Previous studies have found that herpesviruses are associated with aggressive periodontitis (AgP). However, these findings are controversial. This meta-analysis was aimed at clarifying the association between herpesviruses and AgP.We identified eligible case–control studies evaluating the association between herpesviruses and AgP from PubMed and Embase databases in October 2015. Original data were extracted and quality assessment was done. Overall odds ratios (ORs) and 95% confidence intervals (CIs) were estimated. Random-effects model was determined. The stability was evaluated by sensitivity analysis. Finally, Egger’s funnel plot was used to investigate the publication bias.p = 0.0008, OR = 6.11, 95% CI = 2.13–17.51); nevertheless, evidence of publication bias for EBV was considerable . Human cytomegalovirus (HCMV) and Herpes simplex virus type 1 (HSV-1) had significant association with AgP . Sensitivity analyses showed the results yielded consistency, and no significant publication bias was observed for HCMV. The association between Herpes simplex virus type 2 (HSV-2) and AgP was inconclusive .Twelve case-control studies involving 322 patients and 342 controls were included in the present meta-analysis. The included case-control studies were assessed as high quality. The quantitative synthesis results for Epstein–Barr virus (EBV) showed significance (10 studies: This meta-analysis suggests that HCMV and HSV-1 are significantly associated with AgP. However, due to the heterogeneity among studies these conclusions should be cautiously interpreted. There is insufficient evidence to draw any conclusion between EBV, HSV-2 and AgP based on the currently limited data. Aggressive periodontitis (AgP), characterized by early age of onset and tendency for familial aggregation, generally affects young patients, who show early and rapid periodontal breakdown with disproportionate amount of dental plaque in the lesion sites . The etiet al. [et al. [Herpesviruses have been implicated in the etiopathogenesis of human periodontal disease since 1990s. A meta-analysis trying to demonstrate the association between herpesviruses and chronic periodontitis have been published . The eti [et al.  reportedHence, the present study was conducted aiming at clarifying the association between occurrence of herpesviruses and risk of AgP by performing a meta-analysis based on available case–control studies .This study was in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines (More details were shown in Fei Li and Ce Zhu conducted computerized search of PubMed and Embase databases in October 2015 to retrieve relevant case–control studies investigating the association between herpesviruses and AgP. Terms employed for literature retrieve included: (1) “virus”, “herpesvir*”, “EBV”, “CMV”, “HCMV”, “HHV”, “HSV”, “Epstein–Barr virus”, “cytomegalovirus”, “herpes simplex virus”, “Human herpesvirus”; and (2) “aggressive periodontitis”, “parodontopathy”, “periodontal disease”, “periodontal”, “paradontosis”. The literature search was performed on English-language articles without any other restrictions (Electronic search strategy of PubMed database was shown on Studies were considered eligible if they met the following inclusion criteria: (1) studies were designed as case–control studies ; (2) studies investigated the association between herpesviruses and AgP; (3) study samples were collected from these locations: biopsy, subgingival plaque, or gingival crevicular fluid; (4) the methods for herpesviruses’ detection were as follows: polymerase chain reaction (PCR), nested PCR, multiplex PCR, or real-time PCR; (5) all participants in the case and control groups were systemically healthy; and (6) the original articles provided available data, or we can obtain available data from the authors by inquiring email.Studies were excluded if they met the following exclusion criteria: (1) studies were not of case–control design; (2) participants with systemic disease were involved in the case and control groups; (3) study samples were collected from saliva; (4) no available data could be obtained; and (5) study population were duplicate.Potential inclusion was considered by screening title and abstract of all retrieved articles. Then full text was obtained for possible qualified articles. The same two reviewers independently assessed full text according to inclusion and exclusion criteria, eligible studies were submitted for final inclusion.Data extraction was conducted in duplicate from included studies by the same two reviewers. The extracted data included first author, publication year, race of the study population, gender, mean age, number of patients and controls, sampling method, sample type, method of sample analyse, and detection rate of each herpesvirus. Controversial issues were resolved through discussion. Authors were directly contacted if crucial data was missing in original articles.The methodological quality of each studies were assessed independently by the same two reviewers using the Newcastle–Ottawa Scale (NOS) . Total qP value less than 0.05 was considered as statistically significant and all test were two-sided.All statistical analysis was carried out using RevMan version 5.1  and STATA version 12.0  software. We estimated ORs and corresponding 95% CIs to measure the association between herpesviruses and risk of AgP. We didn’t have the assumption that all studies share a common effect, thus random-effects model was determined for all the quantitative synthesises. Additionally, the stability of the quantitative synthesis was evaluated by sensitivity analysis. One study was omitted sequentially, then the calculated combined OR for the remaining studies were assessed. We explored potential publication bias by constructing funnel plots and plot asymmetry test. Egger’s funnel plot asymmetry test (linear regression method) was performed to investigate the publication bias. The process of study selection was shown in p = 0.0008, OR = 6.11, 95% confidence interval CI = 2.13–17.51) (Forest plots of the association between occurrence of herpesviruses and risk of AgP were shown in 3–17.51) .p = 0.009, OR = 3.63, 95% CI = 2.15–6.13)  .p<0.001, OR = 19.19, 95% CI = 4.16–79.06)  .p = 0.20, OR = 3.46, 95% CI = 0.51–23.51) (Two eligible studies were examined to investigate the association between HSV-2 and risk of AgP. The pooled OR was estimated based on random-effects model (1–23.51) . The assOnly one study included covered the association between HHV-7 and risk of AgP . VZV, HHV-6, and HHV-8 haven’t been reported in included studies.p < 0.001) (p = 0.332). For the number limitation of articles included, sensitivity analysis for rest members of the herpesvirus family were not assessed.Publication bias was treatedusing Egger’s funnel plot asymmetry test (linear regression method) according to herpesvirus type. Significant publication bias for EBV was detected using Egger’s funnel plot asymmetry test  . No signAggressive periodontitis is a high-risk and multi-factor disease which would result in the early loss of human teeth. The conventional pure bacterial pathogenicity theory of periodontal diseases was somewhat too weak to cover all the manifestation of AgP. Since mid 1990s when herpesviruses emerging as putative pathogens in periodontal diseases , more anSeveral recent reviews , 23–26 hAll the included studies reported adequate definition for patients in case group. The diagnosis criteria for “aggressive periodontitis” was based on the 1999 Consensus Classification  except fFrom the current meta-analysis, we concluded that HCMV and HSV-1 have significant association with increased risk of AgP. Both sensitivity analysis and publication bias test showed that the overall estimates were comparatively robust. Nevertheless, the significant pooled OR from quantitative synthesis for EBV was inconclusive because of considerable publication bias was found. Insufficient evidence was obtained to support the association between HSV-2 and HHV-7 and AgP since only two eligible studies for HSV-2 and one for HHV-7 were included. Additional high-quality, large scale studies are needed to achieve an unprejudiced conclusion. The rest members of the herpesvirus family were not covered in the studies included in our meta-analysis.Porphyromonas gingivalis has the potential to trigger EBV by increasing the activity of the BZLF1 gene, which encodes the key protein for the transition from latency to the lytic replication cycle [Porphyromonas gingivalis and EBV increase the gingival crevicular fluid visfatin levels, which might stimulate the expression of matrix-degrading enzymes and the breakdown of periodontal tissues [The exact pathogenic mechanisms of herpesviruses in periodontitis remain unclear. To the best of our knowledge, herpesviruses intervene in the inflammatory process by altering the immune mechanism and immune response in direct or indirect ways. Herpesviruses may exert their pathogenicity by a direct effect on different cells in the periodontium, virus-induced alteration of host immune defences, and enhancement of virulence of pathogenic bacteria . Wara-Ason cycle , 32. Ano tissues .Several limitations should be acknowledged in our meta-analysis. First, significant heterogeneity was detected among included studies in quantitative synthesis for HCMV and HSV-1. This may be caused by the differences on participants , sampling methods , sample type  and analysis methods . However, we were unable to conduct subgroup analysis owing limited data. The conclusions should be cautiously interpreted. Second, confounding effect of age exist as a challenging task, although we have extracted the participants’ age distributions from each included study. Third, all included studies were published in English, leading to the limitation of data source and possibility of publication bias. According to the results of Egger’s funnel plot and Begg’s rank correlation test, publication bias for EBV was considerable, which means the result for EBV and risk of AgP might be inconclusive. However, there was no observable publication bias for HCMV and HSV-1. Last, the conclusion of this study was based on 12 independent studies and 664 subjects, which might be insufficient to quantify the risk estimate reliably. Especially, only four studies were included for HSV-1, which might not sufficient enough for a robust result.In conclusion, the results from the current meta-analysis suggest that HCMV and HSV-1 are associated with significantly increased risk of AgP. Sensitivity analysis showed similar results. There was no indication of publication bias for HCMV and HSV-1, substantiating the robustness of our findings. Nevertheless, significant publication bias was observed for EBV, and the significant overall OR for EBV was inconclusive. These findings should be interpreted cautiously in view of the considerable heterogeneity among the included studies concerning HCMV and HSV-1. This study might provide a better understanding of the association between herpesviruses and AgP. Future research should be conducted to investigate co-infection with herpesviruses and bacteria and associated host responses in the development of periodontitis.S1 Table* with systematically diseases: Patients with systemic diseases or infections. # Undefined diagnosis: The diagnosis of patients is not appropriate or not clear. ^ No case-control design: Study is not design as case-control style.(PDF)Click here for additional data file.S1 File(DOC)Click here for additional data file.S2 File(DOCX)Click here for additional data file.S3 File(DOCX)Click here for additional data file.


Bcl-2) polymorphism and cancer is under debate and remains elusive. This meta-analysis was performed to evaluate the relationships of Bcl-2 -938 C>A polymorphism (rs2279115) with susceptibility and prognosis of cancer. Odds ratios (ORs) were used to measure the association between Bcl-2 polymorphisms and cancer risk. Hazard ratios (HRs) were used to measure the association between Bcl-2 polymorphisms and cancer prognosis. On the basis of 26 studies about Bcl-2 -938C>A polymorphism and cancer, we found Bcl-2 -938 C>A polymorphism was significantly associated with increased cancer risk in dominant model , recessive model , allelic model  and homozygote comparison. Furthermore, Bcl-2 -938 C>A polymorphism was significantly associated with increased cancer risk in Asians but not in Caucasians. Moreover, Bcl-2 -938 C>A polymorphism was not significantly associated with the prognosis of cancer . Studies with larger samples and gene-environment interactions are needed to validate our findings.The association between B-cell lymphoma 2 ( Apoptosis is a highly programmed cell death, and it can be achieved by two major pathways: death-receptor pathway and mitochondrial pathwayBcl-2 (B-cell leukemia/lymphoma 2) gene, located at 18q21.3Bcl-2 consists of two promoters which have different functions named P1 and P2Bcl-2 geneBcl-2 -938C>A polymorphism is a crucial factor of cell cycle control and cell survivalBcl-2 -938 CC genotype is at high risk for aseptic looseningBcl-2 -938C>A polymorphism may be relevant to the clinical symptoms of major depressive disorderBcl-2 -938C>A promoter polymorphism is associated with susceptibility and prognosis of cancer1617181920212223242526272829303132333435363738Bcl-2 -938C>A polymorphism can influence the susceptibility of cancer and to evaluate the prognostic significance of Bcl-2 -938C>A polymorphism in cancer.The aim of the present study was to investigate whether The PRISMA statement  were folBcl-2 promoter polymorphism (-938 C>A) and susceptibility or prognostic significance in cancer. 2) More than 30 patients and controls were enrolled in studies.3) Studies provided sufficient data to estimate the odds ratio (OR) or hazard ratio (HR) and 95% confidence intervals (CI) according to Bcl-2 promoter polymorphism(-938 C>A). 4) When study patients overlapped with patients in other included studies, we selected the first study published. The two researchers (J. Wang and X. Zhang) read the titles and abstracts independently and excluded the uncorrelated studies; then the full-texts were examined by our review team. The studies would be selected according to the inclusion criteria.If the following inclusion were satisfied, studies would be included in our meta-analysis: 1)case-control studies focused on association between the Bcl-2 polymorphism and cancer risk was extracted by two independent researchers: authors, year of publication, country, tumor type, number of cases and controls analyzed, mean value of age, source of controls  and genotyping method. As for studies investigating the association between Bcl-2 polymorphism and prognostic value in cancer, two researchers independently extracted the following information from the article: authors, year of publication, country, tumor type, number of patients analyzed, distribution of age and gender, genotyping method, HR estimation and median follow-up date. If univariate and multivariate analysis were both reported, we selected the multivariate analysis. Because the multivariate analysis has taken into consideration the confounding factor and is more accurate. If insufficient data  were reported in the article, we tried our best to ask the first and corresponding authors for necessary information by telephone or E-mail.The following information in studies investigating the association between Bcl-2 -938C>A polymorphism and cancer susceptibility, odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were combined to measure the association between Bcl-2 promoter polymorphisms and susceptibility of cancer. Hardy-Weinberg equilibrium (HWE) for each study was determined by Chi square test. The pooled ORs were calculated for the dominant model (WM + MM vs WW), recessive model (MM vs WM + WW), homozygote comparison (MM vs WW), heterozygote comparison (WM vs WW) and allelic model , respectively. As for studies evaluating the prognostic significance of Bcl-2 -938C>A polymorphism in cancer, hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were combined to measure the effective value of Bcl-2 -938 C>A polymorphism on prognosis. If the study didn't report the HRs, the Engauge Digitizer version 4.1 was used to read the kaplane-Meier curves to estimate the HRs and the 95% CIs. In order to reduce reading variability, three independent investigators  read the curves. P values<0.05 indicated statistical significance. Statistical heterogeneity among the studies was evaluated using the Q test and I2 test. When heterogeneity among the studies was observed, the pooled OR/HR was calculated by random-effects models. Sensitivity analyses were performed to identify the potential influence of the individual data set to the pooled OR/HR. These analyses were performed by Review Manager Version 5.1 software (http://ims.cochrane.org/revman). The Begg's and Egger's test was performed by R (http://cran.r-project.org/bin/windows/base). We applied re-sampling statistic and 1000 re-sampling groups were generated using the bootstrap re-sampling procedure40As for studies investigating the association between Bcl-2 -938 C>A polymorphism in cancer risk2829303132333435363738Bcl-2 -938 C>A polymorphism in cancer16171819202122232425262730Bcl-2 -938C>A polymorphism and cancer susceptibility, studies were published between 2007 and 2014. There were 5515 cases and 6290 controls included in our meta-analysis. Studies were carried out in China, Germany and USA. Two studies assessed prostate cancer31Bcl-2 -938C>A polymorphism in cancer, studies were published between 2007 and 2013 and carried out in Japan, Korea, Sweden, China and Germany. Five studies assessed leukemia172125261618Following an initial search, 387 studies were searched in PubMed, 639 studies were searched in EMBASE, 705 studies were searched in OVID, 6 studies were searched in Cochrane Library, 292 studies were searched in Web of Science and 5 additional studies in review article were added to make our search comprehensive. 1017 published studies were identified after duplicated records removed. After excluding unrelated studies by reading titles, abstracts and the full-text, trying our best to communicate with the first and corresponding author to get the necessary data, 26 studies were included in our meta-analysis ultimately. Twelve studies evaluating Bcl-2 -938 C>A polymorphism and cancer susceptibility was found under the dominant model  . However, Bcl-2 -938 C>A polymorphism was not significantly associated with cancer risk in Caucasians . Overall, twelve studies enrolling 5515 cases and 6290 controls were included in our meta-analysis. A statistical significant association between  = 0.04) , recessi = 0.04) , allelic = 0.04)  and homo = 0.04) . And no  = 0.04) . Bcl-2 -Bcl-2 -938 C>A polymorphism was associated with increased cancer susceptibility , and the heterogeneity was obviously reduced.Sensitivity analysis was performed by omitting one study at a time and calculating the pooled ORs again. We performed sensitivity analysis in five different genetic models . When thBoth Begg's funnel plot and Egger's test were performed to evaluate the publication bias of the studies. Bcl-2 -938 C>A polymorphism was significantly associated with increased cancer risk in five genetic models. In dominant model, OR was 1.17, 95%CI: 1.09–1.27, P<0.0001   . Sensiti = 0.97) . Begg's  = 0.97) .Bcl-2 gene polymorphism may be associated with cancer susceptibility and prognosis. Recently, polymorphism in Bcl-2 gene, variant in promoter region -938 C>A (rs2279115), has been reported to be associated with cancer susceptibility and prognosis many times. This might be the first meta-analysis regarding Bcl-2 polymorphism in cancer susceptibility and prognosis significance.Bcl-2 is the founding member of the Bcl-2 family of regulator proteins that regulate cell death. Bcl-2 is specifically considered as an important anti-apoptotic protein and is thus classified as an oncogeneBcl-2 -938C>A polymorphism and cancer, we found that Bcl-2 -938 C>A polymorphism was significantly associated with increased cancer risk in dominant model , recessive model , allelic model  and homozygote comparison. Bcl-2 -938 C>A polymorphism was significantly associated with increased cancer risk in Asian people  but not in Caucasian people . Furthermore, Bcl-2 -938 C>A polymorphism was not significantly associated with the prognosis of cancer .On the basis of 26 studies about 2+ signaling will be triggered in cancer-B cellsBcl-2 gene, variant in promoter region -938 C>A (rs2279115) has been noticed. Bcl-2 -938C>A polymorphism might become a novel maker in cancer susceptibility and prognosis.Bcl-2 plays the canonical anti-apoptotic role and has an inhibitory effect on cell-cycle progression. Bcl-2 acts at two different intracellular compartments, the mitochondria and the endoplasmic reticulumBcl-2 -938C>A polymorphism and susceptibility and prognosis in cancer was carefully investigated. However, some limitations might exist in our meta-analysis. Firstly, in the subgroup analysis, there might be insufficient statistical power to check an association. Secondly, although some authors like Xiao-ou ShuThe association between Bcl-2 -938C>A polymorphism might be associated with increased cancer risk and this association might exist in Asians but not in Caucasians. Moreover, Bcl-2 -938C>A polymorphism was not associated the prognostic significance in cancer. Therefore, well-designed prospective studies including the Bcl-2 -938C>A polymorphism and cancer susceptibility or cancer prognosis with larger sample sizes are needed to validate our findings.In conclusion, this meta-analysis indicates that Supplementary figuresSupplementary excel file 1Supplementary excel file 2


I2 = 0%). Similar null association was also observed when compared the highest category of frequency/duration with never use acetaminophen . Additionally, the finding was robust in the subgroup analyses stratified by study characteristics and adjustment for potential confounders and risk factors. There was no evidence of publication bias by a visual inspection of a funnel plot and formal statistical tests. In summary, the present meta-analysis reveals no association between acetaminophen use and risk of endometrial cancer. More large scale prospective cohort studies are warranted to confirm our findings and carry out the dose-response analysis of aforementioned association.Previous meta-analyses suggested that aspirin was associated with reduced risk of endometrial cancer. However, there has been no study comprehensively summarize the evidence of acetaminophen use and risk of endometrial cancer from observational studies. We systematically searched electronic databases  for relevant cohort or case-control studies up to February 28, 2017. Two independent authors performed the eligibility evaluation and data extraction. All differences were resolved by discussion. A random-effects model was applied to estimate summary relative risks (RRs) with 95% CIs. All statistical tests were two-sided. Seven observational studies including four prospective cohort studies and three case-control studies with 3874 endometrial cancer cases were included for final analysis. Compared with never use acetaminophen, ever use this drug was not associated with risk of endometrial cancer (summarized RR = 1.02; 95% CI: 0.93−1.13,  Endometrial cancer (EC) is the six most commonly diagnosed cancer and the second most commonly diagnosed gynecologic cancer among females worldwide, with an estimated 0.32 million cases in 2012 , late meDuring the past decade, experimental studies have postulated that chronic inflammation is related to endometrial carcinogenesis through several pathophysiologic pathways including elevations in cytokines, prostaglandins, and cyclooxygenase with concomitant oxidative stress, induces rapid cell division and DNA damage which increase the risk of malignancy , 9. NonsTherefore, to help reconcile the aforementioned issue as well as to provide the most recent evidence, we decided to perform the present systematic review and meta-analysis of observational studies to investigate associations between use of acetaminophen and the risk of EC.Our initial search of PubMed, EMBASE, Web of Science, and Cochrane Library databases returned 437 articles. After we screened titles and abstracts, 18 articles qualified for a full review , and one each was conducted in Australia [Table ustralia  and Denmustralia . All incustralia . Five stAccording to quality assessment criteria , for proversus no use and risk of EC , without heterogeneity (I2 = 0%) .Seven observational studies totaling 3874 EC patients evaluated the association between acetaminophen use and risk of EC –21. We oI2 = 0%) when Neill et al. [I2 = 0%), when Setiawan et al. [Null results were observed throughout the subgroup analyses by study characteristics and adjustment for potential confounders and risk factors Table . In addil et al.  was excln et al.  was exclversus no use and risk of EC , with moderate heterogeneity (I2 = 15.2%) .Six observational studies totaling 3816 patients evaluated the association between acetaminophen use and risk of EC –20. We o) Figure . There wI2 = 23.5%) when Bodelon et al. [I2 = 0%), when Setiawan et al. [Negative findings were observed throughout the subgroup analyses by study characteristics and adjustment for potential confounders and risk factors Table . Althougn et al.  was excln et al.  was exclIn this first meta-analysis with 3874 EC patients and 205,186 non EC populations, we found that ever use of acetaminophen was not associated with risk of EC. Additionally, more frequent or longer duration of acetaminophen use was still not associated with EC risk. These negative findings were robust in the numerous subgroup and sensitivity analyses.In vitro studies suggested a higher COX-2 expression in EC cells compared with normal endometrium [in vitro to markedly inhibit the proliferation of EC cells in a time and dose dependent manner [Although there have been increasing evidence that inflammation and the COX pathway are involved in endometrial carcinogenesis, to some extent, the null association between acetaminophen use and EC risk is biologically plausible. NSAIDs act through inhibiting prostaglandin synthesis and may prevent carcinogenesis through COX-dependent or COX-independent mechanisms –24. COX-ometrium , 26, andometrium , 28. Of t manner , 29. Howt manner .Experimental studies have proposed that obesity leads to several proinflammatory processes as well as increases the levels of circulating estrogens , 31. TheAn important strength of our study is that we first comprehensively and quantitatively summarize the evidence of acetaminophen use and EC risk on the basis of observational studies so far. Furthermore, compared with single study, the sample size of the present meta-analysis was relatively large, allowing for a careful evaluation of acetaminophen use. Notably, these findings were consistent throughout the subgroup and sensitivity analyses. Despite these strengths, several limitations merit discussion. First, our meta-analysis included both cohort and case-control studies. Compared with prospective cohort studies, case-control studies are more likely to subject to several bias including recall and selection bias. However, the findings of the present study were similar in subgroup analysis stratified by study design, though significant heterogeneity was observed in case-control studies when summarized the association between frequency/duration of acetaminophen use and EC risk. Second, since the majority of included studies utilized questionnaire to collect the acetaminophen use –20, miscIn conclusion, after summarizing the results of four cohorts and three case-control studies, the present systematic review and meta-analysis failed to find any association between ever use acetaminophen as well as more frequency and longer duration of acetaminophen use and EC risk. Larger prospective cohort studies are warranted to verify our findings and carry out the dose-response analysis of aforementioned association.Following recommendations of the Meta-analysis of Observational Studies in Epidemiology group (MOOSE) , we systReference manager Endnote was used to identify and remove duplicate publications , 36. SubTwo independently investigators (Y-YD and PY) extracted the information such as first author, year of publication, country, and number of endometrial cancer cases and controls/cohort, exposure characteristics, and study-specific adjusted risk estimates with their 95% CIs (including adjusted risk factors if applicable). All differences were resolved by a third investigator (Z-KH). Subsequently, these information was recorded on pretested standard forms. Additionally, these two investigators (Y-YD and PY) assessed the methodological quality of these included observational studies according to the Newcastle-Ottawa quality assessment scale –37.vs. never use acetaminophen, we followed the method proposed by Hamling et al. [Since the low incidence of endometrial cancer, we assumed that estimates of ORs from case-control studies and risk ratio, or RRs from cohort studies were all valid estimates of the RR, and therefore, we reported all results as the RR for simplicity , 38–40. g et al.  to recalg et al.  describeI2 statistic which indicated significant heterogeneity when this value greater than 50% [vs. case-control studies), median number of endometrial cancer cases (≥ 450 vs. < 450), geographic location (USA vs. Non-USA), exposure measurement (questionnaire vs. medication database), and adjustments for risk factors including age, body mass index, parity, oral contraceptive use, and hormone replacement therapy use. Heterogeneity between subgroups was evaluated by meta-regression. Publication bias was assessed by inspecting a funnel plot for outcome and further tested with Begg's [Random effect models were used to summarize the risk estimates of each study. Heterogeneity among studies was assessed with the than 50% . Subgrouh Begg's  and Eggeh Begg's  test. Ad


Background: Previous studies have evaluated the associations between the cholesteryl ester transfer protein (CETP) TaqIB polymorphism (rs708272), the risk of developing composite ischemic cardiovascular disease (CVD) and the concentration of high-density lipoprotein cholesterol (HDL-C), but results remain controversial. The objective of this study was to investigate whether a relationship exists between these factors. Methods: We conducted a meta-analysis of available studies to clarify the associations of the CETP TaqIB polymorphism with HDL-C concentration and the composite ischemic CVD risk in both Asians and Caucasians. All statistical analyses were done with Stata 12.0. Results: Through utilization of the Cochrane Library, Embase, PubMed, Web of Science, Springer, China Science and Technology Journal Database, China National Knowledge Infrastructure, Google Scholar, and Baidu Library, a total of 45 studies from 44 papers with 20,866 cases and 21,298 controls were combined showing a significant association between the CETP TaqIB variant and composite ischemic CVD risk. Carriers of allele TaqIB-B1 were found to have a higher risk of composite ischemic CVD than non-carriers: OR = 1.15, 95% CI = 1.09–1.21, p < 0.001. Meanwhile, 28 studies with 23,959 subjects were included in the association between the CETP TaqIB polymorphism and the concentration of HDL-C. Results suggested that carriers of the B1B1 genotype had lower concentrations of HDL-C than those of the B2B2 genotype: SMD = 0.50, 95% CI = 0.36–0.65, p < 0.001. Conclusions: The synthesis of available evidence demonstrates that the CETP TaqIB polymorphism protects against composite ischemic CVD risk and is associated with a higher HDL-C concentration in both Asians and Caucasians. Composite ischemic cardiovascular disease (CVD), including coronary artery disease (CAD), ischemic stroke (IS), and myocardial infarction (MI) has become a serious public health problem around the world because of their high morbidity and mortality ,2. HowevCETP TaqIB (rs708272) polymorphism is the most common polymorphism in intron 1 of the CETP gene and its mutation can affect the concentration as well as activity of plasma CETP, which affected the level of HDL-C [CETP TaqIB polymorphism in the synthesis of HDL-C and composite ischemic CVD risk, research has remained inconsistent, possibly due to the small sample sizes used in the individual studies.Serum HDL-C concentrations are affected by many genetic and environmental factors. The cholesteryl ester transfer protein (CETP) gene located on chromosome 16q21, encodes the key plasma protein that mediates the transfer of esterified cholesterol from HDL to apolipoprotein B-containing particles in exchange for triglycerides . Mutatioof HDL-C . RecentlCETP TaqIB polymorphism in the synthesis of serum HDL-C and CAD risk, and demonstrated that the CETP TaqIB variant is associated with HDL-C level and CAD risk in Caucasians [CETP TaqIB polymorphism and CAD was observed [CETP TaqIB variant and MI. Their results showed that the CETP TaqIB-B2 allele protects against the development of MI [CETP TaqIB polymorphism and IS. Considering the four meta-analyses above focused only on the association of the CETP TaqIB polymorphism with a single atherosclerotic disease and results were controversial in regards to ethnicity (Asians and Caucasians), we performed this meta-analysis to clarify the role of the CETP TaqIB polymorphism in the synthesis of HDL-C and the composite ischemic CVD risk.In 2005, Boekholdt et al. performed a meta-analysis to evaluate the association the ucasians . Li et aobserved . Cao et nt of MI ,13. No mThe protocol was approved by the Institutional Ethics Review Board (IERB) of the First Affiliated Hospital of Shihezi University School of Medicine (IERB No. SHZ2010LL01). Using the standards of the Meta-analysis of Observational Studies in Epidemiology group (MOOSE)  and the CETP TaqIB polymorphism with AS or HDL-C level; (2) CAD and MI diagnosis required the result of coronary angiography, and the diagnosis of IS depended on the result of magnetic resonance imaging or computed tomography; (3) published in either Chinese or English; (4) for the composite ischemic CVD association, sufficient published data for calculating odds ratios (ORs) with their 95% confidence intervals (CIs); for HDL-C concentrations association, the population, the mean of HDL-C concentrations, and the standard deviations (SD) by genotype should be available.The eligibility criteria for the inclusion of articles in the present meta-analysis were the following: (1) The publication evaluated the associations of the The exclusion criteria were as follows: (1) Duplicate publications; (2) incomplete information; (3) insufficient or insignificant statistical data; (4) review articles.Two reviewers (Minghong Yao and Yusong Ding) independently screened full-length articles according to the pre-specified inclusion criteria. For the composite ischemic CVD association, the following information was extracted: name of the first author, year of publication, study population , source of controls, case/control sample size, minor allele frequency (MAF), genotype counts in the cases/controls, and evidence of Hardy-Weinberg equilibrium (HWE); for HDL-C concentrations association, name of the first author, year of publication, study population , population number, mean of HDL-C concentrations, and their SD by genotype. If key data were not presented in the relevant publications, we tried to obtain them directly from the authors of the relevant studies. When the two reviewers’ opinions differed, a third reviewer (ShuXia Guo) was asked to make final decisions regarding the results.The Newcastle-Ottawa Scale (NOS) was used to assessed the methodologic quality of the individual studies by two reviewers (Minghong Yao and Yizhong Yan) . Each stp-value of less than 0.05 was considered statistically significant. The HWE was assessed using the chi-square test. The strength of associations between the CETP TaqIB polymorphism and atherosclerosis were assessed by summary odds ratios (ORs) with 95% confidence intervals (CIs). Pooled ORs were performed for the allele contrasts as followed: , additive genetic model (B1B1 vs. B2B2), recessive genetic model (B1B1 vs. B1B2 + B2B2), and dominant genetic model (B1B1 + B1B2 vs. B2B2), respectively. A pooled standardized mean difference (SMDs) and its 95% CIs were used for the meta-analysis of HDL-C concentrations and the CETP TaqIB polymorphism. Heterogeneity across individual studies was calculated using the Cochran’s-Q statistic and the I2 statistic (p < 0.10 and I2 > 50% indicated evidence of heterogeneity) [n < 400 were excluded). Potential risk of publication bias was tested by funnel plot and Egger’s test.All statistics were analyzed in Stata 12.0 . All the tests were two-sided and a geneity) ,18. Withgeneity) . Otherwigeneity) ,21. Subsgeneity) . For theCETPTaqIB polymorphism and the composite ischemic CVD [The present study met the PRISMA statements (Checklist S1) and MOOSE guidelines . The stuemic CVD ,63,64,65emic CVD ,60,61,66emic CVD ,57,58,62emic CVD ,61,65,66emic CVD ,56,60,62emic CVD ,42,43,58CETP TaqIB polymorphism and serum HDL-C concentrations. A total of 28 studies with 23,959 subjects were included in the analysis [analysis ,83,84,85analysis ,71,81,83analysis ,82,84,85analysis ,74,76,77CETP TaqIB polymorphism and the composite ischemic CVD, suggesting that carriers of allele TaqIB-B1 have a higher risk of the composite ischemic CVD than non-carriers  , dominant genetic model , and recessive genetic model  were also included in the analysis and results were similar with allele comparison  . The addmparison . SubgrouCETP TaqIB polymorphism and HDL-C concentrations. Our analysis strongly suggested that carriers of the B1B1 genotype had lower concentrations of HDL-C than those of the B2B2 genotype . We also compared carriers of the B1B1 genotype with those of the B1B2 genotype  and B1B2 genotype with those of B2B2 genotype . Subgroup analyses by ethnicity confirmed that the relationship between the CETP TaqIB-B2 polymorphism and the HDL-C concentration in Asians was less consistent than that in Caucasians  and Caucasian subgroup .For the relationship between the  studies ,76,77,80 studies ,50,67,69CETP polymorphism and the composite ischemic CVD risk analysis (B1 vs. B2), the shape of the funnel plot (p = 0.074). For the CETP polymorphism and HDL-C analysis (B1B1 vs. B2B2), neither the shape of the funnel plot (p = 0.058) revealed any obvious asymmetry.Funnel plots and Egger’s test were performed to access the publication bias of literature. For the nel plot  did not nel plot  nor EggeTaqIB-B2 allele was significantly associated with reduction of composite ischemic CVD both in Caucasians and Asians. Additionally, 28 studies with 23,959 subjects were included in the analysis on the association between the CETP TaqIB polymorphism and HDL-C concentrations. According to the results, the TaqIB-B2 allele was significantly associated with a higher level of HDL-C both in Caucasians and Asians. Therefore, it is reasonable to assume that the CETP TaqIB polymorphism is influencing HDL-C metabolism to protect against the development of AS. This result suggests that we can use CETP inhibitors to prevent and treat dyslipidemia and the composite ischemic CVD. In 2014, Keene et al. performed a meta-analysis to investigate association between the CETP inhibitors and cardiovascular outcomes [In the present meta-analysis, a total of 45 studies from 44 papers with 20,866 cases and 21,298 controls, we found that the CETP TaqIB polymorphism and composite ischemic CVD, we performed subgroup analyses based on ethnicity, source of controls, atherosclerotic disease, and study type in the allelic model, additive model, recessive model, and dominant model. Significant associations were found between this variant and susceptibility to composite ischemic CVD in the Caucasian group, Asian group, population-based group, hospital-based group, IS group, CAD group, MI group (except for the recessive model), case control study group, and the subgroup of the cohort study group (except for the recessive model), respectively. For the association between the CETP TaqIB polymorphism and HDL-C, we also performed subgroup analysis based on ethnicity in the B1B1 vs. B2B2 model, B1B2 vs. B2B2 model, and B1B1 vs. B1B2 model. Significant associations were found between this variant and serum HDL-C concentrations in both the Caucasian and Asian group. These results further strengthen the conclusion that the CETPTaqIB-B2 allele protects against atherosclerosis by influencing HDL-C metabolism both in Asians and Caucasians. We also found that the association between CETP TaqIB-B2 polymorphism and composite ischemic CVD risk was stronger in Asians than Caucasians, but the relationship between the CETP TaqIB-B2 polymorphism and the HDL-C concentration in Asians was less consistent than that in Caucasians, which can be attributed to different environmental factors, lifestyle, etc.To create a more comprehensive analysis of the association between the Considering the influence of small-study effects on the overall results, we performed sensitivity analyses by excluding studies with low sample size or without the HWE. However, the corresponding pooled ORs and SMDs were unchanged in all comparisons, indicating statistically robust results.CETP TaqIB polymorphism and composite ischemic CVD or for the CETP TaqIB polymorphism and HDL-C may affect the reliability of the results to a large extent. For the relationship between CETP TaqIB polymorphism and composite ischemic CVD, the heterogeneity can be explained by the source of controls  and ethnicity (Asians and Caucasians); for the relationship between CETP TaqIB polymorphism and serum HDL-C concentrations, the Galbraith plot was used to detect the source of heterogeneity for Asians and Caucasians. We identified four studies were as the main contributors of heterogeneity for Asians [CETP TaqIB polymorphism and serum HDL-C concentrations was unchanged. According to these outlier studies, the heterogeneity may be explained by the HWE, sample size, and disease.Meanwhile, the existence of heterogeneity among the available studies, either for the r Asians ,76,77,80r Asians ,50,67,69There are several potential limitations in our present meta-analysis that should be acknowledged. First, there was significant heterogeneity in our study. Although we used appropriate meta-analytic techniques, we could not completely exclude the influence of the heterogeneity. Second, we may have missed eligible articles reported in other languages because our study only focused on articles published in English and Chinese. Third, the sample sizes of some studies were rather small. In summary, it is well-known that the composite ischemic CVD is affected by multiple environmental and genetic factors. Here, we discussed a single gene polymorphism and its impact on disease; however, several factors remain to be elucidated.CETP TaqIB-B2 allele is associated with a higher serum HDL-C concentration and plays a protective role in composite ischemic CVD risk both in Asians and in Caucasians. Further investigations with the consideration of genetic and environmental interactions are needed.The present meta-analysis shows that the


Publication bias was evaluated by Begg's Test analysis. Pooled analysis indicated that patients with HCC had lower Se levels than the healthy controls . Further subgroup analysis showed this effect to be independent of the study design, race or sample collection. In conclusion, this meta-analysis suggested an inverse correlation between Se level and the risk of HCC in humans patients.Hepatocellular carcinoma (HCC) is the most common cancer type. There is a correlation between selenium (Se) deficiency and the incidence of HCC. To clarify the effects of Se level on the risk of HCC patients, a meta-analysis was performed. A total of 9 articles published between 1994 and 2016 worldwide were selected through searching PubMed, EMBASE, web of science, Cochrane Library, Springer Link, Chinese National Knowledge Infrastructure (CNKI), and Chinese Biology Medicine (CBM), and the information were analyzed using a meta-analysis method. Heterogeneity was assessed by using the I Hepatocellular carcinoma (HCC) is the most common liver cancer worldwide. HCC is as a result of either metabolic toxins such as alcohol or aflatoxin, a viral hepatitis infection (hepatitis B or C) –4. FurthMicronutrients may reduce the risk of cancer, among which selenium (Se) is of particular interest , 8. Se iSeveral studies have investigated the relationship between Se level and HCC risk –21. Yu eWith the search strategy stated before, 9 relevant records were included in our meta-analysis and data were extracted Figure  11, 12,, 23, 24.P < 0.001]. The result of pool analysis showed lower Se level had a relationship with HCC with obvious heterogeneity   = −1.08, 95% CI = , P < 0.001] and cohort study  , P < 0.001] , P < 0.001] and toenail  , CI = −0.95, −0.520P-values was 0.348. Therefore, we can assume there were insignificant in publication bias.Publication bias was detected by Begg's test, the Although little is know about the correlation of Se for HCC, several studies have shown that there is an inverse correlation between HCC risk and Se level. We performed the meta-analysis with the latest resouce on the correlation between HCC risk and Se level. Combining the results from 9 studies, which applied individual levels of Se measured in serum, blood or toenails, indicated that there was a significant high risk of HCC correlate with low levels of Se Figure . As can Evidence indicated several mechanisms for Se antitumous effect. Actually, antioxidant properties of selenoproteins are relevant in protection from cancers . Evidenc2 value was decreased. The result suggested that the major source of the heterogeneity might be the study design. For the age subgroup analysis, the age groups did not match perfectly. We have use an age range of 20–60 years as “adult” and an range of older than 60 years as “older”. However, most of the studies with ages ranging between 20–80 years in HCC patients. Thus, our finding is unlikely to be the result of unequal age ditribution. We were not able to investigate the effect of sex subgroups because of a lack of data. Additionally, Begg's tests results showed that there was no significant publication bias in this meta-analysis.As far as we know, this is the first systematic review to investigate the correlation between Se levels with HCC in patients. However, the limitations of the present study must be considered. The reslut of the present study found a significant heterogeneity. Study design subgroup showed IIn conclusion, this meta-analysis supports an inverse correlation between Se level and the risk of HCC in humans. However, both epidemiological survey and biological research should be further conducted to illustrate and validate whether Se supplement is beneficial for prevention and treatment of HCC. The exact mechanism needs to be further investigated.Studies were identified by searching PubMed, EMBASE, web of science, Cochrane Library, Springer Link, Chinese National Knowledge Infrastructure (CNKI), and Chinese Biology Medicine (CBM) before August 2016, using the following Mesh terms: (“Liver Neoplasms” [MeSH] or “liver cancer” or “Hepatocellular Cancer” or “Hepatic Neoplasm”) and (“selenium”or “Se”). Reference lists of all eligible studies were screened to identify potentially eligible studies. Emails were sent to the authors of identified studies for additional information if necessary.in vitro or laboratory study; (2) animal study; (3) not case-control study or cohort study; (4) based on incomeplete data; (5) review or case report.Studies included in this meta-analysis have to meet the following criteria: (1) human study; (2) case-control study or cohort study studying on correlation between Se and HCC; (3) all patients with the diagnosis of HCC confirmed by pathological or histological examination; (4) studies providing serum levels of Se for both subjects with HCC and healthy controls; (5) subjects with no other diseases and no drugs intake which might influence the levels of Se. Studies were excluded when they were: (1) Data were independently extracted by two reviewers using a standardized data extraction form. Discrepancies were resolved by discussion and if consensus was not achieved the decision was made by all the reviewers. The following data was extracted from every article: first author, year of publication, study design, race, age and sex, sample size, years of follow-up, levels of Se and sample collection.2 statistic was used to determine the level of heterogeneity potential sources of heterogeneity were explored using subgroup analysis to check the influence of the following determinants: study design, race and sample collection. Publication bias was explored Begg's Test. P value less than 0.05 was considered statistically significant.Statistical analysis was conducted by using STATA version 12. The correlation of Se level and HCC was estimated by SMD with 95% CI. Both fixed and random effects models were assessed, but the latter was preferentially used when heterogeneity was detected. The I


Suicidal behaviors (SBs), which range from suicidal ideation to suicide attempts and completed suicide, represent a fatal dimension of mental ill-health. The involvement of genetic risk factors in SB is supported by family, twin, and adoption studies. The aim of this paper is to review recent genetic association studies in SBs including (i) case–control studies, (ii) family-based association studies, and (iii) genome-wide association studies (GWAS). Various studies on genetic associations have tended to suggest that a number of genes  are linked to SBs, but these findings are not consistently supported by the results obtained. Although the candidate–gene approach is useful, it is hampered by the present state of knowledge concerning the pathophysiology of diseases. Interpretations of GWAS results are mostly hindered by a lack of annotation describing the functions of most variation throughout the genome. Association studies have addressed a wide range of single-nucleotide polymorphisms in numerous genes. We have included 104 such studies, of which 10 are family-based association studies and 11 are GWAS. Numerous meta-analyses of case–control studies have shown significant associations of SB with variants in the serotonin transporter gene (5-HTT or SLC6A4) and the tryptophan hydroxylase 1 gene (TPH1), but others report contradictory results. The gene encoding BDNF and its receptor (NTRK2) are also promising candidates. Only two of the GWAS showed any significant associations. Several pathways are mentioned in an attempt to understand the lack of reproducibility and the disappointing results. Consequently, we review and discuss here the following aspects: (i) sample characteristics and confounding factors; (ii) statistical limits; (iii) gene–gene interactions; (iv) gene, environment, and by time interactions; and (v) technological and theoretical limits. There are roughly one million suicides worldwide annually, corresponding to an estimated yearly mortality rate of 14.5 deaths per 100,000 population . SuicideEnvironmental factors such as early adverse experiences, including sexual and physical abuse during childhood, also strongly impact the risk of SB , 20. SomTwo methods are used in particular: genome-wide association studies (GWAS) and gene–candidate association studies. The methodology that has been predominant in the published genetic studies of SB is that of functional candidate–gene studies  –26. ThisAn electronic search of the literature was performed to identify association studies that investigated the link between genetic variants and SB. A systematic search was conducted using PubMed, SCOPUS, and ISI Web of Science. The key words used to conduct the search were: “suicid*” in association with “gene*,” “polymorphism,” “haplotype,” “association,” “linkage,” or “genome wide.” We also examined the reference sections from the selected papers to identify any additional relevant studies.Papers were included in the systematic review if they fulfilled the following criteria: (i) they were published in an English-language peer-reviewed journal from January 2004 to September 2015; (ii) they analyzed the association between any genetic SNP and SB, suicide attempt, or suicide completion; and (iii) they involved adolescent and/or adult subjects. An exclusion of identified irrelevant studies was performed in several steps: (i) duplicates were automatically identified; (ii) studies that referred to non-human subjects were automatically identified; (iii) studies that pertained to cancer research were automatically identified ; and (iv) studies of enrolled patients with self-harm without intent to die were identified. The texts of the studies that passed the initial screening were reviewed in extenso and potentially excluded, based on the same criteria. We clustered the retained papers into “candidate–gene association studies” and “genome-wide association studies.” With respect to the PRISMA statement , the litThe serotonergic pathway has been implicated for several decades as having a major role in the pathophysiology of SB –30. A nuTryptophan hydroxylase, the rate-limiting enzyme in the biosynthesis of serotonin 5-HT), is a pre-eminent candidate for genetic studies of association in numerous psychiatric disorders, including SB . Two gen-HT, is an = 74), and the medical records of those who died could not all be obtained.Three polymorphisms have been examined extensively: A218C, located in a potential GATA transcription factor-binding site, A779C located on intron 7, and A6526G located on the promoter region. The A allele A218C has been identified to be more frequent in suicide attempters compared to non-attempters . Galfalvp = 0.00243; OR = 1.62; 95% CI 1.17–2.24 and p = 0.018; OR = 1.41; 95% CI 1.05–1.91), in the Asian population , but they show no difference in allele frequencies of these loci between affected individuals having attempted suicide at least once and patients with no history of suicide attempts (p = 0.84). In the second part of their article, they conducted a meta-analysis of A218C/A779C and SB among individuals affected with a psychiatric disorder. They failed to find any effect of the TPH1 A779C/A218C SNPs on SB . This result contradicts the hypothesis that TPH1 polymorphisms affect SB independently of mental health status. This is why the authors selected only those studies which had compared allele frequencies in suicidal and non-suicidal patients diagnosed with a psychiatric disorder. Although their study did not take care to distinguish between Asian and Caucasian populations, their results force a more rigorous interpretation of the previously reported association between TPH1 and SB. Thus, one may assume that TPH1 A218C/A779C polymorphisms are associated with increased susceptibility to psychiatric disorders in general, which in turn are characterized by an increased incidence of suicide.Saetre et al.  conducteThe human TPH2 gene, situated on chromosome 12q15, consists of 11 exons and covers a region of roughly 93.5 kb. In 2004, Zill’s team was the first to find significant single SNP (rs1386494) and haplotype associations with suicide completion in a German sample . In thisWe found nine studies that had significant associations in genotypic and/or haplotypic distributions of TPH2 variants between subjects who had SBs and controls , 57, 87.For example, the study by Lopez de Lara et al.  includedThe variant (rs1386494) was previously identified by Zill et al.  but at tZhou et al.  showed tp = 0.0018; p = 0.0173 after 100,000 permutations). The TPH2 rs1386494 C/T polymorphism had significant predictive power in logistic regression analysis (p = 0.0041), displaying an odds ratio of 5.64 (95% CI 1.77–19.58). The haplotype block, which was found in this sample, accords well with the findings of studies conducted by Zill et al.  using antidepressants have been the focus of recent research strategies. Musil et al.  showed tl et al.  and by Zl et al. . Polymorl et al. –91. Howel et al. , 91 or tl et al.   is situated on chromosome 5 (5q11.2-13), and recent studies have found that a common C1019G polymorphism located in its promoter region probably plays a role in depression and SB. Since the first study by Lemonde et al. , which rThe HTR1B gene is an intronless gene that is located on chromosome 6. The study by Zouk et al.  found evp = 0.047).More recently, only the study by Murphy et al.  found a The 5-HT2A receptor gene (HTR2A), located on chromosome 13 (13q14–q21), has been implicated in SB. The polymorphisms, which have received the most extensive investigation, are the A1438G (rs6311) and T102C (rs6313). The genetic analyses carried out by Wrzosek et al.  found a In contrast, no association of T102C with SB was reported in a number of related case–control association studies , 71, 95 p < 0.05) between any SNP and either risk of suicide or a personal history of attempted suicides. Although interactions between 5HTR2A rs6313 and 5HTR1A rs6295 in risk of suicide and between 5HTR2A rs643627 and 5HTR1A rs6295 in a personal history of attempted suicides have been identified , the results did not persist after applying correction procedures for multiple testing. The authors conclude that their study fails to find any association of either 5HTR1A or 5HTR2A polymorphisms with a subject’s current risk of suicide or his/her past history of attempted suicide.Höfer et al.  report nFamily-based association studies constitute an alternative strategy for studying the variants as against case–control association studies. This approach also has the advantage of reducing the false positive and false negative results in cases of population stratification. Use is generally made of the haplotype relative risk (HRR) method . The allp = 0.001], with heterogeneity being low . A meta-analysis by Li and He (The serotonin transporter (5-HTT) plays an important role as a regulator of serotogenic signaling at synapses. The gene of serotonin transport (SLC6A4) is situated on chromosome 17 (17q11.2); it has a common functional promoter polymorphism , which consists of a short (S) and a long allele (L). The L allele of this marker has been found to transcribe the gene two to three times more efficiently than the S allele does . This cai and He  that comWhen a pairing was made between suicide attempters and non-attempters who had the same psychiatric disorders, the carriers of the long allele (L) were found to be associated with reduced suicide risk .A meta-analysis of the results from 18 studies  failed tp = 0.035); a comparable association was also reported between the LA allele and suicide attempts by violent means (p = 0.028). On the other hand, when the traditional biallelic 5-HTTLPR was investigated, no association was detected. These results are different from those found in Caucasian subjects  as regards the genotype and allele frequencies of polymorphisms. This result confirmed an earlier finding of an association between the DRD2-141C Del variant with suicide attempts in a group of German alcoholics .The ADRA2A gene, composed of an intronless, single 3650-bp exon, is situated on chromosomes 10q24-q26, in other words, a region which has been found to be associated with attempted suicides independently of disease phenotypes . A numbeO-methyltransferase (COMT) is encoded by a single gene that is localized on chromosome 22q11.1-q11.2 and represents a major enzyme in catecholamine inactivation. A common SNP, Val158Met in exon 4 of the COMT gene, has been observed as being linked to various psychiatric disorders, one of which being suicide  and between violent suicide victims and controls . Ono et al. (p = 0.036), whereas occurrence of the high-activity COMT Val/Val genotype was significantly less frequent in males having committed suicide than in the male control group .A meta-analysis of six-related studies suggested an association of the COMT Val158Met polymorphism with SB, and this relationship was moderated by gender and the lethality of the suicide attempt . Howevero et al.  found a In contrast, more recent meta-analyses that included new data questioned the association of COMT Val158Met with SB , 112 andMonoamine oxidase A (MAOA), a mitochondrial outer membrane enzyme, is known to cause neurotransmitter degradation, including that of dopamine, norepinephrine, and serotonin. The promoter region of the MAOA gene, itself situated on chromosome Xp21-p11, is polymorphic in terms of how many copies of a 30-bp repeat it has. The alleles observed for this upstream variable number of tandem repeats (uVNTR) polymorphism include some with 3, 3.5, 4, and 5 repeats  . These up = 0.22) or female controls . To better understand these divergent results, it is necessary to view them a new with a developmental approach. Indeed, in 2002, Caspi et al. . De Luca et al. (p = 0.035).Studies designed to investigate the supposed causes of a defective regulation of HPA axis in SB have focused principally on two factors: (i) glucocorticoid receptor feedback mechanisms and (ii) the corticotrophin-release hormone (CRH) signaling system . Associaa et al.  studied p = 0.0041) between variant rs33990840 and 6-SNP haplotypes with suicide attempt (SA) but predominantly concurrent with high depressive symptoms. On the other hand, genetic associations with lifetime diagnoses of depression and anxiety in SA or G × E interactions between AVPR1B variants and SLEs  were not significant. An exploratory screen of interactions between AVPR1B and CRHR1 showed no support for gene–gene interactions on the studied outcomes.In a family-based association study model, using 660 nuclear family trios and 519 healthy controls Ben-Efraim et al.  focused Several lines of evidence from postmortem studies and expression studies indicate that brain-derived neurotrophic factor (BDNF) is a good candidate gene for involvement in SB . FurtherWe have listed a number of studies showing associations between Met allele and SBs in the context of various psychiatric diagnoses, including schizophrenia , bipolarFor example, a Slovenian team demonstrated the association between BDNF rs6265 polymorphism and suicide in a cohort of subjects with completed suicide . In the The control group was made up of subjects who died of natural causes or in road accidents. The authors were only able to demonstrate a statistical difference in haplotype analyses. The haplotype C–A–T–T–C was significantly associated with completed suicide. Additionally, single-marker analysis under four inheritance models with the adjustment for potential confounders, like age, gender, or alcohol dependence syndrome status also failed to reveal any associations. The diathesis–stress model is often used to include the biological and environmental contributions to SB, where the stressor is an environmental factor such as childhood abuse, substance abuse, or the experience of psychiatric illness. It is an approach which we have mentioned several times. The study by Perroud et al.  examinedp = 0.03) in patients with bipolar disorder. The other studied polymorphisms, including rs6265 , were not associated with any comorbidity. Further studies failed to report that Val66Met was associated with suicide attempt . This meta-analysis revealed a trend whereby the Met allele and Met-carrying genotypes conferred a risk of suicide .Zai et al.  carried n = 795), Sears et al. (p ≤ 0.00156). This result is in contradiction with other case–control type studies and with the meta-analysis by Zai et al. . However, a meta-analysis that included three studies that used completed suicide as subjects .Recently, Ratta-Apha et al.  performesubjects , 136 faip = 0.0015). In addition, a significant interaction was reported between the variants of BDNF and NTRK2 (p = 0.0003).With respect to the NTKR2 gene, Kohli et al.  showed aStrauss et al.  studied p < 4.0 × 10−4) of four to seven SNPs in length, all containing the minor risk C allele of SNP rs2268115. As in the study by Ben-Efraim et al. (p < 10−4).In a population made up of 660 trios, Sokolowski et al.  reportedm et al. , the autLaje et al.  reportedp = 0.008), vesicle-associated membrane protein 4 (VAMP4) (p = 0.004), and prenylated Rab acceptor 1 (RABAC1) (p = 0.006) genes are over-transmitted in suicide attempt. In an independent replication sample comprised of 190 trios, the authors confirmed the data for the SCN8A (p = 0.005) and VAMP4 (p = 0.019) genes.In a sample of 77 trios (suicide attempters and both their parents), Wasserman et al.  investigAlthough SB is an important public health issue, few studies have been devoted to its genetic aspects. However, the hereditary component of SBs in adolescents has been well identified. The study by Brent et al.  is a refp = 0.76) and the TDT method . In the same population, Zalsman et al. (N = 35), (ii) non-suicidal psychiatric inpatient adolescents (N = 30), (iii) adolescents admitted to psychiatric emergency rooms due to a suicide attempt (N = 51), and (iv) a community-based control group (N = 95). The authors found that homozygosity for T (TT) of the HTR2A 102T/C polymorphism is associated with lower impulsivity (p = 0.03) and aggression (p = 0.01) compared with TC carriers and that a low activity MAOA was significantly associated with suicidality (p = 0.04). However, their analyses found no significant association between alleles of 5HTTLPR gene and suicidality.The oldest study we identified goes back to 2001 . Given tn et al.  tested Tn et al.  in four n = 155) sufferers who participated in the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) trial, Brent et al. (n = 18), even when they controlled for related covariates and treatment effects. Even though the number of suicidal events remains low, the authors correctly described the sample, the suicidal events were well characterized, and the effects of the treatment were taken into consideration in the analysis. In addition, this study is interesting from a pathophysiological point of view because the FKBP5 gene codes for a protein that decreases the sensitivity of the glucocorticoid receptor to the effect of corticosteroids. This result is consistent with previous studies linking SB with the insensitivity of the HPA axis to feedback and increased secretion of cortisol  provides a substantially higher resolution than linkage and the potential to tag common causal variants . ResearcWe identified 11 GWAS. Table p = 0.01, odds ratio 4.9), and another SNP (in IL28RA) was reported as suggestive.Laje et al.  followed−7) proved to be a single-nucleotide polymorphism (rs11143230) that was located 30 kb downstream of a gene that encoded guanine deaminase (GDA) on chromosome 9q21.13. In addition, treatment-specific SNPs , drug × treatment interaction SNPs  together with a number of genes  from an additional candidate–gene analysis were all reported as suggestive associations. Menke et al. , and the other three SNPs had an intergenic location. One SNP in GDA . These results, at genome-wide level, emphasize the importance of a polygenic neurodevelopmental etiology in SB. This is true not only for SBs but also for some other psychiatric disorders, especially in children and adolescents, for whom a developmental and integrative approach is essential.Over the last decade, many teams from around the world have attempted to identify associations between genetic markers and SBs. It is recognized by all that single genes might not explain the full risk of developing SBs. In summary, we have identified several studies that have shown an association of genetic polymorphisms with SBs, in line with previous reviews –33. The p < 5 × 10−8)  , 144 faiSeveral pathways have been mentioned in an attempt to understand the lack of reproducibility and disappointing results. Consequently, we shall now review and discuss the following: (i) sample characteristics and confounding factors; (ii) statistical limits; (iii) gene–gene interactions; (iv) gene, environment, and by time interactions; and (v) technological and theoretical limits.The ability to identify significant associations and the relevance of such information to suicidality is linked both to the number of subjects in each group and to the method used to define the groups. Although the family transmission of suicidality would tend to suggest that suicide is a separate phenomenon from psychopathology , there iTurecki  suggesteSecond, variations in the definition of SB in the studies on genetic association are considerable, a fact which would tend to render comparisons between the results obtained somewhat rash. The definition of suicidal ideation includes suicide threats or thoughts that produce no action, and the precise clinical definition of the concept is still inadequate and confusing. A number of studies offer evidence showing that suicidal ideation is very different, in terms of phenotype, from suicide attempt. An excess level of suicidal ideation was observed in the family environment of suicide victims, but it was not found to be significant once adjustments were made to take account of psychiatric disorders . The sugSome have proposed the use of eminently heritable phenotypes in genetic analyses as being the most promising way of identifying real genetic associations. A strategy of heritable intermediate phenotypes (endophenotypes) has been proposed by the American Foundation for Suicide Prevention . A numbeIn the genetics of complex disease, it is necessary to limit both type I and type II errors. The value of studies concerned with allelic association is mainly a function of the size of the samples, the effect size of the susceptibility loci, how strong the linkage disequilibrium with a marker is, and how frequently susceptibility and marker alleles occur. Multiple testing, the rates of false positives and statistical significance levels are important issues in genetic association studies. Several statistical techniques are being developed for multiple comparison correction, but the ability to replicate findings of genetic associations in unrelated population samples is still the ultimate benchmark for complex disease genetics . GWAS pip-values. An independent replication sample is then analyzed by constructing, for each subject, a polygenic score consisting of the weighted sum of its trait-associated alleles, for some subset of top ranking markers . According to the CDCV hypothesis, common diseases are triggered by common variants, with effects that range from small to modest. According to the alternative theory, the “common disease rare variant” (CDRV) hypothesis, there is an extremely high level of allelic heterogeneity for complex traits, with disease etiology being the collective result of numerous rare variants having moderate to high penetrances.In terms of its practical implications, the issue may be split up into two parts. Should the CDCV hypothesis be valid, then the application of the paradigm of positional cloning to the task of mapping disease genes would be considerably facilitated since a common allele would be more easily located. If, on the other hand, common diseases are caused by rare variants, then the task of identifying such genetic susceptibility variants would represent a real challenge. Although there exist a substantial body of evidence to suggest that the CDCV and CDRV theories are both valid, a model for complex traits which would come closer to reality is likely to be that functional variants occur over a wide range of allele frequencies from rare to common, even for the same susceptibility gene . The tecFor identifying rare variants, exome sequencing in families is more effective than case–control studies. Given that disease alleles are shared among affected family members through identity-by-descent, the number of alleles needing to be considered could be limited by segregation analysis. However, this method is more difficult with suicide, which is a rare event.cis or trans effects which are potentially far-reaching. Based on single-nucleotide polymorphism array data, Gross et al.  have no greater intrinsic pathogenic potential than a single-nucleotide change, but their size means that they can potentially raise or reduce the gene product at each CNV intersecting a gene or to modify the genomic environment with s et al.  followedUsing subjects who were collected as part of STAR*D, Perlis et al.  genotypeFurther to that, Nadeau et al.  raises tThe more recent contribution made by epigenetic studies would appear to be an interesting path for understanding SBs. Epigenetic mechanisms, such as DNA methylation and chromatin restructuring, can be altered by environmental factors but the complexity of the epigenome is not fully understood . The recIn conclusion, although the studies on the heritability of SB have shown a strong genetic component, genetic association studies have failed to clearly identify specific markers contributing to this genetic liability. Numerous genes appear to be involved in the emergence of SBs. Several neurobiological pathways are involved, with multiple interplay of genetic and environmental factors. While the complexity is daunting, advances in statistical and genetic methodologies as well as increasingly informative developmental studies can help sustain an approach of guarded optimism. A better understanding of the genes that are involved in SB and their interaction with genetic and non-genetic factors could help in the development of more effective screening, prevention, and management of SB.All authors contributed to the design of the study. BM participated in the design of the study and drafted the manuscript. PG participated in the design of the study, collected the data, and helped to draft the manuscript. DC helped to draft the manuscript. CL conceived the study, participated in its design, and drafted the manuscript. TF helped for discussion. All authors have reviewed and approved the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Coronary artery disease (CAD) is a most important cause of morbidity and mortality worldwide as well as in Pakistan. Recent studies have shown that the combination of obesity, insulin resistance and fluctuation in circulating adipocytokines levels is associated with the pathogenesis of coronary artery disease. Omentin-1 is recently found adipocytokine that is highly expressed in visceral adipose tissue. It has anti- inflammatory properties and is negatively correlated with ischemic heart disease. Therefore, this study was designed to investigate the relationship between omentin-1 Val109Asp polymorphism and CAD in Pakistani population.A total of 350 subjects were included in the study. Two hundred fifty were diagnosed with coronary artery disease while 100 served as healthy controls. PCR-RFLP was performed at Dr. A Q. Khan Institute of Biotechnology (KIBGE) to analyze Val109Asp polymorphism. In this, case control study SPSS software version 16  was used for data analysis. Continuous variables and categorical variables were presented as mean±SD or in percentage. Independent sample test and chi-square test was performed to compare the differences in means between cases and controls. Genotype distribution was analyzed by chi-square test and results were presented as percentage and frequency. Multivarible regression analysis indicated that Val109Asp SNP might be an independent risk factor for CAD susceptibility after adjustment for some well- known CAD risk factors including age, gender, body mass index, smoking, hypertension, diabetes mellitus and lipid abnormalities. There was estimation of odd ratios (OR) and 95% confidence intervals (CIs) to determine the correlation between genotypes and the risk of CAD. (p> 0.05). Genotype frequencies were compared by Chi-square test.There was prevalence of Omentin-1 Val109Asp polymorphism in both case and control groups. However, Val/Asp (heterozygous mutant) genotype was detected more frequently in patients with CAD, OR(95%)=1.921; CI=1.173-3.1469 in comparison of Asp/Asp and Val/Val genotypes.Individuals having Val/Asp heterozygous gemotype of omentin-1 gene polymorphism are at more risk of developing CAD in Pakistani population, further studies are required in different populations and ethnicities to confirm our findings. Coronary artery disease (CAD) is emerging as the principal killer of the 21st century in both developed and developing countries. Globally 17.4 million deaths, that is29% of all deaths occur due to CAD, per year.9Recent studies have shown that Serum levels of omentin-1 significantly reduced in coronary heart disease and associates negatively with markers of atherosclerosis including: body mass index (BMI), waist circumference, HDL and hsC-reactive protein. So, omentin-1 may serve as a novel biomarker for early detection of CAD.This study aimed to establish local perspective as there is paucity of local data and was designed to determine whether omentin-1 gene polymorphism is a predisposing factor in development of CAD in Pakistani population because coronary artery disease and its management is emerging as a great challenge to deal with, hence, data collected from this study will help in establishing the role of omentin-1 in pathophysiology and therapy of CAD.This study was approved by the ethical review board committees of concerned institutions. A total of 250 patients were enrolled in this study between the period of January 2016 to April 2016 in Karachi Institute of Heart Disease (KIHD), Civil Hospital Karachi (CHK) and Darulsehat Hospital Karachi. All patients had undergone coronary angiography. CAD was defined as more than 50% obstruction of one or more coronary arteries. Severe chest pain, ST segment elevation and T wave inversions in more than two leads in ECG, elevated Troponin-I >0.01ng/ml) and positive stress test for ischemia were indications of angiography. The acute infections, malignancy, valvular heart disease, liver disease (ALT >59 units/L) and renal disorders (Creatinine >1.2 mg/dl) were excluded from the study. History of risk factors such as diet, lack of exercise, smoking, family history of cardiac disease, hypertension, diabetes mellitus, and hypercholesterolemia was recorded. Age and gender matched 100 controls were included in this study. Controls were defined as individulas had negative exercise tolerance test or less than 50% stenosis of coronary arteries on angiography, moreover, those control subjects who reported arthritis, diabetes, renal disorders and history of recent infections were excluded from the study. All participants were informed about the methods and benfits of this medical research and their informed consents were taken.2. Waist circumference was measured between upper margins of iliac crests and lower border of rib cage. Morning blood samples were collected in EDTA tubes after 12 hour overnight fasting. Routine lab tests including serum cholesterol, triglycerides (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), fasting blood sugar (FBS), serum creatinine were analyzed by an automated analyzer (Olympus Irish branch) in hospital laboratory.The history of disease was recorded in detail, Body mass index of all participants were calculated as kg/met al.,1988). Extracted DNA was quantified by Nano drop (Thermo scientific USA). The integrity of DNA was checked by resolving 3ul of genomic DNA in 0.8% agarose gel in horizontal gel electrophoresis.Genomic DNA was extracted from whole blood via salting out extraction method  by the set of F-primer 5′-AATCAGAAGGCAGTCCTCCC-3′ and the R-primer 5′-TCGGGGAGCACAGAGTGTAC-3′ . For PCR, total 50μl volume was prepared containing genomic DNA, 0.2 mM dNTPs, 1X PCR buffer of pH-8.3, 1.5mM MgClAccI restricyion enzyme which recognized +326A/T polymorphic site and cut it into two fragments of 274 and 197 bps. The digested products were visualized on 2.5% of agarose gel. Individuals with Val/Asp (GTC/GAC) genotype had 471bp, 274 bp and 197 bp fragments, subjects with Asp/Asp(GAC/GAC) genotype had 471 bp fragments and subjects with Val/Val (GTC/GTC) showed two fragments of 274 bp and 197 bp.PCR products were purified and treated with 10U of In this study SPSS software version 16  was used for data analysis. Continuous variables and categorical variables were presented as mean ± SD or in percentage. Independent sample t-test and chi-square test was performed to compare the differences in means between cases and controls. Genotype distribution was analyzed by chi-square test and results were presented as percentage and frequency. Multivariate logistic regression analysis was performed with adjustment for age, BMI, waist circumference and the prevalence of smoking, hypertension, diabete and family history of CAD. The association of AT genotype and CAD was estimated using dominant model (defined as AT vs. TT+AA) and recessive model (defined as TT+AT vs. AA), respectively. Odds ratios (OR) with their 95% confidence intervals (CI) were reported. A multivariate logistic regression analysis was used for association analyses with adjustments for age, gender, BMI, smoking, hypertension, and diabetes mellitus. P-value<0.05 was considered statistically significant. There was estimation of odd ratios (OR) and 95% confidence intervals (CIs) to determine the correlation between genotypes and the risk of CAD (p> 0.05).In current study, 250 patients diagnosed with CAD  and 100 control subjects with normal blood vessels  were recruited. The demographic, clinical and anthropometric parameters of the both case and control groups are shown in The present study has established that omentin-1 gene Val109Asp (326 +A/T) missense polymorphism is frequently present in both groups of current population, However, Homozygous genotype Asp/Asp was more often in control subjects , whereas CAD patients were detected with increased heterozygous mutant genotype Val/Asp . The current study had indicated that the ‘T’ allele at position 326 in exon 4 of omentin-1 gene acts as a dominant allele in relation to increased risk of CAD while, homozygous genotype Asp/Asp reduces the risk of developing CAD . To the It has been documented by various resent studies that the adipose tissue is not just a fat deposit but it also acts as an endocrine tissue and produces numerous hormone like proteins called adipokines including: leptin, adiponectin, vaspin, TNFa, IL 6, IL 10, resistin, visfatin and omentin.In current study CAD patients were recruited from three different centers of Karachi, belong to different ethinic groups. The common factor that observed was central obesity even with normal BMI. As omentin-1 expressed from visceral fats so it seem reasonable to investigate the omentin-1 polymorphism and coronary artery disease. So the data from this study will help the researchers to investigate the pathophysiology behind the association between polymorphism and CAD, which is still unknown.Current study made evident that there is a significant association between omentin-1 polymorphism and risk of developing coronary artery disease.This is perhaps the first study in Pakistan that has established a significant association between omentin-1 Val109Asp polymorphism and coronary artery disease. It also revealed that heterozygous Val/Asp genotype of omentin-1 gene is more associated with risk of developing CAD in Pakistani population while healthy subjects were found with more Asp/Asp genotype, however studies with different ethnicities are required to confirm our findings.Our study, to best of our knowledge, is the first study in Pakistan that established the association of omentin-1 gene with coronary artery disease. This study not only revealed the genetic aspect of coronary artery disease but also provide a local data which help in future studies.


GNβ3 C825T polymorphism and irritable bowel syndrome (IBS). However, the results remain inconclusive and controversial, particularly for the data derived from different ethnicities and IBS subtypes. Therefore, we performed an updated meta-analysis to evaluate this association. All eligible case-control studies that met the search criteria were retrieved from multiple databases, and eleven case-control studies were included for detailed evaluation. The pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated to assess the strengths of the association between GNβ3 C825T polymorphism and susceptibility to IBS and its subtypes. Our meta-analysis found no significantly associations of GNβ3 C825T polymorphism with IBS risk in all populations. Whereas the C allele was demonstrated to be a decreased risk factor for constipation predominant IBS (IBS-C) in allele model. Additionally, the CC genotype was found to be associated with increased diarrhea predominant IBS (IBS-D) risk in recessive model. Subgroup analysis by ethnicity revealed that these associations held true for the Asian subpopulation. In conclusion, this meta-analysis suggests the C allele of GNβ3 C825T might be associated with a decreased risk of IBS-C, and the CC genotype of GNβ3 might be associated with increased IBS-D risk.Several studies have reported an association between  Accowith IBS –12.GNβ3 (rs5443) is associated with alternative splicing of the gene and its protein activity, and an increased intracellular signal transduction compared with unmodified Gβ3 protein [GNβ3 C825T polymorphism and the risk of IBS has been intensively investigated. However, the community is still unable to reach a consensus, particularly regarding the data from different ethnicities and IBS subtypes [GNβ3 C825T polymorphism and susceptibility to IBS [GNβ3 C825T polymorphism and different IBS subtypes with respect to ethnicity. Therefore, we conducted an updated meta-analysis including all published studies accompanied with ethnic subgroup analyses and IBS subtype analyses to clarify whether GNβ3 C825T was associated with the development of IBS and its subtypes.G-protein, consisting of an α, β, and γ subunit, is an intracellular second messenger signalling protein linked to a transmembrane receptor , 14. The protein , 16. Thi protein , Alzheim protein , hyperte protein , obesity protein , Insulin protein , Vasculo protein , and fun protein . Recentlsubtypes , 24–30. y to IBS . Howevery to IBS –30. MoreGNβ3 C825T polymorphism and different IBS subtypes  risk. The main characteristics of the included articles were summarized in Table As showed in Figure GNβ3 C825T was estimated from the 1000 Genomes. The present samples indicated that 100% power to evaluate the association between this polymorphism and IBS. And the power to evaluate the associations between this polymorphism and IBS subtypes  were 88.1%, 98.3% and 93.9%, respectively. The power analysis indicated that these recruited samples could provide sufficient power in identifying the association between GNβ3 C825T polymorphism and IBS and its subtypes.Before implementation of this meta-analysis, statistical power was assessed with the assumptions:α err prob = 0.05, OR = 1.25 (corresponding to a “weak to moderate” gene effect) for the SNP, and minor allele frequencies(MAF) of GNβ3 C825T polymorphism and risk of IBS was observed under all genetic models  , while no evidence of significance was identified in other genetic models . In the subgroup analyses by ethnicity, the significant association was found among Asians under all genetic models  except for the recessive model  , while no evidence of significance was identified in other genetic models . In the subgroup analyses by ethnicity, the significant association was found among Asians under allele model  and recessive model , while no evidence of significance was identified in other two genetic models  of the SNP GNβ3 C825T (rs5443) is 0.50 in the East Asian population (EAS), whereas the MAF is 0.31 in the European population (EUR) and the MAF is 0.38 in the Ad Mixed American population (AMR) based on the data from the 1000 G. In accordance with our partial findings, a previous meta-analysis performed by Pan ZG et al. [GNβ3 C825T polymorphism and 3 IBS subtypes . The major reason of this discrepancy is that this previous meta-analysis did not include all the published articles and did not assess the association between this polymorphism and IBS subtypes with respect to ethnicity. In contrast, our meta-analysis included all the eleven relevant published studies with a larger sample size of cases and controls, which gave a greater statistical power to evaluate the association than the previous study. Additionally, our study included four studies in Asian group and four studies in Caucasian group to evaluate the association between GNβ3 C825T polymorphism and IBS subtypes, which gave a more detailed analysis to assay the association and showed a more reliable result.In the present study, we used four models to estimate the relationship between  studies –12 that GNβ3 C825T gene polymorphism and IBS and its subtypes with respect to ethnicity. The genotype distributions in all of the controls were consistent with HWE, except one for one study reported by Lee et al. [To the best of our knowledge, this is the first meta-analysis to explore the relationships between e et al. . HoweverGNβ3 C825T and subsequent IBS.Nevertheless, there were some limitations in the current study. First, only articles in English and Chinese language were included; thus, studies written in other languages were neglected. Second, although we performed a systematic searching strategy to identify eligible studies, there was still probability that few studies so called “grey literatures” were not included. Third, due to the limited data, we did not carry out subgroup analysis to other factors, which may participate in the progression of IBS, such as age, infection, social psychology, and other living habits. Finally, IBS is a common gastrointestinal disorder in the human population; particularly in females . However, none of the original studies accounted for gene-gender interactions. Further studies are needed to clarify whether gender-related differences affected the polymorphism of GNβ3 C825T may be associated with a decreased risk of IBS-C, while the CC genotype of GNβ3 may be associated with increased IBS-D risk. However, due to the above-mentioned limitations, a well-designed large-scale study that includes ethnicities, IBS subtypes and psychosocial factors is required to confirm the findings of the current meta-analysis.In summary, this meta-analysis suggested that the C allele of or “IBS”) AND  AND (“G protein beta3” or “G protein β3” or “GNβ3”). Furthermore, the references of all retrieved articles were also checked by hand to identify additional potential studies. The languages were limited to English and Chinese. We inclusion all studies that (1) evaluated the association between GNβ3 polymorphism and the risk of IBS; (2) used a case control design; (3) provided sufficient data of allele and genotype frequencies of SNPs or required information could be calculated; and (4) if serial studies on the same population were published, only the most recent or the largest research study was included. Additionally, we excluded reviews, abstracts, and redundant and animal studies.According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement , we searGNβ3 genotype distributions and alleles in the case and control groups.Two independent investigators extracted relevant data from all included studies on the basis of the inclusion criteria, and a third investigator verified them. The following information was extracted from all of enrolled studies: the surname of the first author, publication year, country of origin, ethnicity, sample size, genotyping method, and the The quality of included studies were assessed by two investigators independently on the basis of Newcastle-Ottawa Scale (NOS) , which bP < 0.05 was considered statistically significant. Studies with the controls not in HWE were subjected to a sensitivity analysis [GNβ3 polymorphism with the risk of IBS was assessed by the pooled ORs with the corresponding 95% CIs under the following genetic models: allele model (C vs. T), codominant model (CC vs. TT and CT vs. TT), dominant model (CC + CT vs. TT), and recessive model (CC vs. CT + TT). The heterogeneity between studies was determined by the Cochrane's Q-statistic test [I2 statistic. When I2 > 50% or PQ ≤ 0.1, which suggest substantial heterogeneity, a random-effects model (DerSimonian-Laird method) [P < 0.05 was considered statistically significant). All analyses were conducted using the STATA 12.0 software packages.The HWE of the genotype distributions in the controls of the include studies were tested by the Chi-square test, analysis . The powanalysis . The asstic test , and the method)  was used method)  was appl method)  was used