample . The strQ statistic (PQ) and the I2 statistic. Values for PQ < 0.10 and I2 > 50% indicate a presence of heterogeneity among studies [Heterogeneity across individual studies was calculated using Cochran's  studies , 50, andP < 0.05 was considered representative of statistically significant publication bias). The analyses were performed using Stata software11.0 .Sensitivity analyses were performed based on HWE (studies without HWE were excluded) and NOS score (studies with score ≤ 6 were excluded). Begg's funnel plot and Egger's regression test were conducted to identify possible publication bias in the current meta-analysis . When we performed a subgroup analysis, there was significant association between T280M polymorphism and the susceptibility to AS in the CAD group in dominant model (P < 0.01), codominant model (P < 0.01), additive model (P < 0.01), and allelic model (P < 0.01), but not in recessive model (P > 0.01), suggesting that the 280M allele carriers decreased the risk of CAD in the heterozygous state. The significant association between T280M polymorphism and the susceptibility to AS was also found in the ICVD group in recessive model (P < 0.01) and additive model (P < 0.01), but not in dominant model (P > 0.01), codominant model (P > 0.01), or allelic model (P > 0.01), suggesting that the 280M allele carriers increased the risk of ICVD in homozygote state. Then, we considered the TT genotype as the baseline risk, we found TM genotype was a protective role for AS , codominant model (P < 0.01), additive model (P < 0.01), and allelic model (P < 0.01), but not in recessive model (P > 0.01), suggesting that the 249I alleles decreased the risk of CAD in heterozygote state. Significant associations were also found between this variant and the susceptibility to AS in the population-based (PB) group in recessive and additive models (P < 0.01 for each). Then, we considered the VV genotype as the baseline risk; we found VI genotype was a protective role for AS  and IITM genotypes , suggesting that the VITM and IITM genotypes were protective roles for AS (For V249I-T280M combined genotype (Table S2), when we took VVTT genotype as a baseline risk, significant discrepancies were found in VVTM genotype .There were nine combined genotypes in Table S2; six studies identified the extremely rare VVTM genotype. Linkage disequilibrium (LD) analysis showed a strong association between the T280M and V249I polymorphisms . ThirteeP < 0.001; P = 0.14; Haplotype frequencies of each study and the total sample are reported in  CX3CR1 T280M polymorphism or for the V249I polymorphism. This suggested that the overall results of this meta-analysis were statistically robust. The main results of sensitivity analyses are shown in Sensitivity analyses were conducted to determine whether modification of the inclusion criteria of the meta-analysis affected the final results. The included studies were limited to those conforming to HWE or the high quality studies (NOS score ≥ 7); the corresponding pooled ORs were not materially altered, either for the CX3CR1 T280M and V249I polymorphisms, significant heterogeneity existed in the overall comparisons in five genetic models. We performed subgroup analyses based on the ethnic (Caucasians and Asian), atherosclerotic diseases , and source of control ; heterogeneity was distinctly reduced; although it was still significant, we could not point out other possible sources of heterogeneity. The data were shown in Table S3.For bothPQ < 0.1, I2 = 69.2%). When the 249V-280T haplotype was taken as the baseline risk, we showed obvious heterogeneity in the 249I-280 M haplotype . For the CX3CR1 V249I polymorphism, no obvious asymmetry was observed in any genetic model according to the visual assessment of funnel plot .Begg's funnel plot and Egger's regression test were performed to assess potential publication bias. For thenel plot  displaysnel plot . The res CX3CR1 polymorphisms and AS risk were included in the final meta-analysis. According to the GRADE approach, the quality of the evidence of CX3CR1 T280M polymorphism was very low in dominant model and allelic model, moderate in recessive model and additive model, and low in codominant model (Table S1). For the CX3CR1 V249I polymorphism, GRADE suggested that the quality of the evidence was moderate in recessive model, codominant model, and additive model, low in dominant model, and very low in allelic model (Table S1).In this study, twenty-five articles involving the associations between the CX3CR1 polymorphisms and the risk of AS in five genetic models. To make a more comprehensive analysis, subgroup analyses were performed based on ethnicity, atherosclerotic disease, and source of controls. For the CX3CR1 T280M polymorphism, Apostolakis et al. [ CX3CR1 V249I polymorphism, significant associations were found between this variant and the atheroprotective effect on AS in CAD and PB groups. These results suggested that the 249I allele carriers reduced the risk of CAD in heterozygote state. The above statistical results were based on Bonferroni correction to control for the multiple testing in view of under investigation.The overall findings showed that there was no association between thes et al.  showed tFor the combined genotype, the VITM and IITM genotypes played an atheroprotective effect on AS. The combined VVTM genotype was more common in the cases than in the controls; however, the rarity of the VVTM genotype makes any conclusion rather unsafe. LD analysis indicated a strong association between T280M and V249I, and a protective role of the 249I-280M haplotype was also observed in the control population compared to case subjects. No association was observed between the 249I-280T haplotype and the susceptibility to AS. These results were consistent with those of a previous study .Considering the studies without HWE or with low NOS score may influence the overall results, subsequent sensitivity analyses restricted to the studies with HWE or high NOS score were performed, but no corresponding pooled OR was materially altered in the dominant, recessive, codominant, additive, and allelic models. These results suggested that the studies without HWE or low score should not be considered as a factor influencing the overall results. CX3CR1 T280M or for the CX3CR1 V249I polymorphism. Heterogeneity should not be ignored and should be carefully factored in the interpretation of the final results. For the CX3CR1 T280M and V249I polymorphisms, the heterogeneity can partly be explained by the ethnicity (Caucasians and Asian), subtype of atherosclerotic diseases , and source of control .Heterogeneity of the included studies is the most important drawback when the genotypic data were analyzed, either for the CX3CR1 T280M and V249I polymorphisms, were relatively small, not having enough statistical power to explore the real association. Thirdly, AS is a complex disease and involves potential interactions of gene-environment. However, many eligible studies included in this meta-analysis did not consider the environmental factors. Therefore, studies with larger sample sizes and better design are needed.However, some limitations of this meta-analysis should be acknowledged. Firstly, there was significant heterogeneity in this meta-analysis. Heterogeneity may affect the precision of overall results, despite the use of appropriate meta-analytic techniques with random-effects model. Secondly, in the subgroup analyses, the sample sizes in some subgroup, such as the PAD and CAA groups of the CX3CR1 280M and 249I allele carriers had atheroprotective roles on AS in heterozygote state, and the 280M allele carriers were associated with the susceptibility to AS in homozygote state. The combined genotypes of VITM and IITM also had atheroprotective roles on AS. Consequently, this effect may be attributed to the haplotype of 249I-280M. However, the results should be interpreted with caution because of its limitations. Further studies with large sample size, especially with the consideration of gene-gene and gene-environment interactions, are needed to confirm our findings.The present meta-analysis suggested that theChecklist S1: The PRISMA 2009 checklist. Figure S1: Forest plot for CX3CR1 T280M polymorphism and AS risk in CAD group (TM versus TT). Figure S2: Forest plot for CX3CR1 T280M polymorphism and AS risk in ICVD group (MM versus TT). Figure S3: Forest plot for CX3CR1 V249I polymorphism and AS risk in CAD group (VI versus VV). Table S1: GRADE profile evidence of the included studies. Table S2: Genotype distribution in cases and controls. Table S3: Heterogeneity test of CX3CR1 T280M and V249I polymorphisms and risk of AS in each subgroup.


Aim. Periodontitis is an inflammatory disease that affects the teeth supporting structures, triggered by periodontal pathogens, and is influenced by environmental and genetic factors. Genes encoding molecules related to the immune response, such as cytokine, are the main candidates for polymorphisms analysis and may be possibly associated with this pathology. A G/C promoter polymorphism on the IL6 gene has been shown to affect basal IL-6 levels. The aim of this study was to investigate the association between the IL6 c.-174G>C polymorphism and periodontitis in individuals from Vitória da Conquista, Bahia, Brazil. Material and Methods. Three hundred and thirty individuals  were genotyped for the IL6 c.-174G>C by MS-PCR technique. Concentrations of salivary IL-6 were determined by ELISA method. Results. The IL6 c.-174G>C polymorphism was associated with periodontitis when comparing the distribution of genotypes between patients with periodontitis and control subjects. The GC genotype appeared as a protective factor for periodontitis. Results showed increased levels of salivary IL-6 in periodontitis patients. Nevertheless, there was no relationship between the concentrations of IL-6 and genotypes when comparing the case and control groups. Conclusions. Our data indicate an association between IL6 c.-174G>C polymorphism and periodontitis and showed that IL-6 may be considered an important marker for periodontitis. Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia, is considered the most important pathogens in periodontal disease [Periodontal disease is an inflammatory condition brought about by the interaction between microorganisms that compose supragingival and subgingival biofilms and the host inflammatory response . Some of disease , 3.α), stimulate the production of secondary mediators which in turn amplify the inflammatory cascade. This continuing amplification process results in the increased production of proteases and osteoclastic signals that lead to connective tissue and bone destruction [The inflammation progression induces the production of persistent inflammatory signals by the cells of periodontal tissues. Such persistent signals, represented by the proinflammatory cytokines, for example, interleukin-1 (IL-1), interleukin-2 (IL-2), and tumor necrosis factor-alpha . Written informed consent was obtained from all participants before starting the study.From March 2010 to August 2012, a total of 330 residents of Vitória da Conquista, Bahia, Northeast Brazil, aged between 14 and 69 years of both genders, were recruited to this study. The number of the sample was representative according to the sample size calculation. The subjects were submitted to anamnesis and received a complete periodontal examination including supragingival/subgingival calculus, bleeding on probing (BOP), probing depth (PD), and clinical attachment loss (CAL). The diagnostic criteria for periodontitis were referred to the 1999 International Classification of the Periodontal Disease and Conditions . IndividEpithelial cells were obtained from all subjects for genomic DNA extraction. The sampling was made by scraping the oral mucosa using a custom-made sterile wooden spatula, which was then immediately immersed in a 2 mL sterile microtube. For IL-6 levels determination, individual saliva samples (5 mL) were collected by expectorating into disposable tubes. The samples were stored at −20°C until assayed. Saliva was not stored longer than 2 months. IL6 promoter polymorphism was performed by the mutagenically separated polymerase chain reaction (MS-PCR) [μL reaction mixture which included 100 ηg of genomic DNA solution, 1 U of Taq DNA polymerase , and primers in the following concentrations: 5 ρmol IL-6G; 15 ρmol IL-6C; 3 ρmol IL-6 complementary strand primer. Thermal cycling conditions were initial denaturation at 94°C for 10 min, followed by 45 cycles of amplification at 94°C for 20 s and annealing at 57°C for 1 min 20 s, with extension for 1 min 20 s at 72°C, with a final extension for 5 min at 72°C. The specificity of MS-PCR for the different genotypes was confirmed by direct sequencing of genomic DNA (data not shown).Genomic DNA was extracted with an alkaline solution as previously described . Extract(MS-PCR)  using sp(MS-PCR) . AmplifiμL) of the MS-PCR products were separated by size on 4% agarose gels stained with ethidium bromide (0.5 μg/mL), visualized under ultraviolet (UV) light (Transilluminator) and photographed at appropriate photodocumentation system (LABImage L-PIX (H.E.), Loccus Biotecnologia, Brazil). PCR products that were 121 base pairs (bp)  and 136 bp  in length could be distinguished readily.Aliquots . The levels of IL-6 in the samples were obtained by comparison with the standard curve generated from the standards supplied by the manufacturer.The IL-6 levels were measured using the whole saliva samples by the enzyme-linked immunosorbent assay (ELISA) according to the manufacturer's instructions . The 96-well microplates were read at 450 χ2) measured the association between the independent  and dependent (periodontitis) variables. All variables with P < 0.20 in the χ2 were included in multivariate analysis using logistic regression. A backward deletion strategy was applied, and those variables with P values equal to or less than 0.05 remained in each of the final models. Goodness of fit was evaluated using the Hosmer-Lemeshow test, while the Stata software version 10.0 was used for data analysis. .The magnitude of the associations between risk factors and periodontitis was estimated by the odds ratio (OR) with a 95% confidence interval (95% CI). The Chi-square test . There was a significant difference in the genotypic frequency distribution when comparing the control subjects with periodontitis patients (P = 0.038), showing an association between this polymorphism and periodontitis   . Our fin IL6 c.-174G>C polymorphism, separating them into case and control groups (P = 0.0099). Observing the protein expression for each genotype, it was found that the CC genotype was associated with increased production of IL-6, but there was no significant difference when comparing the IL-6 quantification among the different genotypes and the case and control groups. Thus, higher salivary concentrations of IL-6 observed in patients with periodontitis may be related to other factors than the genetic influence, especially environmental risk factors, such as bacterial load or poor oral hygiene habits.IL-6 expression was compared with different genotypes for thel groups . A signiIn the studied population, the periodontitis was more prevalent in individuals older than 30 years, in subjects from the lower educational strata, and in those who were using tobacco regularly. The identification of risk factors associated with periodontal disease in different populations enables the implementation of effective interventions for health promotion. Public policies that act for the prevention of periodontitis, with the realization of preventive antismoking campaigns and intensified action in individuals older than 30 years, can minimize the influence of these risk factors and hence reduce the prevalence of the disease in the studied population.Age has been identified in several studies as an important risk factor for periodontitis. Haas et al.  showed tSmoking is considered, by several authors, the main risk factor for prevalence, extent, and severity of periodontal disease , 29. ThoThe educational level has also been evaluated as a risk factor for periodontitis, and low education has often been associated with it , 32, 33.All risk factors can still be added to local infection and result in inflammation of the tissues supporting the teeth in periodontitis, culminating in symptoms such as bleeding gums, formation of periodontal pockets, and alveolar bone resorption, with varying degrees of dental insertion loss , 36. The IL6 c.-174G>C gene polymorphism and periodontitis, considering the frequency distribution of GG, GC, and CC genotypes among the case and control groups (P = 0.038). The GC genotype showed statistically significant relationship with periodontal disease when compared with the other genotypes. Our results are consistent with findings in many different populations [The data relating the polymorphism and cytokine expression may contribute to the identification of genetic factors that play a significant role in the etiology of this disease and confirm the diagnosis and determine the susceptibility of individuals regarding periodontal disease in this population. In the present study, a positive association was found betweenulations , 40. IL6 c.-174G>C polymorphism and periodontal disease in a study of Italian population. However, this study determined that the G allele is one that has a statistically significant association with periodontal disease.In agreement with our findings, Kalburgi et al.  found a  IL6 c.-174G>C, which acts as a preponderant factor in comparison to others regarding the disease, may suggest that other factors, especially ethnic and/or demographic, may be influencing the relationship between genotype and periodontitis.Brett et al. , in an aIn contrast to our data, whose GC genotype was associated with periodontitis, studies have found different results concerning genotypes associated with the disease. The GG genotype was associated with chronic periodontitis in the study conducted in a sample of Brazilian elderly women and in a study with Brazilian Caucasian population , 41, 42. IL6 c.-174G>C and periodontal disease. Fan et al. [ C allele in a study in a Chinese population and found no significant difference in the genotypes distribution for the c.-174G>C polymorphism in the analysis of groups with periodontal disease and coronary artery disease. Similarly, Holla et al. [ IL6,β, IL1 and IFNγ genes and periodontal disease in a study carried out in China. However, in the same study, associations with polymorphisms in IL1α, TNFα, IL4, and IL10 genes were described. A study conducted by Wohlfahrt et al. [ IL6 c.-174G>C polymorphism and other polymorphisms in CTLA-4 DEFB1, ICAM-1, FasL, ICOS, CCR5, OPG, and OPN genes in subjects with periodontal disease from USA. These data are in disagreement with those obtained in our study.There are also studies indicating no association between the polymorphismn et al.  observeda et al.  found noa et al.  showed nt et al.  also rev IL6 c.-174G>C gene polymorphism and periodontitis in different population samples, studies indicate that genetic variation may also result in differences in the expression of the cytokine IL-6 according to the genotype which could culminate in changes in the individual inflammatory response [ IL6 c.-174G>C, even if a higher expression of the protein has been observed among patients with disease.Although controversial results have been observed in the analysis of the association betweenresponse , 49. Mearesponse . The dosThe data in the literature regarding the quantification of IL-6 in salivary fluid, the polymorphism c.-174G>C, and periodontitis are scarce. These findings are in agreement with another report by Loo et al.  who demo IL6-174/-572 polymorphisms, similar to the findings of the present study. Therefore, we believe that the observed higher levels of IL-6 in saliva of patients with periodontitis may be related to other factors prevalent to the analyzed polymorphism. Among these factors, an exacerbated inflammatory response especially stands out due to both environmental risk factors, such as bacterial load, poor oral hygiene habits, and smoking and other genetic factors that are not assessed in our work. The mechanism of multifactorial inheritance described for periodontitis justifies such results, which by definition is a consequence of variations in multiple genes added to the effects of the environment, collaborating together to the risk of developing the disease. The small number of subjects with the CC genotype in the population studied may also be a factor which can explain this result. Nevertheless, Badiu et al. [Concerning the association of the protein dosage and the different genotypes, Smith et al.  showed tu et al.  determin IL6 c.-174G>C gene polymorphism can still be added to the analysis of other factors related to the etiology of periodontitis not evaluated here, including other genetic markers, which could provide us a better result on these interactions, and this is a possible limitation of our study.This paper provides information for a better understanding of the complex interactions between the host immune response, microorganisms, and genetic factors in individuals with periodontitis. However, we believe that the results obtained regarding the IL6 c.-174G>C polymorphism and periodontitis and showed that IL-6 may be considered as an important marker for periodontitis. Further studies in other populations are necessary to confirm these findings and determine the role of this polymorphism in the pathogenesis of periodontitis, as well as the association of the disease with the presence of periodontal pathogens and other genetic variations which could be related to the disease.Our results indicate an association between


Household air pollution (HAP) from solid fuel combustion contributes to 2.6% of the global burden of disease. HAP emissions are an established lung carcinogen; however, associations with other cancer sites have not been fully explored. We conducted a meta-analysis of 18 case–control studies. Using fixed-effects models, utilizing the adjusted odds ratios (OR) and 95% confidence intervals (95% CI) from each study, we evaluated the association between HAP and cervical neoplasia (663 cases and 1747 controls) and upper aero-digestive tract cancers (6022 cases and 15 325 controls). We found that HAP was associated with cervical neoplasia ; oral ; nasopharyngeal ; pharyngeal ; and laryngeal  cancers. The elevated risk for esophageal cancer  was non-significant. HAP was associated with cervical neoplasia among studies that accounted for HPV infection  and smoking . Similarly, our observed associations between HAP and upper aero-digestive tract cancers remained significantly elevated when analyses were restricted to studies that controlled for smoking. No significant publication bias was detected. Our results suggest that the carcinogenic effect of HAP observed for lung cancer may extend to other cancers, including those of the cervix and the upper aero-digestive tract. Further research is needed to confirm these associations in prospective studies.The online version of this article (doi:10.1186/s12940-015-0001-3) contains supplementary material, which is available to authorized users. Around three billion people depend on solid fuels for household energy both in developed and developing countries ,2. SolidEvidence suggests that polycyclic aromatic hydrocarbons (PAHs), a major HAP component, have carcinogenic properties on mucosal and endothelial lining of upper aero digestive tract from inhalation -9. StudiStudies that explored the association between upper aero- digestive and genital cancers with HAP, published between January 1970 and July 2014 were identified by searches of the PubMed and Science Citation Index databases using keywords related to indoor air pollution, cancer and cancer sites (Table The inclusion criteria for our study were: (i) epidemiological studies (case–control and cohort studies) that examined the association between HAP and these cancers; (ii) the study population’s solid fuel use exposures were primarily derived from household cooking and/or heating and not from other forms of urban/outdoor air pollution or occupational exposures; and (iii) the results for the study population were not reported in another publication.Studies were excluded if they were (i) studies written in languages other than English and Spanish; (ii) animal studies; (iii) studies examining only the carcinogens implicated in HAP  pyrene); or (iv) focused on occupational exposure to solid fuel usage or exposure to cooking oil fumes. The initial keyword searches yielded 285 manuscripts of which 60 were selected for abstract review. Of these studies that met our inclusion criteria, 18 studies were reviewed. All of these studies were case–control studies by design, except for one nested case–control study. Refer to Figure Data related to study design, geographical location, population setting, case selection criteria, control selection criteria, exposure assessment methods, the number of cases and controls, participation rates, gender distribution, the type of fuel used, and risk of cancer associated with exposure, crude odds ratio (OR) and 95% confidence interval (95% CI), adjusted odds ratio (OR) and 95% CI, the variables adjusted for, and the limitations of the study were extracted from each study. Since there is no standardized method for HAP exposure assessment, we critically reviewed all the studies to determine the respective exposure assessment method. All studies utilized questionnaire-based methods to determine exposures either qualitatively or quantitative. ORs were extracted for all fuel types  provided by each study. For studies that provided multiple ORs based on various exposure groups, the OR representing the highest exposure group was selected. For example, the groups that experienced the longest duration of exposure or the groups with substantial fuel burning in poorly ventilated kitchens were selected. Since HAP attributed to coal exposures tend to have higher carcinogenic potential than HAP attributed to wood for lung cancer , we seleTable All statistical analyses were performed using the “meta” and “metafor” packages and in-house code developed in the R statistical language version 3.1.0. Heterogeneity among studies was determined using the Q test for heterogeneity. Summary ORs for cancers according to cancer site were then calculated using the adjusted OR and 95% CIs from each independent study. If the adjusted odds ratio was unavailable we used crude odds ratio. Using random and fixed-effects models, summary ORs were calculated for the overall effect of each cancer site and exposure of interest. Given that the numbers of studies were too few to obtain a stable estimate of variance of random effects, and that cancer site-specific ORs calculated using random-effects models were similar to those calculated using fixed-effects models, only results from fixed-effects models are presented. In addition, analyses were conducted to obtain summary ORs for studies that accounted for major known confounders, such as smoking status in upper aero-digestive cancers and HPV in cervical cancer. Exploratory analyses were also conducted based on specific type of fuel used. Publication bias was assessed by visual inspection of funnel plots  ,12, as dFour studies (1000 cases/3450 controls) evaluated the association between oral cancer and HAP Table b and theSix studies (2231 cases/2160 controls) estimated the risk of nasopharyngeal carcinoma from HAP. Four of these studies were conducted in Asia and two in Africa -17,19,26Four studies (1036 cases/3746 controls) assessed the risk of pharyngeal cancer associated with HAP Table . These sTwo studies (339 cases/1455 controls), which were conducted in Asia and Europe ,21, evalFive studies (1416 cases / 4514 controls) evaluated the risk of laryngeal cancer associated with HAP Table d, with nWe conducted exploratory analyses to estimate fuel type-specific summary ORs Table . These aIn precancerous cervical lesions, the summary OR for wood-specific exposure was 10.29 (95% CI = 3.27 – 32.40) ,12. For Globally, 50% of all households and 90% of rural households continue to depend on solid fuels for cooking and heating . An estiOur meta-analysis of epidemiological studies confirms the results observed in animal studies ,29, suggThe carcinogenic potential of HAP has been previously evaluated. HAP is known to cause an increase household air levels of sulfur dioxide, carbon monoxide, fluorine, and known carcinogens such as polycyclic aromatic hydrocarbons (PAHs), benzene, arsenic, 1,3-butadiene and formaldehyde, ,31. ThesThe type of, and relative proportions of, carcinogens released varies by the type of fuel used . StudiesInteresting evidence also emerges from our study that HAP is associated with increased risk of cervical neoplasia despite controlling for the risk factors such as HPV and smoking status . There iOur analysis has multiple strengths. This is the first meta-analysis to summarize the association between HAP and cancers other than lung. Though our study is a secondary data analysis we accounted for major risk factors to the extent possible by evaluating summary odds ratios based on study-specific ORs that adjusted for major confounders. Finally, the body of existing literature supports the biological plausibility for pathogenesis of these cancers. Even though we robustly reviewed the literature to identify all existing studies evaluating these associations, there were only a limited number of studies available for analysis. Another potential limitation is the file drawer effect of unpublished studies; however, our results are unlikely to be influenced by the file drawer effect, especially for upper aero-digestive tract, given the recent interest in HAP in relation to lung cancer . We noteOur results support the hypothesis that HAP is associated with the risk of cancers other than lung cancer. Our meta-analysis, however, should be considered hypothesis-generating until these associations are evaluated prospectively in order to overcome the limitations of the case–control design that was employed by virtually all of the studies included here.


PRKAA1 rs13361707 T > C polymorphism and gastric cancer (GCa) susceptibility were inconclusive. To derive a more precise estimation of the association, we conducted a large-scale GCa study of 1,124 cases and 1,194 controls to confirm this association in an Eastern Chinese population. Our results showed that the C allele of PRKAA1 rs13361707 increased the GC risk in the study population . In addition, the association of C allele with an increased GCa risk was still significant in subgroups, when stratified by age, sex, tumor site, drinking and smoking status. Moreover, the findings in the present study were validated by our further meta-analysis. In summary, these results indicated that the C allele of PRKAA1 rs13361707 was a low-penetrate risk factor for GCa.Published data on the association between  Helicobacter pylori (HP) infection (70–90%) in developing countries (compared with 25–50% in developed countries) might be a potential risk factor for GCa  in the study population. The population attributable risk of CT, CC, CT/CC alleles were 0.53%, 11.51% and 4.4% respectively.Table In the stratified analysis presented in Table PRKAA1rs13361707 T > C SNP was strongly associated with increased GCa risk in several genetic model . More importantly, the pooled data from the final four studies still showed a strong association between rs13361707 and GCa risk, indicating the stability of the results of this meta-analysis.For the subsequent meta-analysis, we found four primary studies , 24–26. Apart from environmental and lifestyle factors for GCa risk, genetic factors in the GCa development were important in identifying at-risk populations for cancer prevention. To our knowledge, the present study was the first to demonstrate the strong association of rs13361707 SNP with an increased GCa risk in a large eastern Chinese population under five genetic models. All results consistently showed that the C allele of rs13361707 increased the risk of GCa.PRKAA1, a subunit of the AMPK pathway, is critical to cellular activity and cancer development, and studies have demonstrated its role in cell differentiation, apoptosis, autophagy, and cancer progression –30 as wePRKAA1rs13361707 in GCa risk in an eastern Chinese population under several genetic models. However, a previous GWAS study [The major finding in the present study is a confirmed strong association between AS study  confinedAS study  indicateThere are some limitations in the present study. First, although age, sex, smoking status, drinking status, and tumor site were taken into consideration for subgroup analysis, other important risk factors, such as diet and HP infection, that were missing in this study, which may have also contributed to the etiology of GCa. New classification of tumor types is also important, which may have a different genetic basis in the etiology . Second,PRKAA1 rs13361707 was a risk factor for GCa. However, future studies should incorporate HP infection status and Lauren classification, which may lead to our better, comprehensive understanding of the association between the PRKAA1 rs13361707 SNP and GCa risk.In conclusion, the present study confirmed that the C allele of This study included patients who were recruited from our ongoing molecular epidemiology study of GCa, and the cases and controls were described previously –19. BrieAccording to a relevant protocol, we extracted DNA from peripheral blood. The rs13361707 SNP was genotyped by the TaqMan assay with ABI7900HT real-time PCR system as reported previously [2 test was used to assess the differences in the distribution of demographic characteristics between cases and controls. Hardy–Weinberg equilibrium (HWE) was tested by goodness-of-fit χ2 to evaluate the expected distributions of genetic frequency in the controls. The association between SNP and GCa risk was assessed by odds ratio (OR) and 95% confidence intervals (CIs) in heterozygous (CT vs TT), homozygous (CC vs TT),dominant (CT+CC vs TT), recessive (CC vs CT+TT), respectively. OR values were calculated by univariate and multivariate logistic regression models. Moreover, logistic regression tests for each genetic model were adjusted for age, sex, drinking and smoking status. Furthermore, associations between the PRKAA1 rs13361707 SNP and GCa risk were also stratified by age, sex, smoking or drinking status, and primary tumor site. We applied Bonferroni correction for multiple testing using 0.0038 as significance level. All statistical process above was achieved by SAS software The χP < 0.05 determined by the t test as suggested by Egger. All statistical process was achieved by STATA version 10.0 .To validate our results, we performed a mini meta-analysis with studies searched from Medline, PubMed and Embase. After using the search terms and inclusion and exclusion criteria as described in previous studies , 22, all


Recently, more and more studies investigated the association of inflammation parameters such as the Platelet Lymphocyte Ratio (PLR) and the prognosis of various cancers. However, the prognostic role of PLR in cancer remains controversial.We conducted a meta-analysis of published studies to evaluate the prognostic value of PLR in various cancers. In order to investigate the association between PLR and overall survival (OS), the hazard ratio (HR) and its 95% confidence interval (CI) were calculated.heterogeneity <0.001). Subgroup analysis revealed that increased PLR was a negative prognostic marker in patients with gastric cancer , colorectal cancer , hepatocellular carcinoma , ovarian cancer  and non-small cell lung cancer (NSCLC)  except for pancreatic cancer .A total of 13964 patients from 26 studies were included in the analysis. The summary results showed that elevated PLR was a negative predictor for OS with HR of 1.60 (95%CI: 1.35–1.90; PThe meta-analysis demonstrated that PLR could act as a significant biomarker in the prognosis of various cancers. For a long time, cancer is one of the leading causes of death and a major public health problem worldwide Recently, more and more evidence showed that a systemic inflammatory response could play an important role in the development and progression of cancer A systematic review of the studies about PLR in predicting the prognosis of various cancers was performed. Studies were identified by searching PubMed, Embase and Web of Science databases using the following search terms: PLR, platelet-to-lymphocyte ratio, platelet lymphocyte ratio or platelet-lymphocyte ratio with cancer, neoplasms or tumor and prognosis or outcome. Both free text and MeSH search for keywords were used. The last search was updated in March 12, 2014. The “related information” function was used to broaden the search and all abstracts, full texts and references were reviewed. Study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement The search was conducted by two authors (Huang and Du). We read titles and abstracts of all candidate articles. Articles that could not be categorized based on title and abstract alone were retrieved for full-text review. Articles were independently read and checked for inclusion criteria of articles in this study. Any disagreements were resolved through consensus with a third investigator (Zhou).Studies were considered eligible if they met the following criteria: (a) studied patients with any type of cancer; (b) investigated the association of pre-treatment PLR and overall survival (OS); (c) published as a full paper in English. Studies were excluded based on the following criteria: (a) letters, reviews, case reports or laboratory studies; (b) studies had duplicate data or repeat analysis; (c) lack of key information for further analysis; (d) non-human research.P value.Two investigators evaluated and extracted the data independently under the guidelines of the Dutch Cochrane Centre proposed by Meta-analysis of Observational Studies in Epidemiology (MOOSE) P values were two-sided.All the survival results were estimated as the hazard ratio (HR) for each study. If possible, the HR and 95% confidence intervals (95% CI) were obtained directly from each study publication. When the data was not directly reported, a mathematical estimation was done by calculating the necessary data according to the methods published by Parmer et al By the initial search, 630 potentially relevant articles were identified. Then 519 articles were excluded because of obvious lack of relevance. After carefully reading the articles, 95 were excluded . Finally, 26 articles heterogeneity <0.001; heterogeneity <0.001) and in Caucasian populations . When different cancer types were considered, PLR was a negative prognostic marker in patients diagnosed with gastric cancer , colorectal cancer , hepatocellular carcinoma , ovarian cancer  and non-small cell lung cancer (NSCLC)  except for pancreatic cancer . When performing subgroup analyses stratified by analysis method,we found that increased PLR was a negative predictor for OS both by univariable analysis  and multivariable analysis . Considering different cutoff values, PLR was a negative prognostic marker for the data applying<or = 160  and the data applying >160 . These studies used triple subsets of PLR cutoff revealed the similar results .The main results of this meta-analysis are listed in The results showed that year of publication (p = 0.431), ethnicity (p = 0.782), cancer type (p = 0.208), analysis method (p = 0.200) and cutoff (p = 0.721) did not contribute to the source of heterogeneity.We used the leave-one-out sensitivity analyses by removing one study per time to check if individual study influenced the results. The result pattern was not obviously impacted by any single study . Begg’s To date, a variety of predictors have been found and applied in the prognosis of various carcinomas, such as TNM stage, genetic factors, and inflammatory factors. Many inflammatory markers now can be detected in peripheral blood before treatment. Thus, inflammatory marker is a relatively cheap and convenient predictor. Recently, an authoritative article indicated that inflammation with the interaction between various inflammatory cells and extracellular matrix played a crucial role in tumor microenvironment to tumorigenesis The analysis combined the outcomes of 13946 cancer patients from 26 individual studies, indicating that elevated PLR significantly predicted poor OS. Subgroup analyses revealed that worse OS with high PLR could be found both in Asian populations and Caucasian cases. Additionally, elevated PLR was a significant negative prognostic marker for various cancer types. When differently analysis strategies were considered, PLR had prognostic value for poor outcome by univariable analysis or multivariable analysis. Cut off values of PLR used in the enrolled studies were various. As shown in As shown in There were several limitations of this study need to be carefully considered. This study was constrained to studies published in English language only. So publication bias cannot be excluded. In addition, heterogeneity among these studies were relatively large that might be caused by different countries, histological type of cancer or/and other factors. In order to reduce the heterogeneity, different cutoff values of PLR or univariate or multivariate regression model have been conducted in our study. Moreover, due to lack of appropriate data, the association of PLR and other important clinical parameters was not explored. Furthermore, most of the patients included in this meta-analysis suffered from digestive system neoplasms. In the future, studies with more types of cancers and larger sample size are needed to present more reliable results.In conclusion, the meta-analysis firstly shows that an elevated PLR is a negative predictor for survival for various cancers.PRISMA checklistChecklist S1.(DOC)Click here for additional data file.


A: OR = 0.77, 95% CI = 0.74–0.80), and a positive association was found for the minor allele G of rs17810546 . The co-dominant model of genotype effect confirmed the significant associations between RGS1 rs2816316/IL12A rs17810546 and CD. No evidence of publication bias was observed. Our meta-analysis supports the associations of RGS1 and IL12A with CD and strongly calls for further studies to better understand the roles of RGS1 and IL12A in the pathogenesis of CD.The pathogenesis of celiac disease (CD) has been related to polymorphisms in the regulator of G-protein signaling 1 (RGS1) and interleukin-12 A (IL12A) genes, but the existing findings are inconsistent. Our aim is to investigate the associations of two single-nucleotide polymorphisms (SNPs) (rs2816316 in RGS1 and rs17810546 in IL12A) with CD risk using meta-analysis. We searched PubMed and Web of Science on RGS1 rs2816316 and IL12A rs17810546 with CD risk. Odds ratio (OR) and 95% confidence interval (CI) of each SNP were estimated. All statistical analyses were performed on Stata 12.0. A total of seven studies were retrieved and analyzed. The available data indicated the minor allele C of rs2816316 was negatively associated with CD (C  Most paet al.  identifiet al. .et al. [+ T cell produces pro-inflammatory cytokines and results in Th1 response, which is dominantly regulated by INF-γ [Recently, a two-stage genome-wide association study (GWAS) found the contribution of the regions on chromosome 1q31 and 3q25 containing the regulator of G-protein signaling-1 (RGS1) gene and interleukin-12 A (IL12A) gene in the development of CD in European populations . Both ofet al.  have repet al. . By inteet al. . While Iet al. . Activatby INF-γ .Several studies have assessed the role for RGS1 rs2816316 (C/A) and IL12A rs17810546 (G/A) in CD development ,16,17,18According to the search strategy and inclusion criteria, seven studies involving 20 sub-study collections were identified about the associations of RGS1 and IL12A polymorphisms with CD ,16,17,18et al. [et al. [et al. [The detailed characteristics of the seven included studies are described in et al.  and Dubo [et al.  included [et al.  that didThe results of bias assessment are presented in vs. A) was estimated by the fix-effect model with less across-study heterogeneity , with a pooled OR of 0.77 (95% CI = 0.74–0.80) (p = 0.622) and Peters (p = 0.775) tests suggested no existence of publication bias. The results in vs. A) were stable without any publication bias. The sensitive analysis was performed to make sure that no individual study was entirely responsible for the pooled results. In Seven studies reported association between rs2816316 and CD, which involved 14,936 cases and 24,794 controls. Hardy–Weinberg equilibrium (HWE) test showed no study was considered to be disequilibrium. The pooled frequency of the minor allele C was 14.0% (95% CI = 13.6%–14.5%) in the CD groups and 17.5% (95% CI = 16.9%–18.2%) in the control groups. The population-attributable risk (PAR) for allele C was 4.19%. The odds ratio (OR) (C 74–0.80) A. This r1 (AC vs. AA)  and the OR2 (CC vs. AA)  were homogenous. The pooled ORs were estimated by the fix-effects model for OR1  and OR2 , both of which were significant. Harbord and Peters tests in OR1  and OR2  as well as contour-enhanced funnel plot  was estimated by the fix-effect model with less across-study heterogeneity , with a pooled OR of 1.37 (95% CI = 1.31–1.43)  and contour-enhanced funnel plot  A. This rnel plot D suggest1 (AG vs. AA)  and OR2 (GG vs. AA)  were homogenous. The pooled ORs were estimated by the fix-effects model for OR1  and OR2 , both of which were significant. Harbord and Peters tests in OR1  and OR2  and contour-enhanced funnel plot . Nevertheless, this limitation is made up for by the relatively large sample sizes . Second, controls in Italian population are not in Hardy–Weinberg equilibrium [In summary, our meta-analysis indicates that RGS1 and IL12A are both associated with CD, especially in European populations. The associations should be validated by large-scale, well-designed epidemiological studies in the future.Studies concerning the associations of RGS1 and IL12A polymorphisms with CD were searched from PubMed and Wed of Science by two reviewers independently. The updating date was 20 August, 2015. The detailed search strategy was as follows: (celiac disease or CD) and (polymorphism or SNP or rs2816316 or rs17810546) or  or (interleukin-12 A or IL12A). We only considered studies published in English and Chinese. We scanned the titles and abstracts of all relevant articles, manually examined reference lists for additional relevant publications and obtained the full texts of all possibly relevant studies. For multiple articles published with the same subjects, we selected the latest and most complete one.Any human population-based association study was included only if it met all three criteria: (1) evaluation of the RGS1 (rs2816316) or IL12A (rs17810546) polymorphism and CD; (2) odds ratio (OR) and its 95% confidence interval (CI) was presented or could be calculated; and (3) there was clear diagnosis of CD. We contacted the authors to acquire indispensable information when their data were incomplete. Studies that did not provide data were excluded.p-values for the Hardy–Weinberg equilibrium HWE test in control groups were extracted  [i.e., Q test was significant), the cause of heterogeneity was explored by sensitivity analysis. A random-effect model was used if I2 > 50%, otherwise, a fixed-effect model was used. The population-attributable risk PAR for mutant allele was calculated based on the results from a discrete-time model [The statistical significance of the pooled OR was determined by the Mantel-Haenszel method. The across-study heterogeneity of allele effects was checked using a Q test and was quantified by extreme) . If heteme model .vs. AA (OR1) and Aa vs. AA (OR2). The model of genetic effect, measured by the parameter lambda (λ: the ratio of logOR2 to logOR1), was then estimated by the model-free Bayesian approach. The λ represents the heterozygote effect as a proportion of the homozygote variant effect. Furthermore, the λ-value ranges from 0 to 1. We get information about the genetic mode of action as follows: λ = 0 suggests a recessive model (Aa + aa vs. AA); λ = 1 suggests a dominant model (AA + Aa vs. aa); λ = 0.5 suggests a co-dominant model . λ > 1 or λ < 0 indicates a homozygous or heterosis model, although this is rare. The best genetic model, once identified, is used to collapse the three genotypes into two groups and re-pool the results. WinBugs 1.4.2 was used with vague prior to distributions for parameter estimation . The models were run with a burn-in of 1000 iterations, followed by 10,000 iterations for parameter estimation.We supposed that A and a were wild-type and mutant alleles, respectively; and AA, Aa and aa were common homozygous, heterozygous, and minor homozygous, respectively. The model-free approach was used to estimate the genotype effect, and two types of ORs for each study: aa The Harbord and Peters test were adopted to assess and quantify the publication bias. Additionally, a novel Contour-enhanced meta-analysis funnel plot method was used to combat publication biases . In the In conclusion, our study identified RGS1 rs2816316 was negatively associated with CD. In the other hand, IL12A rs17810546 was positively associated with CD. Further studies are required to elucidate how these variants contribute to the susceptibility of CD.


Studies reporting mean and standard deviation of S100B blood levels both in cases and controls were included in the meta-analysis. The meta-Mean Ratio (mMR) of S100B blood levels in cases compared to controls was used as a measure of effect along with its 95% Confidence Intervals (CI). 20 studies were included totaling for 994 cases and 785 controls. Schizophrenia patients showed 76% higher S100B blood levels than controls with mMR = 1.76 95% CI: 1.44–2.15. No difference could be found between drug-free patients with mMR = 1.84 95%CI: 1.24–2.74 and patients on antipsychotic medication with mMR = 1.75 95% CI: 1.41–2.16). Similarly, ethnicity and stage of disease didn't affect results. Although S100B could be regarded as a possible biomarker of schizophrenia, limitations should be accounted when interpreting results, especially because of the high heterogeneity that remained >70%, even after carrying out subgroups analyses. These results point out that approaches based on traditional categorical diagnoses may be too restrictive and new approaches based on the characterization of new complex phenotypes should be considered.S100B is a calcium-binding protein secreted in central nervous system from astrocytes and other glia cells. High blood S100B levels have been linked to brain damage and psychiatric disorders. S100B levels have been reported to be higher in schizophrenics than healthy controls. To quantify the relationship between S100B blood levels and schizophrenia a systematic literature review of case-control studies published on this topic within July 3 S100B is a calcium (Ca2+)-binding protein secreted mainly by glial cells; it belongs to the S100 proteins family At intracellular level S100B exerts a proliferative function, but effects of extra-cellular S100B depends upon its concentration, as in nanomolar concentrations it promotes cell promotion and differentiation, while in higher (micromolar) concentrations it induces cellular death S100B secretion is increased by pro-inflammatory cytokines Due to its functions, trophic actions on neurons and astrocytes and involvement in inflammatory response, S100B seems to be linked to neurodevelopemental and inflammatory hypothesis of schizophrenia pathogenesis Also, a S100B gene haplotype involved in increased S100B expression is associated with schizophrenia Many studies in the last years showed increased S100B levels in the serum/plasma of patients with schizophrenia, as reported in older meta-analyses by Schroeter et al. New studies on the relationship between S100B blood levels and schizophrenia have been carried out after Schroeter et al. meta-analyses of 2009, enabling us to carry out an updated review and stratify subgroups of patients taking into account the effect of potential effect modifiers, not only treatment and age, but also ethnicity, stage of disease, and factors related to the methodology of included studies, like selection of cases and controls, comparability between cases and controls and S100B measurement.S100B could be considered a biomarker for glia alterations and neuroplasticity, that can be easily obtained from peripheral human blood. Accordingly, S100B blood levels could be regarded as an intermediate phenotype useful for disease stratification.In order to assess the relationship between circulating blood levels of S100B and schizophrenia, we carried out a systematic review and meta-analyses of case-control studies on this topic. We aim at quantifying the difference in S100B peripheral blood levels in cases and controls and at exploring if this difference is modified by factors linked to ethnicity, stage of disease, treatment and methodological characteristics of the included studies.rd 2014 using the following search terms: (schizophrenia AND (S100 OR S-100)), without any restriction on language. The references of retrieved articles were also checked in order to search for additional articles. Studies were included in the systematic review if they were case-control studies comparing the serum or plasma S100B levels between schizophrenia patients and healthy controls.Studies were identified through MEDLINE, Scopus and Web of Knowledge sources from their inception up to July 3Data from papers that were eligible for the meta-analysis were extracted by two authors (K.A and A. F) independently. For each study we extracted the following information: first author's name, year, country, number of cases and characteristics, medication status, disease phase (chronic/acute), case definition, number of controls and characteristics, percentage of males, age (years), mean and standard deviation (SD) of S100B plasma/serum level in cases and controls.If more than one article was published by the same author groups, we contacted the corresponding author (CA) in order to check if patients and controls were different. If more than one article was published by the same author using the same case series, we selected the study with the largest number of subjects. In the case were the number of controls was not written in the article but it was stated that controls were age and sex matched, we assumed that case and controls had been recruited in the same number. When mean and SD of S100B blood levels for schizophrenic patients and healthy controls were not reported in the paper, we contacted the CA to ask the data; in cases where we were not able to retrieve it we excluded the study from the meta-analysis; when S100B blood levels were reported only separately for subgroups of patients we calculated pooled mean and SD from the published data; when data were expressed as Mean±Standard Error (SE), SD was calculated from SE using the formula: SD = SE×√n; in two cases where it was not stated if data were reported as mean±SD or ±SE, we asked CA for the information; in one case we used a more conservative approach and assumed that data were reported as mean±SD, as we were not provided with the information by the CA.Critical appraisal of studies included in meta-analysis was performed according to the Newcastle-Ottawa scale (NOS) For each study a Mean Ratio (MR) with 95% Confidence Intervals (CI) was calculated and a pooled estimate, meta-MR, was computed weighting MRs according to the variance and the number of participants in the study 2 statistic. In order to take into account possible sources of heterogeneity a conservative random-effects approach, that model takes into account the inter-study effect variance, was adopted In order to test heterogeneity chi-square analyses were performed To rule out the presence of publication bias formal testing and graphical evaluation were used Stata Statistical Software: Release 13. College Station, TX: StataCorp LP) was employed for all statistical analyses.The Stata statistical software / Scale for Assessment of Negative Symptoms SANS The overall quality score of studies according to NOS is reported on 2 = 94.4%. Results are reported in In the meta-analysis of studies including both drug-free and chronically medicated patients cases showed higher S100B blood level than controls, with meta-MR = 1.76 (95% CI: 1.44-2.15), Q test for heterogeneity = 342.3, p<0.001, IStratified meta-analyses revealed similar higher values in cases than controls, with no evidence of difference in subgroups regarding detection of S100B in plasma or serum, medication status, stage of the disease, ethnicity, selection of cases and controls and source of controls .After removing studies one by one in a sensitivity analysis no study showed to affect meta-analyses estimates. Visual analysis of funnel plots and Egger's test revealed the absence of publication bias (p<0.914).2 = 92.5%.When considering the quality of studies included in the meta-analysis the NOS scores ranged from 2 to 9. After including in the meta-analysis only studies with a NOS score >5 S100B in peripheral blood was significantly increased in schizophrenia patients, with an almost double level in cases than controls.During the last twenty years the S100B protein has gained attention in the research area for peripheral biomarkers of schizophrenia We carried out a meta-analysis including both the studies considered in those of Schroeter et al., 2009 Subgroups analyses showed that S100B levels were similarly higher in cases than controls regardless of medication status and stage of disease. Results of single studies were controversial with studies reporting higher levels in medicated than drug-free schizophrenics Moreover, S100B circulating blood levels have been reported to be both positively correlated with illness duration On the contrary, results on the relationship between S100B blood levels and psychopathology remained inconclusive, with studies reporting in turn no correlation As psychiatric symptomatology is assessed in the various studies by using different rating scales much more standardization should be necessary. Finally, cumulative quantitative analyses of psychopathological data and blood S100B levels should have required the access to individual patient data.S100 proteins can be regarded as trophic regulation factors In animal models, elevate S100B levels may lead to greater susceptibility to environmental stimuli by means of increased plasticity at brain level, particularly hippocampus Last but not least, when interpreting results on S100B concentrations and schizophrenia a number of limitations should be considered.The extent of heterogeneity between studies was high and it remained considerable (>70%) Even if subgroups analyses didn't reveal difference in the meta-estimates according to cases and controls selection, the large discrepancies between studies regarding cases and controls selection should be considered; in particular not all studies enrolled consecutive cases, community controls, age- and gender-matched controls and only 2 studies Heterogeneity between studies could reflect the underlining high level of etiologic heterogeneity of neuropsychiatric disorders. Giving that psychiatry diagnoses essentially rely on symptoms checklists and that neuropsychiatric disorders are complex with often overlapping symptoms, the need for diagnostic tools, that are as much possible objective and specific, strongly emerges A promising path of research in the effort of overcoming heterogeneity is to go beyond the classical diagnostic phenotypes and to consider diseases characteristics in a dimensional way.Regarding this, even if data on the relationship between S100B levels and psychopathology are different across studies, it is an interesting finding that most studies found a correlation with S100B plasma/serum levels and psychopatology, particularly with negative symptomatology A new generation of biomarkers could be discovered if the traditional reductionist assessments based on single-pathways analyses and categorical diagnoses is overcome in order to adopt a Systems Medicine approach. System-level models of interactions between measurements carried out at tissue, cellular and molecular levels coupled with clinical features, are currently developed aimed at identifying new disease phenotypes This ideally would significantly enhance the chances to discover new complex phenotypes and, hinging on a new re-defined taxonomy, to possibly find (panel of) biomarkers with solid clinical utility for diagnosis, treatment and rehabilitation planning and prevention in the context of preventive, predictive, personalized and participatory -P4- medicine integrative strategies Checklist S1PRISMA Checklist.(DOC)Click here for additional data file.


Colorectal cancer (CRC) is the most common cause of cancer death worldwide. Numerous studies have identified the roles of survivin −31 G/C and angiotensin-converting enzyme insertion/deletion (ACE I/D) polymorphisms in CRC risk; however, the results remain inconclusive. This study was to investigate associations between these two polymorphisms and CRC susceptibility.A comprehensive literature search was conducted to collect relevant case–control studies published between 2000 and 2014. The extracted data were statistically analyzed, and the odds ratios (ORs) with 95% confidence intervals (CIs) were employed to estimate the strength of association.P < 0.00001). This association was also found in other genetic models (P < 0.00001). Stratified analysis by ethnicity showed significant association in each genetic model among the Asian population. For ACE I/D polymorphism, five studies included 758 cases and 6,755 controls. No significant association was found in any genetic models.A total of 11 studies were included in the meta-analysis. For survivin G/C polymorphism, six articles reported 1,840 cases and 1,804 controls. Overall, we found the frequency of C allele is higher in CRC cases than that in the healthy controls (57.2% vs. 48.0%), and C allele significantly increased the risk of CRC compared to G allele in allele model (OR = 1.46, 95% CI = 1.33–1.60, Our results showed that survivin −31 G/C polymorphism might contribute to risk of CRC, especially in the Asian populations. However, the ACE I/D polymorphism is not a genetic factor concerning the risk for CRC. More studies with larger sample sizes are required in the future. Colorectal cancer (CRC) is one of the three most common cancers in the world and is a major contributor to cancer-related death . Each yeThe survivin gene, located in chromosome 17q25, is the smallest member of the inhibitor of apoptosis (IAP) gene family . It is aThe angiotensin-converting enzyme (ACE), a major component of the renin-angiotensin system (RAS), plays a crucial role in the regulation of circulatory homeostasis such as blood pressure and serum electrolytes . It is lNumerous studies have shown the association of these genetic polymorphisms with CRC ,15-25. HA comprehensive literature search was conducted using the online electronic database of Embase, Medline, PubMed, CNKI , and Wanfang. We retrieved the relevant articles published between January 2000 and March 2014 using the following terms: “colorectal cancer or colorectal carcinoma”, “angiotensin-converting enzyme or ACE”, “survivin”, and “polymorphism or variant or mutation” as well as their combinations. The references of retrieved articles were searched manually. When the same authors or laboratory reported the issue on the same group of people, only full-text articles of the most recent studies were included.The inclusion criteria were as follows: 1) case–control or cohort studies, 2) evaluating the contribution of survivin −31 G/C and ACE I/D polymorphisms with CRC risk, 3) the results presented in odds ratio (OR) with its 95% confidence interval (CI), and 4) genotype distributions in the cases and controls were available to extract.Two investigators independently assessed the data from the included studies. Any disagreement was discussed with a third expert to reach a final consensus. The following information was extracted: the name of first author, publication year, country, ethnicity, sample size, genotyping method, and the genotype frequencies in the cancer cases and controls.Z test was employed to determine the significance of the pooled ORs, and a P value less than 0.05 was considered statistically significant. The per-allele model , dominant model , recessive model , and additive model  were examined to assess these association. The I2 test and the Q statistic test were used to assess the between-study heterogeneity. The Mantel-Haenszel (M-H) fixed-effects model is used when the P value is more than 0.10 for the Q test and less than 50% for I2; otherwise, the random-effects model is used. The publication bias was assessed by visual funnel plot inspection. Review Manager  was used to conduct the statistical analyses. All the tests were two sided.The overall effect was measured by ORs with its 95% CI. The The initial search identified 284 references. Of those, 107 records were excluded for duplication and 177 articles were judged potentially relevant. Following the title and abstract screening, 40 full-text articles met inclusion criteria. Overall, a total of 11 studies (eight in English and three in Chinese) were finally included in this review. Figure Of the 11 case–control studies, there were five studies of Asians and six of Caucasian. For ACE I/D polymorphism, five studies containing 758 cases and 6,755 controls were included. For survivin G/C polymorphism, six articles reported 1,840 cases and 1,804 controls. Table P < 0.00001). This significant association was also found in other genetic models  as shown in Figures P < 0.00001; CC vs. GG: OR = 1.88, 95% CI = 1.52–2.33, P < 0.00001; CC + GC vs. GG: OR = 1.41, 95% CI = 1.17–1.70, P = 0.0003; CC vs. GC + GG: OR = 1.70, 95% CI = 1.44–2.01, P < 0.00001) in a fixed-effect model. Among the Caucasian population, Figure P < 0.0001). No relationship was found in other genetic models (P > 0.05).Table I2 was less than 50% and the P value was greater than 0.01, suggesting no heterogeneity was present. As shown in Figure P = 0.48). No significant association was found in other genetic models .Table A single study included in the meta-analysis was deleted each time to reflect the influence of the individual data set to the pooled ORs. The corresponding pooled ORs were not materially changed, which confirmed the stability of our overall result. The shape of funnel plots did not reveal any evidence of funnel plot asymmetry Figure .Figure 7CRC is a major cause of morbidity and mortality worldwide. Although surgical resection remains a curative option for CRC treatment, most patients with CRC are not suited for surgical operations because of the advanced stage of the lesions when diagnosed. Thus, there is an urgent need to identify newer biomarkers to evaluate the severity of this disease, predict the prognosis of patients, and target the pathogenic genes.Recently, survivin has been reported to be overexpressed in almost all human tumors. It is considered as a tumor-associated antigen for immune-based clinical approaches in CRC . ResearcSurvivin acts as an antagonist of apoptotic cell death and functions as a regulator of mitosis ,32. It iMuch evidence indicates that ACE associated with the pathology of carcinomas. It is differentially expressed in several malignancies. ACE is a monomeric glycoprotein that is distributed in many tissues and biological fluids . ACE canP > 0.05). This is in accordance with meta-analysis conducted by Liu et al. and Zhang et al. [Previous meta-analysis showed that the ACE I/D polymorphism is associated with hepatocellular carcinoma (HCC), indicating that this polymorphism contributes to HCC progression in the Chinese population . Recent g et al. ,45.Several limitations were presented in this meta-analysis. Firstly, the number of included studies in the subgroup analysis was small which may have a relatively lower power. Secondly, other covariates such as age, sex, and smoking condition should be considered if they are available in each individual study to obtain a more precise result. Thirdly, the gene-gene interaction which is important in developing complex diseases should also be included.In conclusion, the results from the present meta-analysis suggest that the survivin −31 G/C polymorphism might be correlated with an increased risk of CRC, indicating it may serve as a biomarker of disease progression. However, ACE I/D polymorphism is not associated with CRC risk. Further large and well-designed studies in various populations are needed to confirm our results. Moreover, the studies of gene-gene and gene-environment interactions between these polymorphisms and CRC risk should also be performed and considered.