OR = 1.23, 95%CI = 1.04–1.44), AA vs. GG , and AA vs. AG+GG genetic models ; however, the non-significantly increased risk was shown in AG vs. GG  and AA+AG vs. GG genetic models . Cumulative analysis showed that the association changed from non-significant to significant with new studies accumulated and the CIs became more and more narrow, sensitivity analysis indicated results were statistically robust. Stratified analyses of confirmed of HWE, Asians, Caucasians, and population-based controls obtained results similar to that of overall analysis. There was no evidence of publication bias. In summary, current evidence demonstrates that TNF-a G-308A polymorphism might be associated with AgP susceptibility, especially in Asians and Caucasians.Association between tumor necrosis factor-α (TNF-α) G-308A (rs1800629) polymorphism and susceptibility to aggressive periodontitis (AgP) were inconsistent, hence we performed this meta-analysis to clarify the association between them using Comprehensive Meta-Analysis v2.2 software. 16 case-control studies were searched from the PubMed, Embase and CNKI databases up to February 2, 2015. The meta-analysis showed a significantly increased risk in A vs. G ( Aggressive periodontitis (AgP) is featured of the rapid rate of disease progression, onset in healthy individuals without large accumulation of plaque and/or calculus, and with genetic familial trait12With the deepen research of human gene, the more extensive evidence of pathogenesis of periodontitis has been provided910111214et al. performed a meta-analysis and indicated that TNF-a -308 A allele was associated with periodontitisIn 2013, Song We followed the recommended Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statementOR) with its 95% confidence interval (CI) was reported; (v) when more than one publications covered the same study population, we only included the study with higher quality and more comprehensive information. Animal experiments, conference abstracts, and comments were excluded. Studies with AgP patients who had any systematic diseases, such as diabetes mellitus, coronary heart disease were also excluded.According to the “PICOS” principleA systematical search to retrieve published literatures from PubMed, Embase, and CNKI (China Knowledge Resource Integrated) databases was conducted up to February 2, 2015. The following key words and subject terms were used: “tumor necrosis factor alpha”, “TNF-α”, “TNF-alpha”, “periodontitis”, “periodontal disease”, “polymorphism”, “mutation”, and “variant”. Hand-searching of listed references of included studies, previous meta-analysis, and recent reviews was also performed to identify additional studies.OR with its 95%CI.The process of the data extraction was independently conducted and cross checked by two authors, and a third author participated in the discussion in case of divergence. We extracted the information as follows: the first author and year of publication, study area, ethnicity, smoking status, genotyping methods, the source of the controls, Hardy-Weinberg equilibrium (HWE) of control, and numbers of eligible genotyped cases and controls with the exhaustive data of each genotype distribution or the OR with its 95% CI in the allelic contrast (A vs. G), recessive model (AA vs. AG+GG), dominant model (AA+AG vs. GG), and co-dominant model (AA vs. GG and AG vs. GG) were calculated to assess the association between TNF-α G-308A polymorphism and AgP risk. First, heterogeneity among included studies was detected using I2 and Cochran Q statistics, and the value of I2 ≤50% and p > 0.1 indicates low heterogeneity and using fixed-effects model, otherwise the random-effects model is used1718192122242122The A total of 194 citations was yielded and finally 16 case-control studies involving 905 cases and 1270 controls were included272829303132333435363738394041OR and 95%CI of Allele comparison30Seven studies both included smokers and non-smokers30313334353729323638402728OR = 1.23, 95%CI = 1.04–1.44; OR = 2.07, 95%CI = 1.11–3.87; see OR = 2.09, 95%CI = 1.13–3.86; see OR = 1.06, 95%CI = 0.85–1.32; see OR = 1.06, 95%CI = 0.85–1.31; see The overall analysis showed a significantly increased risk in A vs. G  and symmetric funnel plots , gender, habits , stress, certain genetic polymorphisms, etc, future researches should try to strictly control various confounding factors to ensure the reliability of the results with explicit and strict inclusion criteria of cases. Thus, there are some points we recommend for further practices and researches. As we know, smoking is a risk factor and influence the treatment effect of periodontitis48How to cite this article: Wei, X.-M. et al. Tumor necrosis factor-a G-308A (rs1800629) polymorphism and aggressive periodontitis susceptibility: a meta-analysis of 16 case-control studies. Sci. Rep.6, 19099; doi: 10.1038/srep19099 (2016).


Epidermal growth factor (EGF) plays a pivotal role in cell proliferation, differentiation, and tumorigenesis of epithelial tissues. Variation of the EGF +61A/G (rs4444903) can lead to an alteration in EGF production and/or activity, which may result in individual susceptibility to gastric cancer. Studies investigating the association between EGF +61A/G polymorphism and gastric cancer risk produced inconsistent results. The aim of this study was to quantitatively summarize the evidence for such an association.Eligible studies on the association between EGF +61A/G polymorphism and gastric cancer risk were identified by search of electronic databases including PubMed, EMBASE, Cochrane Library, and Chinese Biomedical Literature database (CBM). Data were extracted by two independent authors and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association. Metaregression and subgroup analyses were performed to identify the source of heterogeneity.P = 0.038; GG + AG vs. AA: OR = 1.256, 95% CI 1.025–1.539, P = 0.028; GG vs. AG + AA: OR = 1.265, 95% CI 1.002–1.596, P = 0.048). In subgroup analysis by ethnicity, source of control, study quality, and HWE in controls, significant increased gastric cancer risk was observed in Asians, population-based studies, high quality studies, and studies consistent with HWE. In subgroup analysis according to tumor location, and histological type, significant association was observed in all subgroups.Finally, six case–control studies with 1547 gastric cancer cases and 2762 controls were eventually identified. Overall, significant increased gastric cancer risk was found when all studies were pooled in the meta-analysis (GG vs. AA: OR = 1.438, 95% CI 1.021–2.025, This meta-analysis suggested that the EGF +61A/G polymorphism contributes to increased gastric cancer risk, especially in Asian populations. Further well-designed studies based on large sample size in diverse populations are needed to confirm this association. H. pylori) infection was the major risk factor for gastric cancer [Gastric cancer is one of the most common cancers and the second leading cause of cancer-related death in the world ,2. Despic cancer ,4. Additc cancer ,6. HowevEpidermal growth factor (EGF) is a member of the EGF superfamily, which also includes transforming growth factor-α, heparin-binding EGF-like growth factor, epiregulin, betacellulin and amphiregulin . As a grIn light of the important biological function of the EGF +61A/G polymorphism, emerging epidemiological studies have been performed to investigate the association of EGF +61A/G polymorphism with gastric cancer risk, but the results remain inconsistent and underpowered. Some studies suggested that EGF +61A/G polymorphism was associated with an increased susceptibility to gastric cancer -17. HoweA comprehensive literature search in Pubmed, Embase, Cochrane library, and CBM was conducted using the following combined keywords: ‘EGF’, ‘epidermal growth factor’, ‘polymorphism’, ‘SNP’, ‘genetics’, and ‘gastric cancer’. The latest search was performed in September 2014. There was no restriction on time period, sample size, population, language, or type of report. Additional studies were identified by a hand search of the references cited in the reviews and the retrieved articles. In addition, we also used the “Related Articles” function in PubMed to search other potential eligible studies. If more than one study was published using the same or overlapped data, only the study with the largest sample size was selected. The study was performed according to the proposal of Meta-analysis of Observational Studies in Epidemiology group (MOOSE) .Studies included in the meta-analysis were required to meet the following criteria: (1) case–control or cohort studies which investigated the association of EGF +61A/G polymorphism with gastric cancer; (2) provided an odds ratio (OR) with 95% confidence interval (CI) or other information for estimating OR (95% CI); and (3) the control group did not include malignant tumor patients. Studies were excluded if one of the following existed: (1) duplicate of previous publication; (2) no control population; (3) insufficient information for data extraction; and (4) case reports, conference abstracts, reviews, editorials, and letters.Two authors independently assessed the quality of the studies by scoring according to the predetermined criteria Table  which waTwo authors (Xiaolian Zhang and Xianjun Lao) independently extracted data and reached consensus on all of the items. For each study, the following information was sought: first author, year of publication, country of origin, ethnicity of the study population, numbers of cases and controls, genotyping methods, matching criteria, source of control, ascertainment of cases, and distribution of genotypes and alleles in both groups. The tumor location and histological type of the gastric cancer cases were additionally recorded for the stratified analysis. When the genotype frequencies in a study were not provided, we contacted the authors to get the relevant information by e-mail or telephone.We assessed HWE in the controls for each study using a goodness-of-fit test (chi-square or Fisher’s exact test), and a P < 0.05 was considered as significant disequilibrium. The strength of the association between EGF +61A/G polymorphism and gastric cancer was estimated using ORs with the corresponding 95% CIs. The pooled ORs were performed for codominant model , dominant model (GG + AG vs. AA) and recessive model (GG vs. AG + AA).Q test was PQ < 0.10, suggesting the existence of heterogeneity, the pooled ORs were calculated using the random-effects model (the DerSimonian and Laird method) [Q test was PQ ≥ 0.1, indicating the absence of heterogeneity, the fixed-effects model (the Mantel–Haenszel method) [The Chi-square-based Q test was used to assess the statistical heterogeneity among studies . If the  method) . Otherwi method)  was usedSensitivity analysis was performed by sequentially excluded the individual studies to assess the robustness of the results. Begg’s funnel plot and Egger’s regression asymmetry test were performed to evaluate the publication bias . If the Based on the search strategy, seven studies evaluating the EGF +61A/G polymorphism and gastric cancer susceptibility were identified. One of these articles was excluded because it was not case–control or cohort study . Manual P = 0.038; GG + AG vs. AA: OR = 1.256, 95% CI 1.025–1.539, P = 0.028; GG vs. AG + AA: OR = 1.265, 95% CI 1.002–1.596, P = 0.048). In subgroup analysis by ethnicity, significant increased gastric cancer risk was found in Asian populations , but not in Caucasian populations. In stratified analysis according to source of control, significant increased gastric cancer risk was observed in population-based studies , but not in hospital-based studies. In subgroup analysis by study quality, significant increased gastric cancer risk was observed in high quality studies , but not in low quality studies. In stratified analysis by HWE in controls, significant increased gastric cancer risk was found in studies consistent with HWE , but not in studies inconsistent with HWE. In subgroup analyses according to tumor location and histological type, significant association was observed in all subgroups.As shown in Table PQ = 0.074; GG vs. AG + AA: PQ = 0.048; Table Statistical significant heterogeneity among studies was observed in the association analysis between the EGF +61A/G polymorphism and gastric cancer risk in the overall populations , providing statistical evidence of the funnel plots’ symmetry. The results suggested that publication bias did not present in this study.Begg’s funnel plot and Egger’s test were performed to assess the publication bias of literatures. The shape of the funnel plot did not reveal any evidence of obvious asymmetry Figure . Then, tThe epidermal growth factor (EGF), which was identified as a potent mitogenic peptide, has multiple biological functions including induction of DNA synthesis, proliferation, differentiation, and tumorigenesis of epidermal and epithelial tissues through interaction with its receptor EGFR ,31. MounIn the present study, we observed that the EGF +61A/G polymorphism presented a risk factor for gastric cancer in Asian populations, but not in Caucasian populations. The inconsistent results among diverse ethnicities demonstrated different roles of the EGF +61A/G polymorphism on gastric cancer risk in different ethnic genetic backgrounds. Nevertheless, because of the limited number of studies among Caucasians included in this study, the observed association between the EGF +61A/G polymorphism and gastric cancer in Caucasians may be caused by chance, because study with small sample size may have insufficient statistical power to determine a slight effect or may have produced an unstable estimation. In this study, there was only one study for Caucasians concerning the EGF +61A/G polymorphism on gastric cancer risk . MoreoveIn subgroup analysis according to the source of control, statistical significant increased gastric cancer risk was observed in population-based studies, but not in hospital-based studies. The reason may be that the hospital-based studies have inherent selection bias because of the fact that the controls in hospital-based studies may just represent a sample of ill-defined reference population, and may not be representative of the study population or the general population . When stIt was possible that the selection bias could have played a role in the present meta-analysis, because the genotype distribution of the EGF +61A/G polymorphism in the control populations deviates from the law of HWE in one of the eligible studies . PreviouPQ = 0.074; GG vs. AG + AA: PQ = 0.020). To identify the sources of heterogeneity, we performed subgroup analyses and meta-regression analysis. Subgroup analyses by source of controls and study quality revealed that the heterogeneity still existed in hospital-based studies and low quality studies. Then we performed meta-regression analysis to further identify the source of heterogeneity. Meta-regression analysis revealed that the HWE in controls was the major source of the heterogeneity. When excluding the HWE-violating study, all PQ values in the overall populations and subgroup analyses were greater than 0.10. Interestingly, the summary ORs in the overall population and subgroup analyses were not materially changed by excluding this study, suggesting that our results were robust and reliable.One of the main concerns in a sound meta-analysis is the heterogeneity which exists between studies because heterogeneous data are liable to result in misleading results, and finding the sources of heterogeneity is one of the most important goals in a meta-analysis ,41. In tH. pylori positive and so on. Therefore, non-differential misclassification bias was possible because these studies may have included the control populations who have different risk of developing gastric cancer. Second, our results were based on unadjusted estimates and a more precise analysis could be conducted if more individual data were available, this would allow for adjustment by other covariates such as the quantity of salty food consumption, drinking, smoking and H. pylori infection. Third, the number of studies included in the meta-analysis for Caucasian population was relatively small and there was only one study in the Caucasian group, which may lead to insufficient statistical power and generated a fluctuate estimation.Some limitations of this meta-analysis should be mentioned. First, the controls of the eligible studies were not uniformly defined. Although the controls were mainly selected from healthy subjects, some had benign disease such as chronic gastritis, Despite the limitations, this meta-analysis strongly suggests that the EGF +61A/G polymorphism contributes to increased gastric cancer susceptibility, especially in Asian populations. Further studies with large sample size and well design in diverse ethnicities should be conducted to further investigate the association.


APOC3 on plasma lipid and risk of CAD in a Chinese population.The disorder of triglyceride (TG) metabolism leading to hypertriglyceridemia is an independent risk factor for coronary artery disease (CAD). Variants in the apolipoprotein C3 (APOC3) gene were found to be associated with elevated TG levels. The purpose of this study was to investigate the effect of two polymorphisms (1100 C/T and 3238 C/G) of APOC3 gene polymorphism was analyzed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).The study population consisted of 600 patients with CAD and 600 age- and gender-matched controls. The APOC3 3238 GG genotype  and APOC3 3238 G allele  than controls. The findings are still emphatic by the Bonferroni correction. When stratifying by hyperlipidemia, CAD patients with hyperlipidemia had a significantly higher frequency of APOC3 3238 GG genotype  than without hyperlipidemia. The APOC3 3238 G allele was significantly associated with increasing plasma TG levels and very-low-density lipoprotein cholesterol (VLDL-C) levels both in cases and controls (P < 0.001).Patients with CAD had a significantly higher frequency of APOC3 3238 G allele might contribute to an increased risk of CAD as a result of its effect on TG and VLDL-C metabolism.The  Coronary artery disease (CAD), one of the most common cardiovascular diseases, is the leading cause of morbidity and mortality worldwide . It is cAPOC3 gene, mapped to chromosome 11q23, was involved in transport and clearance of chylomicron remnants, and very-low-density lipoprotein (VLDL) and HDL from the bloodstream [APOC3 gene: 1100 C/T and 3238 C/G [APOC3 3238 C/G polymorphisms have been found to be associated with altered plasma TG concentrations [Apolipoprotein C3 (APOC3), a component of triglyceride (TG)-rich lipoproteins and high-density lipoprotein (HDL), was mainly synthesized in the liver and to some extent in the intestine . APOC3 godstream , 13. Two3238 C/G , 15. Thetrations .APOC3 3238G allele was a risk factor for CAD in Indians [APOC3 on plasma lipid and risk of CAD in a Chinese population.Recently, case–control study has suggested that the  Indians –19. HoweA hospital-based case–control study was carried out in 600 patients with CAD and 600 age- and gender-matched controls from January 2012 to January 2014 in the Yantai Yuhuangding Hospital and Clinical College of Yanbian University, China. Based on WHO criteria, CAD cases were defined as those having severe angiostenosis (>50%) in at least one major coronary artery determined by angiography. The control group was composed of age- and gender-matched subjects who had undergone a coronary angiography in the same recruitment period as the CAD patients, without angiographic evidence of CAD. Controls selected also had at least one conventional predisposing factor of CAD. The controls were required to have no history or ECG signs of angina pectoris, myocardial infarction, or other cardiovascular diseases. In addition, similar to the cases the controls were all required to be born in China to native Chinese Han parents. To confirm the diagnosis, two physicians reviewed the hospital records and validated each case. The Institutional Ethical Committee approved this study, and all participants gave written informed consent according to the Declaration of Helsinki.APOC3 gene polymorphisms. Based on the GenBank reference sequence, the PCR primers designed for APOC3 1100 C/T and 3238 C/G were 5′-AGA GGC CGA TCC ACC CCA CTC AGC C-3′ (forward) and 5′-GGC GGT CTT GGT GGC GTG CTT CAG G-3′ (reverse); 5′-CAT GGT TGC CTA CAG AGG AGT-3′ (forward) and 5′-TGA CCT TCC GCA CAA AGC TGT-3′ (reverse), respectively. The amplified PCR products were digested with SstI (3238 C/G) and SacI (1100 C/T) . Details of PCR conditions have been described elsewhere [The commercially available Qiagen kit  was used to extract DNA from peripheral blood leukocytes. Genomic DNA was isolated from 20 g/L ethylenediaminetetraacetic acid (EDTA) or sodium citrate anticoagulated 3–5 ml venous blood and stored at 4°C. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay was applied to assess the x2 goodness-of-fit test. Differences between continuous variables were assessed by Student’s t test, while those between categorical variables were evaluated using Pearson x2 test. The existence of differences in genotypic frequencies between groups was assessed by means of Pearson x2 test and calculating the odds ratio (OR) with the 95% confidence intervals (CI). OR adjusted for other covariables  were determined using logistic regression models. We also use the Bonferroni correction for total number of independent comparisons. A P-value was considered significant at a level of <0.05.All statistical tests were performed using the program SPSS . Linkage disequilibrium was calculated by EXCEL and the method of Chakravarti et al. . Hardy–WP < 0.001), diabetes (P < 0.001), obesity (P < 0.001), hyperlipidemia (P < 0.001), TG (P < 0.001), TC (P < 0.001), HDL-C (P = 0.002), LDL-C (P = 0.001) and VLDL-C (P < 0.001) were risk factors of CAD  and APOC3 3238 G allele  than controls  than without hyperlipidemia   were associated with the metabolic syndrome [The sistance . A case–ts on TG . A popultes risk . APOC3 gwith HIV . A case–syndrome . A case–bese men . A case–hropathy . A case–pulation . A case–syndrome , 40.APOC3 3238 G allele might contribute to an increased risk of CAD is still unclear, it is widely suspected that as a result of its effect on lipid metabolism. A meta-analyses of 29 Western prospective studies involving 262,525 participants indicated moderate and highly significant associations between triglyceride values and CAD risk [APOC3 3238 C/G polymorphisms were associated with higher serum triglyceride levels [APOC3 3238 G allele was significantly associated with increasing plasma TG levels and VLDL-C levels.Although the exact mechanism by which the CAD risk . The Boge levels . Our stuStrength of this study was a relatively large sample size. Several limitations of our study should be addressed. First of all, potential selection bias might have been present, because this is a hospital based case control study and the subjects may not be representative of the general population. Second, this study only considers a Chinese population that may limit the application of these findings to other ethnic populations. Third, CAD is induced by multiple genes and environmental factors, which were not explored in the present study.APOC3 3238 G allele might contribute to an increased risk of CAD as a result of its effect on TG and VLDL-C metabolism. Additional studies are needed to confirm this finding.In conclusion, our study suggested that the


Systemic inflammatory factors are inconsistently associated with the pathogenesis of chronic obstructive pulmonary disease (COPD). We conducted a systematic review and meta-analysis to summarize the evidence supporting the association between systemic inflammation and the risk of COPD. Pertinent studies were retrieved from PubMed, EmBase, and the Cochrane Library until April 2015. A random-effects model was used to process the data, and the analysis was further stratified by factors affecting these associations. Sensitivity analyses for publication bias were performed. We included 24 observational studies reporting data on 10,677 COPD patients and 28,660 controls. Overall, we noted that COPD was associated with elevated serum CRP , leukocytes , IL-6 , IL-8 , and fibrinogen levels  when compared with control. However, COPD was not significantly associated with TNF-α levels when compared with control . Our findings suggested that COPD was associated with elevated serum CRP, leukocytes, IL-6, IL-8, and fibrinogen, without any significant relationship with TNF-α. Chronic obstructive pulmonary disease (COPD) is one of the major causes of death . COPD isSeveral retrospective studies have suggested that active inflammation marked by increased serum levels of tumor necrosis factor-α (TNF-α), interleukin (IL-6), and C-reactive protein (CRP) was associated with the progression of COPD –15. HoweIn 2004, Gan et al  conducteOur study was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Statement issued in 2009  25]. We. We25]. The literature search was undertaken by two authors independently. Any inconsistencies between the two authors were resolved by group discussion to arrive at a consensus. The inclusion criteria of studies were: (1) patients with COPD; (2) participants in control group without COPD; (3) studies reporting at least one of the following markers: CRP, IL-6, IL-8, TNF-α, leukocyte, or fibrinogen levels in COPD and control groups; and (4) studies reporting mean, standard deviation and sample size for comparison of case and control for each inflammatory factor. In case of studies without adequate data, we contacted the authors or searched similar articles, which reported sample populations to obtain the unpublished results.Data extraction and assessment were performed independently by two reviewers. Publication information , characteristics of patients and control , and outcome variables  were extracted. Any disagreement was resolved by consensus with a third reviewer.Two reviewers independently evaluated the quality of the included study using the Newcastle-Ottawa Scale (NOS) , which w1 predicted. Sensitivity analyses were also conducted by removing each individual study from the meta-analysis [We examined the relationship between markers of systemic inflammation and COPD pathogenesis on the basis of the mean, standard deviation, and sample size in each group, published in each study. Standard mean difference (SMD) was used as a summary statistic. The SMD was significant when the 95% confidence interval (CI) did not include 0. We pooled the SMDs for each inflammatory marker and COPD pathogenesis using random-effects models ,28. Heteanalysis . Egger [analysis  and Begganalysis  tests weThe primary search produced 3,942 records. After scanning titles and abstracts, we excluded 3,868 irrelevant or duplicate articles. A total of 74 potentially eligible studies were selected, and after detailed evaluation, 24 observational studies ,34–42 weA total of 21 cohorts in 20 studies reported an association between CRP and the pathogenesis of COPD. The pooled SMD showed that COPD was associated with higher CRP levels when compared with control  and 9 cohorts (8 studies) for IL-6 and IL-8 levels, respectively. The pooled analysis of the relationship between IL-6 and IL-8 levels with COPD pathogenesis suggested that COPD patients showed higher IL-6 , and included a total of 10,677 COPD cases, and 28,660 controls. Results from pooled analyses showed that COPD was associated with an elevated CRP, leukocyte, IL-6, IL-8, and fibrinogen levels when compared with control group, without any significant differences in TNF-α levels. These results enable us to refine the definition of clinical phenotypes and monitor the response to existing and new therapeutic strategies, and assist physicians with accurate therapeutic decision-making.A previous meta-analysis  suggesteMost of our findings were consistent with previous studies. However, several studies reported inconsistent results. Aaron et al  suggesteWe observed that COPD was associated with elevated IL-6, and IL-8 levels when compared with control. However, several studies included in our study reported inconsistent results. Harting et al  suggestePrevious study suggested that fibrinogen was probably a useful biomarker to stratify individuals with a high or low risk of COPD exacerbation . In our No significant association was seen between TNF-α level and the pathogenesis of COPD. In our pooled analysis of 10 studies, five reported that COPD was associated with elevated TNF-α level, whereas two studies found COPD associated with lower TNF-α level, and the remaining 3 reported no significant relationship. A previous meta-analysis  also sugThe strengths of our study relate to the large sample size allowing us to quantitatively evaluate the relationship of systemic inflammation with the pathogenesis of COPD. Therefore, our findings are potentially more robust than those of any individual study. Further, we summarized six important markers and their potential role in COPD, and explored the relationships in several specific subpopulations.The limitations of our meta-analysis relate to the use of pooled data. Individual data were not available, which precluded a more detailed and comprehensive analysis. In addition, meta-analyses always use published studies, and publication bias is inevitable.In conclusion, the results of our study indicate that systemic inflammatory markers play an important role in the pathogenesis of COPD. Further large-scale studies are needed to corroborate the findings, before providing recommendations for identifying clinical phenotypes and monitoring therapeutic response.S1 Checklist(DOC)Click here for additional data file.


LEP) and leptin receptor (LEPR) genes on T2DM. This study aimed to investigate the association between these gene polymorphisms and T2DM by a systematic review and meta-analysis. Published studies were identified through extensive search in PubMed and EMBASE. A total of 5143 T2DM cases and 5021 controls from 14 articles were included in this study. Five functional variants in LEPR were well evaluated. Meta-analysis showed that rs1137101 (p.R223Q) was significantly associated with T2DM in all genetic models: allele model  = 1.13–1.42), dominant model , homozygote model , and recessive model , with minimal heterogeneity and no indication of publication bias. Similar associations with T2DM were also found for rs62589000 (p.P1019P) and 3′UTR ins/del, although the data was obtained from a small number of studies. For the other two polymorphisms rs1137100 (p.R109K) and rs8179183 (p.K656N), they were not significantly associated with T2DM. Our results provide robust evidences for the genetic association of rs1137101 (p.R223Q) in LEPR with T2DM susceptibility.Leptin is a hormone protein regulating food intake and energy expenditure. A number of studies have evaluated the genetic effect of leptin ( Type 2 diabetes mellitus (T2DM) is a group of metabolic disorders with insulin secretion deficiency or insulin resistance (IR) and characterized by hyperglycemia. The prevalence of diabetes increases significantly in recent decades, affecting about 6% of adult population globally. Therefore, it is one of the major health care challenges in the world . T2DM isLeptin is a hormone protein important in regulating food intake and energy expenditure for energy balance, fertility, and metabolism, which are mediated by the cell surface leptin receptor (LepR) , 6. It iLERP) on chromosome 1p31. Several functional variants with possible biological effects on metabolism regulation have been extensively investigated for the genetic predispositions on diabetes and its complications. These gene polymorphisms include rs1137101 (p.Arg223Gln or p.R223Q), rs1137100 (p.Arg109Lys or p.R109K), rs8179183 (p.Lys656Asn or p.K656N), rs62589000 (p.Pro1019Pro or p.P1019P), 3′-untranslated region (UTR) ins/del, rs1805134 (p.Ser343Ser or p.S343S), and rs2228301 (p.Asn567Asn or p.N567N) [LepR is encoded by the leptin receptor gene  sufficient genotype distribution data in case and control groups; (4) study samples being unrelated individuals drawn from clearly defined populations; (5) written in English. The exclusion criteria were defined as studies on animals, case reports, reviews, abstracts, editorial comments, and reports with incomplete data.A comprehensive literature search was conducted in online databases, MEDLINE  and EMBASE (via Ovid) engines up to July 2015. The following medical subject headings and keywords were used for search strategy: “leptin”, “leptin receptor”, “LEP”, “LEPR”, “gene(s)”, “polymorphism(s)”, “mutation(s)”, “variant(s)”, “diabetes”, “diabetic”, “DM”, and “diabetes mellitus”. References lists of the retrieved articles and reviews were also screened for additional articles not captured by electronic search. Eligible studies were defined as the following criteria: (1) case-control study; (2) investigating the association between T2DM andThe following information was extracted from each study: first author, year of publication, country of studies, ethnicity, sample size, age, gender, allele/genotypic frequencies, and body mass index (BMI). If the test for Hardy-Weinberg equilibrium (HWE) was not reported, it was tested by the genotype data. The quality of studies was evaluated independently by two investigators (M. M. Yang and J. Wang) according to the Newcastle-Ottawa Scale (NOS). Uncertainties were resolved by discussions or by consensus with a third reviewer (J. J. Fan). NOS evaluated studies with a star-rating system ranging from 0 (lowest) to 9 (highest) stars, which was based on three study components, including selection, comparability, and outcome assessment. Studies with more than 5 points were evaluated as qualified. LEPR polymorphisms and T2DM risk. The regression coefficients and the associated standard errors  were combined using meta-analytic software. The combined ORs were, respectively, calculated by four genetic models . HWE among controls was evaluated by χ2 test and P < 0.05 was considered as significant disequilibrium. Both Cochran's Q statistic testing degree of heterogeneity across studies and the index I2 statistic quantifying the proportion of heterogeneity between studies were calculated; P value less than 0.10 for the Q-test and I2 above 50% were considered as statistically significant. If there was significant heterogeneity, the random effects model would be used to analyze the pooled ORs; otherwise, the fixed effects model would be applied. We used univariate random effects metaregression to investigate the potential sources of heterogeneity, such as, ethnicity, sample size, source of control, and publication years. Sensitivity analysis was used to assess the stability of results by systematically removing each study and reassessing the significance, whereas funnel plot and Egger's test were used to assess the potential publication bias. Statistical analyses were conducted by Review Manager .Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CI) were used to estimate the association strength betweenP values of each SNP were presented in The search and selection process of included studies was presented in PQ = 0.13, I2 = 38%). Our result demonstrated a positive correlation between R allele of p.R223Q and T2DM risk. Significant association was also observed under other genetic models   yielded a pooled OR of 1.27 (95% CI: 1.13–1.42) with minimal heterogeneity  .I2 = 0%) except mild heterogeneity in the dominant model (I2 = 27%).For p.R109K variant, seven studies containing 3536 cases and 2268 controls were included. The pooled analysis showed that R109K had no significant association with T2DM susceptibility for all genetic models: allele , dominant model , homozygote model , and recessive model  . The ORsI2 ≤ 25%, The association between p.K656N and T2DM has been examined in five studies, including 2018 cases and 1641 controls. Overall, no significant association was observed in any genetic models. The genetic effects were homogeneous across studies , and the random effect model was therefore used but no significant association was observed    . Regardi, resp.) . Two varP = 0.015) and source of control (P = 0.029) contributed heterogeneity, while ethnicity (P = 0.648) and publication year (P = 0.429) did not. Regarding rs62589000 (p.P1019P), the sensitivity analysis showed that the data from Lu et al. apparently influenced the overall results; therefore, the pooled ORs need be taken into account [P = 0.524 for rs1137101).In order to examine the influence of each study set to the pooled ORs, sensitivity analysis was performed by omitting one study in each time. For the variants, rs1137101 p.R223Q), rs1137100 (p.R109K), and rs8179183 (p.K656N), the ORs were not significantly influenced by individual data, indicating that our results were statistically stable and robust. Metaregression was performed to detect the source of heterogeneity for the significant finding of rs1137101; the results indicated that sample size P = 0.0 and sourQ, rs1137 LEPR and T2DM, we, for the first time, conducted a systematic review and meta-analysis to examine the associations of LEPR polymorphisms with T2DM risk. For this meta-analysis, five of the most commonly investigated LEPR SNPs were analyzed. Among them, p.R223Q was found to be significantly associated with T2DM, which remained significant even after sensitivity analysis. Genetic effect with allele R showed a positive association with T2DM from 1.19- to 1.82-fold under different genetic models. This result provides robust evidence for the genetic impact of leptin on diabetes, which will lead to further biological function investigation.In recent years, numerous studies have been conducted to evaluate the genetic influence of leptin to T2DM susceptibility. While the reports in different ethnic groups often yielded contradictory results, the inconsistencies could be due to the lack of power in each individual study with limited sample size as well as the heterogeneous data and methods. To confirm the association of LEPR p.R223Q  leads to an amino acid alteration from Arg to Gln located in the regulatory domain of the LEPR protein. Study by Murugesan et al. found that the levels of leptin, insulin, and body mass index (BMI) were significantly increased with homozygous and heterozygous variants of p.R223Q and showed significant difference between cases and controls [It is well known that obesity is a major link to T2DM, especially characterized by insulin resistance . As leptcontrols . These rcontrols . RegardiFor other two functional variants, p.R109Q and p.K656N, no significant associations were found with T2DM under any genetic models, implying that these two variants might not contribute to the risk of T2DM. With regard to p.P1019P and 3′UTR ins/del, significant association was identified with T2DM, but the results were largely influenced by particular article and a limited number of studies were available. Therefore, these associations should be carefully interpreted, and further examinations in larger cohorts are warranted.There are a number of limitations in our current meta-analysis. Firstly, only 14 available studies were enrolled. The number is not enough for every variant in the meta-analysis, such as p.P1019P and 3′UTR ins/del. Secondly, the small sample size conferred limited statistical power for exploring real association, especially for the subgroup analysis. Thirdly, as a multifactorial disease, a more precise analysis on T2DM-related factors should be conducted, such as BMI, age, and environmental exposure; however, some studies did not provide the detailed information. LEPR gene with T2DM. Our results suggested that the polymorphism rs1137101 (p.R223Q) has strong association with T2DM susceptibility. More studies in larger cohort and functional analyses of LEPR are required to reinforce the results and elucidate its biological roles in diabetes.To the best of our knowledge, this is the first meta-analysis to investigate the association of


PTPN22 single nucleotide polymorphism (SNP) rs2476601 is associated with JIA susceptibility. It was recently reported in an Australian study that this association is restricted to females and is not observed in males. A significant source of inconsistency amongst the literature on autoimmune disease susceptibility genes stems from an inability to replicate genetic findings across different racial or ethnic groups. We therefore attempted to generate further evidence of the female-specific association of rs2476601 in a homogeneous Greek population.Juvenile idiopathic arthritis (JIA) is an autoimmune disease characterized by persistent chronic arthritis. Disease risk is believed to be influenced by both genetic and environmental factors. It is well established that the PTPN22 was associated with increased risk of JIA in this Greek sample . Sex-stratified analyses showed that, once again, the risk association was restricted to females  supporting the prior findings.We genotyped rs2476601 in 128 Caucasian JIA patients  and 221 healthy controls  from Northern Greece. Overall, PTPN22 in JIA.Our data demonstrates that this sex-specific pattern of association is broadly applicable to different populations, and provides further impetus to undertake mechanistic studies to understand the impact of sex on  Autoimmunity is believed to result from a combination of genetic factors and environmental triggers and one feature that is shared among many autoimmune disorders, including juvenile idiopathic arthritis (JIA), is the increased proportion of females that develop the disorder. The reason for the observed sex bias remains elusive, and relatively few studies have comprehensively investigated this phenomenon from a mechanistic perspective, especially in JIA.JIA is the most common chronic arthritis of childhood  and is aAccumulated evidence indicates that ethnic heterogeneity may complicate genetic association studies in rheumatic diseases –7. TherePTPN22) has been repeatedly associated with a wide range of autoimmune diseases, including JIA [A non-synonymous SNP, rs2476601 , located in the gene encoding protein tyrosine phosphatase nonreceptor 22  were available for analysis. Only patients who fulfilled the 2001 revised International League of Associations for Rheumatology (ILAR) criteria for JIA and gave their informed consent were eligible for the study. Cases were of mixed ILAR subtype, as detailed in [In this case-control association study, one hundred and twenty eight JIA patients , followed in the Rheumatology Units of the 4ailed in . Two hunailed in . All patPTPN22 rs2476601 (XcmI) polymorphism by restriction fragment length polymorphism (RFLP) analysis as described previously [Genomic DNA was isolated from peripheral blood leukocytes by using the commercial kit PUREGENE  according to the manufacturer’s instructions and genotyping was performed for the 2) test both in case and control groups. The HWE test was performed in combination with an analysis for ascertainment bias for dominant/recessive models  by using the program "Calculate" . Further statistical analyses were undertaken using Stata v14 . Logistic regression was used to generate ORs and 95 % CIs for the association of rs2476601 with JIA. For analyses where logistic regression could not be performed because of the absence of the minor allele in any one group, we used the Gart method [P-value. We also performed a ‘pooled control’ analysis , following past work on PTPN22 and JIA in other populations [P value less than 0.05 was considered significant.Initial statistical analyses were performed using GraphPad Prism statistical program . All cases and controls used in the analysis were unrelated. The genetic variant under investigation was evaluated for deviation from Hardy–Weinberg equilibrium (HWE) by comparing observed and expected genotype frequencies by means of chi-squared  in a direction consistent with previous findings. When stratified by sex, we observed association of rs2476601 with increased risk of JIA in females . The wide confidence interval reflects the small sample size, and the fact that no minor alleles were observed in female controls. The pooled-control analysis, which hypothesizes that male JIA risk is not affected by rs2476601 and therefore male cases are essentially controls, further supported an association of rs2476601 with female JIA . In males, no association between rs2476601 and JIA was observed . Exclusion of systemic JIA cases did not materially alter the findings. This sex-specific pattern of association, including the direction of effect, is consistent with the prior study conducted in Australian, US and Norwegian samples [Allele frequencies of the PTPN22 rs2476601 specifically with JIA in female patients in a population from Greece.Over the last decade, several studies have investigated candidate genes to discover or confirm associations with JIA phenotypes (e.g. ). ImportPTPN22 contributes to the modulation of negative T cell selection in the thymus and downregulation of autoreactive T cells in the periphery [PTPN22 polymorphism may be mainly relevant to females [eriphery . It has eriphery . As a coeriphery , the obs females .PTPN22 rs2476601 shows a wide variation in “T” allele frequencies among different ethnic populations, with a North–South gradient in Europe ranging between 15.5 % (north) and 2.1 % (south) [. [ (south) . Lee et PTPN22 SNP and the risk of JIA by independent replication in a Greek population, demonstrating the broader applicability of this finding across various ethnic groups. This locus is of particular interest in this context given that the genetic variant under investigation occurs at different frequency in the Greek population compared to other European populations. The importance of comparative studies in populations of different ethnic and/or racial origins is high in any attempt to conclusively define the genetic architecture of JIA and the magnitude of the effects of specific risk alleles in different populations.In conclusion, our results provide additional evidence for a female-specific association between the rs2476601


Previous studies on the association between the −94ins/del ATTG polymorphism and cancer risk reported conflicting results. To clarify this relationship, we performed a meta-analysis of 21 case-control studies involving 6127 cases and 9238 controls. We used pooled odds ratios (ORs) with their 95% confidence intervals (95% CIs) to assess the association. We found that the NFKB1 promoter −94ins/del ATTG polymorphism was significantly associated with cancer risk in four genetic models . Stratified analyses revealed a significant association between the polymorphism and ovarian, oral, and prostate cancers. Similar results were determined in an Asian population and not in a Caucasian population. Thus, our results suggested that the polymorphism can contribute to cancer risk. Moreover, the polymorphism can exert race- and cancer-specific effects on cancer risk. Further large-scale and functional studies are necessary to elucidate this possible effect.Nuclear factor- Cancer is a major public health problem worldwide; it is the primary and secondary causes of death in economically developed and developing countries, respectively . The gloκB (NF-κB) was initially identified in 1986 as a transcription factor which binds to a 10 bp DNA element in kappa immunoglobulin light-chain enhancer in B cells [κB family consists of p50 (NF-κB1), p52 (NF-κB2), p65 (RelA), c-Rel (Rel), and RelB. The major form of NF-κB is a heterodimer of the p50 and p65/RelA subunits which are encoded by the NFKB1 and NFKB2 genes, respectively [ NFKB1 gene is mapped to chromosome 4q24 and encodes a 50 kDa DNA-binding protein (p50) that can act as a master regulator of inflammation and cancer development [Nuclear factor- B cells . The NF-ectively . The humelopment . NFKB1 gene elicits a regulatory effect on the NFKB1 gene [ NFKB1 promoter −94ins/del ATTG polymorphism and cancer risk [ NFKB1 promoter −94ins/del ATTG polymorphism and cancer risk.A common insertion/deletion polymorphism  in the promoter region of thecer risk –12. Howehttp://www.ncbi.nlm.nih.gov/pubmed/) was performed with the following key words: , , and . The search was limited to human studies in English. All eligible studies were retrieved. The reviews and references of eligible studies were hand-searched for additional relevant publications. The most recent or complete study was selected when more than one publications contain overlapping data. A flow diagram of the study selection process is presented in A comprehensive literature search for relevant articles published  in PubMed  according to the inclusion criteria listed above, and the result was reviewed by a third investigator (Jun Tao). The following data were collected from each study: surname of first author, year of publication, ethnicity, genotyping method, source of controls, frequencies of the genotypes in cases and controls, cancer type, and Hardy-Weinberg equilibrium (HWE) of genotype distribution among controls. Ethnicity was categorised as “Asian” or “Caucasian.” Studies that investigated more than one type of cancer were regarded as individual datasets only in subgroup analyses according to cancer type. No minimum number of patients was required for this meta-analysis. Articles that reported different ethnic groups and countries or locations were considered different study samples for each category cited above. NFKB1 promoter −94ins/del ATTG polymorphism and cancer risk was estimated through pooled odds ratio (OR) with its corresponding 95% CI. Pooled ORs were calculated for insertion allele versus deletion allele, ins/ins versus del/del, ins/del versus del/del, ins/ins + ins/del versus del/del, and ins/ins versus ins/del + del/del. Subgroup stratification analyses by ethnicity and cancer type were conducted to identify the association of the −94ins/del ATTG polymorphism with cancer susceptibility.The strength of association between theQ and I2 statistic tests, where I2 > 50% indicated heterogeneity [I2 was significant (>50%); otherwise, the fixed-effects model was selected. The allele frequencies of the NFKB1 promoter −94ins/del ATTG polymorphism from the respective study were determined by allele counting. In addition, a chi-square test was used to determine whether or not the observed frequencies of genotypes conform to HWE. Pooled OR in the current meta-analysis was performed by weighting individual ORs by the inverse of their variance. The significance of the pooled OR was determined by the Z-test. In addition to the comparison among all subjects, we performed stratification analyses by cancer type  and ethnicity. Begg's funnel plot and Egger's test were adopted to evaluate the publication bias in our meta-analysis [The between-study heterogeneity of the studies included in this meta-analysis was evaluated using the ogeneity . The rananalysis , 15. All NFKB1 promoter −94ins/del ATTG polymorphism were extracted from all eligible studies. In total, this meta-analysis included 3 bladder cancer studies, 4 colorectal cancer studies, 2 ovarian cancer studies, 2 oral cancer studies, 2 prostate cancer studies, and 8 studies with the “other cancers.” Of the 21 studies, 14 were conducted among Asians and 7 were conducted among Caucasians. All cases were clinically pathologically confirmed.A total of 21 case-control studies involving 6127 cases and 9239 controls were analysed. The characteristics of all studies are presented in The results of HWE test for the genotype distribution in the control population are shown in  NFKB1 promoter −94ins/del ATTG polymorphism and cancer risk across the four genetic models ins/ins versus del/del, OR = 1.47, 95%, CI = 1.11—1.93; dominant model, OR = 1.26, 95%  CI = 1.03—1.53; recessive model, OR = 1.26, 95%  CI = 1.05—1.51; and ins allele versus del allele, OR = 1.19, 95%, CI = 1.05–1.35 (http://dx.doi.org/10.1155/2014/612972).The pooled ORs of the included case-control studies revealed a statistically significant association between the.05–1.35 . StratifP = 0.004).Publication bias was evaluated by Begg's funnel plot and Egger's test, and the visual asymmetry was determined in the funnel plot analysis . We furtκB serves important functions in pathogenetic regulation and influences cancer development and aggressiveness by enhancing tumour angiogenesis, antiapoptosis, and proliferation and by repressing immune response [κB in various malignancies [ NFKB1 encoding the p50 subunit of NF-κB modulates gene activity. This polymorphism has been recently reported to influence cancer risk.NF-response , 33, 34.gnancies , 36, inc NFKB1 promoter −94ins/del ATTG polymorphism and cancer among Asians and Caucasians [A meta-analysis of all eligible studies in 2010 suggested that the deletion allele serves as a protective or risk allele for cancer susceptibility among Asians or Caucasians, respectively . Howeverucasians , 32. Howucasians  found anucasians .κB1). The insertion allele is reportedly associated with the increased promoter activity and enhanced NFKB1 mRNA expression [In this study, we analysed 21 eligible case-control studies with 6127 cases and 9239 controls. The results of this meta-analysis revealed a significant association between insertion allele careers and enhanced cancer risk. The probable mechanism behind the observed association may be linked to the enhanced expression and activity of p50  is mediated by its function as a component of the transcription factor NF-κB, which is among the major signalling pathways involved in the cellular response to environmental stress [κB signalling pathway [κB1) signalling pathways participate in cellular proliferation by increasing IL-5 [NFKB1) [The major effect of p50  , 12, 17, NFKB1 gene might function as a prominent factor in these cancers. Therefore, further investigations are warranted to validate ethnic difference and cancer specificity in the effect of this functional polymorphism on cancer susceptibility.In the stratified analyses, the increased cancer risk remained in subgroups of Asians but not in those of Caucasians. The ethnic differences in the allele frequencies may be caused by natural selection or balance to other related genetic variants. Possible differences in genetic backgrounds and gene environment may also interact with the etiology. The increased cancer risk also remained in the subgroups of ovarian, oral, and prostate cancers. This result suggested that theThis study has several limitations. First, significant between-study heterogeneity was detected in some comparisons and may be distorting the meta-analysis. Second, the genotype distribution among controls did not completely agree with HWE. However, the association between the insertion allele and cancer risk in the overall population and in the Asian population became pronounced when the six studies that deviated from HWE were excluded. Third, the studies included in the analysis used different genotyping methods with different quality control issues that may have also influenced the results. Fourth, publication bias was observed in our study, which may affect the validity of conclusion. In the stratified analysis, we found that the publication bias was significant among the Asian groups and other cancer groups but not significant among the Caucasian, bladder, and colorectal cancer groups. The sample sizes of the included studies were diverse, and most of them were insufficiently large. These conditions might partly interpret the publication bias. Finally, only three controls were population based; thus, they may not represent the general population. Therefore, the results of this study should be interpreted with caution. NFKB1 promoter −94ins/del ATTG polymorphism is associated with cancer risk. Well-designed studies with representative sample sizes are necessary to validate these findings.In conclusion, theThe meta-analysis result of the studies which did not deviated from HWE.Click here for additional data file.


A number of studies have reported the association of sexual problems with ankylosing spondylitis (AS); however, the results have been conflicting. The present study aimed to investigate the impact of AS on sexual function. To develop a more comprehensive understanding of sexual function in patients with AS, a systematic review and meta-analysis of the literature up to 2013 was conducted. Studies that assessed the impact of AS on sexual function by adopting the International Index of Erectile Function or the Female Sexual Function Index (FSFI) scoring system were included. Statistical analysis was performed using Review Manager statistical software (version 5.2). The weighted mean differences were calculated by employing a fixed or random effects model. A total of 484 cases from five studies were identified as being well-documented and included in the meta-analysis. Compared with healthy controls, male patients with AS have a significant reduction in sexual function scores of erectile function (−3.07), orgasmic function (−1.17), sexual drive (−0.72) and intercourse satisfaction (−1.89). Female patients with AS have a lower FSFI score in domains of desire (−0.34) and arousal (−0.87). In conclusion, AS has a certain impact on the sexual function of male patients. AS appears to have a greater influence on the sexual function of males compared with that of females. However, the mechanism by which AS affects sexual function requires further evaluation by further studies of a larger population of patients. Ankylosing spondylitis (AS) is a systemic chronic rheumatic disease that presents with inflammatory back pain, asymmetrical peripheral arthritis, enthesitis and extra-articular features . Apart fThe effect of rheumatologic diseases, particularly AS, on sexual function has been explored ,6. A preThe aim of this study was to summarize the existing evidence and explore the effect of AS on sexual function by conducting a systematic review and meta-analysis.The meta-analysis was reported in accordance with the recommendations of the Preferred Reporting Items for Systemic Review and Meta-Analyses (PRISMA) and the Meta-analysis of Observational Studies in Epidemiology (MOOSE) as closely as possible ,11.The following digital databases were searched to identify relevant trials: PubMed, Embase and the Cochrane Library. In addition, Chinese databases were searched, including the CNKI Scholar, VIP, Chinese BioMedicine (CBM) and WanFang databases. Up-to-date information regarding AS-related sexual function up to May 2013 was retrieved from these databases.Different search strategies were combined, as follows. For the English-language databases, free text such as ‘sexual activity’, ‘sexual function’, ‘impotence’ or ‘erectile dysfunction’ and ‘Marie-Struempell disease’ ‘Bechterew disease’ ‘ankylosing spondylarthritis’ or ‘ankylosing spondylitis’ were used. For the Chinese databases, free text terms were used, including the Chinese translations of terms meaning sexual function, erectile dysfunction and AS. In order to collect an adequate number of trials, the reference lists of relevant publications were also searched to identify additional studies.The focus of the analysis was on studies of sexual function in AS regardless of gender, publication status or language. Studies were selected for analysis if they satisfied the following criteria: i) Studies that assessed the association between sexual function and AS; ii) the subjects enrolled were diagnosed with AS according to modified New York criteria for AS ; and iiiFor repeated studies of the same data, authors of reports were contacted to clarify ambiguity. If the author could not be reached, the first published study was considered as original. Two reviewers selected articles independently. Based on the PRISMA requirements, a flow diagram of the study selection was generated.The relevant data was extracted by two independent investigators, and discrepancies between the two abstractors were resolved by consensus, or re-evaluated by a third reviewer. The validated Newcastle-Ottawa Scale instrument was adopted to independently assess the quality of each study . A star The IIEF index covers five domains: Erectile function , intercourse satisfaction , orgasmic function (OF), sexual drive (SD) and overall satisfaction (OS) (two questions each with a maximum score of 10). The FSFI index includes domains of sexual desire, arousal, lubrication, orgasm, satisfaction and pain during sexual intercourse. In case of vagueness or absence of outcomes in the articles, the authors were contacted and related data was extracted by consensus if the authors were unavailable.2, τ2 and Higgins I2 tests, and a P level <0.1 was considered significant. A Z score was adopted to assess the overall effect with significance set at P<0.05. Publication bias was evaluated by the Egger test and represented graphically by funnel plots when the number of included trials was ≥5. To minimize the clinical heterogeneity, subgroup analyses for male sexual function and female sexual function were conducted.The correlation of sexual function with AS was evaluated using Review Manager meta-analysis software . Weighted mean differences (MDs) and the 95% confidence interval (CI) were calculated for continuous data. A fixed-effect model was applied to combine these MDs to get an overall MD, also known as an effect estimate. A random-effects model was used if heterogeneity across studies was present. Heterogeneity was evaluated via the χA flowchart of the study selection process is shown in Three studies assessed the impact of AS on male sexual function, involving a total of 364 participants of which 172 were male patients with AS ,18,19. TAs the number of included studies in each subgroup was <5, funnel plot analysis and Egger tests were not conducted to test publication bias.The number of trial participants with AS ranged from 37 to 70. The statistical heterogeneity among the studies was found to be significant regarding the results for OF and OS (both P<0.1). Consequently, the random-effects model was applied to pool the results. The pooled results displayed statistical significance with the exception of OS . Significant differences were identified in scores of EF , OF , SD  and IS . Accordingly, the random-effects model was applied to combine these domains. The pooled results displayed no significant difference between patients with AS and healthy controls in sexual function, with the exception of desire  and arousal . However, no effects were found on total FSFI , lubrication , orgasm , satisfaction  and pain , OF (−1.17), SD (−0.72) and IS (−1.89). Compared with healthy controls, female patients with AS have a lower FSFI score in domains of desire (−0.34) and arousal (−0.87).AS may have a greater impact on male sexual function than on that of females. The possible reasons are as follow. Firstly, it has been reported that males are more often affected by AS than females ,23 and pThe pathogenesis of sexual problems in patients with AS is complicated and multifactorial. Several underlying mechanisms might be involved in the effect of AS on sexual function. Firstly, tumor necrosis factor α (TNF-α) plays a pivotal role in the pathogenesis of AS, and TNF-α concentrations are increased in the circulation  and synoSeveral limitations of the present study should be noted. Firstly, although the number of participants included in this meta-analysis is larger than that in an individual study, the sample size may be not large enough. In the current meta-analysis, numerous studies were excluded due to inconformity with the IIEF or FSFI scoring system. Secondly, all the participants were recruited from Turkish populations. The association of sexual problems and AS may differ in populations from other ethnic origins. Additionally, there was a considerable heterogeneity in the subgroup of female sexual function in AS. It is hypothesized that differences in the quality of studies, participant characteristics and disease activity are responsible for the heterogeneity. In view of this, all of the conclusions require careful consideration.In conclusion, there is an association between sexual problems and AS. AS appears to have a greater influence on the sexual function of males than that of females. Early diagnosis of sexual dysfunction is essential for AS patients with sexual problems. Therefore, physicians should be aware of the effect of AS on sexual health and it is recommended that special attention is given to all domains of life, not only disease activity and physical function.


Toll-like receptor 4 (TLR4) is a receptor of lipopolysaccharide in the signaling transduction of gastric epithelial cell. It plays a pivotal role in activation of innate immunity and pathogen recognition and thus acts as a modulator in the development and progression of gastric cancer. Growing studies explored the association of polymorphisms in TLR4 with susceptibility to gastric cancer, but the results have remained controversial and conflicting. To investigate the effect of two selected TLR4 (+896A/G and +1196C/T) polymorphisms on gastric cancer, we performed a meta-analysis.A comprehensive search was conducted to identify all eligible case-control publications investigating the association between TLR4 polymorphisms and gastric cancer risk. Odds ratios (OR) and corresponding 95% confidence intervals (CI) were used to assess such association.Up to March 26 2014, 10 published case-control studies from PubMed and EMBase were available, involving a total of 1888 gastric cancer patients and 3433 control subjects. In the overall meta-analyses, a significantly increased gastric cancer risk was detected in TLR4 +896A/G polymorphism  and TLR4 +1196C/T polymorphism , similar results were obtained in the subgroup analyses of Caucasian, whereas no associations were detected in any genetic models of non-Caucasian.The overall results suggest that TLR4 polymorphisms (+896A/G and +1196C/T) may be associated with a significantly increased gastric cancer risk in Caucasian. Gastric cancer is one of the most common malignancy and the third leading cause of cancer death worldwide, with an estimated 952,000 new cases and 723,000 deaths occurred in 2012 Chronic inflammation is well known to play a critical role in initiating and promoting several human cancers including gastric cancer. TLRs activation contributes significantly to the initiation and maintenance of inflammatory response, dysregulation of TLRs signaling may lead to an imbalance state between pro-inflammatory and anti-inflammatory cytokines, and then to an increased susceptibility to chronic inflammatory diseases and cancer Many SNPs in TLR4 have been detected and studied, but two of the most typical SNPs in the fourth exon of coding sequence, +896A/G (ID: rs4986790) and +1196C/T (ID: rs4986791), were explored and reported extensively for the gastric cancer susceptibility A systematic search was conducted using the PubMed and EMBase databases (last search was updated on March 26 2014), with the following search details: TLR4 [All Fields] AND  OR “genetic polymorphism” [All Fields] OR “polymorphism” [All Fields]) AND (“stomach neoplasms” [MeSH Terms] OR (“stomach” [All Fields] AND “neoplasms” [All Fields]) OR “stomach neoplasms” [All Fields] OR (“gastric” [All Fields] AND “cancer” [All Fields]) OR “gastric cancer” [All Fields]). With the purpose of identifying the extra eligible studies, the references cited in the publications or review articles concerning this topic were manually searched too. Our search was limited to English-language articles. The identified studies in our meta-analysis met the following criteria: (1) studies investigating the association of TLR4 polymorphisms (+896A/G or +1196C/T) with gastric cancer risk; (2) case-control studies and studies included available genotype frequencies; (3) inclusion of comprehensive data to calculate odds ratio (OR) and 95% confidence interval (CI); (4) publications with full-text article. Major criteria for excluding studies were: (1) precancerous lesions or benign tumors; (2) without control subjects; (3) duplicated previous publications; (4) the control subjects did not meet the Hardy-Weinberg Equilibrium (HWE). At last, 10 case-control published studies from PubMed and EMbase were available, including a total of 1888 gastric cancer patients and 3433 control subjects for the TLR4 polymorphisms (+896A/G and +1196C/T). The PRISMA checklist was available as supplementary material, as displayed in Two investigators (QZ and CCW) performed the data extraction independently, and then conducted consensus decision to resolve the disagreements. All study personnel were blinded throughout the meta-analysis. For each study, the following information was collected: the name of first author, publication year, country, ethnicity, design, genotyping method, number of cases and controls, genotype and allele frequencies for cases and controls, and HWE of controls.P-value more than 0.05 was considered to meet HWE. Meta-analysis for TLR4 polymorphisms was performed by using the software Stata 12.0 . The association of the TLR4 polymorphisms (+896A/G and +1196C/T) with risk of gastric cancer was estimated by odds ratios (OR) and 95% confidence intervals (CI). The significance of pooled OR was measured by the Z-test, and statistical significance was determined as a 2-sided P-value less than 0.05. We measured the association of allele G and allele T (additive model) with gastric cancer risk, and made comparisons with heterozygous model (AG vs. AA) and (CT vs. CC). Heterogeneity assumption was conducted with a χ2-based Q-test. If the P-value>0.05 for Q-test, thus demonstrating that all studies were lack of heterogeneity, then fixed effect model was adopted to merge studies (the Mantel-Haenszel method) The HWE was recalculated in the present meta-analysis according to the HWE principle and formula P>0.05).A total of 41 studies were identified by using different combinations of MeSH terms on PubMed and EMbase. According to the inclusion and exclusion criteria, 10 case-control studies that consisted of a total of 1888 gastric cancer patients and 3433 control subjects were included in this meta-analysis P = 0.000) (P = 0.000) (P = 0.005) (P = 0.010)  with gastric cancer risk was also observed. In all genetic comparisons, fixed effect model (Mantel-Haenszel method) was used as a result of no obvious heterogeneity    . The sig= 0.000) . Moreove= 0.005) , as well= 0.010) . Besides I2<50%) . However I2<50%)  G vs. A.We conducted sensitivity analysis to evaluate the root of heterogeneity. There was no heterogeneity in heterozygous, dominant models and additive models in TLR4 +896A/G and TLR4 +1196C/T polymorphisms. Besides, no single study qualitatively affected the pooled OR, as demonstrated by sensitivity analysis , which sP = 0.436; P = 0.436; P = 0.602; P = 0.466). Egger's test also suggested that there was no obvious statistical publication bias under the heterozygous and additive models .Publication bias within each study might not represent all studies. We performed Begg's funnel plot and Egger's linear regression test to assess the publication bias of all included studies. As demonstrated in Extensive genetic and epidemiological evidence indicates that chronic inflammation imposes great risk for the development and progression of many kinds of cancers Although the important role of TLR4 polymorphisms in the development of gastric cancer has been reported in recent years, the results are inconsistent. Garza-Gonzalez et al reported that there was no correlation between TLR4 polymorphisms and gastric cancer in Mexican ethnicity However, there are several limitations of the current meta-analysis, which must be taken into consideration. Because the homozygous genotypes of TLR4 gene (GG and TT) were almost completely absent in the population studied, homozygous and recessive models were absent in the present study. To reconfirm this result, more cases about comprehensive population (Western countries and Asian countries) should be included in the study on the association of TLR4 SNPs with gastric cancer. In addition, articles in other languages (not English) were excluded, which may deviate the results. Besides, subgroup analysis according to gastric cancer site (cardia and noncardia) and histological type, and risk factor analysis for different precancerous lesions according to its type, could provide us more valuable information, but the sample size and individual original data limitations hinder a statistically significant analysis. Finally, TLRs induce the expression of pro-inflammatory genes on gastric mucosa, and the interactions between environmental carcinogens  and host cells, that could be used to elucidate the mechanism by which TLR4 +896A/G and +1196C/T polymorphisms increase risk of developing gastric cancer. More original data need to be obtained to interpret the gene-environment interactions and subsequent gastric carcinogenesis.In conclusion, this meta-analysis demonstrates that TLR4 +896A/G and +1196C/T polymorphisms probably increase the susceptibility to gastric cancer mainly in Caucasians, while the susceptibility to gastric cancer in Chinese and other Asian population need to be proved in future large scale studies. Although genome-wide association studies (GWAS) are important procedures for the discovery of genetic variations and the reliability of meta-analysis, there are no available previous GWAS on this subject, thus, we have performed sensitivity analysis and publication bias test to avoid such potential discrepancy in this meta-analysis, which suggests no obvious selection bias and confirms the reliability and stability of our results. Since gastric cancer is a multifactorial and multistep disease, it is important to perform well-design and large scale studies, including comprehensive individual data, homogenous patients and underlying source population based controls, standardized genotyping methods to thoroughly reveal the association of TLR4 polymorphisms with gastric cancer risk.Checklist S1PRISMA meta-analysis checklist.(DOCX)Click here for additional data file.


The effects of dairy products on human health have been studied for years. However, the relationship between dairy products as well as calcium intake and the risk of lung cancer is still inconclusive. A total of 32 studies regarding this association were identified from the PubMed and Web of Science databases through April 1, 2015, including 12 cohort studies and 20 case-control studies. After pooling the results of individual studies, the summary RRs (relative risks) of lung cancer for the highest versus lowest intake were 1.05 (95%CI: 0.84–1.31) and 1.08 (95%CI: 0.80–1.46) for total dairy products and milk, respectively. The results on the consumption of cheese, yogurt and low-fat milk were also negative, and the RRs for total and dietary calcium intakes were 0.99 (95%CI: 0.70–1.38) and 0.85 (95%CI: 0.63–1.13), respectively. After stratifying by potential confounders, the results remained consistent in most subgroup analyses. Our study indicates that intake of dairy products or calcium was not statistically associated with the risk of lung cancer. This negative finding provides a conclusive answer to the disease association issue based on current evidence, and suggests that further efforts should be made to find other nutritional risk factors for lung cancer. Important components of our diet, dairy products provide a variety of nutrients for humankind, and their effects on human health have been the target of research investigations for years. Milk was once believed to be quite healthy and was recommended strongly in dietary guidelines worldwide. However, concerns regarding the side effects of dairy products on human health have also existed for some time, a recent large cohort study reported that higher milk intake even increased the incidence of fracture and overall mortality, which aroused an intense debate regarding the consumption of milk productsConsidering the diverse effects of dairy products, the connection between dairy intake and specific diseases, especially cancer is a topic worth studying. Previous studies have reported inconsistent results with different cancers. For instance, studies showed that milk and calcium intake might protect against colorectal cancer2As one of most common cancers in both the males and females, lung cancer is the leading cause of cancer-related death worldwide1012We searched related publications in the PubMed and Web of Science databases through April 1, 2015, with search key words including ‘diet’ or ‘foods’ or ‘dairy’ or ‘milk or ‘cheese’ or ‘yogurt’ or ‘calcium’ combined with ‘lung cancer’ or ‘lung carcinoma’. The reference lists of selected articles were also reviewed to locate additional studies. We restricted our literature search to full-length papers in English.Studies were eligible for the meta-analysis if they met the following criteria: 1) case-control or cohort design; 2) exposure of interest was dairy consumption  or calcium intake; 3) outcome was lung cancer incidence or mortality; and 4) the estimates of relative risk (or hazard ratio or odds ratios) with corresponding 95% CIs were available. When several studies overlapped or were reported repeatedly, the most recent study with the longest follow-up was included in our analysis.We extracted the following data from each original study: author’s name, publication date, location, gender, study design, number of cases, sample size, dietary assessment, case ascertainment, exposures of interest, comparisons, ORs (odds ratios) or RRs (relative risks) with their 95% CIs, and the adjusted variables. We also evaluated the quality of each study according to the Newcastle-Ottawa scale, which is primarily applied to observational studies in systematic reviewsI2 statistics, when the P value for the Q statistic was <0.1 or the I2 was >50%, the studies were considered to be substantially heterogeneousWe extracted the most fully adjusted relative risks with their 95% CIs (the highest vs the lowest category) from each study, and pooled their logarithms to obtain the summary estimatesP < 0.1 indicated a statistical significance. If publication bias was present, we employed ‘trim and fill’ methods to adjust for the bias. We performed all statistical analyses using STATA 12.0 , and all tests were two-sided.Considering the heterogeneity across studies, we conducted sub-group analyses by study characteristics, and performed meta-regression analyses to investigate the potential sources of heterogeneity. To assess the impact of specific study on the overall results, we carried out sensitivity analyses by recalculating the pooled estimates after removal of one study each time. We evaluated publication bias with the use of the Egger test and Begg’s rank correlation method, A total of 26 studies focused on the association between dairy consumption and lung cancer risk were identified, and an additional 6 studies that reported the calcium intake and lung cancer risk were found, including 12 cohort studies and 20 case-control studies. Among them, 12 studies were conducted in Europe, 12 in the Americas, 7 in Asia, and 1 in the South Pacific. The sample size ranged from 159 to 492, 810, with a sum 765, 752 for dairy products and 581, 187 for calcium intake, and the number of lung cancer cases ranged from 56 to 4, 278. Notably, six publications1920212223The quality scores ranged from 4 to 9 with a mean of 6.52, among these studies, 16 were recognized as high quality. In most studies, the adjusted confounding variables covered age, gender and smoking status, however, total energy intake, body mass index and consumption of other foods were not common, especially in the low-quality studies. The study selection process is summarized in Nine case-control studies and 4 cohort studies reported the association between total dairy consumption and lung cancer risk. After pooling all results, the summary RR was 1.05 (95% CI: 0.84–1.31), as shown in 2526I2 = 44.0%, P-heterogeneity = 0.04). However, univariate meta-regression analysis indicated that none of the confounders, including study design, location, quality, publication year and number of cases were significantly associated with the heterogeneity. We also conducted a sensitivity analysis in which one study was omitted each time sequentially, and the recalculated RRs ranged from 0.97 (95% CI: 0.80–1.17) to 1.08 (95% CI: 0.87–1.37), indicating that no individual study influenced the overall result significantly. No evidence of publication bias was indicated by Egger’s test (P = 0.62) or from Begg’s test (P = 0.76).A high heterogeneity was observed among all the studies , with a high heterogeneity (P < 0.05), and the covariate could explain 35.61% of the variance across studies. Multivariate meta-regression analysis with other covariates also confirmed this finding (P = 0.012). Sensitivity analysis by removing one study each time demonstrated that the pooled results remained unchanged. We found no significant publication bias, either from Egger’s test (P = 0.30) or from Begg’s test (P = 0.41).To explore the source of heterogeneity, meta-regression analysis was conducted, and the result suggested that only ‘publication year’ was associated with heterogeneity significantly  and Begg’s test (P = 0.47) did not show any publication bias from the included studies.Ten studies reported the association between cheese intake and lung cancer risk, and the summary RR was 0.83 (95% CI: 0.62–1.12) after combining all the results, with substantial heterogeneity . We did not carry out further sub-group analyses because the included studies were few. No publication bias was found for yogurt , or for low-fat milk .Our analysis of five studies on the association of yogurt (or sour milk) intake and lung cancer risk found an RR of 0.88 (95% CI: 0.62–1.25). There was also no significant association  between intake of low-fat milk (or skim milk) and lung cancer risk after pooling the results of three studies2628I2 = 81.40%, P-heterogeneity < 0.01) using a random-effects model. Pooled analysis of only 3 studies3031I2 = 75.00%, P-heterogeneity = 0.02). There were not enough data on the particular calcium source from dairy or supplements to analyze. Further sub-group analyses were not carried out, and the publication bias was not evaluated, due to the limited number of included studies.Different dietary exposures were reported in the included studies, since calcium is available both from foods and supplements. Six studies3031323334In this meta-analysis, we found that the intake of dairy products, including total dairy, milk, cheese, yogurt, or low-fat milk, as well as calcium were not significantly associated with lung cancer risk. The association remained unchanged when stratified by study design, gender, geographic area, quality and smoking status. Our results are consistent with the findings from the largest cohort study I2 = 0.00%, P-heterogeneity = 0.43), indicating that vitamin D supplements are not likely to be helpful for lung cancer prevention. The consistency of the results from different types of dairy products, calcium and vitamin D intake, supported the null association to some degree.Dairy products are nutrient-rich foods, which contain carbohydrates, fatty acids, proteins, vitamins, minerals and small bioactive molecules. However, the effects of dairy products on human health are just as complex as their constituents, and the role of dairy products in cancer development remains controversial. On one hand, some studies showed that dairy might be beneficial for cancer prevention as it contains various minerals and vitamins373940et al recently performed a large cohort study that demonstrated that individuals with lactose intolerance, who consumed less milk or dairy products had a lower risk of lung cancerin vitro or in animal models are quite few, which might be explained by the fact that their relationship is not close, since negative results often remain to be unpublished.On the other hand, some others argue that high content of lactose, D-galactose in milk might promote oxidative stress, which will induce aging, chronic inflammation and other injuries to the organism. Consistent with this view, Ji As a systematic quantitative method, meta-analysis is useful to reveal those possible associations that are not so obvious in individual studies. It also allows more sub-group analyses to be stratified by confounders, thus it enables a reliable conclusion. However, several shortcomings should also be noted in our analysis. First, to increase the sample size, both case-control and cohort studies were included in the meta-analysis, as a known fact, retrospective studies are susceptible to recall and selection bias. Indeed, there are some differences in the results of case-control studies and cohort studies, however, the differences were not statistically significant, except that the result of cheese intake in cohort studies was inversely significant , which might be explained by the small number of studies included.Secondly, since different exposure ranges and dietary assessment were used in original studies, we did not perform dose-responses effect analyses, and the lack of association also reduced the need for performing this analysis. The limitations described above contributed to high heterogeneity across studies, other factors like baseline characteristics of the population, ascertainment of lung cancer cases and different adjusted confounders also influenced the results. Specifically, high heterogeneity was found in our meta-analysis, especially in lower-quality or case-control studies, in according with our expectations. Meta-regression analyses were used to explore the sources of heterogeneity, however, significant factors were not easily located. In particular, lung cancer is a highly heterogeneous disease with various genetic backgrounds, which may have contributed to increased discrepancy between studies.In addition, in our sub-group analyses, because of different dietary patterns between Western and Eastern countries, the results from Asia were relatively few, which weakened the statistical power. However, we did not observe much differences in the results between Asian and Western countries. Another problem was the confounder of smoking, as shown in Lastly, both the incidence and mortality of lung cancer were included in our study, and interestingly, subgroup analyses stratified by outcome showed that there were significant differences between the two groups in the categories of dairy and cheese intake .


CRP gene are important in the development of cancer. The current meta-analysis was performed to investigate the association between CRP polymorphisms 3407 A>G (rs2808630) and 29 A>T (rs1417938), and the risk of developing cancer. A search of the relevant literature was conducted using the PubMed database to identify eligible studies published up until March 25, 2014. Five case-control studies involving 888 cases and 3,167 controls for the 3407 A>G polymorphism, and six case-control studies involving 3,110 cases and 5,951 controls for the 29 A>T polymorphism were included in the current meta-analysis. The pooled odds ratios with 95% confidence intervals were calculated using the fixed- or random-effects model. Meta-analysis identified no association between the CRP 3407 A>G and 29 A>T polymorphisms, and overall cancer risk. Additional stratified analysis by cancer type did not reveal any significant associations in the genetic models investigated. The findings of the present study indicated that CRP 3407 A>G and 29 A>T polymorphisms are not associated with cancer risk.Accumulating evidence indicates that polymorphisms in the  Chronic inflammation is important in the development of cancer at a number of sites in the body . C-reactCRP gene is located on chromosome 1q21-q23, and transcription is predominantly stimulated by interleukin (IL)-6 and IL-1β, which are produced in various cell types, including inflammatory cells (such as T cells and macrophages), endothelial cells, fibroblasts and esophageal cancer cells  are the most common type of variation in the human genome and may influence disease susceptibility by affecting sequence coding and splicing . Previoucer risk –10. Howehttp://www.ncbi.nlm.nih.gov/pubmed) was searched for relevant articles published prior to March 25, 2014. The following keywords were used: C-reactive protein or CRP, polymorphism and cancer. Additional studies were identified by conducting a manual search of the reference lists of reviews and the retrieved studies.The PubMed database  the studies were case-control; and iii) the number of individual genotypes for CRP 3407 A>G and 29 A>T polymorphisms in cancer cases and controls, respectively, were stated. In addition, the exclusion criteria included: i) Original or insufficient data regarding the individual genotypes for CRP 3407A>G and 29A>T polymorphisms in cancer cases and controls; ii) review articles and case studies focused on the prognosis associated with genetic polymorphism and iii) duplicated publications.All of the included studies met the following criteria: i) The association between Two independent researchers systematically extracted the relevant data from all of the studies that met the inclusion criteria using a standardized form. The following information was collected: First author’s name, publication year, country, ethnicity, cancer type and total number of genotyped cases and controls. If the study reported more than one ethnicity, the population was termed mixed.CRP 3407 A>G and 29 A>T polymorphisms, and the risk of developing cancer. The pooled ORs were determined for recessive , dominant , co-dominant  and additive  models. Furthermore, between-study heterogeneity was assessed by calculating the Q-statistic using the χ2 test and Ph<0.05 was considered to indicate statistically significant heterogeneity. If the results were heterogeneous, the pooled ORs were calculated using the random-effect model; if the results were not heterogeneous, a fixed-effect model was used. In addition, a Begg’s funnel plot was constructed to examine any potential publication bias, and sensitivity analysis was performed to estimate the influence of excluding each individual study on the summary OR values. All statistical data were analyzed using Stata software .Crude odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were used to assess the strength of association between the CRP polymorphisms with respect to cancer were identified; however, following a review of the titles, abstracts and articles, the inclusion and exclusion criteria identified five 3407 A>G polymorphism studies involving 888 cases and 3,167 controls, and six 29A>T polymorphism studies involving 3,110 cases and 5,951 controls for inclusion in the present meta-analysis ; GG+GA vs. AA, ; GG vs. AA, ; GA vs. AA, ; and G vs. A, ] or the 29 A>T polymorphism and overall cancer risk . In the subgroup analysis by cancer type, the results also indicated that CRP 3407 A>G and 29 A>T polymorphisms were not associated with prostate, lung and colorectal cancer.Evaluation of the association between The OR was not statistically different when excluding each individual study by sequence, demonstrating that no individual study significantly affected the pooled OR and clarifying the stability of the results of the present meta-analysis. The shapes of the Begg’s funnel plots, constructed to assess possible publication biases of the included studies, did not reveal any evidence of obvious asymmetry, which indicates a lack of publication bias .CRP 3407 A>G and 29 A>T polymorphisms and cancer risk. In the present study, no association was identified between CRP 3407 A>G and 29 A>T polymorphisms and the overall cancer risk in all of the genetic models investigated. In the subgroup analysis based on cancer types, no association was identified between these polymorphisms, and prostate, lung and colorectal cancer. These findings indicate that CRP 3407 A>G and 29 A>T polymorphisms may not be risk factors for the development of cancer.To the best of our knowledge, the present study is the first meta-analysis to comprehensively assess the association between However, a number of limitations should be considered when interpreting the results of the present analysis. Firstly, the present results were based on unadjusted estimates, whereas a more precise analysis may have been conducted if individual data were available. Secondly, the relatively small subpopulation samples may have reduced the statistical power of the analysis; therefore, additional studies with a larger sample size are required to fully understand the association. Thirdly, the present analysis did not consider the possibility of gene-environment interactions, which may have influenced the effect of the polymorphisms on cancer risk.CRP 3407 A>G and 29 A>T polymorphisms are not associated with cancer risk, particularly in prostate, lung and colorectal cancer.In conclusion, the present meta-analysis indicates that