The search strategy identified 912 papers, 22 of which were included in our meta-analysis. Having evaluated a total of 2,876,136 subjects, the results suggest a protective effect of dietary fibre intake on RC prevention. The effect Size (ES) was . Moderate statistical heterogeneity  was found. However, no publication bias was found, as confirmed by Egger’s linear regression test . The findings suggest that dietary fibre intake could be protective against RC, with a clinically relevant reduction of RC risk. Identifying preventive measures to avoid the development of RC, especially by following a healthy lifestyle including healthy diet, is pivotal.The aim of this systematic review and meta-analysis was to evaluate the association between dietary fibre intake and rectal cancer (RC) risk. In January 2019, a structured computer search on PubMed/Medline, Excerpta Medica dataBASE (EMBASE) and Scopus was performed for studies reporting the results of primary research evaluating dietary fibre intake in women and men as well as the risk of developing RC. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations were followed. Highest vs. lowest fibre concentrations was compared. The Egger test was used to estimate publication bias. Heterogeneity between studies was evaluated with I Colorectal cancer is the third most common cancer worldwide, after lung and breast cancer. It represents 10% of all cancers, excluding non-melanoma skin cancer, and it is the second leading cause of cancer-related death worldwide, accounting for approximately 1.8 million new cases and almost 900,000 deaths in 2018 ; on the Approximately one-third of cases of colorectal cancer are located in the rectum, and most of these are rectal adenocarcinomas . ColorecColon and rectum, in spite of their similar anatomical features and close contact, play different roles in the digestion process, and therefore have different underlying pathophysiological mechanisms. For instance, transit time is lower within the colon, compared to the rectum where the faecal mass is stored before expulsion through defecation. These differences, as well as the different homeostatic mechanisms, may play a role in the development of cancer, and should be taken into consideration when studying the colon and rectum. Nevertheless, even though several studies have investigated the association of plant food and fibre intake with colorectal cancer , only a limited number of studies have examined the possible associations of these dietary habits with rectal cancer.Although it is not easy to investigate rectal cancer alone, we performed a systematic review and meta-analysis aimed at estimating the potential association between dietary fibre intake and reduced risk of rectal cancer development.We performed this systematic review and meta-analysis following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines . A strucThe retrieved references had to report the results of primary research evaluating dietary fibre intake in women and men, as well as the risk of rectal cancer development, in order to be included in the systematic review. Furthermore, only studies published in English and for which the full text was available were included in the analysis. No time filter was added; animal model studies, non-original papers ; studies reporting different outcomes and data not expressed as risks  were excluded. Moreover, because our aim was to evaluate the effect of daily dietary fibre intake, studies investigating the effect of fibre supplementations were not included in the review. ® for Windows, was adopted in order to systematically record the main qualitative and quantitative data extracted from the included studies. The quantitative data recorded were: amount of fibre intake, sample size, duration of the study (expressed in years), and outcome (expressed as risk). When the adjusted estimated risks were available in primary studies, these were used preferentially. Body Mass Index (BMI), smoking behaviour, gender and age were the main confounding factors considered. Qualitative data included: name of first author, year of publication, country where the study was conducted and the modality to collect dietary information. Moreover, characteristics of the subjects were also recorded . Corresponding authors were contacted by e-mail when detailed information was not available. The reference lists were additionally screened in order to collect further related articles.All the collected studies were first screened according to the title and abstract. The full text was obtained only for potentially useful papers. Article screening and data extraction of the selected studies were conducted in double blind by two independent researchers (VG and TS). Any potential disagreement was solved through discussion between the two researchers. If the disagreement persisted, a third researcher was consulted. Data were collected only from articles satisfying the inclusion/exclusion criteria. A pre-defined spreadsheet, elaborated using Microsoft ExcelTwo researchers (VG and DN) independently undertook a quality evaluation of the included articles, using the checklist elaborated by The Cochrane Collaboration . The Coc2 and I2 tests. I2 values > 75% means high heterogeneity, while values between 50 and 75% are considered as moderate heterogeneity. If the I2 is between 25 and 50%, it is considered as low heterogeneity, and below 25% as no heterogeneity. The graphical evaluation of the Funnel plot and the Egger’s regression asymmetry test were used to estimate potential publication bias. Statistical significance was set at p < 0.10  based on 2,876,136 participants  was found. However, no publication bias was found, as demonstrated by the symmetry of the Funnel plot and confirmed by Egger’s linear regression test  (icipants a. Modera= 0.816) b.p-value = 0.005)] based on 2,440,460 participants, and moderate statistical heterogeneity  was found. No publication bias was found as confirmed by Egger’s linear regression test .In order to estimate the effect of fibre intake without potential overlapping cohort studies, two of the three multi-centric EPIC cohort studies were excluded. Bingham et al. 2003 and Bingham et al. 2005 were excluded, while Murphy et al. 2012 was included because it was the most recent EPIC study and the number of included countries was higher compared to the previous ones ,25,26. Mp-value = 0.042)] based on 1,479,569 men, with a moderate statistical heterogeneity  ] based on 495,222 women. However, no statistical heterogeneity was found . The funnel plot was symmetrical as confirmed by Egger’s linear regression test .The analysis including only studies that reported separate data for males obtained a pooled ES =  based on 2,867,781 individuals  was found. The Funnel plot was symmetrical, showing no potential publication bias, as confirmed by Egger’s linear regression test  , ividuals a. Modera= 0.501) b.p-value = 0.093)] based on 2,432,969 participants. Moderate statistical heterogeneity  was found. No publication bias was found, as confirmed by Egger’s linear regression test .Furthermore, because of the potential overlapping effect, we removed studies using the same cohort. A borderline, weak inverse association was found with an ES =  based on 8355 participants  was found. No publication bias was found as confirmed by the symmetry of the Funnel plot and by the Egger’s linear regression test  , icipants c. Modera= 0.596) d.p-value = 0.017)] based on 1,663,792 participants  was found. However, no publication bias was found as shown in the Funnel plot and confirmed by Egger’s linear regression test  , icipants a. Modera= 0.679) b.p-value = 0.079)] based on 1,110,491 subjects, with no statistical heterogeneity  (p = 0.367). When analysing only the studies conducted in America, a significant inverse association was found with an ES =  based on 1,541,364 subjects. A moderate statistical heterogeneity was found  (p = 0.663). Considering only the studies conducted in Asia, a borderline, weak, inverse association with an ES =  based on 224,281 subjects, with moderate statistical heterogeneity  was found (p = 0.371).The included studies were conducted in Europe, America and Asia. The analysis including only studies conducted in Europe obtained a borderline, weak, inverse association with an ES = . The consistency of this result has been confirmed after removing studies using same cohort population. The subgroup analysis by gender shows a higher protective effect for males, compared to females, although this could be due to the different sample size between the two groups: in fact, the analysis conducted among males involved a total of 1,479,569 men, compared to 495,222 females. Furthermore, the highest strength of the association between dietary fibre intake and rectal cancer was found focusing on case-control studies. This could be due to the natural history of rectal cancer, characterized by a long latency, which is better appraised using a case-control study design. Nevertheless, case-control studies are more prone to potential recall bias; however, the high number of participants included and the time frame of observation might mitigate this disadvantage. On the contrary, cohort studies are more prone to selection bias, and maintaining a follow up might be difficult, especially in studies where the outcome requires a long duration of the follow-up . BecauseEven though dietary fibre is resistant to human enzyme digestion, it does not pass through the intestinal tract without any effects. The protective effect of dietary fibre and the risk of developing rectal cancer have to be ascribed both to physical mechanisms and prebiotics effects. The gut microbiota is able to metabolize some toxic food compounds (for instance heterocyclic amines), which can be directly bound or transformed into less noxious elements, thus reducing the cancerogenic risk for the host’s intestinal epithelium. In addition to this, flourishing evidence shown a relationship between dietary fibre structure and fermentation rate. It seems that the fermentation rate is modified by the type and mixture of dietary fibres ingested. In particular, fast-fermenting fibres,  delay the fermentation of other gut bacteria , due to Alistipes, Akkermansia, Halomonas and Shewanella were related to rectal cancer [However, recent studies showed a different microbiota impairment in colon or rectal cancer. Indeed, a reduction of Lactobacillaceae was related to colon cancer, while a reduction in Bifidobacteriaceae abundance and a significant increase of the genus l cancer ,42. The l cancer . Thus, al cancer ,44.Therefore, intestinal health is based on the balance between host’s diet and pool of commensal microorganisms. The microbiota profile varies largely between individuals and, even though the healthy microbiota has not been completely defined yet, evidence has confirmed the impact of diet on this . Albeit,Before generalizing the results of this meta-analysis, some aspects need to be taken into consideration. Dietary fibre intake was mainly assessed through questionnaires, and even if FFQ is a consolidated method, not all the included studies used a validated questionnaire. Moreover, using an FFQ, recall bias cannot be excluded, while the food diary and the 24-hour recall are gold-standard tools. However, because the food intake is mainly self-reported, regardless of the instrument used, social desirability bias cannot be eliminated. Because of recall and social desirability bias, misclassification or under/over-reporting of fibre intake might result in a modified grade of association. Furthermore, no information on processing methods are reported in the original studies, and according to recent evidence, the processing method is associated with alteration of fibre microstructure that in turn is associated with changes in biological effects ,47. All In conclusion, our findings confirm the potential beneficial association between dietary fibre consumption and a reduced risk of colon cancer, particularly in men. Nutritional educational programmes should be improved in order to educate people on the major impact of diet on health and on the potential beneficial effects of having a healthy diet.


Helicobacter pylori infection (HPI) has been decreasing in developed countries, with an increasing prevalence of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) at the same time. The aim of our meta‐analysis was to quantify the risk of BE in the context of HPI.The prevalence of BE with data on prevalence of HPI from inception until December 2016. Odds ratios for BE in HPI were calculated by the random effects model with subgroup analyses for geographical location, presence of dysplasia in BE, and length of the BE segment.A systematic search was conducted in 3 databases for studies on BE cases and 390 749 controls. The overall analysis showed that HPI reduces the risk of BE; OR = 0.68 . Subgroup analyses revealed risk reduction in Asia OR = 0.53 , Australia OR = 0.56 , Europe OR = 0.77 , and North‐America OR = 0.59 . The risk was significantly reduced for dysplastic BE, OR = 0.37  for non‐dysplastic BE, OR = 0.51 , and for long segment BE, OR = 0.25  in case of HPI.Seventy‐two studies were included in the meta‐analysis, including 84 717 HPI is associated with reduced risk of BE. Subgroup analyses confirmed that this risk reduction is independent of geographical location. HPI is associated with significantly lower risk of dysplastic, non‐dysplastic, and long segment BE.This extensive meta‐analysis provides additional evidence that  The source of heterogeneity was one of the foci of their discussion and they concluded that both selection and information bias potentially contributed to their results.There are multiple individual studies, both with evidence for and against the risk reduction in case of HPI. In 3 of the 4 previous meta‐analyses, HPI proved to reduce the risk of BE.The above meta‐analyses have not published analytical results of subgroup analysis for geographical location of the study populations, for the segment length of the BE, and for the presence of dysplasia in BE. Our aim was to update the most recent meta‐analysis which included studies until 201022.1An epidemiological meta‐analysis and systematic review was performed using the Preferred Reporting Items for Systematic Review and Meta‐Analysis Protocols (PRISMA‐P).2.2A systematic search was conducted in PubMed, EMBASE, and COCHRANE databases, from inception to December 2016. Records were managed by EndNote X7.4, software  to exclude duplicates.PICO items of the strategy were: (P) adult population with BE, (I) past or current HPI, (C) patients without BE, and (O) prevalence of HPI with and without BE.Helicobacter pylori or H pylori or H. pylori or Helicobacter). Additional articles were identified from the reference lists of eligible primary studies.Keywords for the computer‐aided search were (Barrett's OR Barrett's metaplasia OR Barrett metaplasia OR Barrett's oesophagus OR Barrett's esophagus OR Barrett oesophagus OR Barrett esophagus) AND  and BE from the same population were thoroughly scrutinized and only one record with the highest number of BE cases was included in the meta‐analysis. Articles from identical populations where the prevalence of HPI was more detailed for different lengths of BE were excluded from the overall analysis, but they were included in the subgroup analysis for BE segment length. All types of observational studies, such as case control and cross‐sectional studies were included, regardless whether they were prospective or retrospective. Non‐human studies and review articles were excluded.2.4Numeric data were extracted by 3 investigators and manually populated onto a purpose designed Excel 2016 sheet . Data were collected on year of publication, study type, geographical location, number of cases and controls, and basic demographics  in both groups and method(s) of HPI testing. Most importantly, data were collected on the prevalence of HPI in BE cases and controls, also in dysplastic and non‐dysplastic BE and in different segment lengths of BE, for further subgroup analysis. Data on prevalence of HPI by CagA‐positive strains were also collected. Other relevant findings were mentioned in an additional column as free text. The data extraction was reviewed and conflicts were resolved by the first author.2.5Helicobacter pylori infection prevalence data from individual studies were extracted and raw data  were calculated, followed by the calculation of odds ratios (ORs) and 95% confidence intervals (CIs) for risk of BE in case of HPI. Adjusted ORs from the original articles were not extracted. Pooled estimates were calculated with random effects model using the DerSimonian‐Laird method.I2 statistics, where Q exceeds the upper tail critical value of chi‐square on k−1 degrees, and I2 represents the percentage of effect size heterogeneity that cannot be explained by random chance. As suggested by the Cochrane Handbook, I2 values were interpreted as moderate (30%‐60%), substantial (50%‐90%), and considerable (75%‐100%) heterogeneity.All calculations were performed by Stata 11 data analysis and statistical software .2.6The assessments of both the risk of bias and the risk of quality were done at the outcome level.A modified Newcastle‐Ottawa Scale for case control studies was used for the quality assessment of the individual studies included in our meta‐analysis, with the following items, and the result of the assessment was graphically demonstrated in a table with color codes, green: low risk of bias; yellow: moderate or unknown risk of bias; red: high risk of bias.The questions for the risk assessment were as follows:1Was the case definition clear? aYes, with positive endoscopic features of BE and supporting histology (green).bYes, without history of BE (yellow).cNo clear description of diagnosis of BE (red).2Were the BE cases representative? aYes, consecutive BE cases, without significant exclusion criteria (green).bNo, significant exclusion criteria or no description (red).3Was the selection of controls without selection bias? aYes, community controls (green).bHospital controls  (yellow).cNo clear definition of controls (red).4Was the definition of controls clear? aYes, with an endoscopy excluding BE (green).bNo or no endoscopic exclusion of BE (red).5Were the BE cases and controls comparable? aYes, with both age and sex matched (green).bYes, with age or sex (yellow).cNo (red).6H. Pylori test result, or vice versa? Was the investigator blind to the presence of BE, when reading the result of aYes, the study description clearly states it.bNo or no clear description.7Was the same method used to test HPI in BE and controls? aYes (green).bNo or no description (red).33.1Our search strategy initially identified 1705 potential studies. Removal of duplicates was followed by screening first the titles, and then the abstracts, leaving 96 studies for full‐text review, including 8 additional studies identified in the reference lists of the primary eligible studies.3.23.2.1P < .001) by the calculation from the data of the 70 studies, including a total of more than 90 000 BE cases and nearly 400 000 controls. Heterogeneity was substantial, I2 = 84.0%.Our results confirmed an overall risk reduction OR = 0.68 , 14 studies; in Australia, OR = 0.56 , 3 studies; in Europe, OR = 0.75 , 31 studies, and in North‐America, OR = 0.59  19 studies. The low number of studies with considerable selection and information bias from South‐AmericaSubgroup analyses showed risk reduction in Asia, OR = 0.56 . Fischbach et al calculated an OR = 0.38 (95% CI: 0.189‐0.781), and our result confirms their finding. The forest plot of this subgroup analysis is shown in Figure There were 4 additional studies reporting the prevalence of CagA‐positive HPI in relation to BE, in addition to the studies identified by Fischbach et al3.2.3Prevalence of HPI for different segment lengths of BE was detailed in 7 studies and data were suitable for meta‐analysis.P = .001). In SSBE, the pooled OR was not statistically significant, but there is likely a risk reduction, OR = 0.63 . The results on USSBE or intestinal metaplasia at the cardia are not suitable for any conclusion, but there does not seem to be a reduced risk. The results are detailed in Figure The risk reduction was statistically significant in the long segment BE (LSBE) subgroup OR = 0.25 . We note that the study by Henihan et alThe risk reduction was significant for dysplastic BE in case of HPI, OR = 0.37 . The results are detailed in Figure In non‐dysplastic BE, the risk reduction was also significant, OR = 0.51 . There was substantial and considerable heterogeneity among studies in all subgroups. The detailed results are shown in Figure Stratification by the different control groups was possible for 4 subgroups of studies with population, gastro‐esophageal reflux disease (GERD), endoscopy, and other controls as indicated in Table H. pylori testing method was possible for 4 subgroups of studies with histology from the stomach, histology from the esophagus, serology, and rapid urease test as indicated in Table H. pylori testing by histology from the stomach and serology. Heterogeneities in all subgroups are substantial, save for serology where the studies showed no significant heterogeneity . The detailed results are shown in Figure Stratification by the P < .001) with substantial heterogeneity . The detailed results are shown in Figure We identified 12 studies, which clearly stated that only new Barrett's cases were included or previously diagnosed BE cases were excluded.3.2.6P < .001, but not in the subgroup analyses on the CagA status (P = .188), the segment length of BE (P = .051), the presence of dysplasia (P = .16), and the newly diagnosed BEs (P = .465).The Egger's tests calculated significant publication bias in the meta‐analysis of all 70 studies, A visual inspection of the funnel plot of the overall assessment from the 70 studies revealed asymmetry, Figure 3.2.7The results of our quality and risk assessment by the modified Newcastle‐Ottawa scale for case control studies are shown in Table It is important to note that our meta‐analysis includes 78 studies of the meta‐analysis by Fischer and our quality and risk assessment revealed both selection and information bias, which had been reported by Fischbach et alLack of clear definition of BE. Although most of the studies defined it by endoscopy and histology findings at the same time, these diagnostic criteria show variability in time and place.The BE cases included in the studies were often limited by many exclusion criteria.We found only one study in which the controls truly represented the populationSelection of controls in endoscopy is necessary in the exclusion of asymptomatic Barrett's patients from the controls, but it means that these controls go through a gastroscopy with the purpose of investigating gastrointestinal symptoms, which most likely influences their prevalence of HPI even if there is no gastritis or ulcer disease. Patients with gastro‐esophageal reflux disease (GERD) formed the control group in several studies. This also results in bias, as there is convincing evidence that HPI reduces the risk of GERD.Comparability was poor in most of the studies, as only 23 of the studies had age‐ and sex‐matched cases and controls and an additional 7 of them had either sex‐ or age‐matched cases and controls. Some of the studies described significantly different proportion of races in the cases and controls and there is ample evidence that ethnicity influences the prevalence of both HPI and BE.Only 3 studies stated clearly that the investigators were blinded to BE when testing HPI or vice versa. In some of the articles, the study design suggested that the single pathologist involved was obviously aware of the BE and the HPI status when assessing the histology slides for BE and HPI, while in other studies the endoscopist was aware of the BE diagnosis at the time when the rapid urease test was performed. However, the vast majority of the studies did not describe the process of HPI ascertainment; this is also a potential source of bias.Testing of HPI in the studies was performed by the same method in both groups in nearly all studies. However, some articles described alternative methods of HPI testing (ie positive result of rapid urease test and/or histology and/or culture and/or serology and/or stool antigen test) and it is not clear what proportion of these tests were used in the cases and controls.44.1To date, this is the largest and most comprehensive meta‐analysis in this topic and includes data from 5 continents and 72 individual studies. To our best knowledge, this is the first meta‐analysis on the effect of HPI on the length of BE and the presence of dysplasia in BE.4.2Due to the limitations of the studies, the inconsistency of results, the indirect nature of the evidence, and the imprecision and reporting bias, the grade of evidence is low at best, based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool. Therefore, further research on this topic would very likely have an impact.4.3H. pylori testing method, and new diagnoses of BE revealed substantial and in cases considerable heterogeneity among the studies, apart from 3 subgroups in all analytical calculations.Our subgroup analyses for geography, CagA status, segment length of BE, dysplastic BE, control groups, There was no heterogeneity among studies from Australia, South America, and from studies where serology was used to detect HPI. In the subgroup of Australia and South America, the small subsets of studies, 3 and 2 respectively, caution us to conclude that geography accounts for heterogeneity. However, subgroup analyses with smaller or more accurately specified geographic areas could show different results.There were 6 studies in the subgroup with serology as the method of detection of HPI.4.4H. pylori in the pathogenesis of BE is often described as controversial.The role of H. pylori eradication therapy, in addition to bringing us closer to explaining the increasing incidence of BE.If we accept that HPI leads to risk reduction, the following question arises: What could be the cause or mechanism behind this inverse association? This question is not only important from a theoretical, but also from a clinical standpoint: understanding the mechanism is crucial for evaluating the risks and benefits of Helicobacter pylori infection is a proven risk factor for gastric non‐cardia adenocarcinoma and other cancers including lymphoma; however not much is known about its relationship with gastric cardia and EAC.H. pylori positivity, the incidence of non‐cardia adenocarcinomas is also falling.H. pylori on the gastric mucosa: the microorganism causes a corpus‐predominant gastritis, which leads to decreased gastric output. In this case, the esophagus is less exposed to the harmful effect of gastric acid, thus it has a reduced risk for developing BE and EAC.As to why and how exactly could HPI reduce the risk of BE development, several theories exist, but none of them are considered proven. Multiple articles attribute this fact to the effect of of H. pylori.H. pylori and BE reported an even stronger correlation when comparing only the CagA‐positive subgroup instead of all H. pylori‐positive patients.Several studies that did not find a negative correlation between HPI and BE only did so when looking at patients that were infected with a CagA‐positive subgroup Chow et al and Vaezi et al hypothesize that this phenomenon might be caused by the CagA‐positive sting's increased virulence toward gastric mucosa and results in a multifocal atrophic gastritis that also involves the destruction of gastric parietal cells, which further impairs acid secretion (more severely as compared to the CagA‐negative subgroup). Consequently, the reduced acidity of the reflux's convent reduces the risk of complications of GERD, such as BE and EAC.H. pylori lowers the risk of BE through the reduction of gastric acidity. They drew this conclusion because no correlation was found between gastric atrophy and EAC in their study; however, they did find a significant association between gastric atrophy and cardia adenocarcinoma.Contrary to this theory, based on a population‐based Swedish case control study, Ye et al speculates that it is unlikely that H. pylori and BE. They speculate that HPI is associated with reduced risk for obesity, thus not only reducing the likeliness for acidic reflux, but also the insulin level in the blood. This leads to the decreased production of Insulin‐like Growth Factor (IGF), which normally acts as an agent that potentiates the proliferation of Barrett's epithelium.H. pylori, BE is less likely to develop.In a meta‐analysis on the subject, Fischbach et al describes another theory that aims to explain the inverse relationship between H. pylori incidence is traditionally low; however, contrary to expectations, the incidence of BE and distal esophageal tumors is also below average.In contrast to these theories, Kountouras et al highlighted the conflicting nature of data available on this topic via editorial letters written in response to some previously cited articles. He mentions that in the Malay population, H. pylori might be a risk factor for BE, but also describes potential mechanisms to explain this positive connection. He states that H. pylori‐induced overproduction of gastrin contributes to neoplastic progression in Barrett's through pathway signaling. Furthermore, H. pylori also has a pro‐inflammatory effect that might also potentiate the said progression.He not only points to the fact that according to several studies H. pylori is what causes clinicians to pose the question that is penitently described as Hamletic by Zullo et alH. pylori, regardless of coexisting reflux esophagitis or BE. HPI needs treatment, when it is identified.According to our results and the majority of conclusions available in the literature, a persistent HPI would be desirable for the prevention of BE. However, it is exactly the aforementioned atrophic gastritis that acts as the main risk factor for gastric non‐cardia adenocarcinoma. This 2‐sided effect of H. pylori incidence might have other consequences, not necessarily limited to the field of gastroenterology. For example, H. pylori might have an effect in regulating ghrelin and leptin, 2 hormones produced (partly in case of leptin) by the stomach and related to metabolism regulation. The article suggests that with the continuous fall of H. pylori incidence, we might see an increase in diabetes and obesity due to the dysregulation of these hormones.An editorial in Gastroenterology elaborates on the possibility that the decline in P = .025), and Fischbach et alOur results confirm the conclusion of previous meta‐analysesIn summary, HPI is associated with a reduced risk of BE. Our new findings prove that the risk reduction in case of HPI seems to be independent of the geographical location and it is directly associated with the length of the BE segment and the presence of dysplasia in BE.No competing interests declared.Erőss B and Hegyi P designed the research and the study concept; Sarlós P, Szapáry L, and Tinusz B performed data extraction; Erőss B checked the data extracted, Farkas N analysed and interpreted the data; Erőss B and Tinusz B performed quality and risk assessment, Erőss B, Tinusz B, Farkas N, and Hegyi P wrote the article; Vincze Á, Sarlós P, Garami A, and Balaskó M supervised the study; Czopf L, Alizadeh H, Rakonczay Z, and Habon T conducted a critical revision of the manuscript for important intellectual content; all of the co‐authors granted final approval of the version of the article to be published. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file.


Type 2 diabetes mellitus is believed to be a polygenic disorder that develops as a result of a complex interaction between multiple genes and environmental factors. KCNJ11 gene encodes a Kir6.2 protein which forms the inner section of the potassium channels in pancreatic beta cells. Several studies found that KCNJ11 polymorphism increases T2DM risk. Our study aimed to investigate the association between rs5219 polymorphism of the KCNJ11 gene and T2DM in Syrian patients.This case-control study involved 75 T2DM patients and 63 healthy controls. The KCNJ11 rs5219 polymorphism was genotyped by Restriction Fragment Length Polymorphism (RFLP).P = 0.132). The frequency of the KK genotype was higher among the patients’ group (16% vs. 4.8%), and the frequency of the EK genotype was higher among the control group (45.3% vs. 66.6%); however, the differences were statistically insignificant. The KK genotype was significantly associated with T2DM in the recessive model with an OR of 3.81 .The frequency of the risk allele K was similar between the two groups (38.7% vs. 38.1%, This study showed that rs5219 polymorphism of the KCNJ11 gene is an important risk factor for type 2 diabetes mellitus in a sample of the Syrian population. The global rate of diabetes has increased significantly over the past two decades, reaching 451 million in 2017, and it is expected to reach more than 693 million in 2045 [T2DM is believed to be a polygenic disorder that develops as a result of a complex interaction between multiple genes and environmental factors. This genetic component is more likely to be due to single-nucleotide polymorphisms (SNPs) . StudiesSeveral studies have observed an association between KCNJ11 rs5219 polymorphism and T2DM risk. However, there are inconsistent results in previous studies in Asian populations –9, and tThe study is a case-control study. It included 138 participants of Syrian Arab ethnicity, aged above 40 years. The case group included 75 T2DM patients , who were diagnosed according to the American Diabetes Association criteria  or HbA1c ≥ 6.5%) . The conSamples of 5 ml venous blood (2 ml on a dry tube and 3 ml divided into two EDTA tubes) were taken after fasting for about 10 h. The dry tube was centrifuged at 1680 Xg for 10 min, and the glucose level was directly measured. The first EDTA tube was used to measure the hemoglobin A1c, which was stored at 4 °C for 2–7 days until the time of the assay, and the second was used to isolate the DNA and study the genetic variation.Glucose level was assayed by an enzyme-based method (Glucose Oxidase Peroxidase) using the Biosystems kit (Spain), and HbA1c was assayed by an ion exchange resin method using the Biosystems kit (Spain).DNA was isolated from the whole blood using the GF-1 Blood DNA extraction kit . The concentration and purity of the isolated DNA were measured using the Biospecnano device . The isolated DNA was stored at − 20 °C for polymerase chain reaction (PCR). KCNJ11-rs5219 polymorphism was genotyped by restriction fragment length polymorphism (RFLP), and PCR reaction was performed using TECHNE TC512, Gradient Thermal Cycler . A specific area of the KCNJ11 gene was amplified (210 bp) using PCR Master Mix (2X) , and the following primers:Forward: (5`-GACTCTGCAGTGAGGCCCTA-3’)Reverse: (5`-ACGTTGCAGTTGCCTTTCTT-3’)The PCR was carried out under the following conditions: Initial denaturation at 95 °C for 5 min, followed by 35 cycles of (a) 95 °C for 30 s (denaturation), (b) 60 °C for 30 s , (c) 72 °C for 30 s (elongation) and final elongation at 72 °C for 9 min.The amplified DNA fragments (210 bp) were digested using the BanII enzyme  at 37 °C for 2 h. The reaction volume (10 μl) contained 5 μl of PCR product, 1 μl 10X NEB buffer, 0.5 μl BanII enzyme and 3.5 μl nuclease free water. The digested products were separated by electrophoresis on a 2% agarose gel with ethidium bromide and visualized under a UV transilluminator.P-value <  0.05 was considered statistically significant.The statistical program (SPSS 16) was used for statistical analysis. The chi-square test was used to determine whether the genotype distributions were in Hardy-Weinberg equilibrium. The frequency of the genotypes and alleles were compared between the two groups using chi-square test. The odds ratios were calculated using a logistic regression model. The clinical and biological characteristics of the participants are summarized in Table . Signifil. index of purity ranged from (1.7 to 1.9).The DNA concentration of all samples ranged from 10 to 65 ng/μl with an average of 35 ng/ΜWhen a PCR reaction was applied, a band of DNA was produced with a length of 210 bp, .The frequency of (EE-EK-KK) genotypes for the patients’ group was (38.7–45.3% - 16%), and for the control group (28.6–66.6% - 4.8%), respectively. The difference between the two groups was statistically significant, .The frequency of (E – K) alleles was (61.3–38.7%) in the patients’ group, and (61.9–38.1%) in the control group, respectively. The difference was shown to be statistically insignificant, Homozygote model (KK vs. EE): OR: 2.483 Heterozygote model (EK vs. EE): OR: 0.502 Dominant model (EK + KK vs. EE): OR: 0.634 , (Table Recessive model (KK vs. EE + EK): OR: 3.81 .We found that the difference between the three genotypes of KCNJ11-rs5219 polymorphism (EE- EK- KK) in the two groups was statistically significant, . Consequently, the KK genotype is associated with an increase in the risk of T2DM by four times.When assuming a variety of models to evaluate the association between KCNJ11 rs5219 polymorphism and T2DM risk, the recessive model (KK vs. EE + EK) was associated with the T2DM risk with an OR of 3.81   which foIn a study of the Russian population, the KK genotype was associated with an increase in the risk of T2DM by two and a half times , and in It is known that T2DM is a complex disorder caused by the interaction of multiple genetic and environmental factors, and the effects of the same genetic factor on T2DM development are not the same among people, due to their difference in the environmental elements. Many people in Syria suffer from generally poor nutritional habits and a lack of health awareness, in addition to the stress that most people have suffered as a result of the years of war. As these strong environmental elements may increase the impact of the genetic factor in the risk allele carriers, this may explain the high-risk value (four times) in our study in a sample of the Syrian population compared to other populations.This is proven by Keshavarz et al , where tThe high-risk value may also be explained by the sample size (138 participants), which is small for such types of studies, as we noticed very big confidence intervals for odds ratio “OR 3.81 (95% CI 1.024-14.17)”. Therefore, the high-risk value may not reflect the reality accurately, and larger studies are needed.In the control group, we have excluded individuals with positive family history of T2DM and this could reduce the chance of the controls to have the SNPs conferring risks to T2DM, including KCNJ11- rs5219 polymorphism, and subsequently may lead to bias in the selection of individuals. This may also explain the high-risk value in our study.This study showed an association between rs5219 polymorphism of the KCNJ11 gene and type 2 diabetes mellitus in a sample of the Syrian population. This study supports the role of KCNJ11 rs5219 polymorphism in the pathogenesis of T2DM. Larger studies should be performed to confirm this result.


Hyperuricemia coincides with coronary artery calcification (CAC) development, but the role of serum uric acid (SUA) as a risk factor for CAC remains unclear. The objective of this study was to gain an insight into the association between SUA and CAC in adults by performing a meta‐analysis. MEDLINE, EMBASE, the Cochrane Library, and EBSCO (CINAHL) were searched for relevant observational studies published until 2 June 2019. Studies were included only if they reported data on CAC presence (Agatston score > 0) or progression related to hyperuricemia in subclinical adult patients. The pooled estimates of crude and adjusted odds ratios (ORs) and 95% confidence interval (CI) were calculated to evaluate the association between CAC presence or progression and hyperuricemia. A total of 11 studies were identified involving 11 108 adults. The pooled OR based on the frequency of CAC presence showed that patients in the high SUA group had 1.806‐fold risk for developing CAC (95% CI: 1.491‐2.186) under the minimal threshold of hyperuricemia (more than 6 mg/dL or 357 μmoL/L). When SUA levels were analyzed as categorical variables, the pooled estimate of adjusted ORs was 1.48 (95% CI: 1.23‐1.79) for CAC presence. Additionally, for each increase of 1 mg/dL of SUA level, the risk of CAC progression was increased by 31% (95% CI: 1.15‐1.49) with an average follow‐up duration ranged from 4.6 to 6.1 years. Hyperuricemia is closely associated with increased risk of CAC development and CAC progression in asymptomatic patients. The search included all studies published up to 2 June 2019, with no language restriction. The studies were manually screened. A full electronic search strategy (no limits) performed in MEDLINE can be reviewed in the Supporting Information 2.2The study inclusion criteria were: (a) adult subjects; (b) describing the association between hyperuricemia and CAC; (c) the definition of CAC presence determined as the Agatston score over 02.3Two reviewers (LL and XHH) independently screened the titles and abstracts to determine the inclusion of the studies. Full texts of the selected studies were read to further screen for eligible studies. Abstracts from conference or meetings were used to find the related published articles. Attempts were made to contact the original authors for additional details if necessary. Any discrepancy was resolved by a third reviewer (HLB) to reach a consensus.2.4Two reviewers (LL and XHH) independently extracted all data by using a standardized data abstraction excel file to retrieve information about studies features , participants information , cutoff levels for hyperuricemia, outcome definition, confounders, duration of follow‐up, the frequency of CAC presence, and ORs. The primary outcome was the risk estimate for the association between hyperuricemia and CAC. The secondary outcome was the risk for CAC progression. Given only observational studies were found, the Newcastle‐Ottawa Scale was applied for quality assessment2.5The conventional unit (milligram per deciliter) was used for all SUA levels. A conversion rate of 0.01681 (1 μmoL/L = 0.01681 mg/dL) was used to standardize all SUA levels. The cutoff values for hyperuricemia differed among studies (Table Based on the frequency of CAC presence (CAC score > 0) (among both hyperuricemia and normouricemia groups) for each study, the pooled estimates of ORs and 95% confidence intervals (CIs) were calculated to evaluate the crude relationship between SUA and CAC.As for the confounders, adjusted ORs in each study were combined to evaluate the association of SUA as a categorical variable for CAC prevalence. The prediction of SUA on CAC progression was performed by pooling adjusted ORs.I2 statistic. If I2 is <50% and P value is >.1, heterogeneity is acceptable. If I2 is >50% and P value is <.1, we would adopt random effect or a meta‐regression method to find sources for the obvious heterogeneity. To assess the potential publication bias, we conducted the visually symmetric funnel plot and quantified Egger test.We evaluated the presence of heterogeneity across trials by using the P value <.05 was considered statistically significant. All the statistical analyses were performed in Stata 15.1 .A two‐tailed 33.1The initial electronic database search identified 267 articles and there were 77 duplicates. A total of 124 irrelevant articles were excluded after screening by titles and abstracts. One case report and three letters were excluded. After reading the remaining 62 articles in full text, 11 studies3.2The characteristics of the included studies and their participants are summarized in Table 3.3I2 was 43.5% (<50%). In order to reduce the heterogeneity, the data with the minimal threshold level of hyperuricemia (more than 6 mg/dL or 357 μmoL/L) were used for further analysis. There was no change in the pooled result  under fixed model with no observed heterogeneity    which suggested that there was no serious small studies effect.The adjusted ORs extracted from seven studies3.5P = .013).The pooled evaluation of adjusted ORs for CAC progression based on three cohort studies4The results of our meta‐analysis provided a new insight into the association between SUA and CAC development in subclinical patients. We found that the odds of developing CAC were increased by 81% in patients with hyperuricemia. When the highest SUA category was compared with the lowest SUA category, the pooled adjusted estimate showed that the risk of CAC presence was almost 1.5‐fold. Moreover, the risk of CAC progression was increased by up to 1.31‐fold with an average follow‐up duration ranged from 4.6 to 6.1 years.SUA, a novel risk factor, has been associated with the development of subclinical cardiovascular disease (CVD).Since hyperuricemia is a risk factor for early stage of atherosclerosis, therapeutic agents targeting lower uric acid levels would be of interest. Colchicine is widely used, well tolerated, and effective for prevention and treatment of acute gout which is due to hyperuricemia. As uric acid crystals and cholesterol crystals are activated by the same pathway in the pathogenesis of atherosclerosis, colchicine can play a protective role in CVD patientsThere were several limitations in this meta‐analysis. First, a strong publication bias was observed with regards to CAC progression in only three cohort papers. The small sample size publication bias and null results unpublished bias may explain this publication bias. Second, the vast majority of selected 11 studies were conducted in developed countries. The results from this meta‐analysis may not be applied to under‐developed countries where different diet and lifestyle would affect the association. Third, although a multivariable adjustment was conducted in most of the included studies, confounding effects from other unadjusted risk factors may exist. Notably, none of the included studies has been adjusted for diet, which significantly influences the SUA level. Despite these limitations, this is the first meta‐analysis to analyze the relationship between hyperuricemia and CAC.5This systematic review and meta‐analysis showed an association between hyperuricemia and increased risk of CAC development and CAC progression in asymptomatic patients. Our findings suggested that patients with hyperuricemia should be monitored closely for coronary atherosclerosis.W.H.L. and Z.Q.Q. conceived and conceptualized the research idea. L.L., X.H.H. and H.L.B. performed the screening, full text assessment, quality assessment and data extraction and Z.Q.Q. approved the data. L.L. and X.H.H. did data analyses, Z.Y.L. contributed and Z.Q.Q. supervised the analysis. L.L. and X.H.H. framed the results and drafted the manuscript. K.R.B. and W.T. made revisions on the draft and approved the final version. Z.Q.Q. supervised the whole study process and is guarantor.Supporting informationClick here for additional data file.


FSHR) polymorphisms are implicated in premature ovarian insufficiency (POI) remains controversial. Thus, we performed this study to explore correlation between FSHR polymorphisms and POI in human beings.Whether follicle-stimulating hormone receptor  and 95% confidence intervals (CIs) were calculated.Sixteen studies were enrolled for analyses. No significant relationship with POI was found for rs6165 and rs6166 polymorphisms in overall analyses. Further subgroup analyses revealed that rs6166 polymorphism was significantly associated with the risk of POI in Asians with both FEM and REM. Nevertheless, we failed to detect any significant associations with POI for other ethnicities.FSHR rs6166 polymorphism may serve as a potential genetic biomarker of POI in Asians, but not in other ethnicities.Our findings indicated that  Premature ovarian insufficiency (POI) is currently defined as apparent deterioration of ovarian function before the age of 40 in human beings . It is cFSHR polymorphisms may result in dysfunction of FSH, lead to decreased ovarian function and give rise to the development of POI in human beings. The rs6165 and rs6166 polymorphisms are two commonly seen missense mutations of FSHR, the G to A transvertion at these two loci lead to amino acid residue substitution of the corresponding amino acid sequence, and thus these two polymorphisms may affect bonding of FSH and FSHR [FSHR polymorphisms in POI.FSH is a glycoprotein secreted by the pituitary gland, and it plays a crucial role in promoting follicle growth and regulating ovarian function by acting on the FSH receptor (FSHR) . Therefoand FSHR . Previouand FSHR , 10. ConThis meta-analysis was adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline . PotentiFSHR polymorphisms and POI in human beings; b. provide genotypic and/or allelic frequency of investigated FSHR polymorphisms; c. full text in English or Chinese available. Studies were excluded if one of the following criteria was fulfilled: a. not relevant to FSHR polymorphisms and POI in human beings; b. case reports or case series; c. abstracts, reviews, comments, letters and conference presentations. For duplicate publications, we only included the study with the largest sample size for analyses.To test the research hypothesis of this meta-analysis, included studies must meet all the following criteria: a. case-control study on correlation between FSHR polymorphisms in cases and controls. Additionally, the probability value  of Hardy-Weinberg equilibrium (HWE) test was also calculated.The following data were extracted from all included studies: (1) name of first author; (2) year of publication; (3) country and ethnicity of participants; (4) the number of cases and controls; and (5) the genotypic distribution of The Newcastle-Ottawa scale (NOS) was employed to assess the quality of eligible studies from three aspects: (1) selection of cases and controls; (2) comparability between cases and controls; and (3) exposure in cases and controls . The NOSTwo reviewers conducted data extraction and quality assessment independently. When necessary, the reviewers wrote to the corresponding authors for extra information or raw data. Any disagreement between two reviewers was solved by discussion until a consensus was reached.FSHR polymorphisms and POI in all possible genetic models, and a p value of 0.05 or less was considered to be statistically significant. Between-study heterogeneities were evaluated by Q test and I2 statistic. If p value of Q test was less than 0.1 or I2 was greater than 50%, between-study heterogeneities were considered to be obvious. Subgroup analyses by ethnicity of participants were subsequently conducted to obtain more specific results. Overall and subgroup analyses were performed with both fixed-effect models (FEMs) and random-effect models (REMs). Sensitivity analyses were carried out to test the stability of the results. Funnel plots were applied to evaluate possible publication bias.All statistical analyses in the present study were conducted with Review Manager Version 5.3.3 . ORs and 95% CIs were used to assess the strength of correlation between The literature search identified 63 potentially relevant articles. After exclusion of irrelevant and duplicate articles by reading titles and abstracts, 35 articles were retrieved for further evaluation. Another 19 articles were subsequently excluded after reading the full text. Finally, a total of 16 studies that met the inclusion criteria of our meta-analysis were included  and 13 studies about rs6166 polymorphism (640 cases and 1333 controls) were enrolled for analyses. No significant relationship with POI was found for two investigated polymorphisms in overall analyses. Further subgroup analyses by ethnicity revealed that rs6166 polymorphism was significantly associated with the risk of POI in Asians with both FEM  and REM . Nevertheless, we failed to detect any significant associations with POI for other ethnicities (see Table To investigate potential correlations between Sensitivity analyses were carried out to examine the stability of pooled results by eliminating studies that deviated from HWE. No changes of results were observed in any comparisons, which indicated that our findings were statistically reliable.Potential publication biases in the current study were evaluated with funnel plots. No obvious asymmetry of funnel plots was observed in any comparisons, which suggested that our findings were unlikely to be influenced by severe publication bias.FSHR polymorphisms and POI. The overall and subgroup analyses revealed that the rs6166 polymorphism was significantly associated with the risk of POI in Asians under additive comparison. But we failed to detect any positive results for other ethnicities. The stability of the synthetic results was subsequently evaluated in sensitivity analyses, and no changes of results were observed in any comparisons, which indicated that our findings were quite stable and reliable.To the best of our knowledge, this is so far the most comprehensive meta-analysis on correlations between There are several points that need to be addressed about this meta-analysis. Firstly, no obvious heterogeneities were detected in overall analyses for two investigated polymorphisms, which indicated that eligible studies could be considered as homogeneous, and thus synthesize the results of these studies is statistically feasible. Secondly, the pathogenic mechanism of POI is highly complex, and hence it is unlikely that a single gene polymorphism can significantly contribute to its development. Therefore, to better illustrate potential correlations of certain gene polymorphisms with POI, we strongly recommend further studies to perform haplotype analyses and explore potential gene-gene interactions.FSHR polymorphisms and POI may also be influenced by gene-gene and gene-environmental interactions. However, the majority of studies did not consider these potential interactions, which impeded us to perform relevant analyses accordingly [FSHR polymorphisms and POI could not be established. Taken these limitations into consideration, the results of the current study should be interpreted with caution.As with all meta-analysis, this study certainly has some limitations. First, our findings were based on unadjusted estimations due to lack of raw data, and failure to conduct further adjusted analyses for age, gender and co-morbidity conditions may impact the reliability of our findings , 14. Secordingly . Third, FSHR rs6166 polymorphism may serve as a potential genetic biomarker of POI in Asians, but not in other ethnicities. However, further well-designed studies with larger sample sizes are warranted to confirm our findings. Additionally, future investigations are needed to explore the potential roles of other FSHR polymorphisms in the development of POI.Overall, our meta-analysis suggests that the


This meta-analysis was performed to evaluate the relationship between hypoxia-inducible factor-1α (HIF1α) 1790G/A gene polymorphism and the susceptibility to renal cell carcinoma (RCC) and prostate cancer (PCa).Association investigations were identified and included from the Embase, Cochrane Library and PubMed databases on March 1, 2018, and eligible investigations were analyzed by meta-analysis. Odds ratios (OR) were used to express the dichotomous data, and the 95% confidence intervals (CI) were also calculated.In this meta-analysis, we found that the AA genotype of HIF1α 1790G/A was positively associated with the risk of RCC in overall populations, Caucasians, but not for Asians. G allele and GG genotype were not associated with the susceptibility of RCC in overall populations, Caucasians, and Asians. The G allele was negatively associated with PCa susceptibility in overall populations, Asians, but not for Caucasians. GG genotype was negatively associated with PCa susceptibility in Asians, but not for overall populations and Caucasians. HIF1α 1790G/A AA genotype was not associated with PCa susceptibility in overall populations of Caucasians or Asians.AA genotype of HIF1α 1790G/A was positively associated with RCC risk in overall populations and Caucasians. Furthermore, the G allele was negatively associated with prostate cancer susceptibility in overall populations, Asians, and GG genotype was negatively associated with PCa susceptibility in Asians. Renal cell carcinoma (RCC) is one of the most commonly occurring types of tumors in the urogenital system and accounts for ~ 85% of all kidney tumors –4. RCC iHypoxia inducible factor 1α (HIF1α) is the central regulator of the cellular response to low oxygen, and the activity of HIF1α is down-regulated in various human pathologies , 17. DurRetrieval of the relevant published reports were conducted in the electronic databases of Embase, Cochrane Library and PubMed on March 1, 2018, and eligible original articles were recruited into this meta-analysis. The key phrases for retrieval consisted of (“hypoxia-inducible factor OR hypoxia-inducible factor-1α” OR “HIF1α”) and .Inclusion criteria: (1) an endpoint of RCC, PCa; (2) two comparison groups (case vs. control); (3) the presence of detailed data for the genotype distribution.Exclusion criteria: (1) case reports, review articles and editorials; (2) preliminary results not on HIF1α 1790G/A gene polymorphism or RCC, PCa susceptibility; (3) investigations of the role HIF1α gene expression in disease.The following information from each eligible study was independently extracted by two investigators: first author’s surname, year of publication and the number of cases and controls for HIF1α 1790G/A genotypes. Frequencies of genotypes for HIF1α 1790G/A were calculated for each case group and control group, from the corresponding genotype distributions. The results were compared, and disagreement was resolved by discussion. Consistency of data extracted by the 2 researchers was evaluated and disagreements were resolved by discussion.P-value from the heterogeneity test was less than 0.1. Odds ratios (OR) were used to express the dichotomous data, and 95% confidence intervals (CI) were also calculated. A P < 0.05 was required for the pooled OR to be statistically significant. I2 was used to assess the heterogeneity among the included studies.All statistical analyses were performed using Cochrane Review Manager Version 5 . The pooled statistic was determined using the fixed effects model (Mantel-Haenszel method), and a random effects model (DerSimonian-Laird method) was conducted when the Four studies –23 were Four studies –27 were P = 0.006; Fig. P = 0.38; GG: OR = 0.63, 95% CI: 0.20–2.03, P = 0.44; Fig. In this meta-analysis, we found that the AA genotype of HIF1α 1790G/A was positively associated with RCC risk in overall populations (OR = 3.09, 95% CI: 1.38–6.92, P = 0.04; Fig. P = 0.05; Fig. P = 0.47; Fig. The G allele was negatively associated with PCa susceptibility in overall populations and Asians, but not for Caucasians (Overall populations: G: OR = 0.68, 95% CI: 0.47–0.99, In this in-depth meta-analysis, the results indicate that the AA genotype of HIF1α 1790G/A is positively associated with the risk of RCC in overall populations and Caucasians, but not for Asians. The G allele and GG genotype are not associated with the susceptibility of RCC in overall populations, Caucasians, and Asians. The G allele is negatively associated with PCa susceptibility in overall populations and Asians, but not for Caucasians. The GG genotype is negatively associated with PCa susceptibility in Asians, but not for overall populations or Caucasians. However, the HIF1α 1790G/A AA genotype is not associated with PCa susceptibility in overall populations, Caucasians or Asians.Previous, related meta-analyses have been conducted. Li et al.  reportedConsidering our results and the available literature, we suspected that the G allele and GG genotype were negatively associated with PCa susceptibility, and that the AA genotype was a risk factor to induce the onset of RCC. The hypothesis was as follows: Under both normoxic conditions and hypoxia, the HIF-1α G1790A gene polymorphism would be associated with increased transcription activities and enhanced angiogenesis compared to the wild type , 32. TheThere were some limitations in our meta-analysis, as the study sample sizes were low, and we did not explore sources of variability between studies such as adjusting variables, age distribution, and sources of controls. These results should be treated with caution.The present results support the hypothesis that the AA genotype of HIF1α 1790G/A is positively associated with RCC risk in overall populations and Caucasians. Furthermore, the G allele is negatively associated with PCa susceptibility in overall populations and Asians, and the GG genotype is negatively associated with PCa susceptibility in Asians. However, additional investigations are required to confirm these relationships.


The results were consistent both in animal protein intake and in vegetable intake on ovarian cancer. Subgroup analysis by study design did not find positive association either in cohort studies or in case–control studies. Egger’s test (P=0.230) and Funnel plot suggested no publication bias. Based on the obtained results, we conclude that high dietary protein intake had no significant association on ovarian cancer risk. Besides that, it is necessary to develop high quality, large-scale studies with detailed amount of dietary protein intake for verifying our results.The association between dietary protein intake and ovarian cancer had been inconsistent in the previous epidemiological studies. The aim of the present study was to identify and synthesize all citations evaluating the relationship on ovarian cancer with protein intake. The search included PubMed, Embase, and Web of Science from inception to June 2018. Two authors independently selected studies, extracted data, and assessed risk of bias. Relative risk (RR) and 95% confidence interval (95%CI) were calculated for relationship between the dietary protein intake and ovarian cancer risk using a random-effects model. Publication bias was evaluated using Egger’s test and Begg’s funnel plots. At the end, ten citations with 2354 patients were included in meta-analysis. Summarized RR with 95%CI on ovarian cancer was 0.915 (95%CI = 0.821–1.021), with no between-study heterogeneity ( Ovarian cancer is the most lethal gynecologic cancer. The American Cancer Society estimated 22240 new ovarian cancer cases and 14070 ovarian cancer deaths in 2018 [Previous meta-analyses had suggested that cruciferous vegetables intake , flavonoA comprehensive literature search was conducted on platforms of PubMed, Embase, and Web of Science. The last search was performed on June 2018. Free words adopted were as follows: (‘protein’ OR ‘nutrient’ OR ‘nutrition’ OR ‘dietary’) AND (‘ovarian cancer’ OR ‘ovarian tumor’). The reference lists of the full-text articles were manually examined to identify any additional publications relevant to our analysis. The language of publications was restrained to English.The inclusion criteria were as follows: (i) observational studies; (ii) evaluating the association between dietary protein intake and ovarian cancer; (iii) odds radio (OR) in case–control studies and relative risk (RR) in cohort studies and their 95% confidence interval (95%CI) for protein were reported in text or could be computed from given data; (iv) reporting the studies on humans; and (v) studies published in English language. The exclusion criteria were as follows: (i) animals study; (ii) letters or case reports; (iii) articles that provided inadequate information of interest or primary data; and (iv) published not in English.The course of study selection and data extraction was completed by two investigators independently. Excel database was used to extract the following information from included studies: first author’s name, publication year, study design, age, amount of cases and participants, country, protein type, categories of dietary protein, OR/RR with 95%CI on ovarian cancer risk, and adjustment for factors. Any resulting discrepancies were resolved by discussion with the two investigators together.P-values less than or equal to 0.05 were considered as statistically significant. Heterogeneity was examined by Q test and 2I test. P<0.1 in Q test or 2I > 50% indicated statistically significant heterogeneity [Statistical analyses were performed using Stata version 12.0 . RR and 95%CI were calculated to assess the association between dietary protein intake and ovarian cancer risk . Random-ogeneity . Publicaogeneity  and Beggogeneity .A total of 56482 citations were found from the databases and 4 additional records identified through other sources. There were 44781 records reviewed when the duplicates from different databases were removed. Consequently, 44743 citations were removed after viewing title and abstract. Furthermore, 28 citations were removed due to some reasons . At the I2 = 0.0%, P=0.708). Meanwhile, the relationship was not significant either in vegetable protein intake  or in animal protein intake . Nine of the ten studies were from North America, the summarized RR (95%CI) was 0.914 (95%CI = 0.807–1.036). The association of subgroup analysis by study design was not significant. The detailed results are shown in As shown in P=0.230). Publication bias was not found by Begg’s funnel plots , as wellWe conducted this first comprehensive meta-analysis to assess the association between dietary protein intake and ovarian cancer risk. Findings from the above results suggested that higher dietary protein intake compared with lower intake had no significant association on ovarian cancer risk. The association was not significant either in cohort studies or in case–control studies. Nine of the ten studies were conducted in North America, resulted a non-significant association between dietary protein intake and ovarian cancer risk.To our knowledge, protein contains 22 known amino acids. Nine of the 22 are essential amino acids, which cannot be synthesized in the body . Thus, pIn the overall analysis, there was no between-study heterogeneity as shown in Some potential limitations in the present study require attention. First, only English language publications were searched and only English articles were included, therefore, some other language studies were omitted in our analysis. However, no publication bias was found. Second, eight of the ten studies were case–control studies and only two were cohort studies. The retrospective nature of case–control studies and the possibility of bias, recall bias, and confounding factors cannot be excluded. Even so, case–control study was a very important epidemiological approach in the observational study. Otherwise, it is a requirement for evidence from prospective cohort studies. Third, almost all studies included in our analysis were from North America, and the result was consistent with overall pooled result. Therefore, our conclusions may be limited to the North American population and its implications in other populations need to be further investigated. Furthermore, more studies in other populations are wanted to assess dietary protein intake and ovarian cancer risk in the future.Based on the obtained results, we concluded that high dietary protein intake had no significant association with ovarian cancer risk. Besides that, it is necessary to develop high quality; large-scale studies with detailed amount of dietary protein intake for verifying our results.


Background and Objectives: Studies suggest that FAS/FASL polymorphisms are associated with male infertility; however, their results are still inconclusive. Therefore, this systematic review and meta-analysis aimed to summarize and clarify the overall association of FAS/FASL polymorphisms and risk of male infertility. Materials and Methods: Our search was conducted on the databases of Science Direct, PubMed and Google Scholar. For performing the meta-analysis, pooled odds ratio (OR) values with 95% confidence interval (CI) was applied in order to analyze the strength of association between the FAS/FASL polymorphisms and risk of male infertility. A total of seven relevant studies published up to September 2018 were considered. Results: FASL-844C/T genotype results of 559 patients and 623 healthy individuals were included in our study. For FAS-670A/G genotype effect, 751 patients and 821 healthy individuals were explored. Results showed that all analysis models including dominant, recessive and allelic models of FASL-844C/T and FAS-670A/G polymorphism had no significant effect on infertility in men . According to sensitivity analysis, our results were stable. Conclusion: We demonstrated that FAS/FASL polymorphisms might not be an effective factor on male reproductive health. For precise determination of FAS/FASL polymorphisms effects on male infertility, large-scale case-control studies should be performed. Recently, infertility has been increasing dramatically and it has become a major public health problem worldwide affecting about 15% of couples ,3,4,5. AFAS gene and -844C/T in the FASL gene, which might be related to the increased risk of various diseases such as cancer and infertility [FAS gene’s promoter region. Substitution of a G for A at -670 bp causes a mutation in the binding site of STAT1 transcription factor which leads to a decreased transcription level of this gene [FASL gene is associated with alterations in the binding motif of CAAT/enhancer-binding protein β element. A T for C substitution at the position of -844 on the other hand, may affect the expression levels of FASL gene [Because of the small sample sizes and various ethnic backgrounds in some of the already published studies, the existing results are contradictory. Hence, all qualified data needs to be retrieved in order to investigate whether genetic polymorphisms are associated with an increased risk of male infertility. During sperm maturation, several of the dysfunctional sperms are destroyed for which purpose apoptosis, both internal and external pathways, is the main event . On the ertility ,12,13. This gene . The FASASL gene .Several studies have reported an association between the polymorphisms of FAS-670A/G and FASL-844C/T and male infertility risk ,17. CurrResults from different studies were collected from electronic databases of Science Direct, PubMed and Google Scholar (updated March 2018). We used the combination of the key words as follows “polymorphism/genotype/variant”, “FAS/CD95/TNFSF6/APO-1”, “FASL/CD95L” and “male infertility/azoospermia/oligozoospermia/teratospermia”. Study selection criteria were: (1) studies of case-control; (2) studies on human beings, (3) investigation of relationship between the polymorphisms of FAS and/or FASL and male infertility risk, (4) presentation of sufficient data on the sample size, odds ratio (OR) with 95% confidence interval (CI).The exclusion criteria were those studies with no raw data for OR calculation with corresponding 95% CI, case-only, conference abstracts, editorials, case reports and review articles .p-value for Hardy–Weinberg equilibrium (HWE) as listed in Data was extracted from all qualified publications by two authors independently (R. Asgari and M. Bakhtiari) according to the above-listed inclusion and exclusion criteria. The following characteristics were extracted from enrolled studies: the first author’s name, year of publication, country, population ethnicity, genotype frequency for groups of cases and controls, sites of polymorphisms, minor allele frequency (MAF) and p < 0.05 was considered statistically significant. All calculations were performed by Medcalc and CMA 2 software. Finally, we determined the statistical power for all analysis models by PS , version 3.1.2.Hardy–Weinberg equilibrium and MAF were calculated manually. The strength of the association between FAS-670 and FASL-844 polymorphisms with the risk of male infertility was estimated by pooled OR with 95% CI using Der Simonian and Laird (random effects model) or Mantel-Haenszel method (fixed effects model) according to heterogeneity evaluation. Publication bias was identified by Begg’s test and Egger’s test. The level of A total of seven relevant publications, published between 2007 and 2017, were included in the present study. p-value < 0.05) [As shown in  < 0.05) . Additio < 0.05) ,17,18 su < 0.05)  demonstr < 0.05) ,17,20,21The distribution of FASL-844 variants in models of dominant, recessive and allelic was not significantly different between case and control groups A–C. Likep-value and OR were calculated according to random effects except for the recessive model of FAS-670A/G polymorphism .For both FASL-844C/T and FAS-670A/G polymorphisms significant heterogeneity was observed in dominant, recessive and allelic models (except for the recessive model of FAS-670A/G polymorphism) in case and control groups . This rap-value were not altered for FASL-844C/T polymorphism and our results were stable. Funnel plots, Begg’s test and Egger’s test were performed to assess publication bias, of which the results are illustrated in Sensitivity analysis was carried out using accumulative analysis and removing the one mentioned study to evaluate the effect of that individual study on the overall OR. This analysis indicated that ORs or p > 0.05). This result was consistent with the data from certain studies included herein. However, taking a closer look at the data, in the allelic model, the results were almost statistically significant . This is as good a point as any to mention that the difference between p-value cutoff and our p-values might have been avoided upon a larger number of the population studied.For the first time in the present meta-analysis, we studied the genetic relevance between FAS-670A/G and FASL-844C/T polymorphisms of different models and the risk of male infertility. Generally, the current study involved 955 infertile men and 1038 fertile men (as controls) from the populations of Iran, China, India, Turkey and Iraq. Herein, we investigated the role of these variants in male infertility under genetic models of dominant, recessive and allelic. Our combined results failed to find any statistically significant difference, mutation- or genetic-wise between FAS and FASL variants with male infertility  and Asian (Indian and Chinese) patients. Since no such study has been carried out in other to parts of the world, we were not able to perform a subgroup analysis stratified by ethnicity. Another limitation to our study was the data insufficiency of the included studies. Therefore, it was not feasible to carry out subgroup analysis on smoking, alcoholism and age categories.Our meta-analysis showed that FAS/FASL polymorphisms might is not associated with the risk of male infertility. However, polymorphism of FASL-844C/T might affect fertility potential in men. To confirm our results and determining the biological roles of these functional polymorphisms in this condition, more extensive and comprehensive case-control studies in a larger population should be designed.


MnSOD Val16Ala polymorphism and cancer risk has been widely studied, but the results are contradictory. To obtain more precision on the association, we performed the current meta-analysis with 33,098 cases and 37,831 controls from 88 studies retrieved from PubMed, Embase, Chinese National Knowledge Infrastructure (CNKI), and Wanfang databases. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of association. We found that the polymorphism was associated with an increased overall cancer risk . Stratification analysis further showed an increased risk for prostate cancer, Asians, Caucasians, population-based studies, hospital-based studies, low quality and high quality studies. However, the increased risk for MnSOD Val16Ala polymorphism among Asians needs further validation based on the false-positive report probability (FPRP) test. To summarize, this meta-analysis suggests that the MnSOD Val16Ala polymorphism is associated with significantly increased cancer risk, which needs further validation in single large studies.Manganese superoxide dismutase (MnSOD) plays a critical role in the defense against reactive oxygen species. The association between  Cancer is one of the leading causes of death across the world, with an estimate of over 20 million new cancer cases that will occur per year as early as 2025 . AlthougMnSOD gene, located on chromosome 6q25.3, is composed of four introns and five extrons. Currently, several single-nucleotide polymorphisms (SNPs) in the MnSOD gene have been reported, of which the most extensively studied one is Val16Ala. Since this residue is 9 amino acids upstream of the cleavage site, it has also been called Val9Ala (rs4880) polymorphism , dominant model [ versus Val/Val], and an allele comparison . We used the chi-square-based Q test to check the between-study heterogeneity, and the fixed-effects model (the Mantel-Haenszel method) [P > 0.1). Otherwise, the random-effects model (the Dersimonian and Laird method) [The strength of association between the  method)  was used method)  was appl method)  and Egge method) . SensitiP values <0.05 were considered statistically significant.The false-positive report probability (FPRP) was calculated for all the significant findings in the present study. We set 0.2 as a FPRP threshold and assign a prior probability of 0.1 to detect an OR of 0.67/1.50 (protective/risk effects) for an association with the genotypes under investigation , 25. FPRAs shown in For the two studies in the publication  with theMnSOD Val16Ala polymorphism and cancer risk  , Asians , Caucasians , population-based studies , hospital-based studies , low-quality studies  and high-quality studies .The overall results suggested there was a significant association between < 0.001) . In the MnSOD Val16Ala polymorphism and overall cancer risk . Therefore, the random-effects model was used to generate wider CIs. The leave-one-out sensitivity analysis indicated that no single study could change the pooled ORs obviously (data not shown).As shown in P = 0.049), recessive model (P = 0.007), dominant model (P = 0.042), and allele comparison (P = 0.007), but not for the heterozygous model (P = 0.056). Therefore, the Duval and Tweedie nonparametric “trim and fill” method was used to adjust for publication bias. The “trim and fill” method did not draw different conclusions (data not shown), indicating that our findings were statistically robust.Begg's funnel plot and Egger's test were performed to evaluate the publication bias of 88 studies, and we found significant publication bias for the homozygous model . In addition, according to the FPRP results, we confirmed that the MnSOD Val16Ala polymorphism was associated with cancer risk for prostate cancer (heterozygous: FPRP = 0.020 and dominant: FPRP = 0.006), Caucasians (heterozygous: FPRP = 0.008 and dominant: FPRP = 0.045), population-based studies , hospital-based studies , low-quality studies , and high-quality studies (heterozygous: FPRP = 0.119).The FPRP values were calculated for all the significant findings . With thMnSOD Val16Ala polymorphism and cancer risk through 88 studies, and we found that this gene polymorphism was significantly associated with overall cancer risk. Further, stratification analysis revealed that the association was more obvious for risk of prostate cancer, Asians, Caucasians, population-based studies, hospital-based studies, low-quality studies, and high-quality studies. To avoid the false-positive results of the meta-analysis, we performed the FPRP analysis for the significant findings by setting as the prior probability of 0.1, and the results suggested that the association between MnSOD Val16Ala polymorphism and cancer risk for Asians was false positive, which may due to limited sample size.In this meta-analysis, we comprehensively assessed the association between 2− into H2O2, and it plays a critical role in human cells. Studies have revealed that the aberrant expression of MnSOD is involved in many types of cancers. Our current study indicated that the MnSOD Val16Ala polymorphism was significantly associated with an increased overall cancer risk. Previous meta-analyses have also assessed the association of MnSOD Val16Ala polymorphism with cancer susceptibility. The study carried out by Kang [MnSOD Val16Ala polymorphism and cancer risk, consisting 52 studies with 26,865 cases and 32,464 controls, in which no significant association was found between this polymorphism and overall cancer risk. In the subgroup analysis, statistically significant associations were found between this polymorphism and non-Hodgkin lymphoma, lung cancer, and colorectal cancer. Another meta-analysis [MnSOD Val16Ala polymorphism for cancer risk. Some of the significant associations detected in the previous meta-analyses were not found in the present study; for example, MnSOD Val16Ala polymorphism was associated with the risk of hepatocellular carcinoma [MnSOD Val16Ala polymorphism and elevated prostate cancer risk, and no significant association between this polymorphism and breast cancer, which were consistent with previous meta-analyses [MnSOD is a mitochondrial enzyme that converts superoxide radical O by Kang  analyzedanalysis  includinarcinoma , 133, esarcinoma , and lunarcinoma . The disanalyses , 134–137MnSOD Val16Ala polymorphism in breast cancer [MnSOD Val16Ala polymorphism and cancer risk could be modulated by dietary factors. Besides, a previous study had shown that moderate exercise training is beneficial for prostate cancer [In spite of genetic importance, environment factors such as dietary pattern and exercise play important roles in the development of cancer. Recently, several studies have investigated the association between dietary intake of antioxidant-rich foods and t cancer , prostatt cancer , and cert cancer . Despitee cancer , and evie cancer .MnSOD Val16Ala polymorphism and all cancer types, there were still some limitations that should be addressed. First, the number of cases in each study was small (<1000) in all but seven studies [The current meta-analysis has several advantages. First, we included the latest publications in the present study and also the publications written in Chinese. Second, the quality of included studies was assessed by the quality score criteria. Third, the FPRP test was performed to make the results more trustworthy and robust. Although the study is the largest and most comprehensive one regarding the association between  studies , 86, 119MnSOD Val16Ala polymorphism and cancer risk, which should be further validated by single large studies.Despite of these limitations, this meta-analysis indicated there was a significant association between


LPL) is propounded as a risk for stroke. This meta-analysis investigated the association of rs285 and rs320 LPL polymorphism with stroke risk. Stroke is the most common neurological disorder and genetic susceptibility has an important role in its etiology. Polymorphism in several genes such as lipoprotein lipase  with 95% confidence intervals (CIs) were calculated to estimate the strength of this association. Also, the effects of four common polymorphisms  on the molecular aspects of LPL were evaluated by PEgger>0.05). Furthermore, computational analysis revealed that rs268 and rs328 may affect the protein structure  while rs320 could affect the RNA structure .Our data indicated that rs320 significantly decreased the risk of stroke . Moreover, a significant association between rs285 and diminution of stroke risk was seen . Also, the same results were observed after stratifying, without any publication bias (This meta-analysis indicated that risk of stroke was decreased in rs320 and rs285 polymorphisms in the LPL gene. PRKCH (OMIM: 605437), PITX2 (OMIM: 601542), ZFHX3 (OMIM: 104155), ALOX5AP (OMIM: 603700), HDAC9 (OMIM: 606543), ALDH2 (OMIM: 100650), NLRP3 (OMIM: 606416), MMP9 (OMIM: 120361), and LPL (OMIM: 609708) may be related to the risk of stroke  or hemorrhagic 15%). Based on etiology ischemic stroke includes thrombotic or atherosclerotic (50%), small artery occlusion or lacunar stroke 25%), and cardioembolic (25%)  with a 35 kb length, which comprises 10 exons (PvuII) and rs320 (HindIII) polymorphisms are located on introns 6 and 8, respectively. The rs328 polymorphism, located on exon 9, leads to termination codon at 447 (Ser447Ter). A meta-analysis revealed that there is a significant protective association between Ser447Ter and risk of stroke whereas there is no significant association between Asn318Ser and stroke risk  hydrolyzes triglycerides in chylomicrons and very low-density lipoprotein (VLDL) into free fatty acids and the glycerol molecule. Abnormal activity of this enzyme is related to hyperlipidemia and atherosclerosis, and therefore can increase the risk of ischemia. The human oke risk . But, prData sourcesPvuII”, or “rs285”, “HindIII”, or “rs320” in Google Scholar, Science Direct, Clarivate Analytics Web of Science, and PubMed databases.The meta-analysis was performed on the studies that investigated the association of lipoprotein lipase gene polymorphisms with stroke risk. We searched the related articles, published prior to July 2017, using the following terms “cerebral infarction”, “cerebrovascular disorders”, “cerebrovascular accident”, “ischemic stroke”, or “hemorrhagic stroke”, in combination with “lipoprotein lipase”, “LPL”, “point mutation”, “polymorphism”, “single nucleotide polymorphism”, “SNP”, “Study selection and data extractionLPL gene and risk of stroke. 2- Case-control studies. 3- The diagnosis of stroke was confirmed by neuroimaging (CT or MRI). 4- Papers containing the data for estimation of odds ratios (ORs) and 95% confidence intervals (CIs). The following data were extracted from included studies: the names of authors, year of publication, ethnicity, genotyping method, and genotype frequencies in control and case groups.The flowchart of the study selection procedure is presented in Statistical analysisP-value less than 0.05 deviated from the HWE. The association of rs285 and rs320 SNPs of the LPL gene and stroke risk was evaluated by risk difference (RD) and odds ratios (ORs) with 95% confidence interval (CI). Meta-analysis was performed in the following models: additive, co-dominant, dominant, and recessive. The Q test and estimated I2 score were used to calculate the heterogeneity  was calculated for control groups by the Chi-square test. The groups with a ogeneity , and whe applied , otherwi applied . For senion bias , 16. TheIn silico analysis LPL gene (Accession No. NC_000008.11) were deduced from the NCBI database. The ExPASy server (http://web.expasy.org/) was used for analysis of LPL amino acid sequence. The secondary structure of LPL was evaluated before and after Asn291Ser and Ser447Ter substitutions by Choue-Fasman, GOR, and neural network methods (http://cib.cf.ocha.ac.jp/bitool/MIX/). The three-dimensional structure of the protein was obtained from the I-TASSER server and analyzed by Accelrys DS Visualizer 4.0 . The hydrophobic plots for the 291Asn and 291Ser phenotypes were evaluated using the Kyte and Doolittle scale   .Meta-analysisStudy characteristicsHindIII polymorphism and 2 article (comprising 363 controls and 362 cases) were included in the meta-analysis  for analysis , 23-26. analysis . Association of LPL-HindIII and LPL-PvuII with stroke risk LPL-HindIII and stroke risk are summarized in LPL-HindIII and stroke risk in G vs. T , GG vs. TT , TG vs. TT , TG+GG vs. TT , and GG vs. TT+TG   and ischemic  strokes. The stratified analysis for HWE status showed that there is significant protective association between HindIII and risk of stroke in both studies with and without HWE. Moreover, significant decreased risk was observed among studies after stratifying by sample size  . These rple size . LPL-PvuII with stroke risk revealed that there is significant decreased risk in the four following models: P-vs. P+ , P-P-vs. P+P+ , P+P-+P-P-vs. P+P+ , P-P-vs. P+P++P+P- . Even, after the adjusting of the P-values for multiple testing by the Benjamini-Hochberg false discovery rate method, both polymorphisms were still significantly associated with the stroke risk , TG+GG vs. TT model in studies with HWE (PEgger= 0.037), and TG+GG vs. TT model in studies with sample size less than 500 participants (PEgger= 0.037). A sensitivity test was done by removing a study at a time. The results indicated that the estimations before and after the elimination of every study were alike, which suggests the outcome of the meta-analysis was stable (data not shown).Funnel plot and Egger’s test were used to measure the publication bias for the association of analysis . Lack ofanalysis . ExceptiIn silico analysisLPL such as RNA splicing, RNA stability, and function or structure of the protein by bioinformatics tools. Our data revealed that Asn291Ser substitution located near the ligand binding site of the protein  and HindIII (rs320), polymorphisms showed that these mutations do not change the splicing pattern of LPL hnRNA. The NetGene2 data showed that there are no changes in donor and acceptor splice sites for either direct strand (+ strand) or complement strand (- strand) after rs285 and rs320 polymorphisms . Finally, we analyzed the impact of the two aforementioned SNPs on the RNA stability. The data from the RNAsnp software revealed that rs320 substitution has a significant effect on the structure of precursor RNA . However, rs285 has no significant effect on the structure and stability of hnRNA  ( 0.3495) .LPL-HindIII is a protective factor against stroke risk in all of the five genetic models (P<0.05). Also, after stratification, we observed the same results for hemorrhagic and ischemic subtypes. The control groups in the studies of Xing et al. and Zhang et al. deviated from the Hardy-Weinberg principle  and attached to the surface of vascular endothelium lumen by membrane heparin sulfate binding , 33. LPLtructure -40.LPL has been investigated by in silico analysis. Our data revealed that rs285 and rs320 as intronic SNPs have no effect on splicing pattern of LPL, but rs320 has a significant impact on precursor RNA and it may be a source of the protective effect of rs320 in stroke susceptibility. Moreover, bioinformatics analysis showed rs268 and rs328 have a significant influence on the structure of the protein and this result could interpret the meta-analysis results of a previous study  on the molecular aspects of us study . The main limitation of this study is the restriction of included studies to Asian populations especially Chinese. Also, lack of access to original data such as familial history for stroke could affect the calculation of association between aforementioned SNPs and stroke risk.LPL-HindIII and LPL-PvuII polymorphisms may alter the risk of stroke. But studies with larger sample sizes and different ethnicity are required to support these results. Also, studies with evaluation of gene-gene and gene-environment interactions are essential to achieving more accurate results.This meta-analysis suggests that the