Some surveys had inspected the effects of the tumor necrosis factor-α (TNF-α)-308A/G polymorphism on susceptibility to dermatomyositis (DM), and showed mixed results. To briefly review these consequences, a comprehensive meta-analysis was carried out to estimate the relationship between them much more accurately.Relevant documents dated to February 2014 were acquired from the PUBMED, MEDLINE, and EMBASE databases. The number of the genotypes and/or alleles for the TNF-α-308A/G in the DM and control subjects was extracted and statistical analysis was conducted using STATA 11.2 software. Summary odds ratios (ORs) with their 95% confidence intervals (95% CIs) were used to calculate the risk of DM with TNF-α-308A/G. Stratified analysis based on ethnicity and control population source was also performed.555 patients with DM and 1005 controls from eight published investigations were finally involved in this meta-analysis. Combined analysis revealed that the overall ORs for the TNF-α-308A allele were 2.041  in DM. Stratification by ethnicity indicated the TNF-α-308A allele polymorphism was found to be significantly associated with DM in Europeans . The only study conducted on TNF-α-308A/G polymorphism in Asians could not be used in ethnicity-stratified meta-analysis. Meta-analysis of the AA+AG vs. GG (dominant model) and AA vs. GG (additive model) of this polymorphism revealed a significant association with DM in overall populations and Europeans.Our meta-analysis demonstrated that the TNF-α-308A/G polymorphism in the TNF gene might contribute to DM susceptibility, especially in European population. However, further studies with large sample sizes and among different ethnicity populations should be required to verify the association. Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of diseases that affect skeletal muscles. Dermatomyositis (DM) is the most common subtype. Its clinical features are muscle weakness;muscle biopsies which typically show inflammatory cell infiltrates, and specific cutaneous involvement. Although the aetiology of the DM is unclear, genetic factors are thought to contribute to the pathogenesis of DM TNF-α is a potential pro-inflammatory cytokine that plays a prominent role in inflammatory and immune responses, including those observed in DM Previous studies had examined the potential association between the TNF-α -308A/G polymorphism and the susceptibility to DM The electronic databases of PUBMED, MEDLINE, and EMBASE were comprehensively searched, with the following terms utilized: “tumor necrosis factor-α” or “tumor necrosis factor-alpha” or “TNF-α” or “TNF-alpha” and “dermatomyositis” or “idiopathic inflammatory myopathies” and “polymorphism” or “genetic”. All documents were updated to February 2014. The language was limited to English. Additional relevant references quoted in searched articles were also selected.Studies meeting the following criteria were included: (1) case–control studies on the association between TNF-α polymorphisms and DM risk; (2) comprised genotype data; (3) sufficient data for evaluating OR with 95% CI.Studies were excluded if they satisfied the following criteria: (1) studies in which genotype frequencies or alleles could not be ascertained; (2) studies in which family members had been studied; (3) reviews or abstracts; (4) animal studies. For the overlapping studies, only the one with the largest sample size was included in our study.Data was extracted from all selected studies by two independent investigators (SC and QW). Inter-researcher disagreements were resolved by consensus or by a third investigator (YL). The following data was collected from each selected study: author, publication year, ethnicity of the subject population, age of population, study-design (sources of controls), demographics, total numbers of patients and controls, and the frequency of the genotypes and alleles of the TNF-α gene-308A/G polymorphism in cases and controls. Authors of the identified studies were contacted via E- mail if further study details were needed.2 statistic were used to assess whether or not heterogeneity existed among the studies included in this meta-analysis. P>0.10 in Q-test indicated lack of heterogeneity among studies, so that the combined OR evaluated of each investigation was calculated by the fixed-effects model. Otherwise, we used the random-effects model. The I2-statistic was also calculated to evaluate heterogeneity, with I2<25% considered as low heterogeneity, 25%–50% as moderate, and >50% as degree of inconsistency http://www.psycho.uni-duesseldorf.de/app/projects/gpower).Under the dominant model (AA+AG vs. GG), recessive model (AA vs. GG+AG), additive model (AA vs. GG) and allele model (A vs. G), we evaluated the strength of associations between TNF-α gene-308A/G polymorphism and the risk of DM by calculating a pooled OR and 95% CI. The statistical significance of OR was ascertained with Z-test, and P<0.05 was deemed to statistically significant. Applying the fixed-effects model or random-effects model depended on the degree of heterogeneity among studies. The Cochran’s Q statistic and the IUsing electronic and manual searches identified forty-eight potentially relevant articles and twenty of these were selected for full-text review based on title and abstract details The average prevalence of the A allele of the TNF-α-308A/G polymorphism was 23.9% in the control groups. Europeans had a higher A allele frequency than Asian populations (14.4%). Among healthy controls, the frequency of the TNF-α-308A allele in the Asians was 9.5% .2 = 0.0%, Pheterogeneity = 0.945), and the recessive model . Therefore, these two genetic models used fixed-effects model. However, the allele model , and the dominant model  had apparently between-study heterogeneity. Thus, a random-effects model was utilized for these two genetic models. Significantly increased DM risk was found for A allele vs. G allele  .To examine publication bias, Begg’s funnel plot and Egger’s test were performed for the association between TNF-α-308A/G polymorphism and DM risk. The shape of the funnel plots showed almost symmetrical. The Egger’s test and Begg’s test indicated that there was no evidence of publication bias , dominant genetic model  and additive model . In addition, Stratified analysis based on ethnicity was performed. Interestingly, we also found apparent association between TNF-α-308A/G gene polymorphism and Europeans for A allele vs. G allele (P<0.0001), for AA+AG vs. GG (P = 0.001), for AA vs. GG (P<0.0001). The only study performed on the TNF-α-308A/G polymorphism in Asians could not be used in ethnicity-stratified meta-analysis. Therefore, more studies were needed to conduct in Asian population. European population showed a higher frequency of the TNF-α-308A allele (14.4%), while Asians showed a lower frequency of the A allele (9.5%). Thereby, the present study indicated TNF-α-308A allele might increase DM risk.-238A/G, +489 A/G, −1031T/C, −863C/A, −857C/T polymorphisms and DM risk were needed to acquire dependable consequence. Hristova et al. TNF-α is an inducible cytokine, which has an expansive range of pro-inflammatory and immune-stimulatory response. TNF-α gene is located within the HLA class III region in chromosome 6p21.3 DM is a complement-mediated vascular endothelial cell disease, which is associated with perimysium inflammation and peri-fascicular muscle fiber atrophy. In the pathogenesis of DM, large numbers of helper T-cells are found within the perimysium and peri-vascular, which induce inflammatory infiltrates. The endomysium and perimysium inflammatory cells express high levels of cytokine, while macrophages are the primary origin of the cytokine. The influential role played by cytokines in the DM has been acknowledged for long Several limitations from the following aspects should be considered when explaining those findings. First, the number of studies and the number of subjects in researches selected in this meta-analysis were limited, which might furnish insufficient power to estimate the association between TNF-α-308A/G polymorphism and DM risk. It was possible that some connected published studies or unpublished articles with negative conclusions were lost. Therefore, more studies were needed to acquire a more dependable consequence. Second, our outcome was based on unadjusted estimates. Thus, a more accurate analysis could be conducted if individual information were obtainable to permit adjustment. Third, most of the included publications were performed in Europeans; the only study was carried out in Asian population. In this study, ethnicity-specific meta-analysis data were only available for European population, and therefore, our results were only applicable to European group. So future studies should evaluate other population. Fourth, although no evident publication bias was identified, potential bias might have distorted the result of the meta-analysis. Finally, due to limited or unavailable data, effect prompted by age, gender and other environmental factors could not be investigated.This was the first meta-analysis to evaluate the relationship between the TNF-α-308A/G polymorphism and DM risk. Despite of the above limitations, this systematic analysis of the association of TNF-α-308A/G gene polymorphism with DM risk was statistically more persuading than any single study. This meta-analysis reached a strong conclusion that the -308A/G polymorphism might be a potential risk factor for DM susceptibility, especially for Europeans. Accordingly, our results supported the fact that the role of TNF-α-308A/G polymorphism played in the pathogenesis of DM. However, in order to better assess the association between TNF-α-308A/G gene polymorphism with the susceptibility to DM, further investigations should conduct with a larger number of worldwide studies in standardized and unbiased ways.File S1File includes Tables S1–S3. Table S1: Characteristics of the studies and populations on the association between other TNF polymorphisms and DM risk. Table S2A: Characteristics of the studies on the association between TNF-1031 T/C polymorphism and DM risk. Table S2B: Characteristics of the studies on the association between TNF-238 A/G, +489 A/G polymorphisms and DM risk. Table S2C: Characteristics of the studies on the association between TNF-857 T/C polymorphism and DM risk. Table S2D: Characteristics of the studies on the association between TNF-863 C/A polymorphism and DM risk. Table S3: Meta-analysis of the association between other TNF polymorphisms and DM risk.(DOC)Click here for additional data file.File S2PRISMA Checklist.(DOC)Click here for additional data file.


Z test was used to measure the significance ofthe overall effect size. A total of nine eligible cohort studies were included inthis meta-analysis. The expression of CDH17 in patients with diffuse GC wassignificantly higher than in those with intestinal-type GC. Moreover, the tumor depthof invasion differed significantly between patients with positive CDH17 (CDH17+) andnegative CDH17 (CDH17-) GC. However, there were no significant differences betweenCDH17+ and CDH17- GC patients with respect to tumor node metastasis clinical stages,histological grades, or lymph node metastasis. Despite the differences in invasivedepth, there was no significant difference in 5-year survival rates between CDH17+and CDH17- GC patients. Our meta-analysis provides evidence that CDH17 proteinexpression may be associated with the development of GC, suggesting that CDH17 is animportant biomarker that could be useful for the early diagnosis of GC. However,CDH17 levels do not appear to impact overall survival.This study aimed to explore the correlations between cadherin-17 (CDH17) proteinexpression and the clinicopathological features and prognosis of patients withsporadic gastric cancer (GC). Nine relevant studies of 1,960 patients were identifiedusing electronic database searches supplemented with a manual search in strictaccordance with inclusion and exclusion criteria. Statistical analyses were conductedusing STATA 12.0 statistical software. Relative risks and 95% confidence intervalswere determined, and  Gastric cancer (GC) is the fourth most common cancer and the second main cause ofcancer-related deaths worldwide ,2. CompaCDH17) have been implicated in the carcinogenesis and progressionof human cancers, and have become a popular research topic  database, Wanfang database,and VIP database  using the following commonselected keywords: (“stomach neoplasms” or “gastric cancer” or “stomach cancer” or“gastric neoplasms” or “gastric carcinomas” or “stomach carcinomas” or “stomachneoplasms”) and . We also manually reviewed potential relevant articles identifiedusing related search engines.After carefully reading the abstracts and full articles, studies were included ifthey met the following inclusion criteria: 1) the study was a non-randomized clinicalcohort trial investigating the correlation between CDH17 protein expression and theclinicopathological features and/or prognosis of GC; 2) the study enrolled patientsdiagnosed with sporadic GC, which was confirmed by histopathologic examinations usingtissue samples for CDH17 detection collected from the edge of the tumor; 3) thearticle contained sufficient information about CDH17 expression levels; 4) the studyused immunohistochemistry to quantify CDH17 expression; 5) the final outcome of thestudy included a clinical stage, histological grade, and 5-year survival rate, and 6)the study was either in Chinese or English. If studies were identified that werewritten by the same author, only the latest or most complete study was included.Exclusion criteria were: 1) the literature data lacked integrity; 2) the article wasan abstract, review, case report, letter, meta-analysis, or proceedings; and 3) thestudy was a repeated publication or a study with data that overlapped with anotherstudy.With the aim of reducing bias and increasing credibility, two investigatorsindependently collected information from the enrolled papers based on the selectioncriteria and reached a consensus on all the items through discussion. The followingrelevant data were collected from eligible studies, although several articles did notcontain all of the data: surname of first author, time of publication, country andethnicity of subjects, language, age and gender of subjects, study design, number ofsamples, 5-year survival rate, Lauren grade, TNM stage, histologic grade, invasivegrade, and lymph node metastasis (LNM).http://www.casp-uk.net/). The CASPcriteria are scored based on these aspects: if the study determines a clearly focusedissue (CASP01); if the cohort studies are recruited in an acceptable way (CASP02); ifthe exposure is accurately measured to reduce bias (CASP03); if the outcome isprecisely measured to reduce bias (CASP04); a) if the authors take all importantconfounding factors into consideration; b) if they take account of the confoundingfactors in the study design (CASP05); a) if the follow-up of the subjects isadequate; b) if the follow-up of the subjects is sufficiently long (CASP06); theresults of the study (CASP07); if the results are precise (CASP08); if the resultsare reliable (CASP09); if the results can be applied to the local population(CASP10); if the results are consistent with other evidence (CASP11); and theimplications of this trial for practice (CASP12). Discrepancies on CASP scores of theincluded articles were resolved by discussion and consultation with a thirdreviewer.To determine whether the methodological quality of the study in question was high,the two authors used a set of predefined criteria based on those of the CriticalAppraisal Skills Programme  and the I2 test to assess heterogeneity among the studies (I2 test >50%). Otherwise, a fixed effects model was used . To assess the correlations between CDH17 proteinexpression and the clinicopathological features and prognosis of GC patients,relative risk (RR) and 95% confidence intervals (95%CI) were calculated using arandom effects or fixed effects model. The statistical significance of pooled RRs wasestimated using a was used ,19. Weawas used ,21. Univwas used .A total of 45 published studies were identified through electronic and manualdatabase searches. 2=84.2%, P<0.001; TNM stage:I2=83.7%, P<0.001; histological grade: I2=83.6%, P<0.001;LNM: I2=92.3%, P<0.001). Therefore, a random effects model was used.There was no heterogeneity among the four studies associated with invasive depth, soa fixed effects model was used in these cases. Our meta-analysis indicated that,based on the Lauren classification, positive expression of CDH17 in patients withdiffuse GC was significantly higher than in intestinal-type GC . There was also a significant difference in the depth ofinvasion between GC patients with positive CDH17 expression (CDH17+) and those withnegative CDH17 expression (CDH17-) . However,there was no significant difference between CDH17+ and CDH17- GC patients withrespect to TNM clinical stage, histological grade, or LNM ,a random effects model was used. This meta-analysis indicated that there was nosignificant difference in the 5-year survival rates between CDH17+ and CDH17- GCpatients , as shown in A total of six studies reported an association between CDH17 expression and theprognosis of GC patients. Because heterogeneity was observed among the studiesrelated to the 5-year survival rate of GC patients  . MoreoveCDH17 is a unique member of the cadherin superfamily regulating intercellular adhesion.Several studies have reported that overexpression of CDH17 in GC is associated with apoorer prognosis, which is also associated with LNM and deeper invasion ,16.HoweWe discovered that CHD17 was a risk factor for the invasive depth of GC, revealing thatCHD17 might participate in the invasion and metastasis of GC but can not be consideredan independent predictor of GC prognosis. The molecular mechanisms underlying theregulation of GC growth by CDH17 are unknown. However, based on a recent report thatindicated the existence of a trans-interaction between CDH17 and E-cadherin inenterocytes throughout intestinal epithelium development, we predict that CDH17interacts with the Wnt pathway via coordination with E-cadherin or E-cadherin-relatedpartners ,30, althThe specific mechanisms by which CDH17 exerts a potential oncogenic role through theWnt/β-catenin pathway in GC include a decrease in the phosphorylation of glycogensynthase kinase-3β and β-catenin, together with a simultaneous increase ofretinoblastoma protein and decrease of cyclin D1, leading to an inhibition of cellproliferation .Previous studies reported that intestinal metaplasia is a premalignant lesion -36involSome limitations potentially influenced the overall results of this meta-analysis. Forinstance, the small sample size for several outcomes indicated a trend for some resultsbut could not be statistically significant. Additionally, data about age and gender wereincomplete in some of the included studies, which could influence the overallfindings.In summary, we found that CDH17 might be associated with the early development of GC andthat it is clearly involved in local invasion of GC tumors. However, we failed to find arole for CDH17 in GC progression to later stages and did not establish any links tooverall survival in GC.


CI: 0.74–0.86). A stronger association between coffee intake and EC incidence was found in patients who were never treated with hormones, 0.60 (95% CI: 0.50–0.72), and subjects with a BMI ≥25 kg/m2, 0.57 (95% CI: 0.46–0.71). The overall RRs for caffeinated and decaffeinated coffee were 0.66 (95% CI: 0.52–0.84) and 0.77 (95% CI: 0.63–0.94), respectively. A linear DR relationship was seen in coffee, caffeinated coffee, decaffeinated coffee and caffeine intake. The EC risk decreased by 5% for every 1 cup per day of coffee intake, 7% for every 1 cup per day of caffeinated coffee intake, 4% for every 1 cup per day of decaffeinated intake of coffee, and 4% for every 100 mg of caffeine intake per day. In conclusion, coffee and intake of caffeine might significantly reduce the incidence of EC, and these effects may be modified by BMI and history of hormone therapy.This is a dose-response (DR) meta-analysis to evaluate the association of coffee consumption on endometrial cancer (EC) risk. A total 1,534,039 participants from 13 published articles were added in this meta-analysis. The RR of total coffee consumption and EC were 0.80 (95%  The overall cases reported each year is third in rank among the number of new cases and one of the major 4th Rank cvs. low coffee intake group. Recently, an articleAs per our current knowledge, only four published meta-analyses were focused on the involvement of coffee for and EC risk101112Therefore, we designed this meta-analysis with the following objectives: (1) to investigate the epidemiological evidence on the relationship between total coffee intake and EC risk. It also quantifies the association between different caffeine dosages and coffee types and risk of EC; (2) to calculate the DR graph of these associations; and (3) to evaluate the statistical power of the associations and the quality of evidence.This meta-analysis was designed as per the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelinesThe PubMed, Embase and the Cochrane Library databases were searched from inception to May 1, 2015 for studies describing the association between coffee consumption and incidence of EC. The key words used during searching were :  AND (“Coffee” OR “coffee” OR “coffee consumption” OR “coffee intake” OR “coffee drinking” OR “Caffeine” OR “caffeine consumption”). In addition, the references from applicable research papers and review papers were screened to identify studies. In case of duplicated data, the most complete study was only considered for this Meta analysis.The selection of titles and abstracts of the studies were done as the first step for scrutinization. The second selection was done based on a complete review of the paper. The studies meeting the following conditions were only included in this study:(1) Study design was a prospective cohort study;(2) Exposure of interest was coffee intake;(3) Outcome of interest was EC;(4) RR or HR and the corresponding CI of the EC for the maximum versus the minimum level were provided.The RRs or HRs had to be adjusted for potential confounders. Two independent investigators (QZ and ML-L) selected the studies. If the studies did not not meet the all the above criteria, were excluded from this analysis. From the selected studies the information isolated were: first author’s last name; publication year; country of origin; study period; cohort name; duration of follow-up; age at baseline; coffee intake category; number of cases and cohort size of each category;relative risks (with their 95% CI) for each category of coffee consumption, and covariates adjusted for in the multivariable analysis. Two investigators (QZ and HL) independently retrieved the data. This disagreement in the independent analysis was resolved by mutual agreement.The Newcastle-Ottawa Scale17χ2 test and was defined as a P value less than 0.10. Quantification of heterogeneity was assessed by the I2statisticI2 above 50% indicated high heterogeneity. A random effect was implementedet al.p was less than 0.05, unless otherwise specified.Because incidence of EC is low, HR is mathematically similar to RR22The (1) One study(2) Two studies32(3) Three3435Finally 13 articles113738394041424344454647et al.et al.11373839404142444546In the DR meta-analysis, we excluded papers of Jacobsen The 1137394143464738424438451137394041424344471137383943464145384244373839414346CI: 0.74–0.86) . Egger regression tests (P = 0.03) were used to showed publication bias, but not by Begg correlation test (P = 0.66). The estimate was found to be 0.86 (0.80–0.91) after adjusting the six missing studies (3740CI: 0.65–0.92).Heterogeneity among studies was not statistically significant  and both Egger regression test(P = 0.61) and Begg correlation test (P = 0.75) did not detected publication bias. Five comparisons of the four studies384244P = 0.07, I2 = 53%). As such Begg correlation test (P = 0.23) or the Egger regression test (P = 0.47) showed no evidence of substantial publication bias. For the decaffeinated coffee, the summary RR was 0.77 (95% CI: 0.63–0.94). No heterogeneity  and publication bias among studies indicated by the Begg correlation test (P = 1.00) and the Egger regression test (P = 0.88). Tests for subgroup differences showed no significant differences between caffeinated and decaffeinated coffee (P = 0.35) (Fourteen comparisons from thirteen11373839404142434445464774–0.86) . Heterog studies . Four co = 0.35) .2  and in those without hormone therapy . However, no association was observed in the group of BMI less than 25 kg/m2  or among hormone therapy participants . Sensitivity analyses results are in the range from 0.73 (95% CI: 0.67–0.81) to 0.82 (95% CI: 0.76–0.89) for total coffee intake.The subgroup analyses are shown in the P = 0.90), and an increase of 1 cup of coffee per day was associated with a 5%  lower risk of EC (3738P = 0.89) supported a linear model and indicated that an increased intake of 100 mg caffeine per day was associated with a 4%  lower risk of EC (424445P = 0.82), and the results showed that increased intake of 1 cup of caffeinated coffee per day was associated with a 7%  lower risk of EC (P = 0.50), and the results showed that increased intake of 1 cup of decaffeinated coffee per day was associated with a 4%  lower risk of EC  and among participants never received hormone therapy . However, whether the study adjusted for BMI or hormone therapy did not affect the results in our study. The statistically non-significant subgroup differences occurred because of the small number of studies, which did not adjust for BMI (n = 2) or hormone therapy (n = 4) such that there was insufficient statistical power.The prospective cohort study design was included in almost all the studies and little heterogeneity was found in our meta-analysis. Except one study in JapanSeveral mechanisms were explained for the association of the coffee with EC. Caffeine and methylxanthine in coffee may increase amount of sex-hormone-binding globulin, thus reducing the concentrations of sex-steroids and leading to down regulation of endometrial hyper proliferation8The current study has several advantages, compared to the previous published meta-analyses101112There are several limitations of this study as listed below:(1) Most of the studies from America and Europe and only one study conducted in Japan. So more studies need to be included from other part of world much as Asia and South Africa.(2) Coffee intake data were collected using food frequency questionnaires (FFQs). Findings from large population-based studies in Sweden4855(3) Most studies did not distinguish between types of EC. Only one study(4) The possibility of residual confounding due to other risk factors cannot be excluded, although most investigators had adjusted BMI, hormone therapy, and smoking status.(5) Publication bias was detected in the total coffee intake and EC risk. However, we added six studies with null results trend in the funnel plot, the overall effect size still showed a protective effect.(6) The GRADE quality of the evidence was moderate or low, which lowers confidence in any subsequent recommendations.This study meets several of the Hill criteria for causation58In summary, coffee, regardless of coffee type and caffeine dosage, is a potential protective factor against EC in a dose-dependent fashion; the results corroborate the findings of the conclusion of the EC 2013 Report by WCRF/AICR. Further, the association of coffee intake and EC risk may be adapted by BMI and history of hormone therapy.How to cite this article: Zhou, Q. et al. Coffee consumption and risk of endometrial cancer: a dose-response meta-analysis of prospective cohort studies. Sci. Rep.5, 13410; doi: 10.1038/srep13410 (2015).


The 15q25.1 lung cancer susceptibility locus, containing CHRNA5, could modify lung cancer susceptibility and multiple smoking related phenotypes. However, no studies have investigated the association between CHRNA5 rs3841324, which has been proven to have the highest association with CHRNA5 mRNA expression, and the risk of other smoking-associated cancers, except lung cancer. In the current study we examined the association between rs3841324 and susceptibility to smoking-associated nasopharyngeal carcinoma (NPC).In this case-control study we genotyped the CHRNA5 rs3841324 polymorphism with 400 NPC cases and 491 healthy controls who were Han Chinese and frequency-matched by age (±5 years), gender, and alcohol consumption. Univariate and multivariate logistic regression analyses were used to calculate the odds ratio (OR) and 95% confidence intervals (95% CI).We found that individuals with CHRNA5 rs3841324 combined variant genotypes (ins/del+del/del) had a >1.5-fold elevated risk for NPC than those with the ins/ins genotype , especially among ever smokers . The combined variant genotypes acted jointly with cigarette smoking to contribute to a 4.35-fold increased NPC risk . There was a dose-response relationship between deletion alleles and NPC susceptibility .Our results suggest that genetic variants on the 15q25.1 lung cancer susceptibility locus may influence susceptibility to NPC, particularly for smoking-associated NPC. Such work may be helpful to facilitate an understanding of the etiology of smoking-associated cancers and improve prevention efforts. Cigarette smoking is a major public health problem, accounting for 5 million deaths annually worldwide Genome-wide association studies (GWAS) have identified that chromosome 15q25.1, composed of nicotinic acetylcholine receptor genes, including CHRNA5 and CHRNA3, are lung cancer susceptibility regions CHRNA5 rs3841324, a 22 bp insertion (ins)/deletion (del) at position −71 upstream of the transcription start site, has been shown to have the greatest association with CHRNA5 mRNA levels in lung tissue Our previous large epidemiologic study showed that cigarette smoking is a significant risk factor for NPC Four hundred newly diagnosed patients, previously untreated with histopathologically-confirmed NPC without age, gender, and cancer stage or histology restrictions, and 491 cancer-free healthy controls who with no history of cancer, were not receiving treatment for any diseases, and were frequency-matched to the cases with respect to age (±5 years), gender, ethnicity, and smoking status (ever or never) were recruited from Zhongnan Hospital of Wuhan University and Beijing Chaoyang Hospital between January 2006 and December 2012. Human participant approval was obtained from the ethical committees of Zhongnan Hospital of Wuhan University and Beijng Chaoyang Hospital of Capital Medical University. To avoid confounding due to ethnic characteristics, we included only Han Chinese in both the case and control groups. All participants signed written informed consent, completed a questionnaire regarding demographic and relevant risk factor information, and donated 3 ml of blood for CHRNA5 genotyping.5′-AGCAGACAGGGTTGGACCAGAG-3′ (forward); and 5′-CGTGAGACAAAACGAGGGCAGAC-3′ (reverse). The PCR amplification was carried out in a final volume of 20 µL containing 10 ng of DNA, 1 µM of each primer, 0.3 mM deoxynucleotide triphosphates , 3.0 mM MgCl2, 1x HotStarTaq buffer, and 1 unit of HotStarTaq Polymerase . The reaction was started at 95°C for 2 min, followed by 11 cycles of amplification , 24 cycles of amplification , extension at 68°C for 60 min, and 4°C until used. The 15-µL PCR product was added to 5 U SAP enzyme and 2 U exonuclease at 37°C for 60 min, then 75°C for 15 min. The 0.5-µL extension product and 0.5-µL fluorescence PCR product were added to 0.5-µL Lizl 20 SIZE STANDARD and 8.50.5-µL Hi-Di, incubated at 95°C for 5 min, then scanned using an ABI3730XL sequenator. Data from the ABI3730XL sequenator was analyzed using a GeneMapper 4.1 . The expected size of the PCR product was 267 base pairs (bp) for the rs3841324 ins allele and 245 bp for the del allele.We extracted genomic DNA from a leukocyte cell pellet, which was obtained from the buffy coat by centrifugation of 1 ml of whole blood, using the QIAGEN DNA Blood Mini Kit  according to the manufacturer’s instructions. Agarose gel electrophoresis was used following amplification using a fluorescence polymerase chain reaction (PCR). The fluorescence primer sequences for PCR were as follows: CHRNA5 rs3841324 allele and genotype frequencies between the cases and controls were evaluated using a χ2 test. The mean values of age were compared for cases and controls using a Student’s t-test. We estimated the association between CHRNA5 genotypes and the risk of NPC by computing the odds ratios (ORs) and 95% confidence intervals (CIs) by univariate and multivariate logistic regression analyses. We further stratified the genotype data by subgroups of age, gender, smoking, alcohol consumption, and pathology of NPC. For logistic regression analysis, the CHRNA5 genotype was tested with dominant model. We create a dummy variable to represent CHRNA5 coding wild type as 0, heterozygous and rare allele homozygous as 1. In the multivariate logistic regression model, the OR and 95% CI were adjusted by age, gender, smoking, and alcohol consumption. Statistical analyses were performed with Statistical Analysis System softwareand P values<0.05 were considered significant.Statistical Analysis System software  was used for all statistical analyses. Ever-smokers were subjects who had smoked >100 cigarettes in their lifetime, and the remaining smokers were categorized as never-smokers. Ever-drinkers were subjects who drank alcoholic beverages at least once a week for >1 year and the remaining drinkers were categorized as never drinkers. NPC was classified by the World Health Organization (WHO) in 1991 into two categories based on the histologic type, as follows: type I, keratinizing squamous cell carcinoma; and type II, non-keratinizing carcinoma CHRNA5 genotype data, demographic characteristics, and smoking and alcohol consumption status were available for 400 cases with NPC and 491 healthy controls . The del allele was more common among the cases (30%) than controls (25.3%), and this difference was statistically significant , implying that the del allele represented a risk factor for NPC. Similarly, the difference in the CHRNA5 ins/ins, ins/del, and del/del genotype distributions between the NPC cases and controls were statistically significant  and the ins/del heterozygote was more common among the NPC cases than among the controls, the difference were statistically significant . In contrast, although the del/del homozygotes were more common among the cases (8.5%) than controls (8.2%), this difference did not reach statistical significance . Compared to the ins/ins homozygotes, the ins/del heterozygotes were associated with a 55% elevated risk  for NPC, and the del/del homozygotes also had an increased risk for NPC, although not statistically significant . Furthermore, we found a significant dose-response relationship between the number of del alleles and the risk of NPC (P = 0.011).We also test the genotype distributions and allele frequencies of CHRNA5 polymorphism, we performed stratification analysis by age, gender, cigarette smoking, alcohol consumption, and pathology. Because the del/del variant homozygotes were relatively uncommon, we combined the del/del variant homozygotes with the ins/del variant heterozygotes for this stratification analysis (CHRNA5 rs3841324 genotypes and smoking status (P = 0.080), and a significant interaction between CHRNA5 rs3841324 genotypes and age (P = 0.002); however, there was no evidence for an interaction between the CHRNA5 variant genotypes and gender (P = 0.373) or drinking status (P = 0.510) on the risk of NPC. Furthermore, we examined the joint effect of the CHRNA5 rs3841324 genotype and smoking status on the risk of NPC and found that ever-smokers with the CHRNA5 rs3841324 ins/del or del/del allele had a >4-fold increased risk for NPC  compared with non-smokers homozygous for the ins allele  found that in ever-smokers, homozygous carriers of del variants of rs3841324 exhibited a decreased lung cancer risk in females, but had little effect in males in 624 lung cancer patients and 766 healthy controls from a Caucasian population. A study explored the association between the CHRNA5 rs3841324 polymorphism and lung cancer risk in a Han Chinese population and found no significant association, but revealed that 2 least frequent haplotypes, rs3841324 ins/rs3829787 T and rs3841324 del/rs3829787 C were statistically decrease lung cancer risk Several GWAS have demonstrated that genetic variants in CHRNA5 and CHRNA3, located at the 15q25.1 lung cancer susceptibility locus Interestingly, in our studies, CHRNA5 rs3841324 combined variant genotypes (ins/del+del/del) had an increased NPC risk compared to ins allele homozygotes, which is inconsistent with the results for lung cancer in which the del allele was a protective factor for a Caucasian population The current study is the first to report the combined effect of exposure to cigarette smoke and genetic variants at the 15q25.1 lung cancer susceptibility locus on the risk of smoking-mediated cancer. Smokers who had ins/del or del/del genotypes were >4-fold more likely to develop NPC than non-smokers homozygous for the insertion allele, which was much higher than the effect of smoking exposure or genetic variants at the 15q25.1 lung cancer susceptibility locus alone. This findings suggest that genetic variants at the 15q25.1 lung cancer susceptibility locus is an independent risk factor influencing inheritance susceptibility and is also plausible to be a cofactor of cigarettes. Genetic susceptibility and environmental exposure for NPC risk has been widely verified in various populations Another important finding in our study was that the risk of NPC associated with rs3841324 genotypes harboring del alleles was significantly higher for males. The plausible explanation for this observation might be attributed to males being more strongly associated with cigarette smoking. A much higher proportion of males smoke cigarettes and have smoking-associated cancer deaths than females worldwide CHRNA5 genotypes in cases and controls between the two hospitals was not statistically different, and the frequency of the CHRNA5 genotypes in the healthy control group in the current study was similar to those in previous reports with Han Chinese subjects Although conducted in a large, well-characterized case-control comparison, our study had several limitations. First, possible limitations in our hospital-based case-control study design could have introduced some selection bias because subjects were not from the same population. However, all of the subjects were Han Chinese and both areas in which the hospitals were located are low NPC risk regions in China. In addition, we have found that the frequency of the In conclusion, our study demonstrated that genetic variants of the 15q25.1 lung cancer susceptibility locus, rs3841324, are significantly associated with NPC, a smoking-associated cancer other than lung cancer. This observation was especially pertinent to smokers, and could act jointly with cigarette smoking to increase NPC risk, indicating that this genetic variation can serve as a biomarker for the early identification of at-risk populations for smoking-associated cancers. We also noted that the association was most evident in males. This is the first time the role of genetic variants at the 15q25.1 lung cancer susceptibility locus and NPC risk has been examined, which is of value. Further validation of our findings by larger studies and exploration of the underlying molecular mechanisms are warranted.


T: OR = 1.18, 95% CI = 1.06–1.32; The dominant model: OR = 1.18, 95% CI = 1.03–1.33; The recessive model: OR = 1.47, 95% CI = 1.20–1.78; The homozygous model: OR = 1.62, 95% CI = 1.25–2.09; Except the heterozygous model: OR = 1.11, 95% CI = 0.98–1.24). Subgroup analysis revealed a significant association between the +45T>G polymorphism and T2D in an Asian population. Thus, this meta-analysis indicates that the G allele of the ADIPOQ +45T>G polymorphisms associated with a significantly increased risk of T2DM in the Asian population.Recently, a number of studies have reported the association between the single nucleotide polymorphisms (SNPs) +45T>G polymorphism in the adiponectin (ADIPOQ) gene and type 2 diabetes mellitus (T2DM) risk, though the results are inconsistent. In order to obtain a more precise estimation of the relationship, a meta-analysis was performed. In this current study, the Medline, Embase, Pubmed, ISI Web of Knowledge, Ovid, Science Citation Index Expanded Database, Wanfang Database, and China National Knowledge Infrastructure were searched for eligible studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the strength of association. Forty-five publications were included in the final meta-analysis with 9986 T2DM patients and 16,222 controls for ADIPOQ +45T>G polymorphism according to our inclusion and exclusion criteria. The +45T>G polymorphism was associated with an overall significantly increased risk of T2DM (G  Type 2 diabetes mellitus (T2DM) is one of the most common progressive metabolic diseases and poses a substantial burden on health-care systems globally. The International Diabetes Federation (IDF) has estimated that the prevalence of diabetes was 366 million worldwide, and is expected to increase up to 552 million by 2030 . HoweverADIPOQ gene is mapped to chromosome 3q27 [ADIPOQ gene transcription and its secretion [ADIPOQ gene with T2DM have been reported [ADIPOQ gene for T2DM.Adiponectin ) is an important adipocytokine that is secreted by adipocytes and plays a key role in the inflammatory response that is associated with insulin-resistant states and T2DM . The humome 3q27 , displayecretion . In recereported ,10,11,12A total of 260 studies were identified by the literature search. Of these, the first screening excluded 187 citations based on abstracts or titles, leaving 73 articles for full text reports. Applying the study inclusion criteria, 44 studies were included in this meta-analysis . A totalADIPOQ gene +45T>G polymorphism and the T2DM under allelic , dominant , recessive , homozygous , and heterozygous .In the whole population, a significant association was found between the p < 0.001), dominant , recessive , homozygous , and heterozygous . However, in the Caucasian subgroup, there was no significant association between the ADIPOQ gene +45T>G polymorphism and T2DM under allelic , dominant , recessive , homozygous , and heterozygous . . A–E.We first performed a sensitivity analysis by sequence, excluding individual studies to reflect the influence of the individual data set to the pooled ORs. The results showed that none of the individual studies influenced the final conclusion. The corresponding pooled Ors were not altered substantially (data not shown), indicating that our meta-analysis had reliable and stable results.p = 0.023 for allele model, p = 0.016 for dominant model, p = 0.014 for recessive model, p = 0.019 for homozygous model, p = 0.094 for heterozygous model, respectively).Begg’s funnel plot and Egger’s test were performed to determine whether the literature showed a publication bias. Begg’s funnel plots did not exist in overall comparisons except the allelic model and the dominant model shown in A–E, the ADIPOQ gene is located on human chromosome 3q27, where a region composed of three exons that span 17 kb, identified as a susceptibility locus for metabolic syndrome and T2DM, has been reported [ADIPOQ gene +45T>G polymorphism has been suggested to be implicated in the risk for type 2 diabetes, however, association studies have reported conflicting results. This may be due to a small sample size in each of the published studies and the ethnicity of these study populations. However, the results of these studies were still controversial. Therefore, we designed this meta-analysis to derive a more precise association between the ADIPOQ gene +45T>G polymorphism and T2DM risk.The reported ,56,57. Treported ,59. TherADIPOQ gene +45T>G polymorphism and T2DM under allelic, dominant, recessive and the homozygous genetic model, except the heterozygous model. Because the risk allele frequency of +45T>G differed greatly among ethnicities, we performed subgroup analyses according to ethnicity. We obtained the following results: In Asians, the ADIPOQ gene +45T>G polymorphism was significantly associated with risk of type 2 diabetes, while it was not found to be associated with risk of type 2 diabetes in Caucasians. In conclusion, it was indicated that the G allele of ADIPOQ gene +45T>G polymorphism might be a predisposing factor to T2DM in the Asian population, whereas we did not find any association between T2DM and ADIPOQ +45T>G in the Caucasian population. The discrepancy might be caused by differences in the ADIPOQ +45T>G genotype distribution in different ethnic backgrounds [et al. [et al., conducted a meta-analysis to explore the associations of different ADIPOQ SNPs with insulin resistance, T2DM and cardiovascular disease [et al., also observed no association between +45T>G polymorphism and T2DM on the Han Chinese population [vs. T allele of +45T>G might be associated with T2DM risk. One possible explanation is that different populations may have experienced very diverse environmental impacts during their evolution. In addition, different life style as well as study sample size might also have contributed to this difference.In the current meta-analysis, a significant association was detected in the whole population between the kgrounds . This re [et al. , who sho disease . Howeverpulation . Their cetc. [Significant between-study heterogeneity existed in all models, which may affect the results of the present meta-analysis. Common sources of heterogeneity may be attributed to the diversity in ethnicity, sample size, genotype errors, publication bias and different study design  and diagnostic criteria etc. ,64,65. WADIPOQ gene +45T>G polymorphism with type 2 diabetes. Firstly, different genetic background may play a role. T2DM is the result of diverse gene-environment interactions; we could not retrieve more detailed individual data, which were available, such as occupation, histological types and so on. In the Asian subgroup, the result showed a high level of between-study heterogeneity, suggesting that the studies do not estimate the same effect due to different degree of bias. In addition, there are significant differences regarding etiological profiles between high and low incidence areas within Asian. Secondly, our search was limited to published English and Chinese language studies, with studies published in other languages systematically excluded. This may explain some publication bias in our meta-analysis, which may have affected the results of this meta-analysis in as far as those studies that had produced negative results might not have been published. Thirdly, type 2 diabetes is a complex disease which is affected by an interplay between many factors, including environmental exposure, life style, socioeconomic status and individual susceptibility [ADIPOQ gene +45T>G polymorphism and type 2 diabetes, the result needs to be interpreted in cautiously. The total sample size of Asians in this meta-analysis is still relatively small , which may restrict the statistical power for achieving a definitive conclusion. Therefore, case-control studies in larger samples are needed to confirm this correlation.When explaining our results, some limitations of this meta-analysis should be considered. Several possible reasons may account for the difference between Asians and Caucasians in the association of the tibility ,67. It iSome studies have demonstrated that the main insulin-sensitizing action of adiponectin results from decrease in hepatic gluconeogenesis, increase in muscle glucose transport and enhancement of energy consumption and fatty acid oxidation in peripheral tissues with the aim of increasing ATP production ,69. In aPotential eligible studies were identified by systematically searching the Medline, Embase, Pubmed, ISI Web of Knowledge, Ovid, Science Citation Index Expanded Database, Wanfang Database and China National Knowledge Infrastructure up to November 2013. The following free-text word or subject headings ) terms were used: “diabetes mellitus” or “type 2 diabetes” or “type 2 diabetes mellitus” or “T2DM”, “adiponectin” or “adiponectin” or “APM1” or “ACDC” or “ADIPOQ”, “polymorphism” or “single nucleotide” or “single nucleotide polymorphisms” or “variant” or “mutation” or “mutant” or “SNP”. Two independent reviewers performed searches in duplicate. All eligible studies were retrieved, and their bibliographies were checked for other relevant publications. Only published studies with full-text articles were included in our meta-analysis.We reviewed abstracts of all citations and retrieved studies. The following criteria were used to include published studies: (1) Published in English or in Chinese; (2) Case-control study or cohort study; (3) Supplied the available genotype frequencies in cases and controls; (4) Available data to estimate an odds ratio (OR) with 95% confidence interval (CI); and (5) Genotype distribution in controls were in Hardy-Weinberg equilibrium (HWE). Studies were excluded if one of the following existed: (1) No control group; (2) Studies that contained overlapping data; and (3) No report about the genotype frequency, or insufficient information for data extraction.p values for Hardy–Weinberg equilibrium (HWE) in the T2DM and control groups were summarized.Two investigators (Yaofu Fan and Kun Wang) extracted information from all eligible publications independently according to the inclusion criteria listed earlier. Any disagreement was adjudicated by consensus and consulting a third author (Shuhang Xu). The following characteristics were collected from each study: first author, year of publication, country/region, diagnosis criteria for T2DM, genotyping methods, major variant allele frequency in cases and controls, and ADIPOQ +45T>G polymorphism and T2DM risk. Association under four different types of Ors was estimated, including homozygote model (GG vs. TT), heterozygous model (GT vs. TT), dominant model (GG + TG vs. TT), recessive model (GG vs. TG + TT) and an allele contrast model (G vs. T) for ADIPOQ +45T>G polymorphism, respectively. All meta-analysis were performed using Stata statistical software . The HWE was checked by applying a Chi-square goodness-of-fit test. The heterogeneity among the studies was calculated by Chi-square-based Q-tests with significance set at p < 0.05 [Z-test was used to estimate the pooled OR and the significance level was set at p < 0.05. The significance of the pooled OR was determined by the Z-test, in which p < 0.05 was considered significant. A sensitivity analysis was performed to identify potential outliers. Funnel plots, Egger’s test and Begg’s test were used to evaluate publication bias.Odds ratios with 95% CIs were calculated to assess the associations between p < 0.05 . If the p < 0.05 . Or elsep < 0.05 . The Z-tADIPOQ gene +45T>G polymorphism may be associated with susceptibility to T2DM in the Asian population. However, it is still necessary to conduct larger sample studies using standardized unbiased genotyping methods and to explore the association among different ethnicities in the future.This meta-analysis suggests that the


This study aims to investigate the impact of newly diagnosed atrial fibrillation (AF) on future major adverse cardiac events (MACE). AF is the most common form of cardiac arrhythmia and is associated with several other cardiovascular (CV) events. Little is known about whether newly diagnosed AF is an independent factor for future MACE, especially in patients without such a history.We evaluated data from the National Health Insurance Research Database, which represented a retrospective cohort of 713,288 adults in Taiwan from 2006 to 2010. Individuals with previous MACE were excluded. Newly diagnosed AF patients were identified by assigning International Classification of Diseases codes. Propensity score matching adjusted for gender, age, hypertension, diabetes mellitus and dyslipidemia. Cox proportional hazard models estimated future MACE ratios. We compared a total of 3,737 patients with newly diagnosed AF and 704,225 patients without. After matching, there was no difference in baseline demographic characteristics in patients across newly diagnosed AF and non-AF groups. The result showed that newly diagnosed AF in multivariate analysis were associated with increased incidents of MACE (hazard ratio: 3.11-3.51 in different models) and mortality. Newly diagnosed AF without other CV risk factors had 8.45 times the risk of developing future MACE than healthy adults. The more associated CV risk factors in addition to AF, the increased rate of future CV events.Newly diagnosed AF is an independent factor that leads to future CV events after gender, age, hypertension, diabetes mellitus and dyslipidemia matching. AF is associated with a higher mortality rate. Atrial fibrillation (AF) is the most common cardiac arrhythmia and affects more than 1.2% of the general population , heart fInformed consent was waived as the database analysis used de-identified secondary data, and the study was approved by the Institutional Review Board of Chang Gung Memorial Hospital (#98-4060B). All the patient records/information was anonymized and de-identified prior to analysis.The NHI in Taiwan started in March 1995 and provides effective insurance coverage to the entire population. Approximately 96% of the Taiwanese population has registered for the NHI program . Since 1Data on the prevalence and incidence of AF in Taiwanese adults were obtained from the Department of Household Registration Affairs between 2006 and 2010. Randomized NHIRD data from the same period were used for the current study. After excluding individuals younger than 18 years of age, a total of 713,288 participants were analyzed . AF was In order to effectively investigate the relationship between newly diagnosed AF and future MACE, pre-existing events were also excluded, including myocardial infarction , PCI , CABG , HF (ICD-9-CM code: 428.0–428.10), stroke (ICD-9-CM code: 430–437), malignant dysrhythmia , thrombolysis (operation code: 36.0–36.99), cardiogenic shock (ICD-9-CM code: 785.51), pulmonary embolism , and deep vein thrombosis .In Framingham Heart Study, only age, gender, total cholesterol, high density lipoprotein cholesterol, smoking and systolic blood pressure were used to predict future cardiac events . So we uChi-square tests were used to compare categorical variables and Student’s t-test was employed for continuous variables. The Kaplan-Meier method was also used to estimate overall survival, and the log-rank test was used to test the difference between groups. The Cox model was used to estimate covariate values, such as gender, classified age, elderly (≥65 years), AF, hypertension, DM, and dyslipidemia. Finally, both Score and Wald test were considered to verify that these Cox models with parameters can appropriately be estimated from the sample in NHIRD. The criterions for model selection, such as Akaike information criterion (AIC) and Bayesian information criterion (BIC), were adopted for selecting the outcome models from a set of candidate models as well. Data were calculated as means, standard deviations, percentages and confidence intervals. All analyses were conducted by using SAS statistical software, Version 9.3 . A p-value < 0.05 was considered statistically significant.P<0.0001) than the non-AF group. The incidences of future MACE and mortality were also predominant in the AF group (P<0.0001). After matching at a ratio of 4:1, the differences of the baseline characteristics were identical in both groups (P = 1), while future MACE and mortality remained more frequent in the AF group (P = 0.0113 to P<0.0001), and most of the deaths were non-stroke related in both groups. Among these MACE, HF was the most frequent developed event in AF group (27.1%) followed by stroke (21.9%). However, in non-AF group, stroke was the most frequent developed event (19.5%) instead of HF (7.81%). Moreover, both MACE and mortality were significantly different between AF and non-AF groups over time (P<0.0001) when analyzed by using Kaplan-Meier method.The prevalence and incidence of AF in Taiwanese adults increases with age in both men and women . After eP<0.0001 in Model 1 and HR 3.4, P<0.0001 in Model 2), AF , hypertension  and DM patients  (P<0.0001) in multivariate analysis, and there was statistically insignificant in dyslipidemia in Model 2 . The multivariate Cox modeling and model selection were showed in Univariate Cox regression analysis revealed that female, elderly, AF, hypertension, DM and dyslipidemia patient tended to develop more MACE statistically . In orde<0.0001) . HoweverP<0.0001) .Moreover, compared to healthy participants without any CV risk factors, newly diagnosed AF was associated with 8.45 times the risk of developing future MACE  . In addiIn previous studies, the influence of AF on future MACE or premature death did not exclude co-existing CV diseases. The present work is the first large-scale study to show that newly diagnosed AF patients without prior CV diseases associate with a higher risk of MACE, compared to patients without AF. After age, gender, hypertension, DM and dyslipidemia matching, newly diagnosed AF remains an independent risk factor for future MACE. In addition, AF is also a strong predictor of mortality over time.In a subgroup analysis of the Candesartan in heart failure—assessment of reduction in mortality and morbidity (CHARM) program, AF in patients with HF experienced a higher risk of worsening HF and stroke regardless of baseline ejection fraction . In the As expected, age, hypertension and DM were also associated with higher risk of MACE in our multivariate analysis. Similar results have been well established in previous studies , 20, 21,AF is an independent factor for mortality and future thromboembolic events –4. On thPotential limitations of this study should be noted. First, the diagnosis of AF was made by the ICD-9 code from NHIRD but not directly by documented electrocardiography. Although we compared the results with the patients without such coding, there may exist some misclassified cases in either group. In addition, the sustaining pattern of newly developed AF was not recorded in our database, and therefore we could not evaluate the different impacts among permanent, persistent and paroxysmal AF patients. Second, several unmeasured confounders, such as body mass index, smoking, blood pressure level or low density lipoprotein level, which are associated with MACE and CV mortality, were not included in our database. Third, the incidence of MACE was also collected from ICD-9 and operation codes, where the details of such events were not available, such as ST-segment elevation MI or non-ST-segment elevation MI, systolic or diastolic HF, and the numbers of coronary arteries that intervened. Although the NHI system includes almost all of the hospitals and clinics in Taiwan, it is possible that some cases of MACE or mortality did not seek any medical attention. Finally, the study was a population-based cohort study in Taiwan in which the results may not be applicable to other ethnic and racial groups.In conclusion, newly diagnosed AF without pre-existing MACE is an independent factor for future CV events even after matching with other associated CV risk factors. Compared to patients without AF, newly diagnosed AF is also associated with a higher mortality risk. In addition to AF, more associated CV comorbidities increase the rate of future MACE. Further interventional studies to treat newly onset AF itself are needed to determine whether AF is a primary cause or a risk marker of premature death.


IL-18 −607C/A and −137G/C polymorphisms may be associated with the risk of allergic disease; however, individually published results are inconclusive. Therefore, we performed a meta-analysis to clarify whether IL-18 −607C/A and −137G/C polymorphisms were associated with the risk of allergic disease. A total of 21 studies including 5,331 cases and 9,658 controls were involved in this meta-analysis. In the overall analysis and the subgroup analysis according to ethnicity, we did not find significant association between IL-18 −607C/A or −137G/C polymorphism and the risk of allergic disease . However, in a stratified analysis by type of allergic disease, our results indicated that IL-18 −607C/A polymorphism was associated with a significantly decreased risk of allergic asthma in heterozygous comparison and IL-18 −137G/C was associated with a significantly decreased risk of allergic dermatitis in recessive model and homozygous comparison. In the stratified analysis by source of control, IL-18−607C/A showed significantly reduced risk in population-based subgroup, and for IL-18 −137G/C only significantly decreased risk was found in the hospital-based subgroup. Our meta-analysis suggests that IL-18 −607C/A and −137G/C polymorphisms may be protective factors for the risk of allergic asthma and allergic dermatitis, respectively.Recent studies have suggested that  People with allergic disorders such as allergic dermatitis (AD), allergic rhinitis (AR), allergic asthma (AA), and food allergy can experience acute signs and symptoms of disease within minutes of exposure to the associated allergens . To dateγ-inducing factor, is a novel cytokine belonging to the IL-1 family and is produced by a wide range of immune cells, such as monocytes, activated macrophages, and Kupffer cells [γ production and promote Th1 responses [IL-18, formerly called interferon- (IFN-) er cells –9. IL-18er cells . To dateesponses , 12. Howesponses , 14. Indesponses –17. IL-1esponses . Taken tesponses . Howeveresponses –24. ThesIL-18 gene is located on chromosome 11q22 and contains many functional polymorphisms in the promoter region. Many studies show that the variations in IL-18 gene promoter are able to influence IL-18 production and activity, especially the IL-18 gene −607C/A (rs1946518) and −137G/C (rs187238) polymorphisms [ IL-18 −607C/A can alter a cAMP-responsive element binding site and result in a decrease of IL-18 transcription [ IL-18 −137G/C polymorphism leads to a G/C amino acid substitution at position −137 in the promoter region of the IL-18 gene, which could alter the IL-18 promoter activity [ IL-18 polymorphisms may be associated with the risk of allergic disease; however, individually published results are inconclusive due to small sample sizes. Therefore, we performed a meta-analysis of all eligible studies to clarify whether these two polymorphisms of IL-18 gene were associated with the risk of allergic disease, which may promote our understanding of the exact role of IL-18 in the development of allergic disease.orphisms . Giedraicription . The IL-activity , 28. Rec IL-18 −607C/A and/or −137G/C polymorphisms and allergic disease susceptibility (last search updated to November 2013). The search strategies were based on combinations of the following key words: “allergy or allergic disease or allergic disorder” and “IL-18 or −607C/A or −137G/C or rs1946518 or rs187238” and “polymorphism or variant or mutation or genotype or SNP.” There was no limit on time period, sample size, population, or language for minimizing potential publication bias.A systematic search was performed in PubMed, Web of Science, Science Direct, and Chinese National Knowledge Infrastructure (CNKI) databases to identify all the studies on the association betweenStudies consistent with the following criteria were included in the meta-analysis: (1) case-control studies focus on the associations between IL-18 promoter polymorphisms and the risk of allergic disease; (2) all patients meet the diagnostic criteria for allergic disease; (3) sufficient published data for estimating the odds ratio (OR) and their corresponding 95% confidence interval (95% CI). The exclusion criteria of the meta-analysis were (1) studies with duplicate data; (2) studies with incomplete data; and (3) reviews, abstracts, and meta-analysis. In the case of several articles from the same study group, the most complete and recent results were used.Two authors independently extracted the data from the included studies (Cheng and Hao). For each eligible study, the following information was extracted: first author's name, year of publication, country, ethnicity, type of allergic disease, numbers of cases and controls, source of controls , genotyping method, and Hardy-Weinberg equilibrium (HWE). In case of discrepancies, a consensus on each item was reached among the authors. IL-18 −607C/A and −137G/C polymorphisms and the risk of allergic disease. The pooled ORs were calculated for allele model , dominant model (WM + MM versus WW), recessive model (MM versus WM + WW), homozygote comparison (MM versus WW), and heterozygote comparison (WM versus WW), respectively. The significance of the combined ORs was determined by a Z-test and two-sided P value <0.05 was considered significant.The ORs with 95% CIs for genotypes were used to evaluate the strength of the association betweenQ-test and the I2 statistic were performed to evaluate possible heterogeneity (P < 0.10 and I2 > 50% indicated evidence of heterogeneity). A random-effects model or fixed-effects model was used to calculate pooled OR in the presence or absence of heterogeneity, respectively. Subgroup analyses were conducted according to the type of allergic disease, ethnicity, and source of control. Sensitivity analysis was carried out by deleting one single study each time to examine the influence of individual data set on the pooled ORs. Publication bias was evaluated with Begg's funnel plot [P < 0.05 was considered representative of statistically significant publication bias. Data analyses were performed using Stata 11.0  and Review Manager software 5.0 .Chi square-based nel plot  and Eggenel plot , and P < IL-18 polymorphisms and allergic disease, seven articles were excluded, 1 for meta-analysis related to IL-18 promoter polymorphism and asthma risk, 4 with incomplete data (no available genotype frequency), 1 not related to IL-18 polymorphism, and 1 for overlapping data. Finally, a total of 21 articles were identified for data extraction and assessment, including 5,331 cases and 9,658 controls. The studies identified and their main characteristics were summarized in  IL-18 −607C/A [As shown in  −607C/A , 44–50 a −607C/A , 47–49.  −607C/A , 46 and  IL-18 −607C/A and −137G/C polymorphisms and allergic disease risk was shown in A summary of associations between IL-18 −607C/A polymorphism, a total of 4,089 cases and 3,840 controls were included in the meta-analysis. There was significant between-study heterogeneity among all the genetic models . Therefore, random-effect model was applied to synthesize the data. In the overall analysis, we did not find significant association between IL-18 −607C/A polymorphisms and the risk of allergic disease under all models . In a stratified analysis by ethnicity, there was no significant association between IL-18 −607C/A polymorphism and the risk of allergic disease  in Asian and Caucasian populations. In a stratified analysis by source of control, IL-18 −607C/A showed significantly reduced risk in dominant model , homozygous comparison , and heterozygous comparison  in population-based subgroup but showed increased risk in allele model  and homozygous comparison  in hospital-based subgroup.For IL-18 −137G/C polymorphism, a total of 5,067 cases and 9,379 controls were included in the meta-analysis. We found significant between-study heterogeneity under allele model (I2 = 73%), dominant model (I2 = 67%), and heterozygous comparison (I2 = 56%) and the random-effects model was used, whereas the fixed-effect model was used in recessive model (I2 = 39%) and homozygous comparison (I2 = 46%). In the overall analysis, we did not find significant association between IL-18 −137G/C polymorphism and the risk of allergic disease under all models  and homozygous comparison . In the subgroup analysis by ethnicity, the results suggested that IL-18 −137G/C polymorphism was not associated with the risk of allergic disease  in Asian and Caucasian populations. In a stratified analysis by source of control, only significantly decreased risk was found in the hospital-based subgroup under recessive model  and homozygous comparison .ForIn order to assess the reliability of our results, we performed a sensitivity analysis by sequentially excluding individual study. Statistically similar results were obtained after sequentially excluding each study, suggesting the stability of this meta-analysis. IL-18 −607C/A and −137G/C polymorphisms .Potential publication bias in this meta-analysis was estimated using Begg's funnel plot and Egger's test. The shape of funnel plot revealed the evidence of funnel plot symmetry fororphisms , and Egg IL-18 polymorphisms and the risk of allergic disease.The enormous health importance of allergy disease has stimulated much work aimed at identifying susceptibility genes. Investigation into common genetic variation in the human genome has highlighted the contribution of genetics to etiology and pathogenesis of allergic diseases. However, findings are not always consistent. Considering a single study may lack statistical power to provide compelling evidence as a result of small sample size and clinical heterogeneities, we performed this meta-analysis by combining all eligible publications to derive an accurate assessment of the association between in vivo, providing a potential therapeutic target for allergic disorders [ IL-18 genetic polymorphisms have been postulated to be implicated in the development of allergic disease. Large quantities of evidence support the hypothesis that IL-18 genetic polymorphisms may cause the abnormal expression of IL-18, which is responsible for mediating the T-cell regulation, thereby leading to the pathological development of allergic disease.IL-18, belonging to the IL-1 superfamily, is a pleiotropic proinflammatory cytokine, which functions as a crucial regulator of IgE production through balancing the TH1-cell- and TH2-cell-mediated immune responses. A surfeit of IL-18 has been found in patients with allergic diseases, including AA, AD, and AR, in which a predominance of Th1 cells is significant , 20, 51.isorders . Therefoisorders . All of  IL-18 −607C/A and −137G/C polymorphisms were not found to be associated with the risk of allergic disease in the overall analysis. The conclusion of this meta-analysis is different from the previous meta-analysis [In the present meta-analysis, including 5,331 cases and 9,658 controls,analysis . As we k IL-18 polymorphisms and the risk of allergic disease. However, in a stratified analysis by types of allergic disease, our results indicated that IL-18 −607C/A polymorphism was associated with a significantly decreased risk of AA in heterozygous comparison, and IL-18 −137G/C was associated with a significantly decreased risk of AD in recessive model and homozygous comparison. As mentioned above, IL-18 gene promoter polymorphisms at positions −607C/A and −137G/C were associated with their transcription activity. Low promoter activity was observed for the −607A and −137C alleles, whereas higher promoter activity was observed for the −607C and −137G alleles in these positions [ IL-18 −607C/A under three models , but significant increased risk was found in hospital-based subgroup under two models . As for IL-18 −137G/C, only significantly decreased risk was found in the hospital-based subgroup under recessive model and homozygous comparison. The reason may be that the hospital-based controls have a high risk of producing unreliable results because hospital-based controls may not always be strictly healthy individuals and hospital-based controls may have other diseases and also been given the corresponding drugs which exerted a confounding effect on the risk for allergic disease. Thus, we cannot completely exclude the possibility that a true genetic effect was overestimated, and the results of hospital-based studies should be explained with caution. Therefore, a proper and representative population-based high quality study is of great value in case-control studies.Subgroup analyses according to ethnicity revealed similar results, suggesting that the environment they lived in did not play an obvious role in the association betweenositions . Our metThere are several limitations in this meta-analysis that should be considered. First, there is a significant heterogeneity in studies, which may influence the interpretation of the results. Second, in subgroup analysis by ethnicity, the included studies were only Asians and Caucasians. More studies containing the full range of possible ethnic differences in genotype association studies are needed to avoid selection bias. Third, only published data was collected, leading to possible publication bias in this meta-analysis. Forth, it is well acknowledged that many other factors, such as gene-gene or gene-environment interactions, may affect the risk of allergic disease. Determining whether or not these factors influence the results of this meta-analysis would need further investigation. IL-18 polymorphisms and allergic disease. The subgroup analysis indicated that IL-18 −607C/A and −137G/C polymorphisms may be a protective factor for the risk of AA and AD, respectively. In the future, more large-scale studies should be carried out to confirm or refute the relationship between IL-18 polymorphisms and the risk of allergic disease.In conclusion, our meta-analysis provided a more precise estimation based on larger sample size compared with the individual studies. Our pooled results demonstrated no significant association between


Premenstrual dysphoric disorder (PMDD) is a mood disorder characterized with physical and affective symptoms during the luteal phase of susceptible women.DRD3) polymorphism, and Cannabinoid receptor Type 1 (CNR1) polymorphism with PMDD. The aim of this study was to investigate the association of Dopamine D3 receptor ( Fifty one participants with documented PMDD according to the DSM IV criteria and 51 healthy controls were included in this cross sectional study. Symptom severity was measured with daily self-rating, monthly premenstrual assessment forms and psychiatric interviews. The genotyping of DRD3 receptor and Cannabinoid type 1 receptors were performed using Taqmanfluorogenic assay method. DRD3 and CNR1 polymorphism was not different between patients and controls.Distribution of DRD3, and CNR1 polymorphisms in contributing to susceptibility to premenstrual dysphoric disorder.These findings do not support a major role of  Premenstrual syndrome (PMS) is characterized by recurrent psychological and/or somatic symptoms occurring specifically during the luteal phase of the menstrual cycle and resolving during menstruation. Premenstrual dysphoric disorder (PMDD) is the extreme, predominantly psychological end of the PMS spectrum and it is estimated that 5-10% of regularly ovulating women experience PMDD . The cauother axis I disorders such as major depressive disorder, bipolar disorder, and anxiety disorders  including the 5’HTTLPR, serotonin transporter promoter rs25531, serotonin receptor 1A C (-1019) G, and activating protein 2β (AP-2β)   and foun (AP-2β) -18.DRD3) is candidate for a number of psychiatric conditions including schizophrenia, bipolar disorder, and alcohol and drug abuse (DRD3) gene affects patients with major depressive disorder and their response to antidepressant treatment  allele encodes glycine, and the (T) allele encodes serine. Studies to date have shown that polymorphisms in DRD3 gene have associations with schizophrenia, depression, nicotine dependence, and attention deficit-hyperactivity disorder  allele were less likely to respond favorably, particularly if they were females with comorbid anxiety (CNR1 gene (rs1049353). Since polymorphisms in DRD3Ser9Gly and CNR1 receptors are seemed to be associated with anxiety and depressive disorders and as it is known that PMDD shares a range of characteristics with depressive and anxiety disorders; our aim was to investigate whether DRD3Ser9Gly and CNR1 receptor polymorphisms are related to PMDD or not.rs1049353 and rs12720071 are common variants of  anxiety . There aStudy populationThe cross-sectional study was approved by the Harran University Local Ethics Committee, and informed written consents were obtained from each participant. Patients were recruited from consecutive application to the Harran University Research Hospital, Obstetrics and Gynecology Outpatient Clinic, Sanliurfa, Turkey in 2011. The control group was selected from the staff of Faculty of Medicine. 51 patients with PMDD and 51 healthy control subjects between the ages of 18 and 45 years were included to the study. th Edof the Diagnostic and Statistical Manuel of Mental Disorders (DSM-IV). DSM-IV criteria for PMDD require the presence of 5 of 11 specific diagnostic symptoms.All participants reported regular menstrual cycles and none was taking oral contraceptives, hormone replacement therapy or psychotropic drugs. Any women known to have an existing Axis I psychiatric disorder according to the DSM IV criteria was excluded from the study. Clinical diagnosis was determined by precise diagnostic criteria that were outlined in the 4DRD3 and CNR1 receptor polymorphisms and PMDD.These symptoms should be limited to the luteal phase and should not represent amplification of preexisting depression, anxiety, or personality disorder. In addition, they must be confirmed prospectively by daily rating for at least two consecutive menstrual cycles. Control subjects reported no significant premenstrual symptoms. All subjects were evaluated with a semi-structured interview form; which was used to determine the sociodemographic features of the participants. This form also evaluates the symptoms of PMS, family history of PMS and nicotine use. Clinical categorization of PMDD patients and control subjects was determined by prospective symptom rating with the use of the Daily Record of Severity of Problems (DRSP) scale-short form, based on self-assessment reports spanning two consecutive menstrual cycles . The DRSProceduresVenous blood samples were collected in ethylenediaminetetraacedic acid (EDTA) containing tubes. DNA was extracted from peripheral blood leukocytes by salting out procedure .DRD3 Gene Ser9Gly (rs6280) polymorphism:Genotypic analysis of DRD3 gene Ser9Gly, rs6280 polymorphism custom made primers and probes are as follows: Forward primer 5’-TCCCTCTGGGCTATGGCAT-3’, Reverse primer 5’- GCTGGCACCTGTGGAGTTCT-3’, ProbeG(C)5’- YakimaYellow- TGAGTGG(pdC) CA (pdC) CTGAA (pdC) TACA-BHQ-1-3’ and Probe A(T) 5’-FAM- AG(pdC)TGAGTAG(pdC) CA(pdC)CTGAA(pdC)TA-BHQ-1-3’ . Single nucleotide polymorphism amplification assays were performed according to the manufacturer’s instructions. In brief, 25µl of reaction solution containing 30 ng of DNA was mixed with 12.5µl of 2X TaqMan Universal PCR Master Mix (Applied Biosystems) , 900 nmol of each primer, and 200 nmol of each probe. Reaction conditions consisted of preincubation at 60ºC for 1 min and at 95ºC for 10 min, followed by 40 cycles at 95ºC for 15 sec and at 60ºC for 1 min. Amplifications and analysis were performed in an ABI Prism 7500 Real-Time PCR System (Applied Biosystems), using the SDS 2.0.3 software for allelic discrimination (Applied Biosystems).Genotypes were determined using a TaqMan™ fluorogenic 5′-nuclease assay with TaqMan Probes. All reactions were carried out following the manufacturer’s protocol. Primer Express 3.0 (Applied Biosystems) was used to design both the PCR primers and the TaqMan probes. For the CNR1 1359 G>A  polymorphisms:Genotypic analysis of CNR1 1359 G>A  polymorphisms was performed using predesigned TaqMan SNP Genotyping Assays . The Assays-on-Demand SNP genotyping kit was used for the polymerase chain reaction . Single nucleotide polymorphism amplification assays were performed according to the manufacturer’s instructions.The genotyping of CNR1 1359 G>A, codon Thr453Thr, rs1049353, Applied Biosystems) containing two primers and two MGB TaqMan probes. Reaction conditions consisted of preincubation at 60ºC for 1 min and at 95ºC for 10 min, followed by 40 cycles at 95ºC for 15 sec and at 60ºC for 1 min. Amplifications and analysis were performed in an ABI Prism 7500 Real-Time PCR System (Applied Biosystems), using the SDS 2.0.3 software for allelic discrimination (Applied Biosystems). All procedures were conducted in a manner blind to the case status and other characteristics of the participants. Scoring of gels and data entry was conducted independently by two persons.In brief, 25µl of reaction solution containing 30 ng of DNA was mixed with 12.5µl of 2X TaqMan Universal PCR Master Mix (Applied Biosystems) and 1.25 µl of predeveloped assay reagent from the SNP genotyping product . The DRD3Ser9Gly polymorphism . DRD3Ser9Gly in the PMDD and control groups.In total 51 patients with PMDD  and 51 healthy control subjects  were included in the study. There was no significant difference in age, BMI, height, weight, and number of children between PMDD group and controls except for marriage rates. 5.9% of PMDD patients were single, while 29.4% of the controls were single. CNR1 polymorphism in the PMDD and control groups. Genotypes have Hardy-Weinberg equilibrium in DRD3Ser9Gly in the PMDD group (2=1.65 with 1 DF) but the other genotypes are not in Hardy-Weinberg equilibrium.. There was not a significant difference of DRD3Ser9Gly polymorphism between PMDD patients and controls. There was not a significant difference of CNR1 polymorphism between PMDD patients and controls.Allele and genotype frequencies were not different between PMDD patients and controls in CNR1 polymorphism. DRD3Ser9Gly (rs6280) and CNR1 polymorphisms in two groups of regularly ovulating women, one group with clinically diagnosed premenstrual dysphoric disorder and one group of normal healthy controls with no symptoms of premenstrual dysphoria. We found no association of DRD3Ser9Gly (rs6280) polymorphisms in PMDD. The D3 receptor is candidate for being involved in mental disorders. Polymorphisms in the DRD3 gene have been studied in various psychiatric disorders. In a study of 88 patients being treated for schizophrenia with olanzapine, those who were rs6280  homozygotes had greater positive symptom remission as compared with  or  genotypes  is associated with depression and anxiety, we did not find an association between CNR1 polymorphism (rs1049353) and PMDD. Endocannabinoid system may not be the sole responsible in the pathophysiology of PMDD. The previous genetic studies in premenstrual dysphoric disorder were mostly about the serotonergic and noradrenergic systems. To our knowledge, this study is the first reported genotypic analysis of DRD3Ser9Gly (rs6280) and CNR1 polymorphisms in premenstrual dysphoric disorder. There may be several explanations for our negative findings.A preliminary study showed that disorder . Pharmacuoxetine . Our fir suicide . Since CDRD3Ser9Gly (rs6280) and CNR1 polymorphisms and PMDD may be affected by sample size. We were unable to identify either a single genetic marker or a combined polymorphic profile for susceptibility to PMDD. First, clinical categorization of patients with PMDD can be difficult because of the subjective nature of symptom interpretation. Second limitation is the possibility of population stratification. In studies comprising subjects taken primarily from a localized community, it is important to include healthy controls to determine typical genotype and allelic frequencies, although these may not be representative of the wider population. Third, the lack of association between the DRD3Ser9Gly and CNR1 polymorphisms in PMDD. It is not feasible to expect a single polymorphism to be the sole factor that is responsible for PMDD. It is likely that PMDD is a polygenic disorder, but the relative contributions of the various implicated genes are unknown. Cautious interpretation of the present study is warranted, both by the preliminary nature of these findings and by their basis in simple association analysis. Within the limits that are imposed by the sample size, the polymorphisms that were studied here do not represent major risk factors for PMDD. Confirmation of our findings will require independent validation in a larger group of subjects.However, it is the first study evaluating The authors declare that there is no conflict of interests regarding the publication of this paper.