I2 = 52%). However, intake of ≥200 g/day yogurt was significantly associated with a lower risk of CVD in the subgroup analysis. There was a trend that a higher level of yogurt consumption was associated with a lower incident risk of CVD in the dose-response analysis. A daily dose of ≥200 g yogurt intake might be associated with a lower incident risk of CVD. Further cohort studies and randomized controlled trials are still demanded to establish and confirm the observed association in populations with different characteristics.Previous systematic reviews and meta-analyses have evaluated the association of dairy consumption and the risk of cardiovascular disease (CVD). However, the findings were inconsistent. No quantitative analysis has specifically assessed the effect of yogurt intake on the incident risk of CVD. We searched the PubMed and the Embase databases from inception to 10 January 2017. A generic inverse-variance method was used to pool the fully-adjusted relative risks (RRs) and the corresponding 95% confidence intervals (CIs) with a random-effects model. A generalized least squares trend estimation model was used to calculate the specific slopes in the dose-response analysis. The present systematic review and meta-analysis identified nine prospective cohort articles involving a total of 291,236 participants. Compared with the lowest category, highest category of yogurt consumption was not significantly related with the incident risk of CVD, and the RR (95% CI) was 1.01  with an evidence of significant heterogeneity ( Cardiovascular disease (CVD) is still an important public health problem around the world . The preLactobacillus delbrueckii subspecies bulgaricus and Streptococcus thermophilus [Several dietary patterns and individual foods have been demonstrated to exert preventive effects on CVD risk ,6,7. In mophilus . Being amophilus , it willPrevious systematic reviews and meta-analyses have evaluated the association of dairy consumption and the risk of CVD ,13,14,15To the best of our knowledge, no quantitative analysis has specifically assessed the effect of yogurt intake on the risk of incident CVD. Moreover, whether different amounts of yogurt consumption present different impacts on CVD risk is still uncertain. Therefore, we performed a systematic review and meta-analysis to pool the evidence from prospective cohort studies on the relationship of yogurt intake and the incident risk of CVD. Furthermore, we attempted to evaluate the potential dose-response pattern of the association.The present systematic review and meta-analysis was carried out according to a standard process ,17. We sThe authors independently conducted the initial screening process. After removing the duplicate records, we identified the title and the abstract of each eligible article. Unrelated articles were excluded, and articles of interest were included as further evaluation. Any disagreements were resolved by discussion between the two authors.Inclusive criteria: (1) studies reporting the relationship of yogurt intake and the incident risk of CVD (CHD or stroke) by using adjusted relative risks (RRs), hazard ratios (HRs), or odds ratios (ORs) and their corresponding 95% confidence intervals (CIs); (2) studies in which exposures were the fermented milk, but yogurt was the largest contribution to the total fermented milk; and (3) the study design was based on prospective cohort. Exclusive criteria: (1) the data reported individual components of yogurt, such as protein or probiotics; (2) studies that only reported results for total dairy/milk products or combined non-fermented and fermented milk; (3) the studies in which the participants are aged <18 years; and (4) the studies in which the participants are pregnant or lactating females.Data extraction was independently implemented by two authors. Data were extracted from each eligible article including the first author, the published year, the study location, the number of cases and total participants, baseline age and gender of participants, the method of exposure and the outcome measurements, the type of exposure and outcome, duration of follow-up, adjusted variables, and the largest number of adjusted ORs, RRs, or HRs with their corresponding 95% CIs of incident CVD for all categories of yogurt consumption.The Newcastle-Ottawa quality scale (NOS)  was usedp-values less than 0.05 were regarded as statistical significant. Heterogeneity across studies was examined by the I2 statistic which, when greater than 50%, indicated significant results [p-values of less than 0.1 were judged as significant. To evaluate the effect of an individual article on the overall pooled results, a sensitivity analysis was conducted by omitting each article from the overall analysis in every turn. The publication bias was examined through the tests of Begg’s and Egger’s [Statistical analyses were conducted using two sorts of software: Stata  and Review Manager . We applied RRs to measure the effect size for articles using the incident cases of CVD as an outcome. An approach of generic inverse-variance was used to pool the outcome data for the yogurt intake of highest vs. lowest category with a random-effects model. The  results . Additio Egger’s ,21.Generalized least squares trend (GLST) estimation model was used to compute the specific slopes in the dose-response analysis ,23. For Characteristics of each included article are shown in All studies received a quality score of 8–9 stars . All artI2 = 52%). In the stratified analysis by type of outcome, the pooled RRs (95% CIs) of yogurt consumption were 1.04  for CHD, 1.02  for stroke, and 0.87  for the incident CVD events. Sensitivity analysis showed that further exclusion of any individual comparative did not significantly alter the pooled RR, and the RRs (95% CIs) ranged between 0.99  and 1.03 . Exclusion the study by Larsson et al. [p-value = 0.228, Begg’s test: p-value = 0.254).n et al.  reduced p-value for difference >0.1 for each group). Stratified analysis by yogurt dose of the highest category (<200 or ≥200 g/day) significantly affected the association , and ≥200 g/day yogurt intake was significantly associated with lower risk of CVD compared with the reference category, and the RR (95% CI) was 0.92 .As shown in After excluding three articles ,28,29 thThe present systematic review and meta-analysis identified nine cohort articles involving a total of 291,236 participants. Compared with the lowest category, the highest category of yogurt consumption was not significantly related with the incident risk of CVD; however, intake of ≥200 g/day yogurt was significantly associated with a lower risk of CVD in the subgroup analysis. There was a trend that a higher level of yogurt consumption was associated with a lower incident risk of CVD in the dose-response analysis.An increasing number of epidemiological studies have supported the beneficial effects of yogurt consumption on lowering blood pressure, total cholesterol concentrations, total cholesterol, and plasma glucose ,36,37. ACompared with previously published meta-analyses relevant to this topic ,13,14,15Lactobacillus sp., Enterococcus sp., or Streptococcus sp.), consuming time and fat-containing  were not illustrated in all included studies. Some RCTs have indicated that intake of low-fat and whole-fat dairy products may cause different effects on blood pressure, weight and depressive symptoms [Limitations of our meta-analysis should be mentioned. First, considerable heterogeneity has been observed across studies. This is not surprising given the diversity in study characteristics of participants, various doses of yogurt consumption, different type of outcome, and adjusted confounders. Further sensitivity analysis revealed that the study by Larsson et al.  might besymptoms ,43. Thersymptoms , region-In conclusion, the present meta-analysis based on nine independent cohort studies provides a non-significant association between yogurt intake and CVD risk. Daily dose of ≥200 g yogurt intake might be associated with a lower risk of CVD. Further cohort studies and randomized controlled trials are still demanded to establish and confirm the observed association in populations with different characteristics.


Dairy products are major components of daily diet and the association between consumption of dairy products and public health issues has captured great attention. In this study, we conducted a meta-analysis to investigate the association between dairy products intake and cancer mortality risk.After a literature search in PubMed and EMBASE, 11 population-based cohort studies involving 778,929 individuals were considered eligible and included in the analyses. Data were extracted and the association between dairy products intake and cancer mortality risk was estimated by calculating pooled relative risks (RRs) and corresponding 95 % confidence intervals (CIs). Sensitivity analyses and subgroup analyses based on regions, genders and dairy types were performed as well. Potential dose–response relationship was further explored by adopting the generalized least squares (GLST) method.p = 0.893). Subgroup analyses showed that the pooled RRs were 0.97  for milk, 0.88  for yogurt, 1.23  for cheese and 1.13  for butter in male and female, however the pooled RR was 1.50  for whole milk in male, which was limited to prostate cancer. Further dose–response analyses were performed and we found that increase of whole milk (serving/day) induced elevated prostate cancer mortality risk significantly, with the RR of 1.43 .Total dairy products intake was not associated with all cancer mortality risk, with the pooled RR of 0.99 (95 % CI 0.92–1.07, Total dairy products intake have no significant impact on increased all cancer mortality risk, while low total dairy intake even reduced relative risk based on the non-linear model. However, whole milk intake in men contributed to elevated prostate cancer mortality risk significantly. Furthermore, a linear dose–response relationship existed between increase of whole milk intake and increase of prostate cancer mortality risk. Dairy products are major components of daily diet and due to their abundant nutrient elements such as protein, fat, minerals and vitamins, they are listed as core parts of dietary recommendation worldwide . The proIt was universally acknowledged that dairy products intake was closely related to certain health issues. On the one hand, nutrients from dairy products were beneficial for chronic diseases such as cancer. For instance, casein was proved to have potential antimutagenic  and antiA few studies have conducted meta-analyses to investigate the correlation between dairy products intake and cancer incidence risk in colorectal , prostatThis meta-analysis was designed, conducted and reported according to PRISMA statements . SystemaDuplicated studies were first excluded, then titles and abstracts were carefully scanned. Next full texts of potentially qualified studies were reviewed. We included studies if they met all the following criteria: (1) the studies of interest were dairy products intake; (2) the studies were population-based cohort studies and reported cancer mortality data; (3) relative risk (RR), hazard ratio (HR) or odds ratio (OR) estimates with 95 % confidence interval (CI) adjusted for multivariable factors were available or could be calculated; (4) original articles with full texts in English. Studies were excluded according to the following criteria: (1) reviews, letters, unpublished data or comments; (2) those published in languages other than English; (3) not population-based cohort studies; (4) RR, HR or OR estimates with 95 % CI were not available or could not be calculated.The study quality assessment was performed according to the Newcastle-Ottawa Scale . Two revp value for heterogeneity. RRs comparing the highest intake category with the lowest intake category were combined across studies to generate the summary associations. The extent of heterogeneity across studies was examined using the I2 test [2 > 50 % together with p < 0.05 indicated significant heterogeneity. In order to validate the stability of outcomes in the meta-analysis, sensitivity analyses were performed by including studies which only reported all cancer mortality. Sequential omission of each individual study was also performed, while subgroup analyses were carried out to investigate the impact of regions, dairy product types and genders on cancer mortality. Funnel plots were constructed to assess the publication bias, meanwhile the Begg’s rank correlation test and Egger’s regression test was adopted to test the asymmetry and p < 0.1 indicated statistically significant publication bias [The random-effect model was applied to calculate pooled RRs, 95 % CI and  I2 test  and I2 >ion bias .χ2 test and a p value for a non-linear relationship was calculated by testing the null hypothesis that the coefficient of the second spline was equal to zero. Non-linear model was applied in the first place if model verification indicated significance (p < 0.05), otherwise linear model was adopted. The dose–response curves containing RRs with 95 % CI for each dairy product type were constructed, respectively. Heterogeneity was tested using I2 test and I2 > 50 % together with p < 0.05 indicated significant heterogeneity.We then looked for potential dose–response relationship between dairy products intake and cancer mortality risk using the generalized least squares(GLST) method for trend estimation of summarized data . The dosp < 0.05 unless specified.All analyses were conducted using Stata software , and the significance level was set to We identified 1031 publications after searching PubMed and 1625 publications in EMBASE. First of all 172 duplicated studies were removed, followed by the exclusion of 2462 studies after reviewing abstracts and titles carefully. After full-text review of the remaining 22 articles, another 11 studies were excluded for the following reasons: six articles provided insufficient data, four only reported cancer incidence risk and one conference article. References of pertinent articles and relevant reviews were also scanned manually. Finally, the remaining 11 studies –31 with Characteristics of the included studies were shown in Table p = 0.893), as shown in Fig. 2 = 39.8 %, p = 0.092). Begg’s funnel plot and the Egger’s linear regression test were conducted to evaluate publication bias. The shape of Begg’s funnel plot showed no evident asymmetry .In each individual study, RRs of the highest total dairy products intake group versus the control group were introduced. For the association between total dairy products intake and all cancer mortality, ten studies except Kojima’ study were included and the pooled RR was 0.99 . Sequential omission of each individual study was also performed, as shown in Fig. Sensitivity analyses were performed by including studies which only reported all cancer mortality Fig. , and thep = 0.484) in America, 1.00  in countries other than America and 0.97  in Asia, which was in consistent with the above results.Subgroup analyses were conducted according to different regions, dairy product types and genders. Initially, regions were categorized into America, countries other than America and Asia when we explored the association between total dairy intake and cancer mortality risk. We found the pooled RRs were 0.90  for milk, 0.88  for yogurt, 1.23  for cheese and 1.13  for butter, proving that intake of these dairy products was not associated with cancer mortality risk significantly (Table p = 0.032), which was only limited to prostate cancer. In accordance with this finding, skim/low-fat milk intake was not associated with prostate mortality risk, with the pooled RR of 1.00 .Dairy product types were then categorized into milk, yogurt, cheese, butter, whole milk and skim/low-fat milk. In both genders, the pooled RRs were 0.97 . The dose–response curves containing RRs with 95 % CI and doses were constructed , which was in consistent with the previous subgroup analyses results.For each dairy type, we adopted the linear model as well to assess RR due to increase of dairy products, which indicated that increase of total dairy, milk, yogurt, cheese, butter or skim/low-fat milk (serving/day) was not associated with elevated cancer mortality risk Figs. . NeverthSince dairy products contain complex nutrient composition and the amount of dairy products consumption is huge in our daily life, a number of studies have pointed out that dairy products may have impact on health issues such as obesity , diabeteThe current analyses showed that higher total dairy, milk, yogurt, butter and skim/low-fat milk intake was not associated with increased cancer mortality risk, while exposure to highest dose of whole milk intake increased about 50 % of prostate cancer mortality risk. By constructing a non-linear dose–response model, we concluded that low total dairy products intake may be protective against cancer related death, however high dose of total dairy products did not have the protective effect. Through a linear dose–response model, we found that increase of whole milk (serving/day) contributed to elevated prostate cancer mortality risk significantly, while other dairy types did not show the same effect. This might be explained by the hypothesis that luxuriant calcium contained in whole milk would increase the risk of prostate cancer by inhibiting the potential anti prostate carcinogenic nutrient 1,25-dihydroxyvitamin D . BesidesOur study had several crucial strengths. We conducted this thorough systematic search and applied comprehensive analytical approaches to assess the association between dairy products intake and cancer mortality risk. In addition, the studies we included were all population-based cohort studies of high quality. Furthermore, sensitivity analyses and sufficient subgroup analyses were also conducted to ensure the reliability of this study. Finally, we used a non-linear or linear model to fit the dose–response relationship between dairy products intake and cancer mortality risk. The methods of this study were rigorous and were based on guidelines for conducting the present study.However, the current study was restricted by several limitations. First, the number of studies involved was relatively small, partly because cancer incidence risk rather than mortality risk was much more widely reported, thus the association between each type of dairy products and every specific cancer mortality risk was not available because of inadequate data. Second, most of the included studies were performed in Asia or America, and the studies conducted in America did not confine their cohorts to certain ethnic groups, hence the conclusions should be taken cautiously for other ethnic populations. We suggested further population-based cohort studies which investigate the association between dairy products intake and cancer mortality in each individual ethnic should be conducted. Finally a few studies reported different doses of highest dairy intake, which was further discussed in the dose–response analysis.On the basis of the results above, we confirmed that total dairy products intake was not associated with increased cancer mortality risk in both genders, yet low total dairy products intake even reduced relative risk based on the dose–response analyses. However, whole milk intake in men contributed to elevated prostate cancer mortality risk. Furthermore, the linear dose–response relationship existed between increase of whole milk intake and prostate cancer mortality risk.


Reduction mammoplasty (RM) is a proven method of treating macromastia, but the risk factors for postoperative complications have not been clearly identified. Through this meta-analysis, the authors aimed to identify the risk factors of RM complications.An extensive search of the literature describing complications after RM was performed using the PubMed Central, Embase, and Cochrane databases. The following risk factors were extracted: age, body mass index (BMI), tissue resection weight per breast (TRW), smoking and radiation therapy. Odds ratios (OR) were pooled with 95% confidence intervals (CI) to evaluate the relationship between these risk factors and complications after RM.2  and smoking . Infection in those with BMI ≥30 kg/m2 showed a significant difference , as well as wound dehiscence in smokers  and infection in irradiated breasts . However, there was no significant difference in age ≥50 years , combined TRW ≥1000 g .A total of 16 unique studies including 10 593 patients were included in the final analysis. It showed that there was a significant difference in complications in BMI ≥30 kg/m2 and smoking increase the risk of complications. Persons who are obese or irradiated are more likely to develop infections, and smokers experienced a higher incidence of wound dehiscence than did nonsmokers. However, patients aged ≥50 years and TRW ≥1000 g are not associated with complications from RM.BMI ≥30 kg/m Macromastia is a common problem among women, leading to disabling symptoms such as neck, back, and shoulder pain; inframammary maceration; heavy breathing during exercise; and great psychological burdens because of unaesthetic appearance. Reduction mammoplasty (RM) is an approved procedure for women with macromastia, which has effectively relieved existing symptoms with high satisfaction, even though complications have often occurred –4. Risk Postoperative complications after breast reduction include infection, wound healing problems, scars, fat necrosis, seroma, lost nipples and reoperations. The complications occurred after breast reduction would be as high as 40 or 50% in reported studies , 5, 6. MAlmost all the risk factors associated with complications were controversial and no published meta-analysis had investigated it. We therefore performed a meta-analysis of all published prospective and retrospective studies to evaluate the important risk factors in women with macromastia and gigantomastia and provide preliminary guidance for clinical treatment and prognosis.We prospectively defined the study objectives, search paramters, eligibility criteria, and analytical methods.The following electronic databases were searched: The PubMed Central, Embase, and Cochrane Library. They were searched for English language studies using the following headings and keywords: macromastia or gigantomastia. Also used were breast reduction, reduction mammaplasty or reduction mammoplasty. No limitation was put on the date of publication, which covered all previously published studies up to December 2015. In addition, selected study references and review articles were examined for further article sources.The initial selection of studies was performed on the basis of titles and abstracts. Next, two investigators (Min-Xia Zhang and Chun-Ye Chen) independently screened the full text of each selected study using the following inclusion criteria: (1) the study must meet the definition of macromastia or gigantomastia; (2) RM as the only surgical procedure of interest; (3) measured complications of the incidence and risk factors of RM; (4) risk factors were BMI, age, TRW, smoking or radiation therapy, any one of which should be researched in the study; (5) Sufficient data on contrasting groups. Studies were excluded if they contained any one of the following exclusion criteria: (1) case reports, abstracts only, letters, comments or reviews; (2) studies with mixed gender or surgical procedures; (3) virginal, adolescent or pregnant macromastia. To avoid double publication, only the most informative or lastest study was included. This meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement checklist.Data extraction was performed independently by two reviewers (Min-Xia Zhang and Chun-Ye Chen), and any disagreement concerning paper eligibility was resolved by discussion and consensus. The data covered the general characteristics of each study and the outcomes measured. In addition, studies were assigned a level of evidence score.Based on the amount of data available and on clinical relevance, five factors were analyzed including BMI, age, TRW, smoking and radiation therapy.I square test, where p value <0.10 for the Chi squared and I2 ≥50% implied heterogeneity [For each risk factor in our study, odds ratios (OR) and 95% confidence intervals (CI) were calculated for outcomes. A p value <0.05 was judged as statistically significant. Random-effects models were used depended on the heterogeneity of the studies included. Heterogeneity was analyzed with both the Chi squared test ogeneity . The forData was processed in Review Manager version 5.3 from the Cochrane Collaboration.A total of 2532 records were identified by the initial database search, from which 63 full-text articles were retrieved for final review after screening titles and abstracts. Of these, 16 studies that met all predefined inclusion criteria were finally included in our meta-analysis , 17–27. Study characteristics for the 16 included studies are summarized in The study set included altogether 10 593 patients whose demographic features  are displayed in The risk factors with sufficient data of complications available for meta-analysis were BMI, age, TRW, smoking and radiation therapy. The results were expressed as ORs, 95% CIs and p-values.2) and obese (BMI ≥30 kg/m2). BMI ≥30 kg/m2 was the strongest risk factor for overall complications in our meta-analysis based on 6 related studies [2 = 0%). The aggregated results suggest that BMI ≥30 kg/m2 was highly associated with a significant increase in the overall incidence of complications after RM   (2 = 0%).We first divided the patients into two groups: non-obese  . Moreove= 0.004) . The tes2 = 0%). The aggregated results of the 2 studies suggest that age ≥50 years was not associated with a significant increase in the overall incidence of complications after RM   .2 = 50%). Using the random-effect model, the aggregated results suggest that TRW ≥1000 g was not associated with a significant increase in the overall incidence of complications after RM   .2 = 41%). Using the random-effect model, the aggregated results suggest that smoking was highly associated with a significant increase in the overall incidence of complications  (2 = 0%).We combined 6 studies , 20–22 c = 0.06) . In addi = 0.06) . The tes2 = 0%). The aggregated results suggest that breast reduction after radiation lead to a significant increase in the incidence of infection  (2 = 0%).We finally selected 3 studies –27 repor 0.0009) . However 0.0009) . The tesFor observational studies, we applied the Risk of Bias Assessment tool for Nonrandomized Studies (RoBANS), which was compatible with the Cochrane risk-of-bias tool.Even though women undergoing breast reduction were generally young and healthy, postoperative complications were relatively common, with an incidence of 14%-53% in reported studies , 17, 28,2 was classified as “underweight”; a BMI between 18.5 and 24.99 kg/m2 was “normal weight”; a BMI between 25 and 29.99 kg/m2 was “overweight” and a BMI of 30 kg/m2 or more was “obese”  [Increased BMI was the strongest predictor of complications among patients with breast reduction in our meta-analysis. The patients’ weights were categorized as follows: a BMI equal to or less than 18.5 kg/mobesity) . The vasobesity) , 17, altobesity) , 23, 30.obesity) . Our assobesity) . In addiobesity) . Our resOur mate-analysis demonstrated that age at surgery ≥50 years bears no relationship to complications in RM compared with younger patients <50 years. According to a positive study by Shermak MA et al., we diviTRW ≥1000 g was not a significant factor in the overall incidence of complications compared with smaller resections. We had arbitrarily set the crossover point between small and large reductions at 1000 g of tissue per breast . ZubowskAnother strong risk factor for complications after RM in our meta-analysis was smoking. Many other studies supported our results of the effect of smoking status on complication rates, such as Schumacher HH et al., Roje Z 2 = 41%), so we used the random-effect model and sensitivity analysis to evaluate the source of high heterogeneity. The results of sensitivity analysis showed that smoking was also highly associated with complications (p = 0.02) with a low heterogeneity (I = 0%) when excluding one study of Roje Z et al.[Although smoking was significant for complications in our meta-analysis p = 0.06), heterogeneity was also significant  are not mutually exclusive, which might have led to overestimating a complication risk. This study was not designed to provide independent risk factors for complications, for the reporting data was insufficient to do a multivariate analysis. Third, this meta-analysis was an observational study so that a randomized controlled trial was necessary. However, performance of any such study would be difficult. Consequently, there was marked heterogeneity among risk factors. So we attempted to account for heterogeneity using a random-effect model for meta-analysis when the Cochran Q statistic was significant, and find the source of high heterogeneity using sensitivity analysis. Finally, perhaps the biggest limitation of this meta-analysis and an important target for future research was the inability to perform outcome subgroup analyses by operative technique.2 and smoking status are risk factors for complications after RM. Moreover, BMI ≥30 kg/m2 and radiation therapy showed a statistically higher incidence of infection and smokers acquired higher significant rates of wound dehiscence. However, age ≥50 years and TRW ≥1000 g are not associated with post-RM complications. Further large-scale, well-designed studies are urgently needed.This meta-analysis demonstrated that BMI ≥30 kg/mS1 File(DOC)Click here for additional data file.S2 File(DOC)Click here for additional data file.


This study is aimed to conduct a meta-analysis to evaluate the prognostic value of lymphovascular space invasion(LVSI) and to explore the potential association of SNAI1 and SNAI2 with LVSI in ovarian cancer. A systematic literature search in PubMed, ISI Web of Science, and Medline was conducted to identify relevant studies assessing the prognostic value of LVSI in ovarian cancer. The main outcomes analyzed were progression free survival/disease free survival and overall survival. TCGA database was used to explore the potential link of SNAI1 and SNAI2 with LVSI status. A total of 11 eligible studies enrolling 1817 patients were included for the meta-analysis. The overall analysis indicated that LVSI presence was associated with shorter duration of survival in ovarian cancer patients. Multivariate analysis indicated that both advanced stage and SNAI2 expression were associated with increased risk of LVSI presence. Survival analysis indicated that tumors with LVSI presence and high SNAI2 expression were significantly correlated with poorer survival when compared to tumors with both LVSI absence and low SNAI2 expression. In conclusion, LVSI presence was associated with worse clinical outcomes in ovarian cancer. Increased expression of SNAI2 and advanced stage were independent risk factors for LVSI presence. Our findings also emphasizes the potential of SNAI2 in promoting lymphovascular spread of ovarian cancer. Ovarian cancer is the most fatal gynecologic malignancy and most of the patients are not diagnosed until an advanced stage . During Recently, lymphovascular space invasion (LVSI), defined as the detection of tumor cells inside the capillary lumens of lymphovascular system, has emerged as a new risk factor for ovarian cancer progression , 10. TheIn present study, we first conducted a meta-analysis to establish the prognostic value of LVSI presence in ovarian cancer. Meanwhile, we try to explore the potential link between SNAI1, SNAI2, and LVSI status in ovarian cancer using data from The Cancer Genome Atlas (TCGA) database.One hundred fourteen studies were identified by the primary computerized literature search. Of these, 91 publications were excluded because they were either irrelevant to the present study, written in non-English, or laboratory studies. Twenty-three records were further reviewed in detail. Thirteen publications were further excluded because of no survival data or repeated publications. The survival data on LVSI in the TCGA dataset was also included in our meta-analysis. Finally, 11 studies were identified as eligible for inclusion in our meta-analysis , 9–18 . Funnel plot revealed that there was publication bias . One-way sensitivity analysis confirmed the stability of our results . Funnel plot revealed that there was publication bias . One-way sensitivity analysis confirmed the stability of our results  and OS .Even patients at early stage had a relatively lower incidence of LVSI presence, LVSI presence was still associated with shorter duration of PFS . However, patients with both LVSI presence and high SNAI2 expression were significantly associated with shorter OS when compared to patients with both LVSI absence and low SNAI2 expression .Next, survival analysis were conducted. When LVSI and SNAI1 are combined, the survival in patients with LVSI presence and high SNAI1 expression was not significantly inferior to that in patients with LVSI absence and low SNAI1 expression . Previous results showed that SNAI2 increased the motile and invasive ability of ovarian cancer cells , 23. ThiIn conclusion, LVSI presence is associated with worse clinical outcomes. The aberrant expression of SNAI2 and advanced stage are independent risk factors for the LVSI presence in ovarian cancer. This study also emphasizes the potential and importance of SNAI2 in promoting lymphovascular spread of ovarian cancer.A literature search (last search updated to Oct.20th 2016) in Pubmed, ISI Web of Science, and Medline for studies evaluating the prognostic significance of LVSI in ovarian cancer was conducted using the following keywords: (“lymphovascular invasion” OR “lymphatic invasion” OR “vascular invasion” OR “LVSI”) AND (“ovarian cancer” OR “ovarian tumor” OR “ovarian carcinoma” OR “ovarian neoplasms”). Additionally, references lists of retrieved articles were checked for any possible eligible studies. The results were limited to peer-reviewed, English language reports.The studies were considered eligible if they reported survival data in ovarian cancer patients stratified by LVSI status and provided sufficient data for determining an estimate of hazard ratio (HR) and a 95% confidence interval (CI). All articles were scrutinized to avoid inclusion of duplicate data. When the patient populations overlapped between studies, only the most recent or most complete publication was included to avoid duplications.The data extracted for this meta-analysis included the author's names, year of publication, number of patients analyzed, tumor stage, grade, histology, and survival data stratified by LVSI status.We downloaded the level 3 Affymetrix HG-U133A gene expression data from 192 serous ovarian cancer patients with LVSI information in TCGA dataset to analyze the association of LVSI status with the clinicopathological features, and to determine the risk factors associated with LVSI presence.2 index. The pooled HR for survival was calculated by fixed-effects model when the I2≤50%. Otherwise, random-effects model was used. Publication bias was assessed by the funnel plot. The impact of publication bias on the pooled HR was evaluated with the trim-and-fill analysis. Moreover, one-way sensitivity analyses and subgroup analyses were performed to assess the stability of the results. When the number of included studies was less than three, one-way sensitivity analysis was not performed. All statistical tests of the meta-analysis were conducted with STATA version 11.0.HR of each study was extracted directly from the original report. The potential heterogeneity between studies was assessed by the Cochran's Q-test and expressed by the IRisk factors related to LVSI presence was assessed with binary logistic regression test. Multivariate analysis with logistic regression test was conducted to identify independent risk factors for LVSI presence. The optimal cutoff for SNAI1 and SNAI2 was determined by Youden's index. The cutoff with the biggest Youden's index was chosen as the optimal cutoff. Statistical analysis was conducted using SPSS version 16.0.


I2 = 44.4%). Occupational sun exposure was positively associated with the risk of NHL 1.14  in Caucasian population. Common subtypes of non-Hodgkin lymphoma and ultraviolet exposure had the negative results. The pooled odds ratios was 1.16,  for T-cell non-Hodgkin lymphoma; 0.79,  for B-cell non-Hodgkin lymphoma; 1.13,  for chronic lymphocytic leukemia; 1.25,  for males; 1.49,  for females. Data suggested that occupational ultraviolet exposure was a risk factor for non-Hodgkin lymphoma in Caucasian population. While, there had no relationship between occupational ultraviolet exposure and risk of non-Hodgkin lymphoma in general population as well as non-Hodgkin lymphoma common subtypes. Besides, gender specific occupational sun exposure also indicated no association on risk of non-Hodgkin lymphoma.Non-Hodgkin lymphoma is a heterogeneous group of lympho-proliferative disorders. We performed a meta-analysis to summarize the available evidence from case-control studies and cohort study on the inconsistent association between occupational sun exposure and the risk of non-Hodgkin lymphoma. We searched PubMed, ISI web of science, the Cochrane Library, EMBASE and reference lists for relevant articles. Study specific odds ratios or relative risk and 95% confidence intervals were pooled by using fixed-effects or random-effects models. Ten case-control studies and one cohort study were included in the meta-analysis. Overall, the pooled odds ratios for occupational ultraviolet exposure and non-Hodgkin lymphoma risk was 1.15(95% confidence intervals: 0.99, 1.32;  Non-Hodgkin lymphoma (NHL) is a heterogeneous group of lympho-proliferative disorders . As statThe incidence of NHL increased dramatically between 1970 and 1995 .This remarkable rise suggests a major role for environmental factors in the etiology of NHL, thus the hypothesis that solar ultraviolet(UV) radiation may explain this trend emerged in 1992 .As the increasing incidence of NHL mounting studies associated with the relationship between sun exposure and risk of NHL were carried out in westernized countries. But the results have been inconsistent. We therefore undertook a meta-analysis of case-control and cohort studies to quantitatively assess the relationship between occupational sun exposure and risk of NHL and common NHL subtypes.Our systematic literature search details were shown in Figure  based onThe characteristics of the 11 eligible studies were summarized in /relative risk (RRs) of NHL, the adjustments made for confounding and occupational history assessment were shown in Table 2I=44.4%). , therefore we used the random-effect model to calculate the summary OR.In the meta-analysis, the summary estimated for occupational sun exposure showed no statistical association between occupational sun exposure and risk of NHL 1.15. No heterogeneity was observed, thus fixed-effect model was provided.  and B-cell NHL  analyses were presented in Figure Gender specific information on occupational sun exposure and risk of NHL was available in three studies , 33, 36.2I=25.1%, p for heterogeneity =0.21  and Egger’s test (p=0.37) for the association between occupational sun exposure and the risk of NHL. The results indicated no publication bias among these studies. In addition, no publication bias was detected for the positive association between occupational sun exposure and the risk of NHL in Caucasian population, either . To investigate heterogeneity in our meta-analysis, we evaluated sensitivity analysis within the studies. Eleven studies which included in our meta-analysis were the relationship between occupational sun exposure and risk of NHL, two studies were focused on specific types of NHL , 37, so  and Egge1 Figure . The res2I=40.2%, p for heterogeneity =0.12).Data collection method from six studies were in person interview -35, 37, We applied sensitivity analysis on our positive results among Caucasian population. The pooled estimate did not vary substantially with the exclusion of any single study Figure .Our meta-analysis of 11 included case-control and cohort studies indicated that occupational ultraviolet exposure was a risk factor for NHL in Caucasian population. However, there is no association between occupational sun exposure and risk of NHL in general population as well as common NHL subtypes. In addition, gender specific study did not show any association either. Most studies included in our meta-analysis showed no association between occupational sun exposure and risk of NHL except for Nordstorm et al   and ZhanOur main findings showed no association between occupational ultraviolet exposure and NHL risk. When we omitted the study of Asian population our results are positively correlated. Hughes et al reported the pigmentary characteristics and NHL risk. In this study, it categorized the six ethnicity groups including Asian. They have found that the very fair skin compared to brown or olive skin had 44% increased risk of NHL . InteresMany of the studies which included in this meta-analysis reported that there is no relationship between occupational UV exposure and NHL risk, however at the same time, reported the daily, casual UV exposure is a protective factor for NHL , 34, 35.As with any meta-analysis of observational studies, our study has limitations.First, moderate heterogeneity was found across our main analysis, which can be explained by the multiple differences between studies with regard to the study designs, sample sizes, analysis strategies, participants’ baseline characteristics, adjustments for confounders and occupational history assessment methods. For example, the control source of eight studies were population based , 36, 37,Secondly, half of the studies in this meta-analysis relied on self-administered questionnaire, while anther half studies gathered information from interview. The participants may have different attitudes and different understanding towards questions under different methods. Besides, the total occupational sun exposure hours are varies across studies and participants. Finally, in a meta-analysis of published studies, the potential publication bias might influence the results, because studies with null results tend not to be published. Nevertheless, our publication bias test showed no possible bias.In summary, our meta-analysis suggested that occupational UV exposure was a risk factor for NHL in Caucasian population. While, there had no relationship between occupational ultraviolet exposure and risk of NHL as well as NHL common subtypes. Besides, gender specific occupational sun exposure also indicated no association on risk of NHL.We reported this article in accordance with MOOSE  guidelines . We systTo be included in this meta-analysis, studies had to have met the following criteria: (1) NHL cases were medically confirmed by histopathology diagnoses; (2) the study was designed as case-control or cohort study; (3) the occupational sunlight exposure and incidence of NHL were associated; (4) detailed data of odds ratios (ORs) or relative risks (RRs) with 95% confidence interval (CI); (5) All the cases were adult (age≥17 years old). We did not include the studies that only report the death rate of NHL without incidence rate. When there were multiple published reports from the same study population, the most recent or the most informative report was selected for analysis.We extracted the following information from each study: authors’ name, year of publication, study type, study location, sample size (numbers of case patients and control subjects), study period, participation’s age, type of control source, assessment of data collection, and statistical covariates adjustment in the analysis. ORs or RRs with corresponding 95%CIs for each study were either extracted directly from the article or calculated from available raw data.To pool the results of individual studies together, we used a general variance-based method in the meta-analysis. The multivariate adjusted ORs and 95% CIs presented in the literature were used. In situations where the incidence is low, the odds ratio approximates the relative risk, therefore, in looking at studies of NHL (a rare condition), it is acceptable to compare OR and RR estimates . The out2I statistic [2I was from 0% to 40% along with p >0.10 the heterogeneity might not be important. If the meta-analysis has no heterogeneity, fixed-effects model with the Mantel-Haeszel method would be used to combine the individual studies [Statistical heterogeneity among studies was tested with the Q statistic, and statistical inconsistency was quantified with the tatistic . When I2 studies , otherwi studies .There were two studies focused only on specific types of NHL , 37. We The Egger’s test and Begg’s test were used to assess for publication bias , 50. P<0


HtrA1 is expressed in a variety of normal human tissues and seems to be involved in numerous physiological processes as well as tumorigenesis. This study reports the results of a meta-analysis that was performed: to compare HtrA1 expression as mRNA and protein, in cancer tissue versus non-cancer tissue and to assess overall survival in relation to low or medium-high HtrA1 tissue expression.The PRISMA method was used for study selection. OR and HR with 95% confidence interval was used as a measure of effect size as appropriate. A random-effects model was applied to account for different sources of variation among studies. Heterogeneity across studies was assessed using Q statistic. Sensitivity analysis was conducted to check the stability of study findings. Egger’s regression method was applied to test funnel plot asymmetry.Sensitivity analysis indicated the stability of meta-analytic findings in each meta-analysis. The study found a significantly different HtrA1 expression in cancer and non-cancer tissue. The meta-analysis of the prognostic studies showed a different survival according to HtrA1 expression.The present data may provide a contribution to future work directed at exploring the role of HtrA1 in tumor development and progression and at establishing whether it may be used as a promising tissue marker for some tumors.The online version of this article (10.1186/s12885-018-4041-2) contains supplementary material, which is available to authorized users. The members of the widely conserved high-temperature requirement A (HtrA) family of homo-oligomeric serine proteases are involved in a number of mammalian cellular processes that include growth , maintenMammalian HtrA1 is connected to tumorigenesis , 7; in pBy using different experimental techniques, Lorenzi and colleagues  have fouFinally, according to recent evidence HtrA1 downregulation induces the acquisition of phenotypes such as increased proliferation, delayed onset of senescence, altered centrosome number and positioning and polyploidy, all hallmarks of tumor cells .In a previous review, our group explored the potential role of HtrA1 as a tumor marker and/or prognostic factor .This study reports the results of a meta-analysis that was performed: i) to compare HtrA1 expression as protein and mRNA, in cancer tissue (C) versus non-cancer tissue, i.e. healthy control (HC) tissue and normal-looking (NL) tissue; and ii) to assess overall survival in relation to low or medium-high HtrA1 tissue expression in different cancers.clinicaltrial.gov, clinicaltrialsregister.eu). A manual search was also performed. There were no limitations as to the year of publication. Only studies in English were considered. The reference lists of all studies were screened by two independent reviewers (PMA and MM); any disagreements were resolved by a methodologist (EA). The following keys words were used: HtrA1 OR PRSS11 protein, human OR L56 protein, human OR protease, serine, 11 (IGF binding) protein, human OR high-temperature requirement factor A1, human OR HtrA serine peptidase 1, human AND Neoplasm OR Tumors OR Tumor OR Neoplasia OR Cancer OR Cancers. Only studies assessing HtrA1 (mRNA or protein) as a diagnostic or prognostic tumor marker were considered. Studies were selected using the PRISMA statement  , 23, witEffect sizes were pooled across studies to obtain an overall effect size. A random-effects model was applied as a conservative approach to account for different sources of variation among studies. Heterogeneity across studies was assessed using Q statistic, I2, Tau, and Tau2. A significant Q value indicated the absence of homogeneity of results among studies.In addition, to complete the explanation of heterogeneity across study results, moderator analyses were conducted if there were at least 5 studies. The moderators evaluated by meta-regressions were sample size magnitude, % of female, mean age of both genders as appropriated, and year of publication.Sensitivity analysis was conducted to check the stability of study findings and estimate how the overall effect size would be modified by removal of one study.Publication bias analyses were performed when there were at least 4 studies, to control for the fact that published studies may have a larger mean effect size than unpublished studies . The funPrognostic studies were analyzed using the hazard ratio (HR) and its 95% CI as a measure of effect size. To assess the effect of HtrA1 expression on overall survival, patients were dichotomized into two classes: medium-high and low HtrA1 expression. When the HR and 95% CI were not reported in the papers, they were estimated from Kaplan-Meier curves according to Parmar et al. , TierneySearch of the electronic databases according to the above-listed criteria found 59 papers, whereas the manual search found none. There were no duplicates , and Egger’s linear test was not statistically significant: 34 Table , Fig. 2bp < 0.0001, Q = 9.01, p = 0.061, I2 = 55.59, without statistically significant heterogeneity , and Egger’s linear test was not statistically significant, 97 Table , Fig. 3bIn recent years, mounting biological knowledge of disease processes and advances in molecular technologies have increased the interest in biomarkers. In fact, biomarkers are used for patient assessment in multiple clinical settings, both to distinguish an individual with disease from one without disease and to discriminate one disease from another, i.e. for differential diagnosis. Ad hoc immune-histochemical markers can also be used to try and identify the tissue where a tumor has had its origin, to assess the risk of relapse, as well as to evaluate prognosis or response to therapy.In the present study, a meta-analysis was conducted to assess the potential role of HtrA1 as a tumor marker and/or prognostic factor in a number of tumors. Most current studies focus on the role of HtrA1 in tumor development and progression through analysis of its expression as mRNA , 39–41 oBased on these considerations, in this work the studies assessing HtrA1 expression as mRNA and protein were evaluated separately. An important finding of the study was that, in the absence of significant statistical heterogeneity, there was a statistically significant difference between the tumor samples analyzed and HC and NL tissue specimens; this applied both to HtrA1 measured as mRNA and as protein Table ,. The reThe meta-analysis of the prognostic studies showed, in the absence of significant heterogeneity among the studies examined, a different survival according to HtrA1 expression. These findings are in line with the literature, since in some studies HtrA1 has been found to modulated cisplatin- and paclitaxel-induced cytotoxicity and low HtrA1 levels have been seen to correlate with a poor response to drug treatment, whereas higher levels correlated with a greater response , 42.Baldi et al.  have demAnalysis of the moderators assessed in the works selected found no statistically significant differences and there was no publication bias .However, some weaknesses in the data suggest that the results of the present meta-analysis should be taken with caution. First of all, most of the studies are descriptive, preventing a causal inference between reduced HtrA1 levels and cancer. Secondly, the small number of works on the same tumor prevents an analysis by tumor in relation to individual organs. Thirdly, since parameters such as histological type and tumor grade and stage have not been addressed in all the studies, it is impossible to establish how HtrA1 expression varies in relation to these factors. Finally, the different HtrA1 expression, found in papers assessing the same cancer type, could correlate to histological grading, metastasis, and degree of cell differentiation, but were not related to patients’ age or gender, as demonstrated in hepatocellular carcinoma , esophagThe present data may provide a contribution to future research work directed at exploring the role of HtrA1 in tumor development and progression and at establishing whether it may become a promising tissue marker for some tumors. Finally, the present work suggests that clinical investigations sharing a similar approach, especially in terms of study design, should be carried out to improve comparability across studies.Additional file 1: Figure S1.Flow-chart of research strategy. (PDF 252 kb)Additional file 2: Table S1.Excluded papers. (PDF 288 kb)Additional file 3: Table S2.PRISMA Check-list. (PDF 267 kb)Additional file 4: Table S3.Newcastle-Ottawa evaluation for case-control studies. (PDF 82 kb)Additional file 5: Figure S2.Normal-Looking Tissue. Meta-regression of HtrA1 protein: A. Sample size, B. % Female, C. Mean age of entire sample, D. Publication year. (PDF 218 kb)Additional file 6: Figure S3.Normal-Looking Tissue. Meta-regression of HtrA1 mRNA: A. Sample size, B. % Female, C. Mean age of entire sample, D. Publication year. (PDF 1270 kb)Additional file 7: Figure S4.Survival studies. Meta-regression of HtrA1 protein: A. Sample size, B. % Female, C. Mean age of entire sample, D. Publication year (PDF 149 kb)


ADRB3) with both hypertension risk and blood pressure (BP) changes. A systematic search of three publicly-available databases was launched to look for articles published as of December 2016. Qualification appraisal and data extraction were independently done by two researchers. Pooled estimates were expressed as odds ratio (OR) or weighted mean difference (WMD), and their 95% confidence intervals (95% CIs). There were separately 21 (3750/4225 patients/controls) and 17 (6100 subjects) individual studies for hypertension risk and BP changes. Integral analyses revealed that Trp64Arg mutation was associated with the significantly increased risk of hypertension, and particularly, the 64Trp/64Arg heterozygote carriers were 1.23-times more likely to develop hypertension compared with the 64Trp/64Trp homozygote carriers . Publication bias was extremely low for all integral comparisons. In stratified analyses, significance was spotted in populations of Chinese descent, in retrospective studies, in hospital-based studies, in age-matched case-control studies, in studies enrolling patients with mean body mass index < 25 kg/m2 and in studies with total sample size ≥ 240. Heterogeneity was improved for most stratified comparisons. Further in hypertensive patients, the 64Trp/64Arg heterozygote carriers had significantly higher systolic  and diastolic  BP than 64Trp/64Trp homozygote carriers. Altogether, ADRB3 gene Trp64Arg mutation was significantly associated with an increased predisposition toward hypertension and elevated systolic/diastolic BP in hypertensive patients, suggesting that Trp64Arg is an important hypertension-susceptibility marker.This meta-analysis was implemented to test the association of a missense mutation, Trp64Arg, in β3-adrenoreceptor-encoding gene ( Obesity in humans is well acknowledged as the most important, independent risk factor for hypertension . SpeakinADRB3, on chromosome 8p11.23) is rs4994, a missense mutation in the 64th position that substitutes a tryptophan with an arginine, termed as Trp64Arg. This substitution can alter the affinity of β3-adrenoreceptor to norepinephrine and its interaction with G-proteins in adipocytes [ADRB3 gene Trp64Arg polymorphism with hypertension risk and the changes of relevant intermediate phenotypes, such as blood pressure, body mass index (BMI) and fasting insulin [ADRB3 gene Trp64Arg polymorphism with both hypertension risk and blood pressure changes using existing publications.There is evidence that β3-adrenoreceptor expression is partly under genetic control . The extipocytes . Since t insulin . HoweverADRB3 gene Trp64Arg polymorphism with hypertension risk [Using the prescribed keywords, a total of 201 publications in the English language were identified from searching three publicly-available databases. Among them, only 23 publications met preset inclusive criteria , 10–31. ion risk , 26, 28,In view of a low frequency of 64Arg/64Arg homozygote and to avoid a fluctuated estimate, the risk prediction of Trp64Arg polymorphism for hypertension was investigated separately under the allelic, heterozygote-genotypic and dominant models.ADRB3 gene Trp64Arg polymorphism was associated with the significantly increased risk of hypertension under three genetic models mentioned above, in company with moderate or marginally significant heterogeneity as gauged by the I2 statistic , with moderate heterogeneity (I2 = 46.9%). In addition, the genotype distributions of ADRB3 gene Trp64Arg polymorphism deviated from the Hardy-Weinberg equilibrium in 4 studies, exclusion of these 4 studies generated the very similar effect estimates, with slightly improved heterogeneity.The mean frequency of 64Arg allele was 15.86% in patients and 14.18% in controls, with the statistical power to detect the difference of being 83.74%. Integral analyses of 21 individual studies revealed that the mutation of P = 0.705, 0.731 and 0.999 for the allelic, heterozygote-genotypic and dominant models, respectively).Regarding publication bias, the likelihood of significance was extremely low for the three genetic models mentioned above, as supported by the symmetrical Begg's funnel graphs Figure , 3C, 3E Because the heterogeneity in integral analyses was moderate or significant, a string of stratified analyses and meta-regression analyses were implemented to look for the possible reasons in explanation of between-study heterogeneity from other demographic and methodological aspects. In stratified analyses, 21 qualified studies were grouped per ethnicity, study design, source of control populations, genotyping methodology, age-matched condition, BMI in patients and total sample size respectively under the allelic, heterozygote-genotypic and dominant models (Table n = 9) for the association of Trp64Arg polymorphism with hypertension risk under all three genetic models, and no evidence of heterogeneity occurred . By study design, the risk prediction was only significant in retrospective studies (n = 17), with moderate heterogeneity. By source of controls, effect-size estimates were potentiated in hospital-based studies (n = 13) relative to population-based studies (n = 8), especially under the heterozygote-genotypic and dominant models, and there was moderate evidence of heterogeneity. By genotyping methodology, studies using RFLP (restriction fragment length polymorphism) technique reported a significant association of Trp64Arg mutation with hypertension under all three genetic models, and this association was biased by significant heterogeneity. By age-matched condition, the mutation of Trp64Arg polymorphism was significantly associated with the increased risk of hypertension in studies involving age-matched hypertensive patients and normotensive controls (n = 7), and the probability of heterogeneity was considerably improved under the heterozygote-genotypic (I2 = 5.8%) and dominant (I2 = 25.5%) models. By mean BMI in patients at a cutoff value of 25 kg/m2, the risk prediction of Trp64Arg polymorphism for hypertension was significant when analysis was restricted to the studies enrolling patients with mean BMI < 25 kg/m2 (n = 7) under the allelic , heterozygote-genotypic  and dominant , without heterogeneity . Finally, grouping studies by total sample size at the medium cutoff value of 240 found a robust association in larger studies (n = 10) between Trp64Arg polymorphism and hypertension risk under the allelic , heterozygote-genotypic  and dominant  models, respectively, and there was no detectable heterogeneity .When all studies were grouped by ethnicity, significance was only revealed in populations of Chinese descent (P > 0.05) (data not shown).Further meta-regression analyses, when modeling the baseline  and clinical  characteristics, failed to detect any significant contributions on the risk prediction of Trp64Arg polymorphism for hypertension under all three genetic models  and DBP  levels than those with the 64Trp/64Trp homozygote, with no detectable heterogeneity (both I2 = 0.0%). By contrast, BMI was 3.00 kg/m2 higher in normotensive controls possessing the 64Trp/64Arg heterozygote than the 64Trp/64Trp homozygote , without heterogeneity (I2 = 0.0%), while it was 0.70 kg/m2 lower in hypertensive patients. As for total cholesterol, normotensive controls with the 64Trp/64Arg heterozygote had a lower level than those with the 64Trp/64Trp homozygote , without heterogeneity (I2 = 0.0%). No significant changes were observed in FBG, fasting insulin and HDLC levels across Trp64Arg genotypes .Because of the close relation of β3-adrenoreceptor with obesity and lipolysis, besides blood pressure, the levels of other related intermediate phenotypes including BMI, FBG, fasting insulin, total cholesterol and HDLC were also compared across Trp64Arg genotypes. Considering a low frequency of the 64Arg/64Arg homozygote, the 64Trp/64Arg heterozygote is often combined with the 64Arg/64Arg homozygote when assessing the changes of these phenotypes across these genotypes. To avoid deviations from inadequate sample sizes, blood pressure and related intermediate phenotypes were only compared between carriers of the 64Trp/64Trp and 64Trp/64Arg genotypes  and Web of Science, was launched to look for articles published as of December 14, 2016. The prescribed MeSH key terms incorporated “β3-adrenoreceptor” or “β3-adrenergic receptor” or “beta3-adrenoreceptor” or “beta3-adrenergic receptor” or “β3-adrenoreceptor” or “ADRB3” or “3-BAR” or “beta3-AR” in the Title/Abstract, annexed with “hypertension” or “hypertensive” or “blood pressure” in the Title and “genetic” or “polymorphism” or “SNP” or “variant” or “mutation” or “genotype” or “allele” in the Title/Abstract. Search results were primarily confined to the English-only articles involving human beings, irrespective of races or ethnicities or study designs. Search scope was further expanded to include reference lists of the keywords-indexed results to avoid possible omissions. Search process was done by two researchers - Hualing Yang and Dongmiao Cai, and the final publication list was based on congregated results of two researchers by removing duplications with the EndNote citation manager software version X8 (Thomson Reuters).ADRB3 gene Trp64Arg polymorphism between hypertensive patients and normotensive controls or the mean and standard deviation of systolic blood pressure (SBP) and diastolic blood pressure (DBP) in mmHg, and when available other related intermediate phenotypes, including BMI, fasting blood glucose (FBG), fasting insulin, total cholesterol and HDLC across Trp64Arg genotypes; (iii) the genotypes of Trp64Arg polymorphism distinguished by validated methods. Two researchers - Hualing Yang and Dongmiao Cai, independently filtrated eligible articles from all keywords- and references-indexed search results per the inclusive criteria formulated above, and they also fixed all discrepancies with consensus.Inclusive criteria were determined by all listed authors of this study, from the following three respects: (i) study design: either retrospective or nested; (ii) genetic data: the genotype or allele distributions of A data-extraction table in Excel version 2016 was delineated by all listed authors, and extraction process was implemented by the same two researchers - Hualing Yang and Dongmiao Cai. The extracted data of interest contained the first author's family name, year of publication, country of samples collected, race or ethnicity of study subjects, study design, source of control populations, age-matched condition between patients and controls, genotyping methodology, sample size, age, gender, BMI, smoking, SBP, DBP, FBG, triglycerides, total cholesterol, high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol, the genotype or allele distributions of Trp64Arg polymorphism between patients and controls, and the mean and standard deviation of SBP, DBP, BMI, FBG, fasting insulin, total cholesterol and HDLC levels across Trp64Arg genotypes, where existing. Two independently-extracted tables were compared for divergence, and any disagreement was resolved through discussion.ADRB3 gene Trp64Arg polymorphism for hypertension was signified as odds ratio (OR) and its 95% confidence interval (95% CI), and the changes of blood pressure and other related intermediate phenotypes were signified as weighted mean difference (WMD) and its 95% CI. Individual effect-size estimates were combined under random-effects model adopting the method developed by DerSimonian R and Laird N [I2 statistic, a per cent number that can be interpreted as low (I2 ≤ 25%), moderate (I2 > 25% and I2 < 50%) or high (I2 ≥ 50%) [The risk prediction of  Laird N . Statist2 ≥ 50%) . Other s2 ≥ 50%) . The pro2 ≥ 50%)  in the SADRB3 gene Trp64Arg polymorphism in blood pressure regulation and in the pathogenesis of hypertension.The collective findings of this meta-analysis demonstrated that the mutation of Trp64Arg polymorphism was significantly associated not only with an increased predisposition toward hypertension, but also with elevated SBP and DBP in hypertensive patients, suggesting that Trp64Arg polymorphism might represent an important genetic marker in the development of hypertension. These findings will potentially further our understanding for the contributing role of


The aim of this study was used meta-analysis to investigate changes of serum tumor necrosis factor-alpha (TNF-α) in patients with type 1 diabetes mellitus (T1DM).Relevant literatures were identified from PubMed, Cochrane Library, CNKI, WanFang and Chinese-Cqvip databases . Eligible reports were included for pooled analysis of serum TNF-α level and subgroup analysis was performed in relation with age, disease duration and ethnicity.P < 0.001). Similar results were also found among all subgroup analysis of different age, disease duration and ethnicity (with the exception of Asian) . Regression analysis indicated that age (P = 0.680), disease duration (P = 0.957), and ethnicity (P = 0.526) of patients were not significant impact factors for the high heterogeneity. The results were stable according to the sensitivity analysis and no publication bias existed in this meta-analysis.A total of 23 articles  were included for this meta-analysis. Compared with the controls, the patients had significantly increased serum TNF-α level (Serum TNF-α level in T1DM patients has significantly elevated among all age, disease duration and ethnicity groups. Type 1 diabetes mellitus (T1DM) is a systemic disease leading to abnormal fat, carbohydrate, and protein metabolism due to insulin deficiency –5, whichThe role of inflammation in diabetes mellitus (DM) has recently been implicated  and thatTumor necrosis factor-alpha (TNF-α) produced by activated macrophages, CD4+ lymphocytes, natural killer cells, neutrophils, mast cells, eosinophils and neurons, is a cytokine involved in systemic inflammation and always results in acute phase reaction . TNF-α mThis study was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) criteria . The worAll related articles were reviewed using the criteria as follows: (1) Studies focusing on the change of serum TNF-α level in T1DM patients; (2) Case-control research; (3) Patients used insulin alone; (4) Data expressed as Mean ± SD; and (5) Definitions of T1DM met the criteria recommended by the World Health Organization .Exclusion criteria: (1) For duplicated studies and reports, we only included the latest paper into our final analysis; (2) Animal studies, reviews, editorials, case reports, and personal experience summaries; (3) No healthy controls in the study; (4) Original data displayed as figures or no original data reported; and (5) Inconsistent with the inclusion criteria as described above.The Newcastle-Ottawa Scale (NOS) was used to assess the quality of all eligible studies  and the P < 0.1 or I2 > 50%, we selected a random-effect model to account for possible heterogeneity between studies; otherwise a fixed-effect model was used in the absence of heterogeneity [P < 0.05 was considered representative of statistically significant publication bias) [We extracted the data  to clarify the change of TNF-α in T1DM patients versus controls, followed by Chi-squared Q test and I2 statistics to estimate the heterogeneity , 31. Wheogeneity , 33. In on bias) . Stata 1The study selection process was displayed in P < 0.001) (P < 0.001) existed in this meta-analysis.The T1DM patients had significantly increased serum TNF-α level compared with the controls   and signP < 0.01) (P < 0.05) (P < 0.05) except Asia group   , and thr < 0.05) , and fou= 0.439) .P = 0.680), disease duration , and ethnicity of patients , which indicated that age, disease duration, and ethnicity of patients were not significant impact factors for the high heterogeneity in this meta-analysis.Regression analysis was used to explore the source of high heterogeneity of age, disease duration, and ethnicity for the serum level of TNF-α, and the results displayed as follows: age   .TNF-α is highly involved with macrophage activation and increased serum TNF-α level have been observed in insulin resistance stages and diabetes mellitus development , howeverTNF-α level may play an important role and many factors may contribute to the serum TNF-α level in diabetes. TNF-α, as the major physiological and pathophysiological regulators of vascular adhesion molecules, is a key proinflammatory cytokine with widespread metabolic effects, and directly regulate the production of several cardiovascular risk factors , 50. TNFOwning the various biological effects, TNF-α has been proved to have certain catabolic effects on fat cells, and neutralization of TNF-α in obese rats causes a significant increase in the peripheral uptake of glucose in response to insulin, which indicates an important role in the insulin resistance and diabetes that often accompany obesity . TNF-α, Age, disease duration and ethnicity of T1DM patients were focused on in this study. In a previous study , serum TSignificant heterogeneity still existed after subgroups analysis and regression analysis indicated that these factors were not potential sources for the high heterogeneity, and we assume that sources of heterogeneity may be attributed to the diversity in design, sample sizes, measurement errors and so on. Otherwise, sensitivity analysis indicated the results were stable and no publication bias existed in this meta-analysis.Several limitations should be considered when cautiously interpreting the results. Firstly, we could not conduct further subgroup analyses such as by gender, body weight and other factors because of insufficient original data. Secondly, only reports in English and reports in Chinese were chosen and eligible studies might have not been unpublished or published in other languages. Small sample size, limited statistical power and high heterogeneity of the included studies could also influence the results. Furthermore, some reports included in this meta-analysis failed to disclose the status of diabetic complications, which may have impact on the results. All these limitations should be kept in mind when interpreting the findings.In summary, the present meta-analysis indicates that compared with the healthy controls, the T1DM patients have significantly increased serum level of TNF-α. The role of TNF-α in the development of diabetes and diabetic complications warrant future investigation.S1 Appendix(DOC)Click here for additional data file.S1 Table(DOC)Click here for additional data file.


An increasing number of publications are drawing attention to the associations between six common polymorphisms in HOX transcript anti-sense RNA (HOTAIR) and the risk of cancers, while these results have been controversial and inconsistent. We conducted an up-to-date meta-analysis to pool eligible studies and to further explore the possible relationships between HOTAIR polymorphisms  and cancer risk.A systematic retrieval was conducted up to 1 July 2017 in the PubMed, Web of Science, and CNKI databases. Eighteen eligible publications including 45 case-control studies with 58,601subjects were enrolled for assessing the associations between the 6 polymorphisms in HOTAIR and cancer risk. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were analyzed to reveal the polymorphisms and susceptibility to cancer. All the statistical analyses were performed using STATA 11.0 software.The pooled analyses detected significant associations between the rs920778 polymorphism and increased susceptibility to cancer in recessive, dominant, allelic, homozygous, and heterozygous models. For the rs7958904 polymorphism, we obtained the polymorphism significantly decreased susceptibility to overall cancer risk among five genetic models rather than recessive and homozygous models. For the rs12826786 polymorphism, we identified it significantly increased susceptibility to cancer risk in all genetic models rather than heterozygous models. However, no significant association was found between the rs1899663, rs874945, and rs4759314 polymorphisms and susceptibility of cancer.These findings of the meta-analysis suggest that HOTAIR polymorphism may contribute to cancer susceptibility.The online version of this article (10.1186/s12199-018-0697-0) contains supplementary material, which is available to authorized users. In p53 complex signaling pathways, Grossi et al. reported that some lncRNAs can directly or indirectly regulate p53 activity leading to upregulation or downregulation of p53 expression [Long non-coding RNAs (lncRNAs) are a class of particular no-coding RNA molecules with lengths of more than 200 nucleotides (nt), which are mainly produced by RNA polymerase II (RNA pol II) transcription, lack of protein-encoding function, and an open reading frame , 2. Sevepression . In addipression .HOTAIR) is located on between the HOXC11 and HOXC12 coding region in the chromosome 12q13, which consists of five short exons and one long exon [HOTAIR has been indicated in breast cancer [HOTAIR regulates the expression of genes by specifically binding different histone-modified complexes. As one of the regulators of oncogene transcription, HOTAIR remodels PRC2 and desmethylase LSD1 complexes by recruiting chromatin to cause demethylation of Histone H3K27em3, silence of HOXD gene expression, ultimately facilitate tumor proliferation or metastasis at the epigenetic level [HOTAIR also could form regulation network of ceRNAs with miRNA to participate in carcinogenesis of different cancers. Moreover, HOTAIR also acts as miRNA sponge in combination with miR-331-3p or miR-124 [HER2 and other relevant genes and activation of Akt signaling pathway, which could simultaneously interact with p53 pathway to promote proliferation, invasion, and metastasis of tumor cell [HOTAIR was intricately related to various cancers.HOX transcript anti-sense RNA  in rognosis , and clirognosis  and trearognosis . Recentl cancers –29, estr cancers , 30–33,  cancers , glioma  cancers , pancrea cancers , prostat cancers , and ost cancers . Herein,HOTAIR OR lncRNA HOTAIR OR HOTAIR,” “polymorphism OR variation OR mutation,” and “cancer OR carcinoma OR tumor OR malignancy OR neoplasm OR lymphoma OR leukemia.” Moreover, this study further retrieves the references lists of eligible studies to guarantee that all qualified studies are included in the meta-analysis.Eligible literatures were systematically retrieved in several authoritative databases including PubMed, Web of Science, and CNKI databases to search comprehensive and systematic publications up to 1 July 2017, with the following keywords including “long non-coding RNA HOTAIR polymorphisms or genetic variations and the risk or susceptibility of various cancers, (b) case-control designed studies with genotypes distribution of controls followed Hardy–Weinberg equilibrium, (c) studies with available or adequate genotype data for calculation of the odds ratio (OR) with 95% confidence intervals (95% CIs). The main criteria for excluding unqualified researches were as follows: (1) did not focus on cancer risk or susceptibility, (2) did not involve the several HOTAIR SNPs , (3) did not present the sufficient genotype frequency data of cases and controls. Ultimately, a total of 18 articles consist of 14,119 cases and 16,295 controls were included in this meta-analysis (presented in Table Included criteria of eligible studies were as follows: (a) studies estimating the associations between lncRNA follows:  did not P value of Hardy–Weinberg equilibrium (HWE) of control group, adjusted factors in the statistical analysis for each publication, and assessment of article quality. Two investigators reached a consensus on the basis of discussion when they have different opinions.Two investigators (L.J. and L.X.) independently gathered the following information from each qualified publication: the first author’s name, year, country, and ethnicity of eligible publication, type of neoplasm, source of control, genotyping method, numbers of cases and controls, distribution of genotype frequencies as well as allele for cases and controls, Two investigators individually assessed the quality of all included studies according to the Newcastle-Ottawa scale (NOS), and the scale totally comprises subject selection, comparability of cases, and controls as well as ascertainment of exposure.Q test and I2 test were used to examine the heterogeneity between each study, and the random effect model is used to combine the relevant studies when I2 is greater than 50%, otherwise, using a fixed-effect model and merged odds ratio (OR), and 95% confidence interval (95% CI) to evaluate the relationship between cancer risk and HOTAIR polymorphisms. In the current study, sensitivity analysis is to evaluate whether a single study would impact the overall effect value of the integrated researches. Begg’s funnel plots and Egger’s test was performed to uncover underlying publication bias by means of Stata 11. All calculations of the present meta-analysis were operated with Stata 11. P < 0.05 was uniformly regarded as a significant difference.Chi-square test was conducted to evaluate whether genotype distribution of the control group follow HWE. HOTAIR SNPs and cancer risk were presented in Table HOTAIR rs4759314 in 13 studies [The main characteristics of 20 articles on relationship between 6  studies , 36, 37, studies , 31–35,  studies , 30, 38, studies , 27, 29  studies , 34, 37, studies , 35, 37  studies , 24, 26, studies , and 3 oI2 = 13.0%; TT vs.CC: OR = 2.289, 95% CI = 1.815–2.887, I2 = 54.3%; CT + TT vs. CC: OR = 1.422, 95% CI = 1.322–1.529, I2 = 31.10%; TT vs. CT + CC: OR = 2.028, 95% CI = 1.641–2.506, I2 = 57.90%; T vs. C: OR = 1.414, 95% CI = 1.336–1.497, I2 = 48.2%) models. Additionally, the similar relations were obtained both in cancer type (including estrogen-dependent cancers and digestive cancers) and source of controls subgroup. The heterogeneity was conspicuously reduced in both Caucasian and Chinese population according to the results of Table There were a total of 12 eligible case-control studies with 6187 cases and 6897 controls that focused on the associations of rs920778 C>T and cancer risks after excluding the 4 studies  that their controls did not meet HWE as shown in Table I2 = 48.20%; CT + TT vs. CC: OR = 1.233, 95% CI = 1.044–1.456, I2 = 29.50%; TT vs. CT + CC: OR = 1.551, 95% CI = 1.186–2.027, I2 = 40.50%; T vs. C: OR = 1.237, 95% CI = 1.092–1.401, I2 = 34.90%) models, and the associations were similar with the results of hospital-based control subgroup. Moreover, we reanalyze after excluded one study of non-satisfying HWE, the heterogeneity of the merged studies is not improved.For the rs12826786 C>T, this is first meta-analysis to evaluate the relationship in whole population by pooling 5 published studies comprising 1048 cases and 1432 controls. The results of the pooled analyses distinctly indicated that rs12826786 genetic variation was increased with susceptibility of cancer in recessive, dominant, allelic, and homozygous models rather than recessive and homozygous models, and a similar results was obtained in digestive cancers, hospital-based control and MALDI-TOF-MS subgroup. In addition, the heterogeneity of both digestive cancers and MALDI-TOF-MS subgroup was significantly lower than the other subgroups.For the rs7958904 G>C, 6 eligible studies in Chinese population, totally consisting of 5123 cases and 5701 controls after excluded 1 study (Zhou-b) that genotype distribution of their controls did not conformed to HWE. Overall, we identified a significantly decreased susceptibility to overall cancer risk in all genetic  was observed significantly decreased compared with other subgroups. In the study, Fig. P values of t test > 0.05, and the all relevant 95% CIs, including 0, were not listed. These statistical results further supported for the absence of publication bias in five genetic models, and so our results remained credibly and reliably.Results of sensitivity analysis of six polymorphisms identified that any single study not qualitatively changed the all pooled ORs in five genetic models, which indicated that all the results of our meta-analysis remained robust and stable in both Asian and Caucasian population, the results of the heterozygous model are shown in Additional file HOTAIR polymorphisms , and most of which included all studies and did not take into account the rejection of studies that the genotype distribution of controls did not conform to the HWE except Lv et al.’s study [HOTAIR with cancer risk. Overall, the results provided that rs920778, rs7958904, and rs12826786 but not rs4759314, rs1899663, and rs874945 loci are related to cancer risk among Caucasian and Asian populations, among of which rs920778 and rs12826786 increase and rs7958904 decreases cancer risk, respectively. To some extent, these findings denoted that the polymorphisms in HOTAIR may be related to the development of varieties of cancers and offered a novel and compelling evidence for functional analysis of the effects on susceptibility loci to diseases.Previously, there have been several meta-analysis –41 to po’s study . Among tHOTAIR, a functional trans-acting lncRNA specifically transcribed from the HOXC gene, which is situated the antisense strand within the intergenic region between HOXC11 and HOXC12 on chromosome 12 [HOTAIR, and all these evidences have confirmed that HOTAIR expression lead to malignant transformation of normal cells in varieties of cancers such as ovarian cancers [HOTAIR may also be related to cancer risk by modifying the secondary structure of HOTAIR then indirectly involved the relevant signaling pathways. Recently, several lines of published studies have researched the associations of HOTAIR polymorphisms with different cancers susceptibility, whereas their conclusions are discordant. Regarding the HOTAIR rs920778, Zhang et al. identified the SNP impacts HOTAIR expression via the gene intronic enhancer, which is located in between + 1719 bp and + 2353 bp from the transcriptional start site, with higher HOTAIR expression among T allele carriers, through reporter assays, which might be a potential genetic basis or mechanism for altering susceptibility of ESCC [HOTAIR gene, Guo et al. reported that subjects carrying the rs12826786 TT genotype existed a remarkably elevated level of HOTAIR expression than those with the CC genotype in GCA tumor tissue [HOTAIR then affecting the expression of the gene and ultimately impacts the susceptibility of various cancers. Rs7958904 genetic polymorphism, which is located on the exon of HOTAIR gene, we identified the SNP significantly decreased susceptibility to overall cancer risk in all genetic models rather than recessive and homozygous models. Jin et al. also obtained that the rs7958904 CC genotype increased risk of cervical cancer compared with the GG genotypes on the grounds of functional assays, which showed patients with rs7958904 CC genotype existed higher HOTAIR expression than with GG genotype [HOTAIR structure [HOTAIR and HOXC11 expression levels were higher in subjects with the rs4759314 AG genotype than with AA genotype in GC tissues. Simultaneously, they further explored the SNP, in an intronic promoter region, influenced the activity of this promoter and contributed to the expression of HOTAIR and its downstream gene HOXC11 in a genotype-specific way by The Cancer Genome Atlas (TCGA) database, which is an underlying mechanism for GC susceptibility [osome 12 , 43, and cancers , 45, pan cancers , hepatoc cancers –48, and  cancers , 50 to a cancers , 52, whi of ESCC .These cor tissue , the resgenotype . Additiotructure . Besidestructure . Moreovetibility . HoweverHOTAIR polymorphisms how to contribute to cancer susceptibility, and therefore need to broaden the sample size in the Caucasian to further verify how HOTAIR polymorphism affects the susceptibility of the associated cancer. Third, we cannot further calculate gene-environment interactions or cumulative effects of genetic polymorphisms on account of not getting original data. Fourth, after excluding those that did not follow the HWE, the sample size of the included studies is too small for rs874945 polymorphism. Fifth, the adjustment of confounders between the original studies is inconsistent, and the study also cannot unify the adjustment of confounding factors  for all included case-control studies due to not obtaining detailed raw data. Finally, due to most of the original publications did not do gender-based stratification analysis, the study failed to perform subgroup analyses of gender. These deficiencies may fail to correctly reveal how HOTAIR polymorphisms affect the risk of cancer. Thus, pooled results of the presented comprehensive analyses should be elucidated cautiously.In the present meta-analysis, there existed a few limitations potentially. First, the study presented latent language bias due to all published studies only restricted in English. Second, analysis of stratification resulted in smaller sample size in the subgroup that affected statistical efficacy. For example, compared to Caucasian population, most of the studies included in the meta-analysis focused on Chinese population to estimate HOTAIR with rs920778, rs7958904, and rs12826786 might contribute to genetic susceptibility to cancer risk in overall population, whereas rs1899663, rs4759314, and rs874945 had no significant associations. In consequence, well-conducted studies with sufficient sample size are necessarily demanded to further test the association of the abovementioned polymorphisms in HOTAIR and cancer risk, especially in Caucasian and other types of cancers.The meta-analysis provided that three functional polymorphisms of Additional file 1:Table S1. Genotype frequency distributions of HOTAIR polymorphisms and cancer risk. (DOCX 38 kb)Additional file 2:Figure S1. Sensitivity analyses for HOTAIR polymorphisms and cancer risk in heterozygous model. (A) rs920778, (B) rs4759314, (C) rs7958904, (D) rs1899663, (E) rs874945, and (F) rs12826786. (JPEG 754 kb)


Hypertension has been associated with cognitive dysfunction in the general population and patients with Alzheimer’s disease (AD). However, there are contradictory data regarding the potential association between hypertension and diagnosis of Parkinson’s disease (PD), the second most common neurodegenerative disorder after AD. The purpose of this meta-analysis is to synthesize data from cohort studies to explore the potential association between preexisting hypertension and subsequent PD diagnosis.The PubMed and Embase databases were searched to identify all relevant studies. Two independent investigators performed the data extraction. Eligible cohort studies providing risk and precision estimates related to hypertension and PD were selected. Pooled risk ratios (RRs) with 95% confidence interval (CI) were calculated by using a random-effects model or a fixed-effects model. Sensitivity analyses after excluding one study at a time were performed to assess the stability of the results. Publication bias was assessed with Begg’s test and Egger’s test.Seven cohort studies were identified, including 3,170 persons who were confirmed to have developed PD and 339,517 participants who did not have PD during follow-up. The onset of hypertension before PD diagnosis was significantly associated with an increased risk of motor stage PD . This relationship was further confirmed by secondary analyses based on estimates adjusted for potential vascular confounders . After excluding one study at a time, the sensitivity analyses still showed that hypertension history was significantly associated with an increased risk of motor stage PD (RR with 95% CI ranging from 1.11 [1.075–1.35] to 1.42 [1.65–1.83]). No publication bias was observed in this meta-analysis.The findings of this meta-analysis suggest that hypertension may be a risk factor for motor stage PD, which may provide novel insights into the etiology and pathogenesis of this neurodegenerative disorder. However, large-scale well-designed studies that consider various confounders are still needed to further verify and clarify the association between hypertension and PD diagnosis. The incidence of Parkinson’s disease (PD), which is the second most common neurodegenerative disorder after Alzheimer’s disease (AD), rises rapidly with age and affects more than 1.7% of the population over 65 years of age . TraditiThe etiology of PD is largely unknown, which greatly hampers the development of novel preventive or therapeutic strategies for combating this neurodegenerative disorder. PD is a multifactorial brain disorder, in which both genetic and environmental factors play important roles. The inherited forms of PD account for only 10–15% of all cases, and the majority of PD cases are likely due to different combinations of environmental exposures and genetic susceptibility . HoweverAbnormalities in blood pressure (BP) due to autonomic dysfunction can occur even in the early stages of PD, often preceding the onset of the classic motor symptoms of PD . In addiOur meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement  and was The PubMed and Embase databases were searched to identify all relevant literature. The following search strategy was used: (“Parkinson’s disease” OR “Parkinson disease”) AND (“hypertension” OR “high blood pressure” OR “high blood pressures”) in Title/abstract. The subjects of studies and the languages of articles were limited to humans and English, respectively. If more than one article was found that used the same data, we included the study with the largest sample size only. We undertook a database search from April 15 to May 1, 2017.Studies meeting the following criteria were included in this meta-analysis: (1) evaluated the association between hypertension and PD risk; (2) had a cohort design; (3) had clearly stated diagnostic criteria for PD and hypertension; (4) the study population had no history of PD; and (5) the study reported at least a risk [relative risk (RR) or hazard ratio (HR)] with 95% confidence interval (CI) or provided sufficient data to calculate them.Studies were excluded if they met the following criteria: (1) cohort studies that lack the systematic case identification or have bias in patient ascertainment (for PD); (2) did not provide RR/HR and RR/HR could not be calculated from the results; (3) studies without original data such as comments, letters, or reviews; and (4) case–control study design. The case–control study design was not included mainly due to the high burden of orthostatic hypertension observed in PD patients , which mTwo authors (Liyan Hou and Liping Jiang) independently assessed the studies according to the inclusion/exclusion criteria and any discrepancies were resolved by discussion with senior authors (Qingshan Wang and Huihua Li). The extracted information included the first author, publication year, geographical location, study design, number of participants, sex ratio, follow-up duration, PD and hypertension diagnostic criteria, risk estimates for PD and analytical methods. The Newcastle Ottawa scale was used to access the methodological quality of the studies  by two aQ and I2 statistics  with 95% CI (5 studies), lacked a non-PD group (7 studies), lacked a hypertension-free group (1 study), or were case–control designs (15 studies). The excluded studies with the corresponding reasons for exclusion were presented in Figure Seven cohort studies published between 2007 and 2015 included 3,170 persons who met the criteria for PD diagnosis and 339,517 participants who had not met the criteria for PD diagnosis during follow-up. Among them, four studies reported that hypertension is associated with an increased risk of PD –27, wherP = 0.0000, I2 = 97.1%,) was observed, a random-effects model was chosen to calculate pooled RR and corresponding 95% CI. Pooled analysis based on adjusted estimates of seven cohort studies showed that hypertension history before the onset of PD was significantly associated with an increased risk of PD . In one study, researchers did not investigate whether vascular disorders could influence the combined estimates or not. The exclusion of this study still showed a significant association between hypertension and PD  was reduced 20.6% after adjustment for the possibility of confounding vascular factors. After exclusion of one study that did not investigate the effects of vascular disorders on the combined estimates, the impact of heterogeneity was further reduced 23.7%. Since the I2 (52.8%) was still slightly higher than 50%, meta-regression analysis was further used to explore the other sources of heterogeneity. However, all the variables, including publication year, number of PD diagnoses during follow-up, follow-up duration, and sex ratio, could not explain the source of heterogeneity.Substantial heterogeneity was noted in this meta-analysis. However, as seen in Figure The sensitivity analyses performed by excluding one study at a time revealed that hypertension history before the diagnosis of PD was significantly associated with increased risk of PD. The values of RRs with 95% CIs ranged from 1.11 [1.075–1.35] to 1.42 [1.65–1.83].P = 0.548 and 0.790 in Begg’s test and Egger’s test, respectively)  and a real causal relationship between factors is difficult to infer. Therefore, the prospective cohort study design is usually preferred in etiologic epidemiology, although it is more expensive and time-consuming than case–control study design.The subgroup analyses by ethnicity in this meta-analysis showed that hypertension was significantly associated with increased risk of PD diagnosis in the Asian population, but not in the Caucasian population. It is well documented that the prevalence of both PD and hypertension varies by ethnicity. Zhang and Roman  found thCurrently, the mechanisms for linking hypertension and motor stage PD have yet to be investigated. Since the pathogenesis of the selective dopaminergic neurodegeneration in the SN is obscure , the bioHypertension contributes to cognitive decline in both the general population and patients with AD. Previous studies suggested that increased BP is associated with increased brain atrophy, gray matter atrophy, and white matter injury , 52. RecSeveral potential limitations should be addressed for this meta-analysis. First, there were a limited number of eligible studies to obtain raw data regarding hypertension duration, levels of BP, and gender of PD patients for comparison. Our meta-analysis therefore could not provide detailed results on these issues. Second, substantial heterogeneity was observed in the meta-analysis. Although subgroup analysis revealed ethnicity as a potential reason for the heterogeneity, the interpretation of this finding should be cautious due to the small number of studies available for pooling. Meta-regression analysis for geographic locations, publication year, and number of PD individuals failed to reveal the source of heterogeneity, which suggests that other unknown confounders might be involved. Among the subjects, the use of antihypertensive drugs might be one of the important confounders. Nationwide Cohort Studies performed in Finland  and TaiwFurther well-designed studies with consideration of different levels of hypertension are still required to verify and clarify the association between hypertension and motor stage PD/PD diagnosis. In addition, the possible relation between ethnicity, PD diagnosis, and hypertension may warrant further investigation due to the different conclusions derived from the subgroup analysis by ethnicity. Furthermore, experimental studies are also needed to explore the biological mechanisms linking hypertensive status to PD.The results of the meta-analysis confirm and expand the already available evidence suggesting that hypertension may be a risk factor for motor stage PD/PD diagnosis, especially in Asian populations. This may provide novel insights into the etiology of this neurodegenerative disorder. However, more population-based prospective studies which consider various confounders  are still needed to clarify the association between hypertension and PD diagnosis. The results of the meta-analysis underline once more the importance of early diagnosis and correct treatment of hypertension, which may be especially challenging in those with preclinical and prodromal PD.LH and QW conceived the study and wrote the paper; QL and LJ performed the literature search and data extraction; HQ and CG analyzed and interpreted data; HL and J-SH revised the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.