Gastroesophageal reflux disease (GERD) is one of the most common digestive system diseases, which is associated with lifestyle and dietary factors. The main mechanism involved in GERD is affected by demographics, lifestyles, and dietary factors. Tea consumption is reported to be associated with GERD, especially in Asian population. However, the effect of tea drinking on GERD risk is still controversial. The aim of this study was to investigate the relationship between tea consumption and the risk of GERD by meta-analysis.We searched the published research databases such as PubMed and Embase for studies that were published up to March 2018. The search results were reviewed by 2 authors, and studies that complied with the criteria were selected. Odds ratio (OR) and 95% confidence interval (CI) were used to assess the association between tea consumption and the risk of GERD.Twenty-three articles including 30 studies were included in the meta-analysis. The result of meta-analysis showed that tea drinking had no significant association with the risk of GERD. The odds ratio (OR) and 95% CI were 1.12 and (0.98–1.27). In subgroup analysis based on geographical region, tea consumption can increase the risk of GERD in East Asia , while the risk of GERD was decreased in Middle Asia . Besides, in the subgroup of study design, there was a significant association between tea intake and the GERD in cross-sectional study. In no symptom subgroup, the risk of GERD was increased .There was no significant relationship between tea consumption and the risk of GERD overall. However, in subgroup analysis, tea drinking may increase the risk of GERD in East Asia and decrease in Middle Asia. To clarify the causality between tea intake and GERD, a more precise study design will be needed. GERD is a very common gastrointestinal diagnosis and the incidence rate is on the rise. The prevalence of GERD in North America and Europe is 8.8% to 27.8%, while it is only 2.5% to 7.8% of the population in East Asia. Such mechanisms of GERD are affected by demographics, lifestyles, and dietary factors. Among these factors, smoking and obesity are considered as the recognized factors.,4 However, the relationship between GERD and other environmental factors is not yet clarified. Dietary factors such as fat and chocolate are putative risks of GERD, but dietary interventions are not effective in treating GERD.The main mechanism involved in GERD is transient low sphincter relaxation episodes and decreased lower esophageal sphincter (LES) pressures.Camellia sinensis, has been considered a healthy drinking with beneficial effects like anti-aging and antidiabetic for thousands of years. However, tea is also related to some clinical symptoms including heartburn and reflux.,7 Tea consumption is reported to be associated with GERD, especially in Asian population. Theoretically, theophylline, a component of tea, may contribute to relax the LES, leading to esophageal acid reflux. In observational studies, some case–control studies have reported that there is no correlation between GERD and tea consumption,,10 while other studies suggested a positive association between tea drinking and the risk of GERD.–13 Thus, the effect of tea drinking on GERD risk is still controversial. The aim of this study is to perform a meta-analysis on the relationship between tea drinking and the incidence of GERD.Tea, the beverage processed from 22.1A literature search was performed based on PubMed and Embase databases for studies that reported the association between tea intake and the risk of GERD up to December 20th, 2017. The following keywords and their corresponding MeSH terms were used: “tea” or “lifestyle” or “diet” or “dietary” combined with “gastroesophageal reflux” or “GERD” or “esophageal reflux disease” or “esophagitis” or “Barrett's esophagus.”2.2The studies were included by the following selection criteria: a case–control or cohort study design or cross-sectional study; providing information related to association between tea intake and the risk of GERD; providing the odds ratio (OR) or relative risk (RR) data as well as the corresponding 95% confidence intervals (CI) for the highest versus the lowest level of tea intake, or necessary data for calculation.The studies were excluded by the following exclusion criteria: nonepidemiologic studies ; duplicated study; not providing sufficient data to calculate OR (or RR) and CI. Other reasons  for which the studies were not appropriate to be involved in the meta-analysis.2.3The following key information was recorded: the last name of the first author, publication year, country, geographical region, study design, number of cases and controls or total sample size, exposure assessment, diagnosis method, disease type, OR (or RR), the corresponding 95% CI, and the covariates adjusted for in the analysis. Quality assessment was conducted according to the Newcastle–Ottawa scale (NOS). The NOS is divided into 3 parts: selection (4 points), comparability (2 points), and exposure/outcome assessment (3 points). The study with an NOS ≥ 6 was considered as high quality and included in our meta-analysis. The process of data extraction was carried out by 2 independent authors with a standardized form based on inclusion and exclusion criteria mentioned above. Any divergence was resolved by revaluation until consensus was reached. The meta-analysis was approved by the Hospital Ethics Committee  to not re-identify the participants.2.4Q statistic test via I2 value and P value was used to analyze the statistical heterogeneity, which depicts the percentage of variation across studies due to heterogeneity rather than chance. An I2 value of >50% was considered to indicate substantial heterogeneity. When the I2 value was >50%, the random effects model was used, and when it was <50%, the fixed effects model was used. Subgroup analyses according to study design, ethnicity, exposure assessment, and diagnosis method, was performed to assess the potentially important covariates that might exert substantial impact on between-study heterogeneity. Publication bias was analyzed by using Egger's test and Begg's funnel plot. Sensitivity analysis was conducted to describe how robust the pooled estimator was when removing an individual studies at a time. STATA version 12.0  was used for the whole meta-analysis. Statistical significance was set at P < .05.The OR and the 95% CI values were directly extracted from each study, or were calculated from the raw data. For studies where the study population was divided into groups based on the amount of tea intake, we used the groups with the highest and lowest levels of tea intake among the various categories. Pooled analysis was performed to evaluate the association between tea consumption and the risk of GERD. The pooled analysis was shown as forest plot. Chi-square-based 33.1The detailed study screening processes were shown in Figure ,16–18 Therefore, there were 30 estimates of 23 articles in our meta-analysis, among which, 17 were performed in East Asia, 5 were in Europe, 5 were in Middle East, 2 were in North America, and 1 was in South Asia. According to study design, 18 were cross-sectional studies, 9 were case–control studies, and 3 were cohort studies. Among them, 21 were conducted by questionnaire, 9 by interview. For disease diagnosis method, subjects in 13 studies were confirmed by symptom only and those in the other 17 studies by endoscopy.The characteristics of the included studies on tea intake and the risk of GERD are presented in Table 3.2I2 = 79.3%, P < .001) , and these studies showed a significant heterogeneity (P = .674) also showed that there is no publication bias of the meta-analysis about tea intake and GERD. The sensitivity analysis was conducted to assess the stability of the result. When each article was omitted successively, the corresponding result did not change significantly  and endoscopy assessment.,24 In clinical practice, GERD can be determined by common symptoms, such heartburn and acid reflux alone. However, this may be a confounding factor to evaluate the relationship between tea and GERD, since theophylline containing in tea can release chest pain. Besides, content of questionnaire may be another contributor of the heterogeneity in meta-analysis.Among the 30 studies of 23 articles including in this meta-analysis, 17 were performed in East Asia, 5 were in Europe, 5 were in Middle East, 2 were in North America, and 1 was in South Asia. In subgroup analysis by geographical region, there was a significant association between tea and the risk of GERD in East Asia. Tea is more popular in Asian countries than Western countries, and the amount of tea drinking are larger in Asian countries, such as China and Japan.,26 There are many studies focused on the risk of GERD and coffee drinking.,28 However, Kim et al conducted a meta-analysis to evaluate the association between coffee drinking and gastroesophageal reflux disease and found no significant association between the risk of GERD and coffee drinking. This meta-analysis revealed that coffee cannot increase the risk of GERD, even though some study suggested that coffee might change the lower esophageal sphincter pressure. Alcohol is another potential risk factor related to GERD. Recently, a meta-analysis revealed that alcohol intake might increase the risk of GERD. This finding suggested that drinkers should consider to limit the alcohol consumption to prevent the potential injury to the esophagus. Similar to coffee and alcohol, tea is a popular beverage worldwide. Our meta-analysis revealed that tea consumption was not associated with GERD worldwide. But in some geographical region, tea might be a potential risk factor of GERD, such as East Asia and Middle Asia.Besides tea drinking, other dietary and lifestyle factors such as coffee intake, alcohol drinking, smoking and obesity may related to the risk of GERD.R-squared in geographical region and symptoms were 25.44% and 15.37%, respectively. Thus, we conducted subgroup stratified by geographical region, symptoms, study design, exposure assessment, and diagnosis method. In this way, we can reduce the impact of high heterogeneity on the quality of the study to a certain extent. There are some limitations in the present meta-analysis. Firstly, the amount of tea consumption was quite heterogeneous among these studies. We used the highest and lowest exposure of tea intake in each study, though the amount of each study is not the same. In addition, the type of tea, degree of fermentation, the concentration of tea polyphenols and the temperature of tea are also confounding variables in meta-analysis. Secondly, some studies are based on the mixed ethnicity, which may ignore the gene–environment interaction on the risk of Barrett's esophagus. Thirdly, most of studies were cross-sectional study and case-control study. They cannot indicate the direct causality between tea drinking and the risk of GERD. Besides, the majority of the studies did not determine adjustment for confounding variables during the investigation. Fourthly, there exist many types of tea, such as green tea, oolong tea and black tea, whose degree of fermentation, the concentration of tea polyphenols and the temperature of the tea are confounding variables in our meta-analysis. Due to the limited data provided by the previous studies, we cannot clarify these potential heterogeneities in our meta-analysis. Last but not least, we excluded the study focused on the tea with salt, tea with milk, tea, and coffee combined, since these ingredients may have impact on GERD. These limitations can be a cause of heterogeneity in each study, which may affect the outcome of this meta-analysis.To explore the observed heterogeneity, we conducted meta-regression to evaluate the study factors such as geographical region, study design, sample size, exposure assessment, diagnosis method, symptoms, and disease types. The result revealed that the adjusted In conclusion, there was no significant relationship between tea consumption and the risk of GERD overall. However, in subgroup analysis, tea drinking may increase the risk of GERD in East Asia. This suggested that tea drinking may be a potential risk of GERD and should be consider to limit the amount of intake in some GERD patients. Better-designed study is needed to confirm the effect of tea on GERD.Formal analysis: Yuyi Li.Software: Xiaosong Zhi, Cuihong Han.Supervision: Liang Li, Yuyi Li.Writing – original draft: Hongying Cao, Xiaoyi Huang.Writing – review & editing: Xiaosong Zhi, Liang Li, Yuyi Li.


Elevated lipoprotein (a) is recognized as a risk factor for incident cardiovascular events in the general population and established cardiovascular disease patients. However, there are conflicting findings on the prognostic utility of elevated lipoprotein (a) level in patients with coronary artery disease (CAD).Thus, we performed a meta-analysis to evaluate the prognostic value of elevated lipoprotein (a) level in CAD patients.A systematic literature search of PubMed and Embase databases was conducted until April 16, 2019. Observational studies reporting the prognostic value of elevated lipoprotein (a) level for cardiac events (cardiac death and acute coronary syndrome), cardiovascular events , cardiovascular death, and all-cause mortality in CAD patients were included. Pooled multivariable adjusted risk ratio (RR) and 95% confidence interval (CI) for the highest vs. the lowest lipoprotein (a) level were utilized to calculate the prognostic value. Seventeen studies enrolling 283,328 patients were identified. Meta-analysis indicated that elevated lipoprotein (a) level was independently associated with an increased risk of cardiac events  and cardiovascular events  in CAD patients. However, elevated lipoprotein (a) level was not significantly associated with an increased risk of cardiovascular mortality  and all-cause mortality .Elevated lipoprotein (a) level is an independent predictor of cardiac and cardiovascular events in CAD patients. Measurement of lipoprotein (a) level has potential to improve the risk stratification among patients with CAD.The online version of this article (10.1186/s12944-019-1092-6) contains supplementary material, which is available to authorized users. Coronary artery disease (CAD) is a common type of cardiovascular disease. Despite advances in medical sciences, CAD remains the main cause of death in the world . PatientLipoprotein (a) is a large low-density lipoprotein like particle involved in lipid metabolism, coagulation and fibrinolytic systems . ApproxiNo previous systematic review or meta-analysis has focused on the prognostic value of elevated lipoprotein (a) level for mortality in patients with CAD. Therefore, this meta-analysis sought to investigate the prognostic value of baseline blood lipoprotein (a) level for cardiovascular and all-cause mortality and adverse cardiovascular events in CAD patients.This meta-analysis follows the guideline of Preferred Reporting Items for Systematic Reviews and Meta-analyses . A systeStudies were considered for inclusion if they satisfied the following criteria: 1) observational studies enrolling CAD patients; 2) baseline blood lipoprotein (a) level as exposure; 3) reported at least one of the following outcome measure: cardiac events (cardiac death and acute coronary syndrome[ACS]), cardiovascular events , cardiovascular death, and all-cause mortality; and 4) provided multivariable adjusted risk ratio (RR) or hazard ratio (HR) or odds ratio (OR) with corresponding 95% confidence interval (CI) of each outcome measure for the highest versus the lowest blood lipoprotein(a). Exclusion criteria were: 1) participants were not restricted in CAD patients; 2) provided risk estimate according to per unit or per SD increase lipoprotein(a) level; 3) reported unadjusted risk estimate; and 4) meeting abstracts or reviews.Two authors independently extracted and collected the following data: last name of the first author, publication year, country, study design, type of CAD, sample size, percentage of men, mean age or age range, cutoff value of lipoprotein(a), length of follow-up, number of adverse events, fully adjusted risk estimate reported, and adjustment of variables. We assessed the methodological quality of individual studies based on the Newcastle-Ottawa Scale (NOS) for cohort studies . Studies2 statistic (I2 ≥ 50% indicating significant heterogeneity) and the Cochrane Q statistic (p < 0.10 indicating significant heterogeneity). A fixed-effect model was chosen in the absence of significant heterogeneity. Otherwise, a random effect model was used. Funnel plot was scheduled to detect publication bias when more than 10 studies were analyzed. Moreover, we conducted a subgroup analysis by study design, sample sizes, follow-up duration, and whether adjusting statins use or lipids. Sensitivity analysis was performed by removal of one study at each turn to investigate the robustness of the pooling results.All data were analyzed using STATA 12.0 version software .The reported multivariable adjusted risk estimate was used to calculate the prognostic value of blood lipoprotein(a) for the highest versus the lowest level. Heterogeneity between studies was checked using the IThe study selection process is shown in Fig. Table 2 = 61.9%; p = 0.033). Sensitivity analyses revealed no significant changes in the original pooled risk estimates when any study was excluded (data not shown).Five studies , 16, 17 2 = 36.2%; p = 0.140). Sensitivity analyses showed no significant changes in the original pooled effect sizes when any study was removed (data not shown). Subgroup analysis showed that the prognostic significance of lipoprotein (a) level for cardiovascular events was consistently found in each predefined subgroups . Four studies [2 = 71.9%; p = 0.014). Sensitivity analyses by removing any study at each time slightly changed the original pooled effect sizes of all-cause and cardiovascular mortality (data not shown).Four studies , 21, 22 The funnel plot is potentially unreliable for less than the recommended arbitrary minimum number of 10 studies analyzed , so we dThe main findings of this meta-analysis is that an elevated lipoprotein (a) level is an independent predictor of cardiac and cardiovascular events in CAD patients. These patients with the highest lipoprotein (a) level exhibited approximately 90 and 28% higher risk of cardiac and cardiovascular events, respectively, than those with the lowest lipoprotein (a) level. However, elevated baseline lipoprotein (a) level was not associated with an increased risk of cardiovascular and all-cause mortality in CAD patients.The results presented our study are quite consistent with those of previous meta-analysis  showed tOur subgroup analysis further supported the prognostic value of lipoprotein (a) level for predicting cardiovascular events. There was a close association between elevated lipoprotein(a) level and higher risk cardiovascular events in the subgroup with follow-up duration < 2 years in the current meta-analysis, suggesting that the prognostic value of lipoprotein (a) level weakened with the lengthening of the follow-up duration. Kardys’ study  also shoDespite attaining the target low-lipid profile, a number of CAD patients remain at risk for cardiovascular events . ElevateBoth life-style improvement and available lipid-lowering drugs seem to poorly affect blood levels of lipoprotein (a) , 33. MilThe mechanisms accounting for predictive value of lipoprotein (a) among CAD patients remain unclear. One potential explanation may be lipoprotein (a) mediating proinflammatory and antifibrinolytic effects . AnotherSeveral potential limitations of this meta-analysis should be acknowledged. First, this is not an individual-level meta-analysis and patients’ characteristics may have potential to affect the pooling results. Second, the cutoff value of elevated blood lipoprotein (a) level varied across studies and we could not define the appropriate cutoff value of lipoprotein (a) elevation. Third, moderate heterogeneity was observed in the pooling cardiac events and all-cause mortality. The heterogeneity may be partly explained by the subtype of CAD, study design, follow-up duration, methods for measuring lipoprotein (a), and cutoff value of lipoprotein(a) elevation. Fourth, due to insufficient data from the eligible studies, we failed to evaluate the prognostic role of lipoprotein (a) level by continuous data due to insufficient studies. Finally, we did not construct the funnel plot for detecting publication bias due to the analyzed studies was less than the recommended arbitrary minimum number of 10.The current meta-analysis indicates that elevated lipoprotein (a) level is an independent predictor of cardiac and cardiovascular events in CAD patients. As for lipoprotein(a) level is less affected by lifestyle, diet and medical therapy, measurement of lipoprotein (a) level has potential to improve the risk stratification CAD patients. Future well-designed studies are warranted to investigate whether the prognostic utility of lipoprotein(a) level is different subtype CAD patients.Additional file 1:Table S1. Quality assessment of the included studies (DOC 64 kb)Additional file 2:Table S2. Subgroup analyses on cardiovascular events (DOC 41 kb)


Antidepressants are the most commonly and widely used medication for its effectiveness in the treatment of anxiety and depression. A few epidemiological studies have documented that antidepressant is associated with increased risk of dementia so far. Here, our aim is to assess the association between antidepressant use and risk of dementia in elderly patients. We searched articles through MEDLINE, EMBASE, Google, and Google Scholar from inception to December 1, 2017, that reported on the association between antidepressant use and dementia risk. Data were collected from each study independently, and study duplication was checked by at least three senior researchers based on a standardized protocol. Summary relative risk (RR) with 95% CI was calculated by using a random-effects model. We selected 9 out of 754 unique abstracts for full-text review using our predetermined selection criteria, and 5 out of these 9 studies, comprising 53,955 participants, met all of our inclusion criteria. The overall pooled RR of dementia was 1.75 (95% CI: 1.033–2.964) for SSRIs whereas the overall pooled RR of dementia was 2.131 (95% CI: 1.427–3.184) for tricyclic use. Also, MAOIs showed a high rate of increase with significant heterogeneity. Our findings indicate that antidepressant use is significantly associated with an increased risk of developing dementia. Therefore, we suggest physicians to carefully prescribe antidepressants, especially in elder patients. Additionally, treatment should be stopped if any symptoms related to dementia are to be noticed. Dementia is a neurocognitive disorder characterized by cognitive impairment. As the life expectancy of people has been increasing, and the prevalence of dementia has been increasing dramatically , dementiAntidepressants are a commonly and widely used medication for its effectiveness in the treatment of anxiety and depression . DespiteUntil now, there is no particular meta-analysis on the association between antidepressant use and the risk of dementia among the elderly patients. We therefore conducted a meta-analysis of observational studies to evaluate the relationship between antidepressant use and dementia risk. Finding from our present meta-analysis would assist healthcare providers to improve treatment outcome and improve the existing knowledge about antidepressant therapy. In this meta-analysis, we only included studies that reported patients having exposure to antidepressants for at least one month and included patients' mean age more than 50 years.This meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA)  are experts in systematic review and meta-analysis regarding drug-disease and disease-disease associations. We searched for articles on the electronic databases such as PubMed, EMBASE, and Scopus until December 1, 2017, which reported on the possible association between antidepressant use and dementia risk. We used the following search terms as medical subject headlines and keywords: (“Anti-depressant drugs” OR “SSRIs” OR “Tricyclics (TCAs)” OR “Monoamine oxidase inhibitors (MAOIs”) And (“Dementia risk”)  they published as a letter to the editor, editorial, case study, and short communications; (2) patients had less than 30 days' antidepressant use; and (3) studies had a less than one-year follow-up period.were published in Englishreported an association between antidepressants and dementia riskhaving at least 50 participants in both treatment and control groupshaving results demonstrated on OR/HR with 95% CI.having a more than one-year follow-up periodidentified dementia patients with ICD-9/biochemical test or other standard procedureIn this stage, two authors (MMI and TNP) retrieved full-text articles and checked the duplication of included studies. We considered only those studies if they met the following criteria:However, they excluded those articles if they were not an observational study and if the participants are not patients with dementia due to antidepressants. If the study met all inclusion criteria at this stage, our two authors (MMI and TNP) further reviewed to ensure the quality of the final analysis. Any disagreements regarding quantitative information  between two authors (MMI and TNP) were resolved by our main supervisor (YCL) of this study. They also kept some studies for reference, if they provide valuable information regarding their associations.We finally included four studies, and those two authors then garnered information from each of these four studies. They collected the following information from four included studies: (a) author name and publication years; (b) study duration, study location, and study design; (c) condition information ; and (d) odds ratios/hazard ratios with 95% CI for summary calculation.The Newcastle-Ottawa Scale (NOS) was used to evaluate the methodological quality of included observational studies  with 95% CIs to assess the risk of dementia with antidepressants. Odds ratios are close approximations of RR. We therefore combined odds ratios with HRs, resulting in a common estimate of RR . A risk I2 statistic, and its significance was determined based on the accompanying P value in Cochran's Q test. If the I2 value is 0%, it indicates no heterogeneity, and increasing values represent greater amounts of heterogeneity. The I2 values of 25%, 50%, and 75% were considered as low, moderate, and high levels of heterogeneity. However, τ2 values arising from the random-effects models were also used to quantify heterogeneity.A random-effects model was used to reduce the heterogeneity among the studies. We used comprehensive meta-analysis package (Version 3) to draw forest plots and subgroup estimation. The meta-analysis of proportion uses the binominal distribution for analysis. We quantified heterogeneity of the studies using the A total of 754 records were identified through our initial database search. Of those, 745 studies were excluded based on our predetermined inclusion and exclusion criteria. We described full details in method parts. We reassessed the full text of the remaining 9 articles. Finally, 5 studies met all our inclusion criteria and were included in the final meta-analysis. A flow chart showing the study selection is presented in The characteristics of the selected studies are presented in The Newcastle-Ottawa Scale (NOS) was used to assessed the methodological quality of included observational studies. The mean value for the five studies was 7.8 .I2 = 98.553, tau2 = 0.34)  use and development of dementia. SSRI use is significantly associated with an increased risk of dementia when compared with nonuse. The overall pooled increase of dementia in patients with SSRI use was RR 1.75 (95% CI: 1.033–2.964) with significant heterogeneity present ( = 0.34) .I2 = 96.393, tau2 = 0.378) among studies.Four studies provided the risk estimation of tricyclic (TCA) use and dementia risk. The pooled RR for dementia risk was 2.131 (95% CI: 1.427–3.184) with the patients with TCAs . There wI2 = 80.019, tau2 = 0.382)  therapy and risk of dementia. The overall pooled increase of dementia in patients with MAOI use was RR 2.791 (95% CI: 1.086–7.169) with significant heterogeneity present (= 0.382) .Lee et al.  evaluateP value = 0.79).In our study, we showed the visual interpretation and test for asymmetry of the funnel plot of the publications. However, it is well established that the test of asymmetry will not be reliable when the included study number is not substantial .  FigureThis current meta-analysis of observational epidemiological studies suggests that use of antidepressants increased a risk of developing dementia among the elderly population when compared with nonusers. Patients with monoamine oxidase inhibitor therapy had a higher risk of developing dementia than those with tricyclic and selective serotonin reuptake inhibitor therapy. Of importance, these findings would make physicians more cautious when they will consider an antidepressant treatment to their patients with depression. However, the decision to prescribe antidepressant therapy should be made in the light of the stringent clinical evaluation of benefits and risks, more particularly when physicians will prescribe antidepressants to a patient with depression. If antidepressant therapy is needed, it should be used judiciously and for the shorter period of time. Additionally, healthcare providers should routinely monitor the symptom of dementia risk factors such as memory loss, confusion, and disorientation while initiating or rewriting antidepressants to patients.ɛ4 is a major known genetic risk factor that synergistically interacts with depression. Their interaction enhances the possibility of dementia risk, but it is not still well established [The biological mechanisms of the association between antidepressants and risk of developing dementia are still unclear. However, there are various possible ways of explanations for their association. First, the onset of depression before 65 years' age might be linked to the development of dementia and more recent depressive symptoms might link to the prodromal phase of dementia , 21. Sevablished , 23. Secablished . Third, ablished . FurtherOur study has several strengths. First, there is an enhanced statistical power to evaluate any association between antidepressant use and dementia risk. Second, this study evaluates the association in great detail and showed an association of different categories of antidepressants. However, our study has several limitations that need to be addressed. First, we included a small number of studies in our analysis. Second, a meta-analysis of epidemiological studies always has some unmeasured or uncontrolled confounding factors from the original studies. Our study findings had some degree of heterogeneity even though we used a random-effects model in our study analysis that helps to reduce publication bias. Third, we did not provide any information regarding dose differential and risk of dementia due to an insufficient amount of information. Fourth, duration of antidepressant and dementia risk were not evaluated because of restrained data. Fifth, types of dementia risk with antidepressant use were not investigated due to lack of information. Sixth, females are more prevalent to depression and anxiety than males are, and females act differently in the metabolism and distribution of antidepressants , 27, butTill now, no particular treatments are available to improve cognitive and behavioral symptoms of dementia patients. Additionally, antidepressant prescription has been increasing and concerns have been increased due to antidepressant therapy. Therefore, treatment of depression patients with antidepressant therapy should be assessed on a timely basis to reduce any unfavorable effects. If any symptoms are observed, then physicians need to stop antidepressant therapy or treat patients with a low dosage or shorter period of time. It is also indispensable to inform patients or their family about the inauspicious consequence of antidepressant therapy and other treatment options available for their current physical condition. However, to ensure safe and effective treatment, it is high time to provide proper guidelines for patients and healthcare providers.Since our study summarized results from several epidemiological studies, this is why we acknowledge that findings from this study could not clarify whether the observed association between antidepressants and dementia risk is the causal effect or other unmeasured confounding variables . Hence, To our knowledge, this meta-analysis shows the most rigorous and precise analysis regarding antidepressant use and the risk of dementia. Our findings showed a significantly increased risk of dementia with antidepressant therapy. Healthcare providers might preferentially avoid unnecessary prescription of antidepressants to the patients if any symptoms regarding dementia are noticed. Additionally, proper guidelines should be provided for quality and safety treatment.


The association between BIN1 rs744373 variant and Alzheimer’s disease (AD) had been identified by genome-wide association studies (GWASs) as well as candidate gene studies in Caucasian populations. But in East Asian populations, both positive and negative results had been identified by association studies. Considering the smaller sample sizes of the studies in East Asian, we believe that the results did not have enough statistical power.P = 5 × 10− 07, odds ratio (OR) = 1.12, and 95% confidence interval (CI) 1.07–1.17) and in Caucasian populations . But in the East Asian populations, the association was not identified . Besides, the regression analysis suggested no significant publication bias. The results for sensitivity analysis as well as meta-analysis under the dominant model and recessive model remained consistent, which demonstrated the reliability of our finding.We conducted a meta-analysis with 71,168 samples . Based on the additive model, we observed significant genetic heterogeneities in pooled populations as well as Caucasians and East Asians. We identified a significant association between rs744373 polymorphism with AD in pooled populations (The large-scale meta-analysis highlighted the significant association between rs744373 polymorphism and AD risk in Caucasian populations but not in the East Asian populations. Alzheimer’s disease (AD) is the preeminent cause for dementia in the elderly and causes 50–75% dementia types –3. In thP = 3.16 × 10 − 10 [P = 2.6 × 10 − 14 [P = 2.13 × 10 − 09 [P = 2.9 × 10 − 07 [P = 1.1 × 10 − 04 [P = 0.217) and genotype test  [P = 0.038), but not southwest China (P = 0.874). When combining the two parts of populations, they still did not identify any significant association (P = 0.187) [P = 0.660 for dominant model and P = 0.547 for recessive model) [P = 0.06 for additive model) when analyzed 825 AD cases and 2934 controls from Japan [P = 1.19 × 10 − 02, 7.08 × 10 − 03 and 5.75 × 10 − 03 for the dominant model, recessive model and additive model) [Rs744373 is a single nucleotide polymorphism (SNP) that locates upstream of BIN1 gene. In populations of Caucasian ancestry, rs744373 polymorphism was consistently confirmed to be significantly associated with AD risk with  10 − 10 , P = 2.6 10 − 09 , P = 2.9 10 − 07  and P =  10 − 04 . Recentl models) . The res= 0.187) . In Braze model) . Ohara ee model) . AnotherGiven the inconsistent findings in East Asian populations, we believe that the relatively small sample sizes, as well as the genetic heterogeneity of AD susceptibility loci among different populations, may be important factors in the untrustworthiness of the results. In this study, we aimed to collect more studies and samples than before and obtain more statistically significant results by performing genetic heterogeneity test and meta-analysis of the rs744373 polymorphism in the Caucasians, East Asians, and pooled populations.https://www.ncbi.nlm.nih.gov/pubmed) and AlzGene database  with the Keywords “Alzheimer’s disease”, “Bridging Integrator 1” or “BIN1”. We also searched Google Scholar (http://scholar.google.com/) to acquire the articles citing the studies obtained in the PubMed and AlzGene databases. The literature acquisition was updated on December 12, 2017. In addition, we collected as much data as we could by directly contacting with authors. These datasets were not published due to not significant results, etc., and were not included in the previous meta-analysis of rs744373 polymorphism with AD.In order to find all available association studies, we searched the PubMed database  being a case-control study; (2) investigating the association between rs744373 polymorphism and AD; (3) being conducted in East Asian or Caucasian populations; (4) providing the numbers of rs744373 genotypes or sufficient data to calculate them or (5) providing an OR with 95% confidence interval (CI) and the The information was extracted from each study contained: (1) author names; (2) publication year; (3) the sample’s ethnicity; (4) the numbers of cases and controls; (5) the genotyping platform; (6) the frequencies of rs744373 genotypes or sufficient data to calculate them or (7) the OR with 95% CI or sufficient data to calculate them.Since not all studies provided exact genotype numbers, we investigated the association between rs744373 polymorphism and AD risk in this meta-analysis primarily using the additive genetic model. We selected allele C as effect allele and T as reference allele, the additive model can be described as C allele versus T allele .http://www.r-project.org/) to perform the t-test and calculate the OR and MAF values that not available in the original articles.We compared the minor allele frequency (MAF), which is the frequency of rs744373 allele C in this study, and the OR values between the Caucasian populations and East Asian populations. We used the t-test to investigate whether there were differences in the OR values and MAF values between these two populations. We used program R (k-1 (k represents the number of studies included in this studies). Statistics I2 can also use to measure the genetic heterogeneity, which is calculated as:We used the Cochran’s Q test to investigate genetic heterogeneity among different studies. Cochran’s Q test approximately follows a chi-square distribution and its degree of freedom is I2 is in the range of 0–100%, and we divided it into four parts: 0–25%, 26–50%, 51–75%, 76–100%, which respectively represent low, moderate, large and extreme heterogeneity [P-value and I2 value were completed using the program R (http://www.r-project.org/). We choose P < 0.05 or I2 > 50% as discriminant criterion for significant result of heterogeneity test.The statistics ogeneity . We condP-value of Cochran’s Q test was less than 0.05, and I2 value was greater than 50%, we selected the random effect model, otherwise we selected the fixed effect model. The signification of overall OR was measured by Z test.In the meta-analysis, we used fixed effect model (Mantel–Haenszel) or random effect model (DerSimonian–Laird) to calculate the overall OR. And which model to choose depends on whether the genetic heterogeneity is significant or not. If the http://www.r-project.org/).To further test the stability of our results, we conducted a sensitivity analysis by sequentially removing each study in the meta-analysis at a time. We used funnel plots to evaluate the potential publication bias. A symmetrical inverted funnel indicated the results were no bias, and an asymmetrical inverted funnel indicated bias results . Begg’s We obtained 126 articles by searching the PubMed database. Eighty-eight articles were excluded because they were (1) not Case-Control design, (2) not analyzed in East Asian or Caucasian populations, (3) not related with AD, (4) meta-analysis or (5) review articles. We further excluded 24 articles because they did not investigate the association between rs744373 polymorphism and AD or not provide sufficient data. The remaining 14 articles met the analysis requirements. According to the same criteria, we also obtained two articles from the AlzGene database. In addition, we had found one article by searching Google Scholar. We applied for two datasets of two articles (studies) by contacting the author directly. Finally, 37 studies in 19 articles, including 22,395 AD cases and 48,773 control samples, were included in this meta-analysis. More detailed information about selecting studies was described in Fig. t = 5.89 and P = 1.53 × 10− 6. However, the result of comparison of OR values did not indicate a very significant distinction between the two populations (t = 1.75 and P = 0.11).There were 11 studies belong to East Asian populations. The MAF values of rs744373, OR values and other information of these 11 studies listed in the top 11 rows in Table P = 0.001, I2 = 52.3%), East Asians  and pooled populations . Detailed results were described in Table We conducted heterogeneity test of rs744373 polymorphism in different populations, and identified significant genetic heterogeneity in Caucasians . Funnel diagram was described in Fig. Using sensitivity analysis, we identified that the results of meta-analysis remained largely unchanged by excluding any one study Table . The symGWASs showed that SNPs located in upstream of BIN1, particular rs744373, are strongly associated with AD risk . The expBased on the significant association between rs744373 polymorphism and AD risk identified by the GWASs in Caucasian populations, many recent studies had also explored this association in East Asian populations, as described in the introduction. However, the findings of the association studies in East Asian were always inconsistent. Considering a relatively small sample size may result in less statistical power, we collected 37 studies involving 22,395 AD cases and 48,773 controls for the meta-analysis. To the best of our knowledge, this was the largest sample size by far.P = 5 × 10− 07, OR = 1.12, and 95% CI 1.07–1.17) and also in Caucasian populations . The results were consistent with the previous studies. However, in East Asian populations, our results showed a significant genetic heterogeneity of rs744373 polymorphism  and the meta-analysis did not show a significant association between rs744373 polymorphism with AD risk by using a random effect model . The insignificant publication bias results and the consistent sensitivity analysis results showed that our results were reliable.By meta-analysis of the 37 studies, we obtained significant association between rs744373 polymorphism and AD risk in pooled populations , as well as in Caucasian populations . We also obtained negative results in East Asian populations . The consistent results among the three kinds of genetic models demonstrated the reliability of our results. The data was described in Additional file To confirm the findings that were obtained by additive genetic model, we further used the dominant model (CC + CT versus TT) and recessive model (CC versus CT + TT) to investigate the association of rs744373 polymorphism with AD risk based on genotype data of 33,184 samples . As same as the results of additive model, we obtained significant association between rs744373 and AD in pooled populations . The meta-analysis results under the additive, dominant and recessive model indicated a significant association between rs744373 and AD risk in Caucasian populations but not in East Asian populations. The consistent results of sensitivity analysis, as well as the negative results of publication bias analysis, demonstrated the reliability of our findings. We believe that the greater statistically powerful results are helpful for the understanding of AD genetic risk factors in East Asian populations.Additional file 1. Meta-analysis under dominant and recessive model. Table S1. The selected studies investigating the association between rs744373 and AD using dominant model and recessive model Figure S1. Funnel plot of the publication bias analysis under dominant model. Figure S2. Funnel plot of the publication bias analysis under recessive model.


I2 statistic. Overall, eight studies were included in the systematic review; all of the eight studies provided data for NFS, while four provided data for APRI and FIB-4. When comparing the risk estimates for high (>0.676) vs. intermediate + low NFS (≤0.676), we found a nearly fourfold increase in mortality risk, with evidence of heterogeneity . At dose-response meta-analysis, compared to the midpoint of the lowest category of NFS (−2.5), the risk of mortality was about twofold higher for NFS = −0.5  and more than fivefold higher for NFS = 1.5 . When comparing the risk estimates for high (>1.5) vs. medium + low APRI (≤1.5), we found a higher risk of mortality, without heterogeneity . Comparison of the risk estimates for high (>2.67) vs. medium + low FIB-4 (≤2.67) didn’t reveal a significantly higher risk of mortality, with heterogeneity . Dose-response analysis for APRI and FIB-4 was not considered conclusive due to the low number of studies. Based on the results of our meta-analysis, the measurement of NFS can be considered an accurate tool for the stratification of the risk of death in patients with NAFLD.Noninvasive simple scores have been validated to assess advanced liver fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). We performed a systematic review with meta-analysis evaluating if NAFLD fibrosis score (NFS), AST to platelet ratio index (APRI), and Fibrosis-4 (FIB-4) score may also predict mortality. PubMed and EMBASE databases were searched until April 2018. Random-effects models were used to calculate pooled RRs of mortality for highest vs. lowest categories of exposure and to perform dose-response meta-analysis. Heterogeneity was assessed using the Q test and  Nonalcoholic fatty liver disease (NAFLD) has become a major health problem worldwide because of its potential to evolve into cirrhosis and hepatocellular carcinoma (HCC) . Epidemihttp://nafldscore.com/) has shown a good performance for detecting advanced fibrosis and cirrhosis [In the last decade, different noninvasive blood-based and imaging-based biomarkers have been developed and validated for the assessment of liver fibrosis in patients with NAFLD ,6. Simplirrhosis . Excludiirrhosis . Besides prediction of clinically significant fibrosis, in the last five years, retrospective and prospective studies have evaluated the predictive value of simple scores of fibrosis for clinically relevant outcomes such as liver events/transplantation and general mortality ,14,15,16We followed the PRISMA  checklist  for tranUsing a standardized extraction form, data were abstracted from all identified studies. The following information was obtained from each article: (1) first author name; (2) year of publication; (3) study design; (4) country; (5) name or type of cohort; (6) age range of the study population at baseline; (7) tool used for NAFLD diagnosis; (8) follow-up period; (9) number of cases; (10) dose for each category of exposure; (11) relative risks or hazard ratios, with 95% CI; (12) covariates used in adjustments. I2 statistic. The significance for the Q test was defined as p < 0.10. The I2 statistic represents the sum of total variation that could be attributed to heterogeneity. I2 values ≤ 25%, 25–50%, 50–75% and >75% indicated no, small, moderate, and high heterogeneity, respectively. A sensitivity analysis, where possible, was conducted by excluding one study at the time to assess the stability of results. Subgroup analyses were conducted by study design, geographical location, tool used for NAFLD diagnosis, and adjustment for confounding factors. Publication bias was assessed by visual observation of funnel plot  of mortality for highest vs. lowest categories of exposure and for dose-response analysis  Supplem. Heterognel plot . All anaThe search identified 1254 studies, of which 1037 were excluded after reviewing the title, and 202 after reviewing the abstract . Of the For the systematic review on the association between noninvasive scores of fibrosis and mortality in NAFLD patients, eight studies were eligible ,14,15,16Briefly, 4 studies were prospective cohorts ,14,15,16I2 = 92%), with evidence of heterogeneity (I2 = 87%)  , Panel BI2 = 41%, Pheterogeneity = 0.15). The subgroup analysis showed a stronger positive association for the studies that included cases diagnosed using liver biopsy , studies with retrospective design , and studies that adjusted for confounding factors , with evidence of lower heterogeneity   , Panel AI2 = 0%)  , Panel BI2 = 85%, p = 0.009) (I2 = 88%)  , Panel A2 = 88%) , Panel BDose-response meta-analysis of risk estimates was possible only with data from Angulo et al.  for APRIIn this study, we meta-analyzed retrospective and prospective studies conducted so far, reporting data of association between values of NFS, APRI, and FIB-4 with mortality of patients with NAFLD. Our meta-analysis shows that an NFS > 0.676 is associated with about a fourfold higher risk of death as compared with a low or nonhigh value and NFS is associated with higher risk of mortality in a dose-response manner.Among studies included in this systematic review, the study by Kim et al.  was the milieu associated with liver steatosis and fibrosis.Sebastiani et al.  evaluateBesides simple scores, in the last years, several other noninvasive approaches to assess fibrosis in the daily clinical practice have been validated in NAFLD , includiIn conclusion, results from our meta-analysis suggest that the measurement of NFS can be considered an accurate tool for the stratification of the risk of death and thus should be routinely assessed as a screening test for fibrosis in NAFLD patients.


Osteoarthritis (OA) is a degenerative joint disease characterized by joint destruction with cartilage loss and occasional gross derangement of joint integrity. In recent years, several studies have reported the association between angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and knee OA. However, the results were conflicting. To determine the association between ACE gene I/D polymorphism and knee OA, we conducted a hospital-based case–control study with 282 knee OA cases and 316 controls to investigate the association between ACE gene I/D polymorphism and knee OA susceptibility in a Chinese Han population. The present study found that DD genotype or D allele carriers of ACE gene I/D polymorphism increased the risk of knee OA. Stratification analyses of sex, age, and body mass index (BMI) showed significant associations amongst the groups of females, ≥55 years, and abnormal BMI. In addition, the present study made analysis between ACE I/D polymorphism and some clinical features of OA, and found DD genotype of I/D polymorphism was associated with arthralgia. Furthermore, we undertook a meta-analysis together with the present study between this single nucleotide polymorphism (SNP) and knee OA risk. This meta-analysis found that ACE gene I/D polymorphism was associated with increased risk for OA. Stratification analysis of ethnicity in this meta-analysis indicated that I/D polymorphism increased the risk of knee OA amongst the Asians and Caucasians. In conclusion, this case–control study and meta-analysis suggest that ACE gene I/D polymorphism is associated with increased risk for knee OA. Osteoarthritis (OA) is a degenerative joint disorder resulting in destruction of articular cartilage, osteophyte formation, and subchondral bone sclerosis . OA is aAngiotensin-converting enzyme (ACE) gene is localized on chromosome 17 and contains a polymorphism based on the presence  or absence  within intron 16, of a 287-bp Alu repeat sequence within intron 16, resulting in three different genotypes: DD and II homozygous and ID heterozygous. Plasma ACE levels vary with polymorphism. The role of ACE polymorphism has been investigated as a risk factor for several diseases such as inflammatory and immune-related disorders [Several studies have investigated the relationship between OA and the ACE I/D polymorphism , but the2), and K-L grade were collected from medical records. This case–control study was approved by the Ethics Committee of Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College and performed according to Declaration of Helsinki. All patients provided written informed consent prior to participation.A hospital-based case–control design was used in the present study. A total of 282 knee OA patients and 316 healthy controls were selected from Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College between February 2014 and May 2017. The diagnosis of knee OA fulfilled the American College of Rheumatology criteria (1987) . InclusiPeripheral blood samples were taken from all patients and controls, and stored in EDTA tubes. DNA was extracted from blood examples using the QIAamp DNA Blood Mini Kit . The genotypes of ACE gene polymorphism were determined by PCR using primers and conditions described previously ,12. The 2) test to compare the observed and expected genotype frequencies amongst controls. Association between ACE gene I/D polymorphism and knee OA risk was assessed by logistic regression with odds ratio (OR) and 95% confidence interval (CI). χ2 test was used to assess the difference in the demographic characteristics, variables, and the genotypes of the ACE gene I/D polymorphism. Above statistical analyses were performed on SAS software package  with the significant level at P<0.05. To fully investigate the association of ACE gene I/D polymorphism with knee OA, we also conducted a meta-analysis which was performed using the Stata 11.0 software .Hardy–Weinberg equilibrium (HWE) of the SNP genotypes was analyzed by the goodness-of-fit chi-square , and no significant differences in gender and age were observed between the OA patients and controls. A significant association was found in the subgroup of BMI. In addition, disease severity in the knee OA cases and controls was assessed via the Kellgren-Lawrence grade (K-L grade). The controls and cases were concentrated in grade 0–4. Other characteristics of the subjects are presented in The characteristics of the subjects in the case and control groups are summarized in P=0.802). Logistic regression analyses revealed that the DD genotype or D allele carriers of I/D polymorphism was significantly associated with increased risk of knee OA  threshold. As shown in P=0.031; DD+ID compared with II: OR = 1.70, 95% CI = 1.11–2.60, P=0.016; DD compared with II: OR = 1.84, 95% CI = 1.02–3.30, P=0.041; ID compared with II: OR = 1.59, 95% CI = 1.11–2.27, P=0.010; Our meta-analysis indicated that ACE gene I/D polymorphism was associated with the increased risk for knee OA (D compared with I: OR = 1.39, 95% CI = 1.03–1.86, The present case–control study showed that the DD genotype or D carriers of I/D polymorphism was associated with significantly increased risk of knee OA in a Chinese Han population. Additionally, the present study obtained significant associations amongst the groups of females, ≥55 years, and abnormal BMI. Furthermore, the study found DD genotype of I/D polymorphism was associated with arthralgia. Using meta-analysis, we also found that ACE gene I/D polymorphism was associated with increased risk of OA. Similar results were replicated in the stratification analyses of ethnicity, HWE, SOC, and types of OA. In conclusion, this case–control study and meta-analysis found that ACE gene I/D polymorphism is associated with increased risk for knee OA.In previous studies, ACE gene was found associated with rheumatic and autoimmune diseases. OA is an inflammatory disorder, which is associated with these proinflammatory cytokines . AngioteSeveral studies investigated the association between ACE gene I/D polymorphism and OA risk. Hong et al.  found ACIn the subgroup analysis of ethnicity, we found that ACE gene I/D polymorphism increased OA risk amongst Asian and Caucasian populations. However, no significant associations were obtained in the meta-analysis by Lin et al. . In the Several potential limitations of this case–control study and meta-analysis should be considered. First, we cannot conduct the subgroups of some confounding factors due to the lack of corresponding data. Second, our results were based on unadjusted estimates for confounding factors. Third, the sample size of the present study was not large enough, which might make our work underpowered. Fourth, the sample sizes of Caucasians and Arabians were not large enough in this meta-analysis. Fifth, included studies were only involved in Asians, Caucasians, and Arabians, and studies amongst other racial groups are urgently needed. Sixth, the present study only focussed on one gene. Seventh, the present study with limited sample sizes could not provide sufficient evidence to draw a certain conclusion. Finally, we cannot conclude that I/D polymorphisms are susceptibility loci for other types of OA, highlighting the necessity for the further investigation of more types of OA.In conclusion, this case–control study and meta-analysis found that ACE gene I/D polymorphism is associated with increased risk for knee OA. Further multi-center, well-designed studies with larger sample sizes that include gene–environment interactions assessment are warranted to confirm our findings.


Recently extensive focus has been concentrated on the role of miRNAs in the initiation and progression of cardio-cerebrovascular diseases (CCDs) which constitute a range of conditions including cardiovascular diseases ), congenital heart disease (CHD) and cerebrovascular diseases ). An increasing number of studies are evaluating the association between different miRNA polymorphisms and risk of CCDs, but results have been inconclusive. This study represents a comprehensive systematic review and meta-analysis of the association between miRNA polymorphisms and risk of CCDs. PubMed, Embase, Scopus, and Web of Science were queried to identify eligible articles. Odds ratios and 95% confidence intervals were used to assess the association of miRNA polymorphisms with CCD susceptibility. A total of 51 eligible articles evaluating the association of 31 miRNA polymorphisms were identified. Meta-analysis was performed for six miRNA polymorphisms. miR-146a rs2910164 , miR-149 rs2292832 (Nine studies: 4116 cases/3511 controls), miR-149 rs71428439 (Three studies: 1556 cases/1567 controls), miR-196a2 rs11614913 , miR-218 rs11134527  were not associated with overall CCD. miR-499 rs3746444 was associated with CCD (20 studies: 9564 cases/8876 controls). In the subgroups, rs2910164 and rs3746444 were only associated with CVDs, especially CAD. In conclusion, the results support the existence of a role for miR-146a rs2910164 and miR-499 rs3746444 in determining susceptibility to CCDs, especially CAD. Cardio-cerebrovascular diseases (CCDs) consist of several clinically heterogeneous medical conditions which are among the leading causes of death worldwide. Despite significant recent developments in prevention, diagnosis and clinical management, cardiovascular diseases (CVDs) and cerebrovascular diseases (CBVDs) remain a major challenge imposing a heavy burden on healthcare systems. Among different clinical manifestations of CVD, coronary artery disease (CAD), which is characterized by significant stenosis in a major pericardial artery, is more prevalent and bears the larger burden. CBVD, a range of conditions influencing brain and cerebral arteries, represents a major source of morbidity and mortality ,2. A strIt has been shown that a range of environmental and genetic factors contribute to the risk of CCDs. Functional alteration of several protein coding genes has been linked to CCDs pathogenesis, but it was not until recently that an extensive focus has been concentrated on the role of noncoding RNAs, especially microRNAs (miRNAs), in the initiation and progression of CCDs. miRNAs are small endogenous regulatory RNAs involved in the post-transcriptional regulation of most protein coding genes. They regulate key cellular functions and most biological processes that are altered during the initiation and progression of CCDs. Studies have demonstrated that single nucleotide polymorphisms (SNPs) residing in miRNA genes may modulate biological functions of these regulatory molecules by altering their processing, expression, and/or targeting efficiency. Consequently, an increasing number of studies have evaluated the association between different miRNA polymorphisms and risk of CCDs, but results are inconclusive. This study represents a comprehensive systematic review and meta-analysis of the association between miRNA polymorphisms and CCDs.The process of selecting eligible studies is depicted in The meta-analysis was performed for the remaining six miRNA polymorphisms, including miR-146a rs2910164 , miR-149 rs2292832 , miR-149 rs71428439 , miR-196a2 rs11614913 , miR-218 rs11134527  and miR-499 rs3746444 . R2: 30.7%, test of moderators p: 0.02, residual I2: 58.0%, τ: 0.24, residual heterogeneity p < 0.01), the heterozygote , the dominant  and the allelic  contrasts.The significant association between study heterogeneity that was observed in the overall analysis  was presHWD (95% CI): 0.84 (0.67–1.06), p: 0.13, I2: 64.0, τ: 0.26; CAD ORHWD (95% CI): 0.82 (0.65–1.04), p: 0.09, I2: 64.9, τ: 0.26). No statistical evidence of funnel plot asymmetry was observed , were substantially reduced in most cases when analyses were subgrouped by the disease category or the disease type variable. Specifically, heterogeneity was low in all contrasts of the CAD, IS and CBVD subgroups (2 (τ) from 60.2 (0.23) to 37.2 (0.14)), the heterozygote (I2 (τ) from 41.2 (0.13) to 23.3 (0.08)), the dominant (I2 (τ) from 49.5 (0.14) to 19.6 (0.069)), the recessive (I2 (τ) from 60.3 (0.19) to 49.1 (0.15)) and the allelic (I2 (τ) from 59.6 (0.11) to 33.4 (0.063)) model. However, excluding this study had no dramatic impact on the pooled estimates and did not alter the results (OR (95% CI) homozygote: 1.06 (0.95–1.20), heterozygote: 1.04 (0.96–1.13), dominant: 1.05 (0.97–1.13), recessive: 1.04 (0.94–1.16), allelic: 1.04 (0.98–1.09)). Furthermore, no visual or statistical evidence of funnel plot asymmetry due to publication bias was observed : 1.41 (1.06–1.87), p: 0.02, τ: 0.42, I2: 59.7), the recessive : 1.35 (1.03–1.77), p: 0.03, τ: 0.40, I2: 57.7) and the allelic : 1.16 (1.03–1.30), p: 0.02, τ: 0.20, I2: 71.3) models. The lower 95% CI limit of the pooled estimates under the dominant contrast was close to the null value leading to a non-significant but borderline association under this model (RE (95% CI): 1.15 (0.99–1.32), p: 0.05, τ: 0.22, I2: 69.0).For this polymorphism, a total of 20 studies including 9564 cases and 8876 controls were included in the meta-analysis. The calculation of ORs and 95% CIs under the homozygote and recessive models was not possible for one study [2: 59.7), and, therefore, the random-effects model was used in these analyses. Subgrouping led to a reduction of heterogeneity in some but not all cases  model. Moreover, the Galbraith plot analysis revealed that the study by Zhou et al. [2 (τ) from 69.0 (0.22) to 57.2 (0.16)) and the heterozygote model (I2 (τ) from 67.7 (0.22) to 48.3 (0.14)). However, excluding this study had no significant influence on the conclusion of the meta-analysis under these models (dominant OR (95% CI): 1.1 (0.98–1.24), heterozygote OR (95% CI): 1.04 (0.94–1.16)).Statistically significant heterogeneities were present in the overall analyses, with the most heterogeneous contrast being the recessive model : 1.84 (1.24–2.73), p: 0.007, τ: 0.35, I2: 55.9), the recessive : 1.70 (1.15–2.50), p: 0.01, τ: 0.34, I2: 57.2) and the allele : 1.30 (1.04–1.62), p: 0.02, τ: 0.22, I2: 78.4) contrasts (RE (95% CI): 1.91 (1.19–3.07), p: 0.01, τ: 0.39, I2: 62.8) and the recessive : 1.82 (1.19–2.77), p: 0.01, τ: 0.34, I2: 57.3) models  models . The con) models . p value of the Harbord’s test for the heterozygote model , the arcsine test of funnel plot asymmetry was used for these contrasts. The Harbord’s test was used for other comparisons. No statistical evidence of asymmetry in the funnel plots was observed . HowevermiRNAs have attracted a great deal of global attention due to their role in regulating the functions of various cell types engaged in the development and pathogenesis of the cardio-cerebrovascular system. Therefore, it is not a surprise that molecular mechanisms governing their regulation can be functionally pertinent to the pathogenesis of CCDs. Among these mechanisms, the influence of polymorphisms on miRNA function and disease susceptibility has remained elusive and controversial irrespective of intensive research, meriting the need for systematic reviews and meta-analyses. This study performed a comprehensive systematic review and identified numerous studies that evaluated the association of miRNA polymorphisms and risk of CCDs. The results indicated that although several miRNA polymorphisms were evaluated for a possible association with risk of CCDs, there was a lack of sufficient data regarding most of these polymorphisms, and only a few polymorphisms were evaluated in more than three studies allowing the meta-analysis to be carried out. Therefore, for a great proportion of the identified miRNA polymorphisms that were assessed, in as few as just one study a definite conclusion cannot be drawn  [The locus for human miRNA-499 is located in an intronic region of the cardiac β-myosin heavy chain 7B gene (MYH7B) . This reMYH7B) ,74,75.MEF2C) at 3′-UTR [In some cases, miRNA-5p and -3p excised from the same precursor may target distinct transcripts . Co-exprt 3′-UTR . These oRs3746444 (GRCh38 chr20:34990448) overlaps both precursors, residing in the seed region of miR-499a-3p and the 3′ portion of miR-499b-5p. Although this polymorphism may potentially influence the structure and function of both miRNA precursors, currently there is insufficient data regarding its influence on miR-499b. It has been shown that the G allele can be correlated with lower miR-499a-5p expression in breast or lung tissues ,78. TheoTo identify all potentially eligible publications, Embase, PubMed, Web of Science, and Scopus databases were searched using following keywords with respect to specific search tips of each database.  AND (miRNA OR microRNA OR pre-miR OR miR) AND (“single nucleotide polymorphism” OR SNP OR variant OR variation OR polymorphism OR mutation OR locus).The last search was performed on 1 July 2018. References of review articles, meta-analyses, and other relevant articles were also screened to identify all potentially eligible articles. This meta-analysis was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement .Studies should meet the following criteria to be included: (1) Evaluation of genetic association between miRNA polymorphism and susceptibility to any cardio-cerebrovascular disease with a case-control design. The following ICD-10-CM codes were used: Ischemic heart diseases (I20–I25), other forms of heart disease (I30–I52 and Q20–Q26), cerebrovascular diseases (I60–I69); (2) availability of sufficient data for estimating odds ratio (OR) and its 95% confidence interval (95% CI). A minimum of three studies for each miRNA polymorphism should be met to include the polymorphism in the meta-analysis. Studies that met the following criteria were excluded: (1) Meta-analyses, review articles or abstracts; (2) duplicate publications; (3) studies on animals or cell-lines; (4) studies without a case-control design (5) studies that did not report genotype frequencies.Data were extracted from each eligible study and manually checked. Then, items were recorded for each eligible study: The first author, publication year, country, ethnicity, disease category, disease type, source of controls, miRNA name, polymorphism ID, genotyping method, genotype counts for each SNP and number of cases and controls recruited. The disease category was assigned to each study as cardiovascular (CVD), cerebrovascular (CBVD) or congenital heart disease (CHD) and the disease type was considered as either IS (ischemic stroke), CAD (coronary artery disease) or other diseases. p value of the Q test <0.05 or I2 > 50%), the random-effects (RE) model [p < 0.05 was considered significant). A univariate meta-regression was carried out to identify potential sources of heterogeneity. The Galbraith plot analysis was used to examine the heterogeneity [The Meta package for R was used to perform the meta-analysis . The assE) model  was usedE) model . The sigogeneity . Subgrouogeneity . A statiogeneity .p values were two-sided, and a p value < 0.05 was considered statistically significant. All statistical analyses were performed in R (version 3.3.1).In the absence of substantial heterogeneity , a weighted linear regression test utilizing efficient score and score variance proposed by Harbord et al.  was used


The human genome is an under-researched area of pre-operative risk stratification. Studies of genetic polymorphisms and their associations with acute post-operative complications in gastrointestinal surgery have reported statistically significant results, but have varied in methodology, genetic variations studied, and conclusions reached. To provide clarity, we conducted a systematic review and meta-analysis of single nucleotide polymorphisms and their association with post-operative complications after major gastrointestinal surgery.TNF-α-308, which had been assessed in three papers.We performed a literature search using Ovid MEDLINE and Web of Science databases. Studies were included if they investigated genetic polymorphisms and their associations with post-operative complications after major gastrointestinal surgery. We extracted clinical and genetic data from each paper and assessed for quality against the STrengthening the REporting of Genetic Association Studies (STREGA) guidelines. Odds ratios were presented, with 95% confidence intervals, to assess strengths of association. We conducted a meta-analysis on TNF-α-308, IL-10-819, PTGS2-765 and IFN-γ-874. There was significant variability in study quality and methodology. We conducted a meta-analysis on associations between the TNF-α-308 polymorphism and post-operative infection and report an OR of 1.18 (CI 0.27–5.21).Our search returned 68 papers, of which 5 were included after screening and full-text review. Twenty-two different single nucleotide polymorphisms (SNPs) were investigated in these studies. We found that all papers were genetic association studies, and had selected SNPs related to inflammation. The outcome investigated was most commonly post-operative infection, but also anastomotic leak and other non-infectious complications. Statistically significant associations were found for We found biologically plausible associations between SNPs involved in inflammation and post-operative infection, but the available data were too limited and of insufficient quality to reach definitive conclusions. Further work is needed, including genome-wide association studies (GWAS). Quantifying these risks accurately is ever more important as we face decisions to operate on a population that is increasingly older with significant co-morbidities.Gastrointestinal surgical pathology represents a growing challenge to healthcare systems around the world,11 However, these tools involve subjective judgement, and there is evidence that P-POSSUM scoring in particular overestimates risk.14 The genome’s contribution to post-operative complications is under-researched and may better explain variance which is unaccounted for by clinical assessment tools. For instance, there is convincing research linking genetic variation with the host response to sepsis and trauma, but there is limited work investigating this in surgery.18 Single nucleotide polymorphisms (SNPs) are the commonest form of genetic variation,19 and many have been linked to disease.20 For instance, polymorphisms associated with high TNF-α have been associated with sepsis.21TNF-α is a critical cytokine regulating acute inflammation via activation of immune cells, release of large amounts of inflammatory mediators, downstream signalling and endocrine effects.22Current perioperative risk management involves well-established tools such as P-POSSUM and ASA grades.23 with one group reporting three SNPs associated with post-operative myocardial infarction.24 There have been several genetic association studies taking a similar approach in gastrointestinal surgery, which have aimed to identify whether particular polymorphisms are associated with poor outcome. These studies are challenging to interpret and were limited by small sample sizes, incomplete reporting of results, population stratification and implausible effects of individual SNPs, amongst others. To our knowledge, this is the first review examining these publications in a systematic manner. Such work may identify high-risk genes, which if externally validated as part of a clinical tool, could allow clinicians to offer improved risk prediction as part of the increasingly affordable ambition of personalised medicine. Addressing these risks perioperatively, with prehabilitation for example, could reduce future surgical morbidity and mortality.The association between particular SNPs and risk of developing post-operative complications has been explored in cardiac surgery,To systematically review studies in patients who have undergone major gastrointestinal surgery, and whether any single nucleotide polymorphisms are associated with post-operative complications.25 in preparing this review and registered with the international prospective register of systematic reviews, PROSPERO (CRD42019122342) on 15 February 2019.26We followed the guidelines of the PRISMA statementWe searched the electronic databases MEDLINE (using the Ovid platform) and Web of Science for papers published from January 1990 to January 2019. The following free-text terms were used: “surgical procedures”, “gastrointestinal surgery”, “genetic polymorphism”, “single nucleotide polymorphism”, “post-operative complications” and “post-operative outcomes”. For MEDLINE searches, we used the MeSH terms “digestive system surgical procedures” AND “polymorphism, genetic” AND “postoperative complications”. Searches involving MeSH terms included index subheadings. We also reviewed reference lists of both identified articles and review articles for additional relevant studies. We did not have any language restrictions.Studies were independently screened by title and abstract by JB and SL. Both authors subsequently performed full-text review. Any disagreement was resolved by discussion with a third author. We considered a study for inclusion if it met the following criteria: (1) patients underwent major oesophagogastric, hepatobiliary and colorectal resections (elective or emergency), (2) the variation studied was a single nucleotide polymorphism, and (3) post-operative complications were investigated in the 90-day post-operative period. We excluded studies in less major operations, including cholecystectomy, appendectomy and hernia repair. We also excluded outcomes which were not strictly complications, such as analgesic requirement and risk of cancer recurrence. Participants with particular conditions including inflammatory bowel disease, transplant patients and immunocompromised individuals were also excluded.For each eligible study after full-text review, we extracted year of publication, study population, sample size, patient demographics, post-operative outcomes, outcome measure, statistical analyses and statistic presented. Genetic information extracted included frequency of alleles, SNPs of interest, SNP reference identifier (where published), genotype method and locus.27Each study was assessed for quality using the STrengthening the REporting of Genetic Association Studies (STREGA) addendum to the Strengthening Reporting of Observational Studies (STROBE) statement.28 Our p value threshold for Hardy-Weinberg equilibrium was 0.05. If the included studies demonstrated significant heterogeneity, a random effects model was applied. Heterogeneity was assessed with a I2 statistic with values of 25% considered low, 50% moderate and 75% high. Egger’s test assessed for publication bias.Where multiple studies (defined as ≥ 3) reported on the same SNP, a meta-analysis was conducted. The analysis, as well as tests of heterogeneity, and Hardy-Weinberg calculations were performed using the MetaGenyo: Meta-Analysis of Genetic Association Studies tool.30 and one paper excluded for participants who had undergone transplant surgery.31 A further three were excluded due to reporting non-SNP sources of genetic variation, such as insertion/deletion (indel) polymorphisms,34 and four for reporting outcomes which were not of interest.38 This resulted in five remaining studies.43Sixty-eight studies were identified through electronic searches of databases Fig. , and one42 the remainder were Irish,39 Indian40 and Dutch.43 All broadly used a case-control design and all secured ethical review. The vast majority of SNPs examined were from genes involved in inflammation. Two papers also measured pro-inflammatory cytokine levels.42 One of the papers looked predominantly at mouse anastomotic leakage but reported the results of a small SNP analysis in humans.43 Samples sizes ranged from 110 to 239 patients. The number of SNPs examined per study ranged from 1 to 15. Every study reported statistically significant findings. Three of the studies investigated solely infection as the primary outcome,42 whilst one a broad range of complications39 and one examined anastomotic leak.43 Three studies were in patients undergoing oesophagectomies,42 one in colectomies43 and one study examined a broad range of gastrointestinal surgical procedures.40Table 43 Most papers did not use a standardised method of defining the SNP of interest (such as rs number). Although most papers used accepted definitions of surgical operations, one study used a broad definition of major gastrointestinal surgery and did not specify the precise procedures undertaken.40 One paper failed to report participant details such as age, gender or ethnicity.43 One paper did not report a full breakdown of genotype distributions.42 Two of the studies examined the same SNPs but came to opposite conclusions.40 There was highly variable reporting of laboratory methods of genetic analysis.Methodological quality was highly variable. Most papers did not explain how their sample sizes were calculated. Two papers failed to report on Hardy-Weinberg equilibrium.42 and one paper found an positive association with anastomotic leak.43 One of the papers examined, but did not find, a link with non-infectious complications.41All five papers examined polymorphisms associated with inflammation, as illustrated in Table TNF-α-308, IL-10-819, PTGS2-765 and IFN-γ-874  on infection post-operatively41  reported an odds ratio of 1.18 (CI 0.27–5.21), p = 0.281, as shown in Table I2 value of over 80% and Egger’s test p = 0.96. In both comparison models, the meta-analysis failed to demonstrate any significant association between the polymorphism and infectious outcome. Two of the papers came to opposite conclusions about the role of the allele.40Three studies examined the effect of 8 rs180069 on infeTNF-α-308. This polymorphism is involved in production of TNF-α, pro-inflammatory cytokine. Our meta-analysis examined the SNP in the context of gastrointestinal surgery. One study reported patients with the TNF-α-308 GG genotype had fourfold higher odds of a post-operative infection: OR 4.2 (CI 1.7–10.5),39 whilst another reported that it was the AA genotype which was associated with infection with OR 4.17 (CI 1.5–11.48).40 We can compare this with the results of a previous meta-analysis which examined TNF-α-308 in sepsis more generally. This found a much more conservative effect size with OR = 1.32 (p < 0.001) in the A vs G allele model in a much larger data set (n = 9373).45 The differing results could conceivably be explained by statistical error, for the reasons outlined below.This review found that research examining SNPs and post-operative complications has focussed almost exclusively on immunity and infection as clinical outcomes. We identified four polymorphisms of immune cytokine genes were associated with post-operative complications. We also conducted a meta-analysis of the only SNP which was examined by three or more studies, We found that the variety of SNPs identified have not been researched in an organised fashion. Despite the number of SNPs examined (22), there was little overlap between papers in terms of which SNPs were studied. There was poor consistency between findings and results were not replicated. These findings are thus highly vulnerable to type 1 and 2 error. The problem is compounded by the very small size of relevant published research. We only identified five relevant papers in total, and only three which examined non-infectious complications. As Table 46 Results suitable for extensive meta-analysis are essential in genetic association studies but only a minority of positive gene-association results are ever reproducible.48 Large, well-powered samples are required to examine the effect of single polymorphisms on complex multifactorial outcomes,49 particularly when the true effect size may be small. The evidence presented here shows that further meta-analysis is essential because of small sample sizes, but also challenging because too few papers examined the same SNPs.Our work has demonstrated highly variable outcome measures, populations, genotyping methods and conclusions. These methodological issues are common in genetic epidemiology.The scattershot approach taken in the existing literature is unlikely to yield meaningful results. These papers have all been genetic association studies with SNPs pre-selected. This makes the findings vulnerable to confirmation bias.50 It involves a broad range of pro- and anti- inflammatory signals with mediation at the organ, tissue, cellular and molecular levels.52Despite the difficulties we have highlighted, it is biologically plausible that genetic variation leading to a dysregulated immune system could result in post-operative infection or sepsis. Sepsis is a complex entity involving aberrant host responses to an infectious pathogen.TNF-α is a cytokine and pyrogen with a multitude of complex inflammatory effects, produced predominantly by macrophages but also by B and T lymphocytes.54 It induces downstream inflammatory pathways via nuclear factor κΒ activation and arachidonic acid formation.55 It has a synergistic effect with IL-1β and also has roles in apoptotic cell death, macrophage differentiation, IL-6 induction, fibroblast production, B cell proliferation and direct antiviral activity.53 It is also thought to have both pro- and anti-inflammatory roles depending on the phase of the acute insult.55 The TNF-α-308 functional polymorphism has been shown to correlate with variability in TNF cytokine production,56 and individuals who are genetically predisposed to over-express TNF-α suffer more pronounced inflammatory reactions.55 This would be consistent with published meta-analyses linking TNF-α polymorphisms to sepsis generally.45Despite the promising explanatory framework for why a cytokine polymorphism may contribute to post-operative complications, our work shows that the existing data in major gastrointestinal surgery are not clear or strong enough to draw clinically meaningful conclusions at present.There are no genome-wide association studies (GWAS) published in this area. We suggest that an efficient route for answers would be for this type of study to be performed in the first instance, identifying candidate SNPs. These could then be tested in multiple large-scale genetic association studies, which could subsequently be meta-analysed.JB contributed to acquisition and analysis of data, the design and concept of the work, and drafted the manuscript. AH contributed to the conception, analysis and revisions of the work. LA, JH and BK contributed to analysis, interpretation and revisions of the work. SL contributed to the conception, acquisition, analysis and interpretation of data and revisions of the work. All authors approve of the final version of the manuscript.


CYP4V2 polymorphism (rs13146272) as a risk factor associated with venous thromboembolism (VTE). However, due to the small sample size and variance in genetic analysis models, the relationship between VTE and rs13146272 remains unclear. Here, we performed a case–control study to analyse the associations between rs13146272 and VTE in a Chinese population and to compare the differences among various ethnicities. In this study, 226 VTE patients and 205 healthy controls were recruited, and the allele frequency of variant rs13146272 was analysed by a MassARRAY SNP genotyping assay. In addition, 9 case–control cohorts from 5 studies involving 6667 VTE-affected individuals and 8716 control subjects were included in this meta-analysis. Pooled ORs and 95% CIs were calculated to assess the association between rs13146272 and VTE by using different genetic models. Our case–control study results showed that there was no significant association between VTE and rs13146272 under the additive model  in this Chinese population. However, the results of the meta-analysis performed by merging all cohorts showed that rs13146272 was significantly associated with VTE under the additive model, recessive model and dominant model. In the additive and recessive models, the association reached the threshold for genome-wide significance (p < 5.0e−08). In conclusion, our pooled systematic study results indicated that individuals with the A allele had a higher risk of developing VTE than those with the C allele of the rs13146272 variant, but the risk was inconsistent among different ethnicities. Further validation of this association with larger sample sizes and multiple ethnicities is warranted.Genome-wide association studies have identified the  Venous thromboembolism (VTE) is a complex and multi-factorial thrombotic disorder that includes deep venous thrombosis (DVT) and pulmonary embolism (PTE). VTE is a common cause of morbidity and mortality in adult patients. The incidence of VTE exceeds 1 per 1000 in Caucasians; the incidence among Africans and Asians may be lower and higher, respectively . Among aFactor V Leiden, FII (G20210A) and MTHFR (C677T)  OR rs13146272 [All Fields]). The same keywords were also used for the searches at the other databases. Articles published in English or Chinese with English abstracts were included in the meta-analysis.A comprehensive literature search for suitable studies published up to March 2018 was conducted in PubMed, Science Direct, ISI Web of Knowledge, Google scholar and the Chinese database CNKI. Search terms using the Boolean operator in PubMed included but were not limited to the following: (“venous thrombosis” [MeSH Terms] OR VTE[All Fields]) AND (The criteria for including eligible studies were (1) the DVT or PE should be diagnosed with standard criteria in the case group; (2) studies should explore the association between rs13146272 and VTE; (3) variant genotype frequency should be examined with case–control groups. For exclusion, reviews, conference abstracts, republished or duplicate studies and meta-analyses were not considered eligible. We included only the largest data set when more than one study demonstrated the same case–control group of the variant genotype. Animal studies and studies without sufficient variant genotype data were also excluded.The following information was extracted from each eligible study: name of the first authors, year of publication, name of study cohorts, ethnicity, genotype methods and distribution of variants. The validity of data was evaluated by two independent reviewers (YY & QS), and discrepancies were resolved by a third reviewer (YF). If the genotype data of the variants were not complete or available in the eligible publications, the first or corresponding author of the studies was contacted to send their datasets via email. The genotype data of publications were excluded if polymorphic variants in the control population did not follow the Hardy–Weinberg equilibrium (HWE).z test was used to evaluate the significance of the pooled OR, and p < 0.05 was considered statistically significant. Three genetic models, the additive model, dominant model and recessive model, were used to assess the association between the variant and VTE [I2 statistic, and p < 0.05 was considered statistically significant. I2 < 50% indicated a low heterogeneity level, and a fixed-effects model was used to evaluate the effect. I2 ≥ 50% indicated high heterogeneity, and a random-effects model was used for the analysis [p < 0.05 was considered statistically significant. Sensitivity analysis was conducted by omitting one study from the pooled studies at each time point. Differences in age between the VTE and control groups were assessed by Student’s t test. The Chi-square test was performed to compare categorical variables.All statistical analyses were performed using STATA 14.0  and SPSS 19  software. The OR and 95% CIs were measured to evaluate the strength of the association by a fixed-effects model (Mantel–Haenszel method) or random-effects model. The  and VTE . Heteroganalysis . Egger’sanalysis , 29, andp < 0.05). Because some patients refused to participate in all clinical examinations, only the known clinical risk factors, including hypertension, diabetes, cancer and cardiovascular disease, are presented in Table CYP4V2 polymorphism (rs13146272) in VTE patients and controls are summarized in Table The general characteristics of the VTE patients and healthy controls are presented in Table rphism rs3146272 ip = 0.55), recessive model  or dominant model . The models for genetic analysis showed that the CYP4V2 polymorphism (rs13146272) was not statistically significantly associated with an increased risk of VTE in this Chinese population.In our case–control study, the CC genotype  was found in 48.6% of patients, which was much higher than the value in previous reports (approximately 15%) . The genotype distribution and allelic frequencies of all eligible studies are presented in Table In the present study, we included 9 case–control cohorts from 5 studies with 6667 VTE-affected individuals and 8716 control subjects for the meta-analysis. The genotype data were kindly shared by the author (Pierre-Emmanuel Morange), and the genotype data were not included in the analyses of previous publications . The sumI2 < 25% and p > 0.05, which indicates that our studies have very low heterogeneity. Thus, we used a fixed model for further analysis. The association effect distribution is presented in forest plots , was 1.23 the dominant model  and was 1.21 the recessive model . The association effects among rs13146272 and VTE for all genetic models are shown in Table Meta-analysis was performed in conformity with the statements of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) . We usedots Fig. . The assPotential publication bias in this meta-analysis was examined by funnel plots and Galbraith’s tests. Our results demonstrated that there was no sharp asymmetry in the additive, recessive and dominant models Table , Fig. 2.Moreover, the sensitivity analyses of all genetic models showed that the pooled OR fluctuated among confidence intervals. Similar results and conclusions were shown, and no results were markedly altered before and after sensitivity analyses Fig. . CollectCYP4V2 polymorphism (rs13146272) increased the risk of VTE, and the OR was 1.17 with the additive model , was 1.23 with the dominant model  and was 1.21 with the recessive model . Our results showed that the additive and recessive models reached the threshold for genome-wide significance (p < 5.0e−08).In this study, we investigated the association between rs13146272 and VTE risk in the Chinese population. Our case–control study results showed no significant association between VTE and rs13146272. However, when we combined our results with the previous studies for the meta-analysis, the results demonstrated that the association between rs13146272 and VTE risk varied among different ethnicities. Our meta-analysis demonstrated that the CYP4V2 (rs13146272), have been found to increase the risk of developing VTE [CYP4V2, located on chromosome region 4q35 and on genes that are involved in coagulation, was reported to be associated with corneal dystrophy disease and lipid metabolism [CYP4V2 variants and DVT was initially reported in a GWAS study [CYP4V2 region, were also associated with factor XI (F11) levels in some groups [CYP4V2 may be coincident with F11 SNPs. Our study showed that the polymorphisms of rs13146272 only conferred a modest increase in the risk of developing VTE, which indicated that the genetic factors contributing to VTE development may be caused by multiple variants.As VTE is a complex disease that involves various risk factors, several SNPs, such as factor V Leiden (F5 rs6025), prothrombin 20210G > A (F2 rs1799963) and YP4V2 rs146272, haping VTE . CYP4V2,tabolism , 33. TheAS study . Anothere groups . CarrierCYP4V2 polymorphism rs13146272 with VTE, which was consistent with a replication study in white Americans [The findings regarding the association between rs13146272 and VTE were inconsistent among different studies, especially among different ethnicities. A genome-wide association study only partly confirmed the association of the mericans , 21. Themericans , which wmericans . In our CYP4V2 risk alleles among white and black controls was different, but the difference was not statistically significant. In fact, different ethnicities carried genetic diversities and had specific characterizations. Second, subgroup analysis of the association between CYP4V2 and VTE was not performed due to the limited studies for some ethnicities. Third, the genotype detection methods for CYP4V2 differed among the included studies. Thus, these factors could partially contribute to the heterogeneity among the studies. We used very strict recruitment criteria for young healthy individuals. Each subject did not have any cardiovascular diseases among three generations of siblings and were healthy according to physical examination. All of the subjects had a very low possibility of carrying genetic risk factors for VTE. Even though the mean age was significantly different between the VTE and control groups, the effect of age on genetic diversity was very trivial.Our study has several limitations. First, the included studies were based on different populations. The sources of subjects were different, and the methods for analysing aggregated data were difficult to extrapolate. Austin et al.  showed tCYP4V2 likely plays an important role in developing VTE. The actual role of VTE-associated variants should be investigated in larger populations with multi-ethnic subjects in the future.In conclusion, our pooled systematic study results indicated that individuals with the A allele had a higher risk of developing VTE than those with the C allele of rs13146272 variant, but this difference was inconsistent among various ethnicities.