Plenty of studies were conducted to explore the prognostic significance of neutrophil-to-lymphocyte ratio (NLR) in ovarian cancer with contradictory results. This study aims to summarize the prognostic significance of NLR in patients with ovarian cancer. A literature search in PubMed, Cochrane Library, and Embase was conducted. The endpoints were progression-free survival (PFS) and overall survival (OS).p = 0.004, and I2 = 61%). Similarly, high NLR was related to shorter OS . Moreover, high NLR was significantly associated with shorter PFS when the NLR cut-off was less than 3.3 (p = 0.03) or when treatment is operation (p = 0.002). In addition, high NLR was distinctly related to worse OS in Asian people (p = 0.04) or operation (p = 0.04). Eleven studies involving a total of 2,892 patients were identified. The results indicated that patients with high NLR had shorter PFS compared to patients with low NLR in ovarian cancer (HR = 1.55, 95% CI = 1.15–2.08,  High NLR was associated with shorter PFS and shorter OS in ovarian cancer. NLR is potentially a promising prognostic biomarker in patients with ovarian cancer. Ovarian cancer is one of the most common gynecological diseases in oncology, and there were 238,700 estimated new cases and 151,900 related deaths in 2012 all over the world [ p = 0.344) or OS (≤2.60 versus >2.60)  [ p = 0.575) [ p = 0.002) or OS (≤3.02 versus >3.02)  [p < 0.001) and OS (≤3.40 versus >3.40)  [As is well-known, inflammation plays an important role in tumor growth, invasion, and metastasis. And the prognostic value of systemic inflammatory response (SIR) markers has been well studied, which included platelet to lymphocyte ratio (PLR), C-reactive protein, and MicroRNAs , 7. In r= 0.399) , and sim= 0.575) . Besides= 0.007) ; however< 0.001) . Hence, A complete systematic literature search method was implemented using PubMed, the Cochrane Library, and Embase up to December 25, 2016. The search strategy was “((Ovarian cancer) OR (Ovarian Neoplasm) OR (Ovary Neoplasm) OR (Ovary Cancer) OR (Cancer of Ovary) OR (Cancer of the Ovary)) AND ((neutrophil-lymphocyte ratio) OR (neutrophil-to-lymphocyte ratio) OR (neutrophil AND lymphocyte) OR NLR)”. The reference lists were also checked. The irrelevant articles were excluded by scanning the titles or abstracts. The remaining articles were then reviewed comprehensively by reading the full text. p values; (4) published in English.The included study should meet all the criteria as follows: (1) retrospective or prospective studies; (2) focusing on the role of NLR on the prognosis in ovarian cancer; (3) enough data to get the hazard ratio (HR) for progression-free survival (PFS) or overall survival (OS), along with their 95% confidence intervals (CIs) orAll the manuscripts were independently reviewed by two investigators. The following data was abstracted: family name of the first author, year of publication, country of the study, ethnicity of the study, sample size, cut-off value of NLR, therapy, and survival analysis. The HRs of PFS or OS obtained directly or indirectly from published articles were integrated in the meta-analysis according to the study conducted by Tierney et al. . The HR Q test and Higgins I2 across studies. The heterogeneity should be considered when p < 0.05 and/or I2 > 50%, and the random-effect model was used; otherwise, the fixed-effects model was used. Besides, Egger's test and Begg's test were both conducted to evaluate publication bias by Stata 12.0. The sensitivity analysis was conducted by Stata 12.0 to access the robustness of the results. p < 0.05 was considered statistically significant.All the meta-analyses were carried out by Review Manager Version 5.3 software. The prognosis outcomes were explored using the HR, along with the corresponding 95% CI. The prognosis outcomes contained the PFS or OS. The heterogeneity was assessed by Cochran's As shown in https://doi.org/10.1155/2017/7943467), the main adjusted factors in the OS included age, stage, grade, PLR, CA125, and residual disease.As listed in  p = 0.24), with large heterogeneity . Based on the sensitivity analysis conducted by Stata 12.0, Zhang et al. was finally excluded . Therefore, six studies involving 1,726 patients were finally included in the meta-analysis of PFS and the HR of each study was assessed by multivariate analysis. As shown in I2 = 61%, p = 0.03), the random-effect model was employed. The results indicated that high NLR appeared to be a stronger predictor of risk when compared to low NLR . Besides, sensitivity analysis demonstrated that the combined HRs of PFS did not significantly alter when excluding any study by turn . And no publication bias among six included studies was detected .Eight studies reported the PFS; however, the study conducted by Cho et al. was excluded for data deficiencies . As show p = 0.03; I2 = 53%), but no significant correlation between the NLR and PFS was observed when cut-off value ≥3.3. With respect to the therapy, the pooled effect estimates indicated a significant correlation between high pretreatment NLR and operation , but no statistical significance between high pretreatment NLR and chemotherapy was detected.Seven studies were enrolled into the subgroup analysis of PFS. As listed in I2 = 85%, p < 0.0001). The meta-analysis revealed that patients with high NLR might have shorter OS compared to the patients with low NLR . Regarding the subgroup analysis of multivariate analyses, the meta-analysis containing nine studies indicated significant superiority of a low NLR in ovarian cancer , however, with clear heterogeneity . Meanwhile, the sensitivity analysis demonstrated that the combined HRs of PFS did not clearly alter when excluding any study by turn . There was no publication bias among nine included studies . Nevertheless, in the subgroup analysis of univariate analyses, no obvious difference was observed between the patients with high NLR and patients with low NLR .Eleven studies covered the OS and were included into the meta-analysis of OS. As shown in  p = 0.04; I2 = 87%), but no evident correlation between the NLR and OS was found in Caucasian population. In respect to the therapy, apparent correlation between the preoperation NLR and OS was found, and high NLR might predict worse OS when compared to the low NLR ; nevertheless, no significant relationship between the NLR and chemotherapy was observed.As listed in Increasing evidence has indicated that inflammatory response might be involved in the occurrence and growth of various tumors –31. And NLR is easily obtained from a routine blood test without additional cost. And the changes of NLR are breezily detected in the process of treatment of ovarian cancers. Therefore, NLR is a promising predictor in the individual treatment and more and more attention was paid to detecting the role of NLR on the prognosis of the ovarian cancer –24. Sevep < 0.001) [In our meta-analysis, the results showed that high NLR was significantly associated with worse PFS when compared with the low NLR. And study conducted by Badora-Rybicka et al. also covered that pretreatment high NLR was a negative prognostic factor for ovarian cancer in terms of PFS . However< 0.001) . It is i< 0.001) . Besidesp < 0.001), which was assessed by multivariate analysis [Regarding the OS, high NLR was significantly associated with worse OS, especially when the eligible studies were all assessed with multivariate analysis. Besides, the obvious correlation between the high NLR and poor OS was only observed in Asian, not in Caucasian, population. More studies in Caucasian people should be carried out because only two studies were enrolled into the subgroup analysis of Caucasian people. And Badora-Rybicka et al. also reported that high NLR was related to shorter OS compared with low NLR before the operation . Neverthanalysis . BesidesThe highlighted strengths of our meta-analysis are as follows. Firstly, at present, this study was the first meta-analysis to explore the prognostic significance of neutrophil-to-lymphocyte ratio in ovarian cancer. Secondly, eleven studies with a relatively large population were finally included; thus, the results were convincing. Thirdly, the subgroup analyses were carried out based on the NLR cut-off, therapy, and ethnicity; therefore, the analysis was comprehensive. However, some limitations of our study should be considered. Firstly, only one study reported the postoperative NLR on the prognosis of ovarian cancer and was not included into the study; therefore, the study only focused on the pretreatment NLR and on the prognosis of ovarian cancer. Secondly, plenty of analyses had a significant heterogeneity, which might reduce the accuracy of the results. Thirdly, the individual data was unavailable, like drug dose, curative time, and so on. Fourthly, some included studies reported limited information of the therapy; therefore, possible misclassification of therapy might exist in the current meta-analysis.In summary, our study demonstrated that high NLR predicted worse PFS and OS in patients with ovarian cancer, especially significantly associated with shorter PFS when cut-off <3.3 or preoperation, and obviously related to worse OS in Asian people or preoperation. However, the conclusion should be used with caution for the limitations listed above and more multicenter prospective cohorts should be carried out to explore the prognostic significance of neutrophil-to-lymphocyte ratio in ovarian cancer.Supplementary Table 1: the main adjusted factors in the overall survival with multivariable analysis. Supplementary Figure 1: influence analysis of progression free survival excluding study conducted by Cho et al. Supplementary Figure 2: sensitivity analysis of progression free survival excluding two studies conducted by Cho et al and by Zhang et al respectively. Supplementary Figure 3: sensitivity analysis of overall survival assessed with multivariate analysis.


Background: Numerous studies have indicated that there is a possible relationship between GBA variants and Parkinson's disease (PD), however, most of them focused on a few variants such as L444P, N370S. We performed a comprehensive pooled analysis to clarify the relationship between variations of GBA and the risk of PD in different racial groups.Methods: Standard meta-analysis was conducted, including generating inclusion and exclusion criteria, searching literature, extracting and analyzing data.Results: Fifty studies containing 20,267 PD patients and 24,807 controls were included. We found that variants 84insGG, IVS2+1G>A, R120W, H255Q, E326K, T369M, N370S, D409H, L444P, R496H and RecNciI increased the risk of PD in total populations . In subgroup analysis by ethnicity, in AJ populations, variants 84insGG, R496H, N370S increased the risk of PD . In total non-AJ populations, variants L444P, R120W, IVS2+1G>A, H255Q, N370S, D409H, RecNciI, E326K, T369M increased the risk of PD . Among the non-AJ populations, pooled analysis from five different groups were done separately. Variants L444P, N370S, H255Q, D409H, RecNciI, E326K increased risk of PD  in European/West Asians while R120W and RecNciI in East Asians . L444P increased the risk of PD in Hispanics, East Asians and Mixed populations . Lacking of enough original studies, we failed to conduct quantitative analysis in Africa.Conclusions: Obvious racial differences were found for GBA variants in PD. 84insGG and R496H exclusively increased PD risks in AJ populations, so did L444P, R120W, IVS2+1G>A, H255Q, D409H, RecNciI, E326K, T369M in non-AJ populations. N370S increased the risk of PD in both ethnics. In non-AJ subgroup populations, N370S, H255Q, D409H, E326K exclusively increased PD risks in European/West Asians, as were R120W in East Asians. L444P increased the risk of PD in all groups in non-AJ ethnicity. These results will contribute to the future genetic screening of GBA gene in PD. Parkinson's disease (PD), one of the most common progressive neurodegenerative disorders, is characterized by motor and non-motor symptoms. Although the etiology of PD is still unclear, it is convincing that the interaction of genetic factor, environmental factor and aging together contribute to the disease , the homozygous mutations of which can lead to accumulation of glucocerebroside and storage of lysosomal lipid, thus causing Gaucher's disease (GD) , in brain samples from PD patients, which indicated a possible relationship between GBA mutations and the disease  rules.Participants: all PD patients were diagnosed with any accepted criteria without the requirement negative of family history.Interventions: the DNA from peripheral blood of all cases and controls were analyzed using PCR based methods or other accepted methods.Controls: all controls were reported healthy controls or had no PD or other neurological disorders.GBA was reported .Outcomes: the number of cases or controls carrying homozygous or heterozygous variants of Studies: types of all studies were case-control study or cohort study.*” or “PD”) and (“GBA” or “glucocerebrosidase”), we searched the electronic databases including Pubmed, embase, web of science (WOS) and the Cochrane library for English publications up to October 20th, 2017. All searched papers were imported into ENDNOTE for further management. One copy of the overlapping articles from different databases was kept with the help of electronic and manual checking. Two researchers performed the search independently. If there were controversial ideas, the third researcher was asked to solve the debates.With the key words of (“parkinsonGBA exons or specific variants), the sequencing results of specific variants' genotypes and alleles in PD patients and controls. Complete data were independently extracted by two researchers. Due the prominent ethnic heterogeneity, especially in AJ and non-AJ populations   and I2 statistic (>50%) indicated heterogeneity of the analysis. If the heterogeneity was not significant , a fixed-effects model (FM) was used to do the analysis. Otherwise a random-effects model (RM) was applied. Reporting biases were measured by funnel plot analysis. In order to measure the stability of the analysis, sensitivity analysis was performed by removing each individual study in turn from the total and re-analyzing the results from the remainder.Revman 5.3 software was used to do all the statistical analysis. Pooled odds ratio (OR) and 95% CI  were calculated to assess the strength of association between the variants and PD. Heterogeneity across each study was identified by a standard Q test. Q statistic   Figure .p: <0.00001, 0.00005, 0.0008, 0.005, <0.00001, 0.004, <0.00001, 0.0003, <0.00001, <0.0001, 0.0001) with the ORs ranging from 1.78 to 10.49 . In total non-AJ populations, nine variants can increase the risk of PD. Results of variants from the highest OR values to the lowest OR values were L444P, R120W, IVS2+1G>A, H255Q, N370S, D409H, RecNciI, E326K, T369M . Among the non-AJ populations, pooled analysis from five different groups were done separately. In European/West Asians, six variants were associated with increased risk of PD. Variants having highest OR values to the lowest were L444P, N370S, H255Q, D409H, RecNciI, E326K . L444P increased the risk of PD in Hispanics, East Asians and Mixed populations . In East Asian populations, besides L444P, R120W and RecNciI can also increase the risk of PD . For the lack of enough original studies, we were not able to conduct meta-analysis in Africa . The trends of the frequencies' differences between cases and controls reported in gnomAD for the 11 positive variants are comparable with our meta-analysis, and our results were even more significant . As what were done by mutations including L444P, R120W, IVS2+1G>A, H255Q, D409H, RecNciI, E326K, T369M in non-AJ populations . N370S was associated with the risk of PD in both ethnics . In non-AJ populations, data from previous reports showed that the frequencies varied in different areas, such as 0.4% in North America, 1.7% in Norway etc. (Neumann et al., GBA in PD mainly located on exons 8, 9, and 10, such as E326K, T369M, N370S, D409H, and L444P. For future genetic analysis of GBA in PD, taking priority to screen the hot exons 8, 9, and 10 and focusing on those ethnicity dependent risk variants may be more time and money saving (Figures GBA could increase the risk of PD, it does not necessarily mean that the carriers of GBA risk variants would develop PD. Because the etiology of PD is still unclear, genetic background is only one of the interactive factors contributing to the PD pathogenesis.To develop more specific genetic screening strategies, we did subgroup analysis by ethnicities in AJ populations and non-AJ populations based on different features of GBA gene encodes GCase. Heterozygous GBA mutations in PD were associated with decreased GCase activities (Ortega et al., GBA homozygotes were even lower than that of heterozygotes (Alcalay et al., GBA is a main genetic risk factor for DLB (Beavan and Schapira, GBA related PD where GCase co-localized with α-synuclein (Westbroek et al., GBA variants carriers in PD should be paid attention. In previous studies, our group observed unique clinical characteristics of GBA-related PD. Those patients carrying GBA variants were more likely to develop PD at earlier ages, develop bradykinesia as an initial symptom, have a family history and develop non-motor symptoms such as dementia (Zhang et al., GBA screening could be conducted in those special PD patients to increase the detection rate. What's more, patients could get more precise treatment in the future when their clinical features and genetic features were combined together.In clinical use, distinct feature of However, the meta-analysis still has some inevitable limitations. First of all, some original studies without detailed information to calculate OR and 95% CI were not included. Second, the patients and controls of varies clinical features were not separated to do subgroup analysis which may cause biases. Third, due to the limitations of each original study such as the sequencing methods and the sample size, the heterogeneities cannot be totally avoided. For instance, when an original study screened only specific variants, the frequency of other variants may be underestimated.GBA variants to the development of PD is racial dependent. 84insGG and R496H exclusively increased PD risks in AJ populations while L444P, R120W, IVS2+1G>A, H255Q, D409H, RecNciI, E326K, T369M in non-AJ populations. N370S increased the risk of PD in both ethnics. In non-AJ subgroup populations, N370S, H255Q, D409H, E326K exclusively increased PD risks in European/West Asians while R120W in East Asians. L444P increased the risk of PD in all groups in non-AJ ethnicity. Our results will do great help to future GBA screening in clinical use.In conclusion, the contribution of YZ, LS, and BT: Conceived and designed the experiments; YZ, LS, and QS: Performed the experiments; YZ, LS, QS, BT: analyzed the data; YZ, LS, and BT: Wrote the manuscript; XZ, HP, and JG: Reference collection and data management.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.


It is reported that both the homozygous and heterozygous states of GBA mutations which are the causes of Gaucher disease (GD) are linked to the risk of PD. However, the GBA variant p.E326K , which does not result in GD in homozygous carriers, has triggered debate among experts studying Parkinson's disease (PD). In order to determine if the E326K variant of GBA is associated with the risk of PD, a standard meta-analysis was conducted by searching and screening publications, data extraction, and statistical analysis. Finally, a total of 15 publications, containing 5,908 PD patients and 5,605 controls, were included in this analysis. The pooled OR of the E326K genotype analysis was 1.99 (95% CI: 1.57–2.51). The minor allele frequencies of E326K for PD patients and controls were 1.67% and 1.03%, respectively. The pooled OR for the minor allele A was 1.99 (95% CI: 1.58–2.50). According to the subgroup analysis, we found that the significant differences between PD patients and controls for both genotype and allele of E326K also exist in Asians and Caucasians, respectively. In this study, we found that E326K of GBA is associated with the risk of PD in total populations, Asians, and Caucasians, respectively. Further studies are needed to clarify the role of GBA in the pathogenesis of PD. Parkinson's disease (PD) is a common neurodegenerative disorder, with a prevalence of 1% in a population greater than 60 years old .GBA), encoding lysosomal enzyme glucocerebrosidase (GCase), are the cause of Gaucher disease (GD) [GBA mutations are more likely to have an early age onset, initial bradykinesia, and a family history of dementia [GBA in PD patients has found other potentially related variants, including p.E326K . E326K was named in accordance with the tradition nomenclature, which was excluded the first 39-residue signal peptide of GBA protein and is widely used in this field. In fact, it is the same as p.E365K, which was the recommendation of HGVS nomenclature. In the studies conducted by Ziegler's team of researchers [Pathogenetic mutations in the glucocerebrosidase gene (ase (GD) . It is rase (GD) . Moreovedementia . Furtherearchers , the E32earchers , 8. In o∗” or “PD”) and (“GBA” or “glucocerebrosidase”). EndNote was used to manage and organize all searched publications.Databases that included PubMed, Embase, and Web of Knowledge were utilized up to July 30, 2017, with the following key words: (“parkinsonAll eligible studies had to fulfill the following inclusion criteria: (1) case-control design; (2) all PD cases diagnosed accurately according to reported criteria; (3) none of the controls had PD or a neurological disease; and (4) the genotype results of E326K were named by traditional nomenclatures, and HGVS nomenclatures were converted to traditional for both case and control groups. The exclusion criteria were as follows: (1) duplicate articles found in different databases; (2) different manuscripts using an overlapping study population; (3) genetic screening results lacking sufficient data to calculate the odds ratio (OR) and 95% confidence interval (CI); and (4) reviews. Overlapping articles from different databases were excluded with the help of electronic and manual checking. Two researchers performed the search independently. In the case of opposing opinions or decisions, a third researcher was asked to arbitrate.Two authors independently performed extraction of the following information from studies meeting inclusion criteria: publication date (year), first author, country of origin, sequencing method, total numbers, and responsive number of E326K genotypes (GG/GA/AA) and alleles (G/A) in PD patients and controls. If there were conflicts, a third party was asked to make a final decision. In terms of the assessment of a publication's quality, the Newcastle–Ottawa Scale (NOS)  was usedP > 0.1; I2 ≤ 50%), or a random model (RM) was used. Publication bias was measured through funnel plot analysis. Sensitivity analysis was conducted by removing each individual publication from the pool of all the included studies and then reanalyzed the remaining pool to measure the stability of the results.All statistical analyses were conducted in RevMan 5.3 software. Pooled odds ratio (OR) and 95% confidence interval (CI) were applied to measure the strength of associations between E326K and PD. Heterogeneity among all studies was calculated with a standard Q test. A fixed model (FM) was applied when the heterogeneity was not significant . Additionally, the minor allele frequencies of E326K were 1.67% and 1.03%, for PD patients and controls, respectively. The pooled OR for the minor allele A was 1.99, and the 95% CI was 1.58 to 2.50  was used to compare the association of E326K and PD. The heterogeneity was acceptable, with a result of  to 2.50 , which rThe funnel plots of genotype and allele analyses had a small tendency toward negative results Figures  and 5. WGBA were reported in PD. However, the replications of those risk variants mostly were not conducted well. For example, after sequencing the a cohort of 519 PD patients and 544 controls, Mitsui et al. [Our meta-analysis demonstrated that a higher proportion of E326K carriers developed PD and the minor allele A was a risk factor for PD. Previously, over 300 variants of i et al.  found thi et al. , 22, 23.GBA gene has 11 exons, and the common risk variants N370S and L444P were located near E326K. The OR for E326K was 1.99, which indicates a mild risk for PD when compared with mutations manifesting strong effects, such as N370S and L444P. In a multicenter genetic analysis of GBA within the PD population, conducted in 2009 by Sidransky et al. [The y et al. , the ORsy et al. . Moreovey et al. , E326K pHowever, there are some inevitable limitations in this study. First, we did not conduct subgroup analysis according to ethnicity, age at onset, and other related factors due to limited information regarding subgroups. Also, subgroup analysis with an insufficient number of publications may produce a false-positive result. Second, some publications of higher quality were not included due to insufficient data to calculate the ORs and 95% CI. Third, the study did not adjust for age, gender, environment, or other factors.GBA is associated with the risk of PD in total populations, Asians, and Caucasians, respectively. Further studies are needed to clarify the role of GBA in the pathogenesis of PD.In this study, we found that E326K of


Among different toolsaimed at improving risk stratification by complementary methods, the use of geneticinformation has been proposed to enhance risk prediction.4Cardiovascular risk scores, such as the Framingham score, have been strongly recommendedby clinical guidelines on the assessment of cardiovascular risk.5Although many genetic polymorphisms have been associated with increased cardiovascularrisk, the additional value of their use in the clinical practice has not been definedyet. One of the reason for such limitation lies on the fact that atherosclerosis is amultifactorial disease, and the individual role of each polymorphism is limited. Sincemany polymorphisms associated with atherosclerotic disease have been identified, someauthors have investigated combinations of several polymorphisms aiming to developgenetic scores that serve as stronger predictors of cardiovascular risk. Nevertheless,despite great enthusiasm about the role of genetic information on the development ofcardiovascular risk, previous data have suggested that even with the combination of morethan 50 polymorphisms, the best risk stratification achieved was still poor, and of lowclinical value in its current form.6 While lipoprotein lipase genepolymorphism was associated with atherosclerotic load, polymorphism-derived geneticscore was not associated with atherosclerotic load defined by Gensini score in invasiveangiography.In another attempt to assess the role of genetic scores on atherosclerotic disease,Fisher et al. investigated 116 individuals with metabolic syndrome and recent history ofacute coronary syndrome (ACS) to assess the association between several geneticpolymorphisms and the extension of coronary artery disease (CAD).These findings may be explained by several reasons. First, the sample size was relativelysmall for a genetic study. Second, the value of each polymorphism, alone is usuallysmall. In addition, while most studies use gene panels composed of tens of markers, onlyseven markers were used in this study. Finally, the population studied was differentfrom those of population-based studies. Using recent ACS as an inclusion criterion, thepresent study included not only patients with clear evidence of atherosclerosis, butalso with recent history of plaque instability. The selection of individuals with suchdifferent phenotypes may also have affected the development of a genetic score.Despite these limitations, the study expands the literature on genetic assessment of CAD,demonstrating once again that this association is not simple.7In order to make genetic score part of routine clinical care, improvement of geneticsequencing techniques, development of studies involving larger, representativepopulations, and the use of modern data modeling methodologies that incorporate nuancesbeyond the linear association between predictors and outcomes are required.


Genetic factors play an important role in the development of gastric cancer (GC), a prevalent malignancy in Central Asia. Recent studies have shown that single-nucleotide polymorphisms (SNPs) in several genes are associated with increased GC risk, indicating that genetic variation contributes to gastric carcinogenesis. Located on chromosome 8q24.2, the prostate stem cell antigen (PSCA) gene encodes a 123-amino acid glycoprotein related to the cell-proliferation inhibition and cell-death induction activity. SNPs in PSCA gene have been found to be associated with gastric cancer risk in a genome-wide association study, but results were not conclusive. This study aimed to investigate the association between two polymorphic variants of PSCA gene (rs2294008 and rs9297976) and the susceptibility to gastric cancer in Uzbekistan.Two hundred sixty eight patients with gastric cancer and a control group of 248 healthy individuals were included in this study. DNA samples isolated from these groups were genotyped using PCR-RFLP method. Comparative analysis of resulting genotypes showed a statistically significant association between CT genotype and gastric cancer .Comparative analysis of the distribution of genotypes of rs2976392 polymorphism did not show a statistically significant difference; however, analysis of the distribution of the rs2976392 genotypes in a subgroup of young women revealed a statistically significant  increase in the incidence of AA (38%) and AG (56%) genotypes in patients with GC, compared to the controls (20% and 40%).Our findings support that PSCA rs2294008 and rs9297976 polymorphism may contribute to the susceptibility to gastric cancer. Genotyping of these polymorphisms can potentially be recommended as one of the criteria for identification of high risk groups for gastric cancer development in Uzbekistan. Gastric cancer (GC) is the fifth most common cancer in the world, with 952,000 new cases diagnosed in 2012.Carcinogenesis is multi-stage process resulting from both exogenous factors  and endogenous factors . In Asia, the prevalence of Helicobacter pylori (H. pylori) infection varies markedly in different countries, and is an important etiological factor for the occurrence of gastric adenocarcinoma.The Prostate Stem Cell Antigen (PSCA) gene is located on chromosome 8q24.2 and encodes a 123-amino acid cell surface protein with 30% homology to stem cell antigen type 2 (SCA-2).9The first genome-wide association study (GWAS) on GC, performed in Japanese population, revealed an association between SNP rs2294008 of PSCA and risk of the diffuse type of GC. Substitution of C to T at rs2294008 in the first exon creates a novel translation start site (Met instead of Thr), which leads to the extension of the protein by 9 amino acids which changes the transcriptional activity of the gene.13To date, an exploration of the association of the PSCA gene SNPs with GC has not been performed in the Central Asia populations. Uzbeks are the ideal group to investigate in this context, as they represent the largest and fastest growing population in Central Asia. Uniquely positioned on the route of the ancient Silk Road, the Uzbek population is a very interesting population to investigate in regard to its cultural, socioeconomic, and genetic diversity. It is remarkable to note that Uzbek population has been formed by admixture of two or more ancestral populations, thus it offers a unique opportunity for studying the interaction between gene polymorphisms, ethnicity specific genetic factors, as well as environmental contributions to disease occurrence.IL-1B and IL-10.MLH1 (an important gene for DNA mismatch repair that is associated with GC) between Eastern Asians and Western populations have been revealed.18The epidemiology of gastric cancer subtypes suggests there is a difference in the genetic background between Asian and Caucasian groups. For example “allele flip” between Asian and non-Asian groups is observed, most prominently in polymorphisms of The key aim of this research is to investigate the association between two polymorphic variants of PSCA gene (rs2294008 and rs2976392) and link them to GC susceptibility in Uzbek populations.A total of 268 patients  with gastric cancer who underwent surgery in the Internal Medicine department at the National Cancer Center of the Ministry of Health of the Republic of Uzbekistan (NCC MoH UZB) and Tashkent Regional Oncological Dispensary, were recruited from 2011 to 2013. All subjects were unrelated Uzbeks from Tashkent city and various regions of Uzbekistan. All cancer diagnoses were pathologically confirmed. Clinical data and pathological characteristics of patients were collected and confirmed from both their medical records and questionnaire data. The control group constituted of 248 healthy individuals  without a family history of gastric cancer. Cancer patients were recruited through Tashkent Regional Oncological Dispensary. Control cases were obtained from previously implemented study of healthy Uzbekistan people residing in the same catchment area as the majority of our cancer cases.Before taking part in a study all study participants gave their informed consent. The study was conducted according to the standards of the National Ethic Committee of Uzbekistan developed in accordance with the World Medical Association’s Declaration of Helsinki “Ethical Principles For Medical Research Involving Human Subjects” with amendments (2013) and approved by NCC MoH UZB.According to the previously published data, the prevalence of GC in young patients ranged from 4.4% to 16.2% of all GC cases when the cut-point was set at 40 years old.Blood samples (2 ml) were drawn from an antecubital vein, which were collected using vacutainers containing sodium citrate. Samples were stored at −20°C until they were ready for analysis. Genomic DNA was extracted from peripheral blood leucocytes by using DNA extraction kit Diatom™ DNA Prep 200  of each oligonucleotide primer, 0.3 µl (1.5 units) “hot-start” Taq-polymerase, and 3 µl of DNA. PCR amplification was carried out in GeneAmp 9700(Applied Biosystems). The PCR conditions were as follows for rs2294008: 95 °C for 5 minutes, and then 33 cycles of 94°C for 45 seconds, 62°C for 30 seconds, and 72 °C for 30 seconds, and a final extension step of 72°C for 5 minutes. PCR conditions for rs2976392 were: 95 °C for 5 minutes, and then 33 cycles of 95°C for 40 seconds, 60°C for 30 seconds, and 72 °C for 40 seconds, and a final extension step of 72°C for 5 minutes. Protocol for implementing these studies has been developed at the laboratory where this study was conducted.Sense 5′-GAAACCCGCTGGTGTTGACTGT-3′ and antisense 5′-GGGCAAGCAGCACAGCCTAC-3′ for rs2294008; sense 5′-ATCTTTCTGGCCATCTGTCCGCAGCT-3′ and antisense 5′-GGCAGATGGACCACCCGCTG-3′ for rs2976392. PCR mixture(25 µl) consisted of 13 µl of ddH2O, 2.5 µl 10xPCR buffer, 2.5 µl 25 mM MgClPCR products were digested overnight at 37°C with HpyCH4IV (New England Biolabs) for rs2294008 and PvuII (New England BioLabs) for rs2976392 and then separated by electrophoresis on 3% agarose with ethidium bromide staining and were visualized using WiseDoc WGD-30 .The Hardy-Weinberg equilibrium was tested by a goodness-of-fit χ2 test to compare the observed genotype frequencies with the expected ones among the control subjects. Genotypic associations of SNPs were evaluated by Cochran-Armitage trend test, followed by risk assessment using odds ratio (OR) and 95% confidence of interval (CI) computation. All statistical analyses were performed by using STATA software version 12.0 for Windows . A p<0.05 (two-sided) was considered statistically significant.Genotype frequencies of PSCA rs2294008 and rs2976392 polymorphisms in patients with gastric cancer and controls are shown in Comparative analysis of rs2294008 genotypes between patients and controls showed a significant association between the CT genotype and gastric cancer  see . The OR Comparative analysis of the genotype distribution for rs2976392 polymorphism did not show a statistically significant difference between the cases and controls. For the further analysis of rs2976392 genotypes, the group of patients with gastric cancer was divided into 4 subgroups according to gender and age.=0.03, Fisher’s Exact Test) increase in the incidence of AA (38%) and AG (56%) genotypes in patients with GC, compared to the controls (20% and 41%). The OR of developing gastric cancer for carriers of the AA and AG genotype was 2.35 (95% CI: 0.71–7.76) and 1.88 (95% CI: 0.61–5.72), respectively.Comparative analysis of the distribution of alleles and genotypes of rs2976392 polymorphism did not show a statistically significant difference between subgroups of patients and controls for both men and women of advanced age (over 40 years) and young men (up to 40 years)see  and 3. HResults of our study confirm the association between the T allele of rs2294008 (CT genotype) with GC risk. Three previous GWAS studies revealed a significant association of the T allele of rs2294008 with the risk of GC27The results of the present study also indicated that genetic effect of PSCA rs2976392 polymorphism in Uzbek population is only present in the subgroup of women under the age of 40. This is consistent with the fact that complex genetic diseases, such GC are likely to arise due to multiple, potentially interacting, genetic and environmental factors, and therefore are challenging to study. Presumably, many of these environmental and genetic risk factors are interconnected, with other factors, such as ethnicity, specific genetic background, and endocrine factors, and are likely to be key modifiers of these risk factors. This general phenomenon is known as effect modification, and represents an interaction between two or more variables.There is some evidence regarding the potential role of estrogen receptors in the regulation of normal development and functioning of the gastric mucosa cells, as well as in the process of tumorogenesisIt should be noted that there are several limitations of this study. The data concerning subgroup of young women (under the age of 40) with GC may not accurately reflect the prevalence of rs2976392 genotypes in the general population of young women of Uzbekistan because of the small sample size of this subgroup. A large-scale study of young women with GC is needed to evaluate more precisely the contribution of these genotypes to the development of GC in this cohort. Our future studies will evaluate more closely the contribution of Helicobacter Pylori infection to the GC in our cohorts. Overall, considering the burden of GC in Asia, this study is very important for Uzbekistan and the entire Asian continent. In addition, further research on deep sequencing of the PSCA gene is needed to determine the full allelic spectrum of causal variants underlying predisposition to GC and to discover rare variants. It is reasonable to hypothesize that not only the common GWAS variants are responsible for GC risk in Uzbekistan, but also that these loci may contain high effect rare risk variants that have gone undetected by GWAS. It is plausible that future analyses of low-frequency (0.5% ≤ MAF < 5%) and rare (MAF < 0.5%) variants of the PSCA gene using Next-Generation Sequencing (NGS) technologies could explain additional GC disease risk in Uzbekistan.In summary, the results of our research provided preliminary evidence that PSCA rs2294008 and rs9297976 polymorphism may contribute to gastric cancer risk in Uzbekistan. As studies of this nature are rare in Uzbekistan, this research has important implications for both Uzbekistan, and Central Asian population due to high burden of GC. Genotyping of these polymorphisms can potentially be recommended as a criterion for identification of high risk groups for the development of gastric cancer in Uzbekistan.


P-nonlinearity = 0.0378). The present evidence suggests that height is positively associated with increased risk of hip fracture. Further well-designed cohort studies are needed to confirm the present findings in other ethnicities.The association between height and risk of hip fracture has been investigated in several studies, but the evidence is inconclusive. We therefore conducted this meta-analysis of prospective cohort studies to explore whether an association exists between height and risk of hip fracture. We searched PubMed and EMBASE, Web of Science, and the Cochrane Library for studies of height and risk of hip fracture up to February 16, 2016. The random-effects model was used to combine results from individual studies. Seven prospective cohort studies, with 7,478 incident hip fracture cases and 907,913 participants, were included for analysis. The pooled relative risk (RR) was 1.65 : 1.26–2.16) comparing the highest with the lowest category of height. Result from dose-response analysis suggested a linear association between height and hip fracture risk ( Hip fracture is the femoral fracture that occurs between the articular of hip joint and 5 cm below the distal point of the lesser trochanter . As a maPrevious studies have shown that smoking, physical inactivity, and low body mass index were associated with increased risk of hip fracture –8. OtherWe conducted this meta-analysis according to the checklist of the Meta-Analysis of Observational Studies in Epidemiology . A literStudies were included for analysis if they met the following criteria: (1) having a prospective cohort design, (2) considering the association between height and risk of hip fracture, (3) reporting risk estimates with 95% confidence intervals (CIs) for at least three quantitative height categories . Animal studies, reviews, conference abstracts, editorials, and letters were excluded. If a study was reported in more than one article, only the result with the longest follow-up years was used.Two reviewers (W. F. and Y. C.) independently carried out the data extraction. The following data were extracted from each included study: name of the first author, publication year, study name, study location, follow-up years, characteristics of participants (sex and age), number of cases and participants, fracture ascertainment, variables adjusted for in the analysis, and the relative risks (RRs) or hazard ratios (HRs) or odds ratios (ORs) of hip fracture and corresponding 95% CIs for all categories of height.The Newcastle-Ottawa Scale  was usedTo take into account heterogeneity between studies, a random-effects model  was usedP value for nonlinearity was calculated by testing the null hypothesis that the coefficient of the second spline was equal to zero [We assigned the median or mean height in each category to the corresponding RR for each study. When the median or mean height per category was not reported, the midpoint of the upper and lower boundaries was considered the height of each category. If the lower or upper boundaries for the lowest and highest category were not available, we assumed the length of these categories to be the same as the closest category. We examined a potential nonlinear relationship between height and hip fracture risk by using restricted cubic splines with 3 knots at percentiles  of the distribution . A P val to zero .Q statistics (significance level of P≦0.10) and I2 statistics [I2 values of 25%, 50%, and 75% were considered to be low, moderate, and high degrees of heterogeneity, respectively [P values were two-sided and P < 0.05 was considered statistically significant unless where otherwise stated.Heterogeneity between studies was assessed by using atistics . I2 valectively . Subgrouectively , 28. Theectively . This mehttp://dx.doi.org/10.1155/2016/2480693).I2 = 76.2%, P-heterogeneity < 0.05).P-nonlinearity = 0.0378). As compared with individuals who were in the lowest height, the RR of hip fracture for each 10 cm increment was 1.007 (95% CI: 1.002–1.012).P values < 0.05). However, the trim and fill method identified 3 hypothetical missing studies, and the repooled results incorporating the hypothetical studies continued to show a statistically significant association between height and risk of hip fracture .Publication bias was found across the included studies indicated by Begg's and Egger's test  than in men . However, because the CIs for HR of hip fracture are overlapping for women and men, and meanwhile the lower limit of the CI for men includes 1, whether there is a gender difference of association between body height and risk of hip fracture should be further explored.Due to the aging of the population, the number of hip fractures continues to increase , 36. AltOur meta-analysis had several strengths. Because this meta-analysis only included prospective cohort studies, we minimized the potential effect of recall bias on our findings. In addition, each included study had a follow-up period long enough to observe potential association between height and risk of hip fracture. Another strength was that the studies involved a large number of participants; it was therefore possible to detect moderate reductions in risk.Our study also had some limitations that deserve consideration. First, because our meta-analysis was based on observational studies, we could not rule out potential confounding from other fracture risk factors. Although the included studies adjusted for several potential confounders, for example, all studies adjusted for age, three studies adjusted for alcohol intake, and three studies adjusted for smoking, the association between height and risk of hip fracture could potentially be due to residual confounding from other factors related to tall people.Second, although it has been shown that self-report was relatively accurate for hip fracture in adults , 39, howThird, the potential publication bias existed across the included studies indicated that studies reporting positive association between height and risk of hip fracture were more easily published, as indicated by Egger's test and Begg's test. However, when we performed the trim and fill method, the result continued to suggest statistically significant association between height and hip fracture, although the pooled RR was attenuated by the hypothesized missing studies.Fourth, high statistical heterogeneity was found across the studies. One potential source of heterogeneity might be the difference of the number of hip fracture cases between studies, as suggested by the subgroup analysis. Although the heterogeneity may weaken the strength of our findings, the subgroup analysis and sensitivity analysis showed that results from our meta-analysis were robust.Finally, the results of our meta-analysis were based on studies that only involved participants from Europe or the United States. However, the genetic factors and environmental factors with respect to height varied among different ethnicities, especially between east and west. Therefore, the findings of this study should be interpreted with caution among the population from the east.In summary, the results from this meta-analysis of prospective studies indicate that height is positively associated with risk of hip fracture. However, due to residual confounding from other fracture risk factors related to height, the findings from this meta-analysis need to be confirmed by well-designed prospective studies, especially among other ethnicities.Table S1 presented the methodological quality score of included studies assessed by the Newcastle-Ottawa Scale (NOS). Studies that scored 0–3, 4–6, and 7–9 were considered as low, moderate, and high quality, respectively. 5 studies were in high quality while the other 2 studies were in moderate quality.


ALDH2)Aldehyde Dehydrogenase‐2 ( gene G487A polymorphism may be correlated with coronary artery disease (CAD) susceptibility, but a clear consensus has yet to be reached. To elucidate the relationship between the ALDH2 gene G487A polymorphism and CAD within the Chinese population, a meta‐analysis of 5644 subjects from nine individual studies was performed. Pooled odds ratios (ORs) and their corresponding 95% confidence intervals were assessed using random or fixed‐effect models depending the heterogeneity existence or not. Our meta‐analysis found a significant association between ALDH2 gene G487A polymorphism and CAD in the Chinese population under allele , recessive , dominant , homozygous  and heterozygous genetic models . The positive correlation between the ALDH2 gene G487A polymorphism and CAD makes the mutation a strong candidate as a genetic risk marker for CAD. Through further analysis, we also found that A allele carriers of ALDH2 gene G487A polymorphism may be particularly susceptible to CAD.Several studies indicate the mitochondrial  Coronary artery disease (CAD) is a disease that affects many middle‐aged and elderly people and is usually accompanied by hypertension, diabetes mellitus and dyslipidaemia. ALDH2 is a mitochondria enzyme distributed in the various tissues. CAD describes a group of cardiovascular diseases that collectively cause more deaths than any other disease globally. The confluence of genomic and environmental risk factors make CAD difficult to treat effectively, but research on the genomic basis of CAD, has tremendously deepened our understanding of this complex disease.Mitochondrial aldehyde dehydrogenase‐2 (ALDH2) is an enzyme known primarily for its role in alcohol metabolism. Once ethanol is converted to acetaldehyde, ALDH2 facilitates its conversion to acetate. More interestingly, ALDH2 was also found to play significant role in cardiac protection in a range of settings. It was found to alleviate cardiac ischaemic injury by removing 4‐HNE, a highly reactive compound associated with oxidative stress ALDH2, located on 12q24, contains 13 exons. The G487A polymorphism causes the glutamate at position 504 to be replaced by a lysine residue on exon 12 (rs671). While the mutation frequency of this polymorphism is only 5% in Western populations, East Asian populations can have mutations frequencies ranging from 30% to 50% ALDH2 gene G487A polymorphism was associated with decreased high‐density lipoprotein cholesterol (HDL‐C) levels. Taking into consideration data produced by Shaul and Mineo in 2004 indicating a 10% decrease in HDL‐C levels correlated with a 13% increase in CAD risk, the relationship between the gene polymorphism and CAD is a very real possibility Human xon 12 rs71. WhileALDH2 gene G487A polymorphism and CAD have been conducted, but results remain inconsistent. Though Guo et al. et al. et al. Many experiments on the relationship between ALDH2 gene G487A polymorphism and CAD  Evaluation of the relationship of CAD and ALDH2 gene G487A polymorphism. (ii) Coronary angiography was used to diagnose CAD with diagnosis criteria defined as the stenosis of one coronary artery by at least 50%. (iii) Studies were case–control or officially published cohort studies. (iv) The control group genotype followed Hardy–Weinberg equilibrium (HWE).The studies were selected according to the following major criteria: , recessive (AA versus GG+GA), dominant (AA+GA versus GG), homozygous (AA versus GG) and heterozygous (GA versus GG) genetic models were used. The allele model is defined as A allele versus G allele. The relationship of ALDH2 gene G487A polymorphism and CAD was compared using the odds ratios (ORs) and their corresponding 95% confidence intervals (CIs). The chi‐square‐based Q‐tests were used to calculate the heterogeneity among the studies with significance was set at P < 0.05 level Z‐test was used to assess the pooled OR, and the significance was set at P < 0.05 level.Five genetic models were used in the current meta‐analysis: allele , recessive , dominant , homozygous  and heterozygous genetic models . There was significant heterogeneity, however, under allele, dominant and heterozygous genetic models (Pheterogeneity < 0.05). Meta‐regression was performed to find the sources of heterogeneity. Under the allele genetic model , the GG genotype number in the control group (GG0) was detected to be the main heterogeneity source (P = 0.009). In the subgroup analysis stratified by GG0, no heterogeneity was found in the subgroup 1. However, the heterogeneity still existed in subgroup 2 . Under the dominant genetic model , the GG genotype number in the CAD group (GG1) was confirmed to be the main heterogeneity source (P = 0.042). In the subgroup analysis stratified by GG1, there was no heterogeneity in the subgroup 1. However, the heterogeneity still existed in subgroup 2 . Under the heterozygous genetic model , the GA genotype number in the CAD group (GA1) was verified to be the main heterogeneity source (P = 0.002). In the subgroup analysis stratified by GA1, the heterogeneity still existed in both subgroups .Under recessive and homozygous genetic models, no significant heterogeneity was detected in the Chinese population .Using the funnel plot and Egger's test, the publication bias among the individual studies was assessed. No publication bias was found in the Begg's funnel plot under all of the genetic models Figs , 9, 10. ALDH2 gene G487A polymorphism and CAD under allele (OR: 1.830), recessive (OR: 1.920), dominant (OR: 1.593), homozygous (OR: 2.280) and heterozygous genetic models (OR: 3.330) in the Chinese population. Under the allele, dominant and heterozygous genetic models, GG0, GG1 and GA1 were identified as the main sources of heterogeneity, respectively. In the subgroup analysis stratified by GG0 and GG1, heterogeneity was greatly reduced in the GG0 < 160 and GG1 < 150 subgroups under the allele and dominant genetic models, respectively (P > 0.05). Under the heterozygous genetic model, in the GA1 > 100 subgroup, the heterogeneity was significantly increased (P < 0.05). This implies that the ALDH2 gene G487A mutation is an effective genetic risk marker for CAD in the Chinese population with the A allele carriers of ALDH2 gene G487A polymorphism being particularly susceptible to CAD.The present meta‐analysis found a significant relationship between ALDH2 gene G487A mutation people. Narita et al. et al. ALDH2 gene could influence the individual alcohol consumption and drink frequency. Okamoto et al. ALDH2 gene carriers had the less capacity for alcohol than the wild homozygous GG genotype, a result that Yu et al. et al. also performed an updated meta‐analysis on the association of alcohol consumption and CAD mortality, they found that moderate alcohol use was associated with reduced CAD risk The increased risk of CAD may be due to the reduced ALDH2's ability in alcohol consumption in the HDL‐C was highly correlated with the MI, stroke, sudden death, the restenosis after percutaneous transluminal coronary angiography (PTCA) and severe premature CAD et al. ALDH2 gene G487A polymorphism in the Asian population and got the similar conclusion, but in the two meta‐analyses, only seven studies of the Chinese Han population were included. The individual study by Xue et al. in 2007 lacked a control group and so was excluded from the current analysis Both Wang ALDH2 gene G487A polymorphism and CAD. It is well known that the individuals without alcohol consumption have the higher CAD risk than the moderate drinkers ALDH2 gene G487A polymorphism might not have the same role as that in the alcohol users. Furthermore, serum ALDH2 levels can be influenced not only by the ALDH2 gene G487A polymorphism, but also by environmental factors, such as hypertension, obesity, diabetes mellitus and hyperlipidaemia. As CAD is a polygenic inheritable disease, the micro‐effects of many genes may collectively influence the CAD susceptibility. Polymorphisms in other genes such as CD14, Interleukin‐6, methylenetetrahydrofolate reductase, intercellular adhesion molecule‐1, ATP‐binding cassette transporter A1, apo A5, FgB and CETP, plasminogen activator inhibitor‐1 may also affect CAD risk However, our current meta‐analysis still lacks large‐scale or prospective studies on the relationship of ALDH2 gene G487A polymorphism was significantly associated with increased CAD risk in the Chinese population. Individuals with the A allele of ALDH2 gene G487A polymorphism might particularly susceptible to CAD. This conclusion maybe useful in the formulation of a novel personalized approach to CAD treatment. In view of the limitations mentioned above, more studies on the association of ALDH2 gene G487A polymorphism and CAD are needed to further verify the conclusions in a definite manner.In conclusion, The authors have no conflict of interest to disclose.Appendix S1. PRISMA 2009 Checklist.Click here for additional data file.Appendix S2. PRISMA 2009 Flow Diagram.Click here for additional data file.


I read with great interest the article by Toukabri et al. concerning “Prevalence, Etiology, and Risk Factors of Tinea Pedis and Tinea Unguium in Tunisia” . The stuAlthough the paper is interesting, showing some significant statistical differences, the authors used only univariate analysis and not multivariate analysis. Indeed, some factors found to be significantly related with tinea pedis, such as “associated fingernails onychomycosis” and “antifungal therapy,” may not be independent factors as they seem related. A multivariate analysis would have more precisely described the factors most related to the genesis of tinea pedis.Furthermore, the authors did not calculate the odds ratio  for every studied factor. Odds ratio is, in such studies, the most appropriate tool to specify risk factors . Withoutp=0.410) and between patients who attend communal showers and who do not (p=0.631). Another study from Tunisia showed similar findings in multivariate analysis [An interesting result of the study was that there was no significant statistical difference in the frequency of having tinea pedis between patients who practice ritual washing and who do not (not p=0.61. AnotheProspective, multicentre, controlled studies, with multivariate analysis, would better indicate risk factors for tinea pedis and tinea unguium.


Background: Lipoma preferred partner (LPP) and T-cell activation Rho GTPase activating protein (TAGAP) polymorphisms might influence the susceptibility to celiac disease. Therefore, we performed a meta-analysis by identifying relevant studies to estimate the risks of these polymorphisms on celiac disease. Methods: The PubMed, Web of Science and Embase databases were searched (up to October 2016) for LPP rs1464510 and TAGAP rs1738074 polymorphisms. Results: This meta-analysis included the same 7 studies for LPP rs1464510 and TAGAP rs1738074. The minor risk A allele at both rs1464510 and rs1738074 carried risks (odds ratios) of 1.26 (95% CI: 1.22–1.30) and 1.17 (95% CI: 1.14–1.21), respectively, which contributed to increased risks in all celiac disease patients by 10.72% and 6.59%, respectively. The estimated lambdas were 0.512 and 0.496, respectively, suggesting that a co-dominant model would be suitable for both gene effects. Conclusions: This meta-analysis provides robust estimates that polymorphisms in LPP and TAGAP genes are potential risk factors for celiac disease in European and American. Prospective studies and more genome-wide association studies (GWAS) are needed to confirm these findings, and some corresponding molecular biology experiments should be carried out to clarify the pathogenic mechanisms of celiac disease. Celiac disease (CD) is a chronic and immune-mediated enteropathy that is induced by dietary protein gluten  in genetically predisposed individuals . It is aLPP) and T-cell activation Rho GTPase activating protein (TAGAP). Alterations of the actin cytoskeleton and cell shape can be observed in the CD patients’ intestinal mucosa [LPP is localized with paxillin in focal adhesions, and the number of paxillin focal adhesions with LPP is increased in CD fibroblasts. A constitutive alteration in cell shape and adhesion involving LPP occurs in CD fibroblasts, suggesting a correlation between LPP and CD pathogenesis [LPP is considered a substrate of the protein-tyrosine-phosphatase 1B (PTP1B) [In recent years, genome-wide association studies (GWAS) have expanded our understanding of genetic makeup and revealed several possible inherited risk factors in celiac disorders ,8,9,10. l mucosa ,17, whill mucosa . LPP is ogenesis . In addi (PTP1B) . Of note (PTP1B) , which i (PTP1B) . When PTTAGAP is involved in the Rho GTPase cycle [TAGAP propagates the inactive form of the RHO molecule; and it increases the activity of Rho GTPases via phosphorylation, enhancing their intrinsic activity up to fivefold [TAGAP negatively regulates downstream effects; thus, the actin cytoskeleton rearrangement is dysfunctional and lack of unstable [se cycle ,24, whicse cycle ,26,27. Ise cycle . Howeverfivefold . TAGAP nunstable .LPP and TAGAP may interfere with their original function and even promote the progress of CD. In recent years, a number of studies, including GWAS, have reported the association of LPP and TAGAP polymorphisms with CD susceptibility, and many have focused on LPP rs1464510 (A/C) and TAGAP rs1738074 (A/G). However, those studies have drawn inconsistent conclusions due to the limited regions and small numbers of articles. For example, Dubois et al. [LPP rs1464510/TAGAP rs1738074 and CD risk.Mutation of s et al.  and Hunts et al. . Similars et al. . TherefoLPP or 3q28 or rs1464510 or “lipoma preferred partner”) or “lim domain containing preferred translocation protein”) and celiac disease) or ((TAGAP or 6q25 or rs1738074 or “T-cell activation GTPase activating protein”) and celiac disease). The search was limited to English-language and human studies. Only published studies were considered. We scanned the title and abstract of all relevant articles, manually examined reference lists for additional relevant publications and obtained the full text of all possibly relevant studies. If multiple articles were published on the same topic, the most complete and recent study was used.Relevant studies were searched in PubMed, the Web of Science and Embase up to October 2016. The search strategies were as followed: (((LPP (rs1464510) or TAGAP (rs1738074) polymorphism, (2) the outcome was celiac disease and there was a control group, (3) there were sufficient data for extraction  and (4) there was a clear diagnosis of celiac disease. Studies were excluded if: (1) the case and control subjects were biologically related; (2) the insufficient data that were failed to ask for supplementary information from the authors; (3) the studies comprised unrelated data, family studies, animal studies, reviews, or meeting abstracts; or (4) the studies were written not in English.A reviewer independently examined the titles and abstracts of the identified articles. Any human population-based association study was included regardless of subjects’ ethnicity if it met the following criteria: (1) it showed an association between Summary data were extracted independently by reviewers using a standardized data extraction form. We extracted general information as follows: name of first author, year of publication, region of study population, source of controls, genotype method, diagnostic criteria, the number of cases and controls, and the minor allele frequency in cases and controls. Any disagreement was resolved by consensus.Study quality was assessed independently by the same reviewers using a risk-of-bias score for genetic association studies that was developed by Thakkinstian et al.  Supplem. The scop value less than 0.05 were considered statistically significant, except for the heterogeneity tests, in which a p value less than 0.10 was used. It was tested whether the distribution of genotypes in the controls was compliant with Hardy-Weinberg equilibrium (HWE) by a Fisher’s exact test to estimate the quality of studies. If the study was found not to be in HWE with a p value less than 0.05, it was considered to be in disequilibrium. We used both per-allele and per-genotype analysis to estimate the strength of the association between the polymorphism of LPP rs1464510 or TAGAP rs1738074 and CD risks.We used Stata software  and the Comprehensive Meta-Analysis software  for all statistical analyses. All tests with a p value was used to determine whether the overall gene effect was significant (p = 0.05). The heterogeneity of allele effects across studies was checked using a Q test, and the degree of heterogeneity was quantified by I2 . If heterogeneity was present , the cause of heterogeneity was explored using sensitivity analysis. We chose a random-effects model if I2 was greater than 50%; otherwise, a fixed-effects model was used. The population attributable risk (PAR) for the risk allele was calculated based on results from a discrete-time model. If the main effect of the genotype was statistically significant and had the appropriate effect model selection, further comparisons of OR1 and OR2 were explored. Per-genotype analysis: We used the model-free approach to estimate the genotype effect, and two odds ratios—AA vs. aa (OR1) and Aa vs. aa (OR2)—were estimated for each study. The model of the genetic effect, measured by the parameter lambda (λ), which is defined as the ratio of logOR2 to logOR1, was then estimated using the model-free Bayesian approach. Lambda (λ) represents the heterozygote effect as a proportion of the homozygote variant effect. The value of lambda ranges from 0 to 1. We obtained information about the genetic mode of action as follows: If λ = 0, a recessive (Aa + aa vs. AA) model is suggested; if λ = 1, a dominant model (AA + Aa vs. aa) is suggested; and if λ = 0.5, a co-dominant model  is suggested. If λ > 1 or λ < 0, then a homozygous or heterosis model is likely, although this is rare. Once the best genetic model is identified, this model is used to collapse the three genotypes into two groups and to pool the results again. For lambda, WinBugs 1.4.2 was used with vague prior to distributions for the estimation of parameters . The models were run with a burn-in of 1000 iterations, followed by 10,000 iterations for parameter estimates. The Begg and Mazuma rank correlation and Egger’s test were adopted to assess and quantify the publication bias. A sensitivity analysis was performed, and we removed studies one by one to reflect the influence of each study on the pooled OR of the others. In addition, we calculated the classic fail-safe N value using Comprehensive Meta-Analysis software (version 2.0) to quantitatively evaluate the reliability of the results.Per-allele analysis: Suppose that A and a are risk and non-risk alleles, respectively, and AA, Aa and aa are minor homozygous, heterozygous, and common homozygous genotypes, respectively, for each polymorphism. The risk allele frequency in each group was estimated according to the reported genotype data, and overall prevalence along with 95% confidence intervals were estimated for each single nucleotide polymorphism (SNP). The Mantel-Haenszel method was used to determine the statistical significance of the pooled OR, and its Twenty-five, twenty-one and twenty-five studies were identified from PubMed, Web of Science, and Embase, respectively; an additional three studies were identified from references in the included studies . After dThe results of bias assessment are presented in LPP rs1464510 polymorphism and CD, with 14,936 cases and 24,788 controls  across the studies, with a pooled OR of 1.26   (p = 0.100) and Begg and Mazumdar rank correlation (p = 0.284) suggested that no publication bias existed. Publication bias was also tested using a funnel plot (p = 0.00), which suggested that 1032 unpublished negative studies would have to be included to convert the combined p value to a non-significant value.The seven studies reported an association between controls . The poo3, 1.31) . The Eggnel plot . The cla1 (AA vs. CC)  was moderately heterogeneous, and the OR2 (AC vs. CC)  was homogenous. The pooled OR1  and OR2  were statistically significant, which indicated that persons with AA and AC genotypes in LPP rs1464510 had an approximately 58% and 26% higher risk, respectively, of developing CD than persons with the CC genotype. The Egger test did not suggest any asymmetry for both ORs . The λ was 0.512 , suggesting that a co-dominant effect was most likely.The genotype frequency and estimated ORs of LPP rs1464510 are presented in parts B and C of TAGAP rs1738074 polymorphism and CD, with 14,936 cases and 24,788 controls  (part A of p = 0.440) and Begg and Mazumdar rank correlation (p = 0.315) suggested that no publication bias existed. Publication bias was also tested using a funnel plot (p = 0.00), which suggested that 513 unpublished negative studies would have to be included to convert the combined p value to a non-significant value.The seven studies reported an association between controls . The poonel plot . The cla1  and the OR2  were homogenous, and estimated by a fixed-effects model in parts B and C of TAGAP rs1738074 had approximately 37% and 17% higher risks, respectively, of developing CD than persons with the GG genotype. Egger’s test did not suggest any asymmetry for both ORs . The λ was 0.496 , which suggested that a co-dominant effect was most likely.The ORLPP rs1464510 and TAGAP rs1738074 polymorphisms contribute to the susceptibility to CD in European and American.Our meta-analysis suggests that both LPP suffered from moderate heterogeneity, but I² decreased significantly (from 29.52% to 11.63%) when we eliminated The Netherlands data from Coenen et al. [The pooled OR (A vs. C) of n et al. , indicatn et al. . TherefoLPP, which is strongly expressed in the small intestine, participates in the regulation of cell adhesion, cytoskeletal remodeling and maintenance of cell shape and motility [LPP lead to the PTP1B becoming sufficient or even excessive, so more ERK may be activated, and that it may play a functional role in CD enterocyte proliferation. Our results suggested a powerful relationship between CD and the LPP of rs1464510 .TAGAP is a Rho GTPase-activating protein crucial for modulating cytoskeletal changes [TAGAP rs1738074 might increase GTPase activity, which propagates the inactive form of the Rho molecule in the Rho GTPase cycle and leads to negative regulation of downstream effects, thus promoting the development of CD. Our meta-analysis confirmed the involvement of rs1738074 in CD susceptibility , so pathway analysis should be implemented to generate hypotheses for clarifying the biological link between TAGAP and CD [motility ,36, and motility . We infe changes ,12, and  changes . TherefoLPP rs1464510/TAGAP rs1738074 and CD in European populations. Second, all included studies were case-control studies, which might have overestimated the genetic association; a population-based nested case-control study is needed to avoid this bias. Finally, because only English-language literature was retrieved, we may have missed relevant articles written in other languages.There are some limitations of our study. First, we only included European (38197/39725) and American (1528/39725) populations; nonetheless, our results provide a comprehensive overview of the association between LPP rs1464510 and TAGAP rs1738074 are associated with CD susceptibility. Furthermore, the gene–gene and gene–environment interactions should be evaluated, and studies with larger and more diverse samples should be performed to confirm the results of this meta-analysis.In summary, our meta-analysis reveals that both


This systematic review is written to investigate the outcome of cervical cancer. A comprehensive search of PubMed and EMBASE was performed to identify eligible studies. Nineteen studies from thirteen articles with a total of 1,310 participants were included in this meta-analysis. Overall survival (OS), disease-free survival (DFS), and recurrence-free survival (RFS) as a prognosis for cervical cancer were extracted and calculated, if available. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using STATA (version 12.0), resulting in the pooled HRs 0.70 (95% CI: 0.51–0.97) for OS, 1.02 (95% CI: 0.53–1.98) for DFS, and 0.56 (95% CI: 0.40–0.77) for RFS. The results indicated that cervical cancer patients with decreased microRNA expression were associated with shorter OS and RFS. It suggested that microRNAs might be promising markers for predicting the survival rate of cervical cancer. Cervical carcinoma is the third most common female cancer that is closely related to human papilloma virus (HPV) infection. It was estimated that there were half a million new cases and 200, 000 deaths from cervical cancer every year . AdditioMicroRNAs are small noncoding RNAs, about 22–24 nucleotides long, that promote or inhibit tumor growth, progression, and metastasis . The expNineteen studies from thirteen articles with a total of 1,310 cervical cancer patients from China, Iran, and Korea were included in this meta-analysis –18. Thes2 = 85.6%, P < 0.001; DFS: I2 = 85.9%, P < 0.001; RFS: I2 = 50.4%, P = 0.156), so the random–effects model was used to calculate the pooled HR and 95% CI values , so we performed meta-regression analysis to explore the source. The results of the meta-regression analysis indicated that the sample size and cut-off value contributed to heterogeneity across the eighteen studies on OS. Cut-off values, country of origin, sample type, and other factors may have been sources of the heterogeneity in many similar meta-analyses [This meta-analysis is the first systematic assessment of the correlation between microRNA expression and the prognosis of patients with cervical cancer. As this meta-analysis showed, the pooled HR of OS was 0.70 , which suggested that decreased microRNAs expression were associated with shorter OS in patients with cervical cancer. The forest plot revealed heterogeneity in this meta-analysis , which suggested a higher degree of heterogeneity. The results of DFS and RFS did not change. Subgroup analysis on pathology types was not made for their undefined classifications and insufficient related information.In order to explore the source of heterogeneity in this meta-analysis, we also considered the type of cervical cancer. The main pathological classifications of cervical cancer are squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinoma. In the thirteen included articles, most of them had no clear classifications, and a paper by Huang et al. revealed that the patients obtained had neuroendocrine small cell cervical carcinoma (SCCC), which is a less common type of squamous cell cervical carcinoma. After excluding this article, the pooled HR of OS was 0.80  study was written in English; (2) study investigated the prognostic value of cervical cancer patients with survival outcomes; and (3) study detected microRNA expression in tissue, serum, or plasma. An article was excluded in the following circumstances: (1) it was a review, comment, letter, or basic research article; (2) it lacked key information, such as hazard ratio (HR), 95% confidence interval (95% CI), or other useful data for extrapolating; and (3) it was a repeated study including the same samples from the same patients as a study already published. Once overlapping data were used in more than one article, the most complete study was exclusively included in this meta-analysis. Two reviewers independently evaluated the articles identified by the above criteria.We systematically evaluated the methodological quality of all the included studies according to a critical review checklist from the Dutch Cochrane Centre proposed by the Meta-analysis of Observational Studies in Epidemiology . The keyThe data of all eligible studies were independently extracted by two investigators. Disagreements were resolved by discussion. The following primary information was collected: name of the first author, year of publication, country of the study, sample size, disease stage, test method, cutoff value, follow-up time, and HRs of microRNA for OS, DFS, and RFS . If the HRs and 95% CIs were not available, we calculated them using the relevant data provided in the articles or asked for related information by emailing the authors. If only the Kaplan-Meier curves were available, we extracted the relevant data from the graphed survival plots and calculated the HRs and 95% CIs. All calculations used the methods developed by Parmar, Williamson, and Tierney –27.2 statistic . If there was no obvious heterogeneity, a fixed-effects model was used; otherwise, the random-effects model was used. Publication bias was evaluated using the funnel plot and Egger's test  [The pooled HRs of microRNA expression for OS, DFS, and RFS were calculated in this meta-analysis. A pooled HR < 1 means a poor prognosis for patients with low microRNA expression. In contrast, a pooled HR > 1 and a lower limit of the 95% CI of a pooled HR > 1 indicate a poor prognosis for patients with high microRNA expression . Heterogon bias) . All of


The use of dipeptidyl peptidase-4 (DPP-4) inhibitors may be associated with pancreatic cancer and acute pancreatitis. Recent meta-analyses have reported conflicting findings. Therefore, we performed a meta-analysis to assess the risk of both pancreatic cancer and acute pancreatitis associated with the use of DPP-4 inhibitors. We also used trial sequential analysis to evaluate whether the number of patients included was enough to reach conclusions. We included randomised controlled trials lasting 24 weeks or more that compared DPP-4 inhibitors with placebo or other antihyperglycaemic agents. A total of 59,404 patients were included. There was no relationship between the use of DPP-4 inhibitors and pancreatic cancer , and the optimal sample size was reached to determine a number needed to harm (NNH) of 1000 patients. DPP-4 inhibitors were associated with increased risk for acute pancreatitis , with an NNH of 1066 patients, but the optimal sample size for this outcome was not reached. In conclusion, there is no association between DPP-4 inhibitors and pancreatic cancer, and a small risk for acute pancreatitis was observed with DPP-4 inhibitor use, although the latter finding is not definitive. These medications are not associated with severe hypoglycaemia and have a neutral effect on weight. However, there are concerns that the use of DPP-4 inhibitors may be associated with increased risk for pancreatic cancer and acute pancreatitis3.Dipeptidyl peptidase-4 (DPP-4) inhibitors, or gliptins, are incretin-mimetic oral antihyperglycaemic agents whose clinical use has steadily increased over the past ten years2. Another study suggested that DPP-4 inhibitor use was associated with the occurrence of α-cell hyperplasia, that is, increased proliferation and dysplasia, with potential evolution into neuroendocrine tumours4. Later, a pooled analysis of clinical trials with sitagliptin suggested no association between use of this medication and pancreatic cancer5. The lack of association between DPP-4 inhibitor use and pancreatic cancer was evaluated in a pooled analysis including only two large randomised trials, and no association was found6. Recently, three meta-analyses assessed the risk for acute pancreatitis among patients taking gliptins. Li et al. analysed the results of 60 randomised and non-randomised trials and found no increased risk of pancreatitis in patients treated with gliptins compared with controls7. Despite this reassuring finding, the inclusion of observational studies might have influenced the results owing to selection bias. Conversely, two other meta-analyses found contradictory results when analysing the results of three large studies assessing the cardiovascular risk of sitagliptin, saxagliptin and alogliptin3. In these studies, the use of DPP-4 inhibitors increased the risk of pancreatitis. Importantly, the potential cases of acute pancreatitis were adjudicated in these three trials.An early study analysed the FDA reports of pancreatic cancer and concluded that there was a 2.7-fold increase in the risk for pancreatic cancer with DPP-4 inhibitor useConsidering the potential association between DPP-4 inhibitor use and both pancreatic cancer and acute pancreatitis, we performed a meta-analysis including all randomised trials with DPP-4 inhibitor use lasting at least 24 weeks, in order to analyse whether there is an increased risk of pancreatic cancer and/or acute pancreatitis. We also applied trial sequential analysis (TSA) to assess whether the number of patients randomised in these trials was sufficient to reach definitive conclusions.8 and was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under the number CRD42016953346.This systematic review and meta-analysis follows the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) protocolNo patients were directly involved in the study.9. All eligible trials were considered for review, regardless of language. A manual search of the reference lists of key articles was also performed.We performed a systematic literature search for all randomised clinical trials (RCTs) that compared DPP-4 inhibitor use with either placebo or other antihyperglycaemic medications. We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL) and ClinicalTrials.gov from database inception to May 2016. We also searched abstracts from the most recent meetings of the American Diabetes Association and the European Association for the Study of Diabetes. The search strategy used the Medical Subject Headings (MeSH) terms “sitagliptin” OR “saxagliptin” OR “linagliptin” OR “alogliptin” OR “vildagliptin” AND “diabetes mellitus, type 2” AND a validated filter to identify RCTs10.The inclusion criteria were: (1) RCTs, (2) DPP-4 inhibitor use versus any standard of comparison, (3) treatment for at least 24 weeks, (4) definition of events of acute pancreatitis and/or pancreatic cancer, (5) inclusion of patients ≥18 y old, and (6) diagnosis of type 2 diabetes according to the American Diabetes Association criteriaTwo independent investigators (L.C.P. and S.S.B.) selected studies on the basis of titles and abstracts. Studies satisfying the inclusion criteria and those with abstracts that lacked crucial information to decide upon their exclusion were retrieved for full-text evaluation. Both investigators also analysed the selected trials and extracted data; disagreements were resolved by a third reviewer (D.V.R.). The following information was extracted: first author’s name, year of publication, sample size and dropouts, age distribution, gender distribution, trial duration, treatment in use prior to randomisation, acute pancreatitis and pancreatic cancer events.12. In adjudicated trails, the diagnosis was confirmed by the following criteria: symptoms of abdominal pain or vomiting and evidence of pancreatic inflammation  or evidence of acute pancreatitis documented by abdominal computerised tomography, magnetic resonance imaging or ultrasound showing focal, diffuse and inhomogeneous gland enlargement. The quality of each outcome (pancreatic cancer and acute pancreatitis) was evaluated by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach13. Each meta-analysis was rated as high, moderate, low or very low quality.The quality of studies was assessed according to the Cochrane Collaboration tool for risk of bias, including the following six domains: random sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, and other biases such as adjudication of eventsWe compared the events of interest between patients randomised to the use of DPP-4 inhibitors and patients randomised to the control treatment (placebo or other antihyperglycaemic medications). The outcomes of interest were pancreatic cancer and acute pancreatitis.p-value of 0.1 was considered statistically significant) and the I2 test . For studies with no events in either arm, continuity correction was performed to include these data in TSA analyses. To assess whether the length of the trials was related to the outcome, we performed meta-regression, using study duration as a covariate.Data were summarised with direct meta-analysis to compare DPP-4 inhibitors with placebo and other antihyperglycaemic agents. We used the Peto odds ratio and the Mantel-Haenszel test for analysis. We used the Peto odds ratio in the primary analyses as it is more conservative  and is superior when dealing with rare events. Heterogeneity was assessed by Cochran’s Q test  between groups on the basis of previous trial results1. We conducted the TSA with an overall 5% risk of type I error and 20% risk of type II error (power of 80%).Furthermore, to address whether current information is sufficient for firm conclusions, we performed TSA of the identified studies. This analysis is analogous to sample size estimation or interim analysis of a single studyWe evaluated publication bias with visual inspection of funnel plots and with Begg’s and Egger’s tests. If small-study bias was identified, we applied the trim-and-fill method to explore the effect of missing studies on the outcomes.The analyses were performed using the programs RevMan version 5.3  and STATA 12.0 . The TSA was performed with TSA software .Our search retrieved 763 articles. After we scanned through the titles and abstracts and removed all duplicates, 186 articles remained for full-text evaluation. Ultimately, 38 trials were included in the analysis . The analysis included 59,404 patients; 39,970 (62.1%) were men, and the mean age was 57.39 ± 5.12 years. The main characteristics of the included trials are presented in Table The analysis of the funnel plots and Begg’s and Egger’s tests suggested no publication bias for either outcome (pancreatic cancer or acute pancreatitis).– Forest plot for association between DPP-4 inhibitors and pancreatic cancer). Similar results were observed with the Mantel-Haenszel test . When we performed TSA, DPP-4 inhibitors were still not associated with pancreatic cancer , and the number of randomised patients for this outcome surpassed the futility boundary   and with an absolute risk difference of 0.1% (representing a number needed to harm (NNH) of 1066). Mantel-Haenszel analysis showed comparable results . As we aimed to be conservative, TSA was performed to assess whether there was enough information to reach a definite conclusion regarding the association between DPP-4 inhibitors and acute pancreatitis. For this outcome, the number of patients evaluated  did not reach the optimal sample size , and the boundaries of benefit, harm and futility were not crossed . In meta-regression, no interference of study duration with acute pancreatitis was seen .The results of the present review indicate that the use of DPP-4 inhibitors is not associated with increased risk for pancreatic cancer. Furthermore, the TSA meta-analysis confirmed that the number of patients available was enough to reach this conclusion. There seemed to be an association between the use of DPP-4 inhibitors and acute pancreatitis, although the number of randomised patients was not sufficient for a firm conclusion and the estimated risk of acute pancreatitis is small (one patient in 1066 patients treated with DPP-4 inhibitors).2. Other studies have suggested an association between DPP-4 inhibitor use and pancreatic cancer5, but there is still an ongoing debate on this topic. Additionally, several observational studies have explored the association between DPP-4 inhibitors and pancreatitis17. However, owing to study design characteristics, the results may be affected by selection and confounding biases. As there are a great number of randomised trials evaluating these medications, a systematic review and meta-analysis of these studies is recommended to properly address this clinical question.Concern regarding the association between DPP-4 inhibitor use and pancreatic cancer was raised after a review of cases reported by the FDA7 did not find an association between use of DPP-4 inhibitors and acute pancreatitis; however, this review included not only randomised trials but also prospective and retrospective observational cohort studies. Most importantly, the events were not adjudicated. The other two3 found an increased risk of acute pancreatitis in patients treated with DPP-4 inhibitors; however, they included only three large cardiovascular randomised trials, namely, EXAMINE, SAVOR-TIMI 53 and TECOS20. In these trials, a specialised committee adjudicated the diagnosis of acute pancreatitis. None of these reviews performed TSA to evaluate whether the results were definitive, and, more importantly, none of them evaluated the risk of pancreatic cancer associated with use of DPP-4 inhibitors.Before this review, three other meta-analyses evaluated the association between clinical use of DPP-4 inhibitors and acute pancreatitis. The first oneOur study adds new information regarding this point. It included all randomised trials with DPP-4 inhibitor use that lasted for at least 24 weeks and, through TSA meta-analysis, evaluated whether the number of cases was sufficient to support the conclusions. There was a small risk of acute pancreatitis, such that it would be necessary to treat 1066 patients to have one case of acute pancreatitis, but the number of patients included in the meta-analysis was not sufficient to support this conclusion. Notably, owing to the large number of diabetic patients using DPP-4 inhibitors worldwide, a great number of cases of acute pancreatitis might be prevented by taking into account pre-existing risk factors for acute pancreatitis, such as gallstones and hypertriglyceridaemia, when considering whether to prescribe this type of medication.et al.21. Receptors for GLP-1 are largely found in the pancreatic ducts and the pancreatic islets. Acinar and duct cells respond to GLP-1 therapy with proliferation23. A previous study in rats exposed to sitagliptin reported haemorrhagic pancreatitis in one rat and acinar-to-ductal metaplasia in others24. Therefore, the association between incretins and acute pancreatitis is biologically plausible. However, it remains unclear why DPP-4 inhibitors are associated with pancreatitis and GLP-1 agonists are not21.On the other hand, GLP-1 agonist use is not associated with an elevated risk of acute pancreatitis, as recently revealed by a meta-analysis from Storgaard Regarding pancreatic cancer, no association between use of gliptins and pancreatic cancer was observed, and TSA meta-analysis showed that there were enough patients randomised for this observation.The main limitation of our meta-analysis was the duration of the trials , which may be insufficient to evaluate the development of pancreatic cancer. We tried to overcome this limitation by including study duration as a covariate in the meta-regression, and this variable did not have an influence on the outcome. However, we must consider that this analysis might have low power owing to the number of included trials. Another limitation is the criteria used for diagnosis of acute pancreatitis in trials. In adjudicated trails, the diagnosis was confirmed by an adjudication committee and the criteria used were clearly described. However, in non-adjudicated trials, the criteria used are less straightforward. Nonetheless, restricting the analysis to adjudicated studies did not change the results. Furthermore, owing to the design of the present study, we were not able to explore whether there is a specific subgroup of diabetic patients with increased susceptibility to acute pancreatitis. The included trials did not describe the risk factors for this complication, such as hypertriglyceridaemia, alcohol consumption, and previous history of cholelithiasis. The only factor classically associated with acute pancreatitis that was mentioned was smoking status, which was similar in the intervention and control groups.Finally, there is enough information to suggest a lack of association between the use of DPP-4 inhibitors and pancreatic cancer, but not acute pancreatitis. The latter seems to be a continued concern, and additional study data are needed. Despite this uncertainty, the apparent risk is small.Supplementary Dataset 1Supplementary Dataset 2