LIPG) 584C/T polymorphism and susceptibility to coronary artery disease (CAD), but a uniform conclusion is yet to be reached. To better evaluate the true relationship between the LIPG 584C/T polymorphism and the risk of CAD, a meta-analysis of 14 case–control studies with 9731 subjects was performed. Relevant articles published through August 2020 were searched in the CNKI, PubMed, Embase and Web of Science databases. Thirteen articles, including 14 eligible case–control studies with 4025 cases and 5706 controls, were enrolled in the present meta-analysis. The Newcastle–Ottawa Scale (NOS) scores of the case–control studies ranged from 6 to 8. The pooled results indicated that there is a significant association between the LIPG 584C/T polymorphism and CAD in the homozygote comparison model and the allelic comparison model. Subgroup analyses revealed that the LIPG 584C/T mutation significantly decreased the risk of CAD in the subgroups of African, CAD, hospital-based (HB), and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) populations in some genetic models. No publication bias was found in our meta-analysis, which certifies the robustness of the current meta-analysis. Trial sequential analysis (TSA) also confirmed the stability of our results. The results of our meta-analysis indicate that the LIPG 584C/T polymorphism plays a protective role in the incidence of CAD. More high-quality case–control studies on various ethnicities are needed to confirm our results.Several studies have investigated a potential association between the endothelial lipase gene ( Coronary artery disease (CAD), also called coronary heart disease (CHD), characterized by myocardial hypoxia and ischemia is triggered by coronary atherosclerosis . It is aEndothelial lipase (EL), a new member of the triglyceride (TG) lipase family, was first discovered in 1999. EL consists of 483 amino acids, with a molecular weight of approximately 55 kDa and is mainly secreted from endothelial cells and other cells such as hepatocytes and macrophages . CompareLIPG), which encodes the EL protein and is located on chromosome 18q21.1, spans approximately 30 kb with ten exons and nine introns [LIPG. Among these, the 584C/T gene variant (rs2000813) has been the most frequently investigated variant that can lead the amino acid threonine substitution for isoleucine at codons [LIPG 584C/T polymorphism and the risk of CAD; however, the results are still inconclusive and contradictory [. [LIPG 584C/T variation and CAD risk in 2014. Unfortunately, the result of their meta-analysis was still inconclusive. Thereafter, several new studies have investigated the correlation between the LIPG 584C/T polymorphism and CAD risk, but the results of these studies remain inconsistent. Therefore, to elucidate the precise correlation of the LIPG 584C/T polymorphism with CAD susceptibility, we performed this updated meta-analysis.The EL gene  AND (polymorphism OR mutation OR variation OR genotype) AND . Furthermore, to acquire other relevant published articles, the reference lists of the studies and reviews, which were included from the search parameters illuminated above, were searched.A systematic literature network search without language limitations was performed in the CNKI, PubMed, Embase and Web of Science databases to acquire all eligible case–control studies published before 15 August 2020. The relevant search terms included the following:  studies were case–control or cohort; (3) articles reported in Chinese or English; and (4) studies provided precise data for genotype distribution estimation in both groups. Studies were excluded according to the following criteria: (1) not case–control and cohort studies, letters, case reports, reviews or meta-analyses; (2) deficient data; (3) deviating from Hardy–Weinberg equilibrium (HWE) in the control group; and (4) overlapping data or duplicated publications.CAD was defined as acute myocardial infarction (AMI), CHD, CAD, myocardial infarction (MI), acute coronary syndrome (ACS), cardiovascular disease. The included articles fulfilled the following criteria: (1) studies assessed the correlation between the LIPG and the P-value of the HWE test of controls. When we encountered inconsistent evaluations, all researchers were consulted to acquire an agreement regarding the exclusion or inclusion of the study in the present article.Two researchers (Yue-e Wu and Lan Ma) independently extracted data from the qualified articles based on the inclusion criteria. The following information was extracted from the eligible studies: first author, year of publication, ethnicity and country of participants, type of diseases, genotyping method, sources of controls, number of cases and controls for the 584C/T genotypes of The Newcastle–Ottawa Scale (NOS) was used to evaluate the quality of each included study . For theP less than 0.05. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the strength of the relationship between the LIPG 584C/T polymorphism and the risk of CAD in five genetic models: heterozygote comparisons (CT vs. CC), homozygote comparisons (TT vs. CC), recessive model (TT vs. CT + CC), dominant model (TT + CT vs. CC), and allelic comparisons (T vs. C). Stratified analyses were also performed according to ethnicity , types of diseases , genotyping method (polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), Taqman, and PCR), and sources of controls  and population-based (PB)). Differences in terms of a Z-test were considered statistically significant if the P-value was less than 0.05. The Cochran’s Q statistical test and the 2I test were used to measure the heterogeneity within the studies, and the significance was set at P less than 0.05 [The present meta-analysis was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement . Chi-squhan 0.05 . A fixedhan 0.05 . Influenhan 0.05 ,21. Triahan 0.05 . STATA 1The process of screening eligible articles is shown in LIPG 584C/T polymorphism in the cases and controls. Supplementary Table S1 indicated that the studies included in our study were reliable according to the NOS.2I statistics were applied. High heterogeneity was found across studies in all genetic models except for the recessive comparisons. Thus, random-effects analysis was applied to synthesize the data. Moreover, we explored the heterogeneity of all genetic models based on different ethnicities, type of diseases, genotyping method, and sources of controls. However, the significant heterogeneity could not be entirely explained by diverse ethnicities . However, there was no significant association between the LIPG 584C/T polymorphism and the risk of CAD that was identified in Asian and Caucasian populations in all genetic models. In the subgroup analysis stratified by type of diseases, the results indicated that the LIPG 584C/T polymorphism was significantly associated with decreased CAD risk in the subgroup of CAD in three genetic models , and the same results were shown in the HB group  and PCR-RFLP . Detailed results are shown in In the subgroup analysis according to ethnicity, the results showed a decreased CAD risk in African populations under four genetic models  and allelic comparison model . According to the integrated analyses of 14 eligible case–control studies, our study revealed that the LIPG 584C/T polymorphism was significantly associated with a decreased risk of CAD, which suggested that the LIPG 584C/T polymorphism plays a protective role in the incidence of CAD in individuals and that the T allele may be a protective factor against CAD.The present meta-analysis indicated that the LIPG is closely related to the incidence of CAD by affecting the expression of EL. In recent years, more and more attention has been paid to genetic research on CAD, which is not surprising considering the impact of CAD on the health of people around the world [LIPG 584C/T variant and CAD risk. However, the results of these studies are inconsistent or even contradictory. The results found by Ji et al. [LIPG 584C/T polymorphism and risk of CAD; in contrast, Tang et al. [LIPG 584C/T polymorphism was significantly associated with a decreased risk of CAD. Cai et al. conducted a meta-analysis to investigate the true association between the LIPG 584C/T variant and CAD risk in 2014. However, their analysis included only 9 case–control studies, including 3036 cases and 4777 controls, and concluded that there was no significant association between the LIPG 584C/T polymorphism and the susceptibility to CAD. Their results were inconsistent with our study, but three case–control studies of their meta-analysis did not conform to HWE [It has been proven that elevated plasma HDL levels are associated with a protective effect on CAD, and low plasma HDL levels are associated with an elevated risk of CAD . The rolhe world . To datei et al. , Zhu et i et al. , and Jeni et al.  revealedg et al. , Solim eg et al. , and Elng et al.  found sim to HWE . A latesm to HWE , and alsLIPG 584C/T variant had different effects on CAD in different ethnicities. Even results from studies on the same ethnicity were inconsistent. For example, Tang et al. conducted a study including 530 Chinese subjects to assess the relationship between the common variant and CAD risk [LIPG 584C/T variant and CAD susceptibility in Caucasian and Asian populations. Our present study showed that the LIPG 584C/T variant be connected with a decreased CAD risk only in African populations. However, there was no significant association between the LIPG 584C/T polymorphism and the risk of CAD that was identified in Asian and Caucasian populations. This result was not convincing enough, because only one case–control study was included in the African subgroup; therefore, this result needs to be confirmed by more high-quality case–control studies in various ethnicities. When carrying out subgroup analysis by type of diseases, we found that the LIPG 584C/T polymorphism was significantly associated with a reduced risk in the CAD group, but we failed to find a significant risk association in other types. This result may be explained by the inherent heterogeneity of development in diverse diseases types.We noticed significant heterogeneities among the studies and carried out subgroup analyses according to ethnicity. According to previous studies, the CAD risk . They deCAD risk  on the TCAD risk  on the JCAD risk  on the ICAD risk  and Zhu CAD risk  showed nLIPG 584C/T variant and CAD risk. Due to a lack of raw data, such as exposing factors, life habits, gene–environment interactions, interactions between gene–gene and even diverse mutation loci in the same gene factors, a further exact adjustment analysis adjusting for confounding factors could not be carried out. Second, there is still high heterogeneity in our meta-analysis, although we used strict inclusion criteria, accurate data extraction, and rigorous data analysis to perform the present meta-analysis. The persuasiveness of the significant association between the LIPG 584C/T polymorphism and CAD susceptibility was affected. Third, the sample sizes of our study were still small, especially in subgroup analysis. Only one eligible study was included in the analysis of African populations. TSA identified that the cumulative sample size was insufficient. There were not enough eligible case–control studies, weakening the statistical power to detect the real correlation between the LIPG 584C/T polymorphism and susceptibility to CAD. Fourth, the result of our meta-analysis should be interpreted with caution and needs to be confirmed by more case–control studies, because the sensitivity analyses indicated that deletion of certain individual study had an impact on the reliability of our results. Fifth, although Begg’s and Egger’s tests proved that there was no publication bias, it may inevitably exist in our meta-analysis. Only published articles reported in English or Chinese were included in the present study. Some candidate studies may not be included because they were not published, discovered, or because they were not published in English or Chinese.Some inherent drawbacks of our meta-analysis should be illustrated when interpreting our results. First, only unadjusted estimates were applied to evaluate the strength of the relationship between the LIPG 584C/T polymorphism plays a protective role in the incidence of CAD in individuals. The T allele may be a protective factor against CAD. Because of the limitations mention above, more high-quality case–control studies in various ethnicities are needed to confirm our results.In conclusion, our meta-analysis suggested that the Click here for additional data file.


Objective: To systematically review literature evidence to discover the association of ADAMTS7  polymorphisms and the risk of developing CAD (coronary artery disease).Data sources: A related literature search in online databases, including EMBASE, PubMed, and Web of Science was undertaken. The period covered was from 2007 to September 10, 2019.Results: Of 256 citations retrieved, nine relevant studies were selected for detailed evaluation. Five SNPs  in ADAMTS7 gene were identified among included studies. There were 51,851 cases and 89,998 controls included in four studies for SNP rs3825807, 13,403 cases and 11,381 controls included in two studies for SNP rs1994016, 37,838 cases and 38,245 controls included in two studies for SNP rs4380028, 3,133 cases and 5,423 controls included in one study for SNP rs79265682, 103,494 cases and 198,684 controls included in one study for SNP rs28455815. We found most consistent evidence for an association with CAD on coronary angiogram with ADAMTS7 SNP rs3825807 risk allele A in contrast to control G allele, followed by rs4380028 , and rs1994016 .Conclusions: ADAMTS7 polymorphism is likely an important risk factor for development of CAD. Our data also suggest that the ADAMTS7 polymorphism may be a risk factor for CAD progression in patients who already have pathology in their coronary arteries.Review methods: We included all studies in English language that reported correlation between the ADAMTS7 polymorphism and CAD in human cases. Coronary artery disease (CAD), which is characterized by atherosclerosis and narrowing in coronary arteries is a major cause of mortality and morbidity worldwide. Despite reduced CAD mortality over the last decade in developed countries, it is still responsible for about one-third of all deaths worldwide in people aged 35 and older –3.It is known that macrophages play an important role, in orchestra with smooth muscles cells (SMCs) and endothelial cells (EMCs) during inflammatory response that leads to atherosclerotic plaque formation. This includes the secretion of matrix metalloproteinases (MMPs) to extracellular space, and initiation of infiltrating and proliferative responses. More recent studies have revealed that impairment in “efferocytosis” - a process responsible for clearance of debris and remnant of inflammatory response - also results in initiation of inflammatory and proliferative circuits and subsequently plaque formation  4, 5]., 5.4, 5]The complex pathophysiology underlying CAD depends on numerous environment and lifestyle risk factors of its individuals that is investigated through several studies which provide critical information regarding objectives for the primary and secondary preventive measures . HoweverSince the first Genome-Wide Association Studies (GWAS) conducted for CAD in 2007 –8, multiMore recently, the efforts to identify additional loci associated with CAD have revealed the responsibility of genetic factors for a significant percentage of the inter-individual variation in CAD and its progression. This necessitates a meta-analysis to combine the growing evidence to provide a comprehensive understanding of the genetic architecture of CAD, and enable precision medicine approaches by identifying subgroups of patients at increased risk of developing CAD or its complications.One group of genetic factors that falls into this category is the ADAMTS7 , located on chromosome 15: 78,759,203-78,811,431 and has 5 transcripts (splice variants) that code for a proteolytic enzyme-ADAMTS7, which produced and secreted by macrophages, and contains 1686 amino acids. Following activation (through cleavage of the prodomain), the secreted enzyme can bind to cartilage oligomeric matrix protein (COMP), progranulin, and alpha2-macroglobulin , 14 and Thus, the need arises to evaluate the genome data and determine the relationship between ADAMTS7 locus and coronary artery atherosclerotic vascular disease, specifically whether ADAMTS7 polymorphisms are linked to CAD or not.Few human-case studies have showed that single nucleotide polymorphism in the ADAMTS7 gene is potentially responsible for tendency toward development of CAD. However, the results of these studies had not been consistently analyzed together among different patient populations.Here, a meta-analysis was executed based on all eligible studies to assess the association of ADAMTS7 polymorphism with susceptibility to CAD, and to investigate the effects of ADAMTS7 polymorphism on progression of the disease in patients.Our search terms produced 161 results on EMBASE, 30 results on PubMed, and 65 results on Web of Science, for a total of 256 records. Hand search of reference lists of articles identified an additional two studies , 18. AftOur review included nine studies published between 2011 and 2019 and incorporated data collected from different countries . Five SNYou et al.  conducteChan et al.  conducteSchunkert et al.  reportedReilly et al.  carried Lu et al.  conductePeden et al.  studied Matsunaga et al.  studied In 2016 Assimes et al.  reportedPereira et al.  studied Their data revealed that at the end of the follow-up (mean 5.3 years), the estimated survival was 89.8%, 82.2%, and 72.3% for GG genotype, AG, and AA genotype respectively after about 70 months and remained for about 168 months.To our knowledge, this is the first universal systematic review of the worldwide literature based on electronic database searches to assess different aspects of genetic variation in ADAMTS7 gene and its association with CAD. We found promising outcome data favoring for the importance of genetic evaluation in patients with preexisting risk factors and/or patient with history of CAD without traditional CAD risk factors.We assessed nine studies that investigated the relationship between ADAMTS7 polymorphism and the presence of CAD. These trials were conducted in different countries. Our data reveals that ADAMTS7 was consistently related to CAD identified by coronary angiography. Moreover, the outcome of CAD in the patient with angiographic proven CAD, in the long-term follow up, confirmed the influence of ADAMTS7 polymorphism on CAD. These findings suggest that genetic assessment should be considered, both in the development of CAD and also in patients who are already suffering from it, to get a better understanding of coronary artery involvement as a major cause of mortality, especially when familial history suggest the possibility of genetic involvement.In the other studies, the interaction of genes and environment have produced an interesting observation that allelic variation at rs7178051 that are associated with reduced ADAMTS7 expression confers CAD protection, which is stronger in never-smokers than in cigarette smokers , 27. EnhOur review has weaknesses inherent to systematic review approaches. There are several members of the ADAMTS that identified, however the relevant data regarding the role of the other member of ADAMTS and their effect on the development of the coronary artery disease are limited, and further studies required. Our review includes few studies, which limits the strength of conclusions that can be drawn. Further studies, warranted to confirm our findings in larger patient population and wider geographic area. Furthermore, it is ripe for research to see how the genetic changes in ADAMTS7 would be translated into changes in plasma level of ADAMTS7 in patients with CAD.The systematic review of the literature and meta-analysis were developed and conducted according to the PRISMA  guidelines . Our stuA related literature search in online databases, including EMBASE, PubMed, and Web of Science were undertaken. The following search terms were used: ("ADAMTS7 Protein" [Mesh] OR adamts7 [tw] OR “adamts 7” [tw] AND English [lang]) for the period of 2007 to September 10, 2019. Search results were limited to human studies and also in the English language. Review articles with data on ADAMTS7 were also checked, in order to identify studies that were missed by our database search. In addition, we reviewed articles unavailable online by obtaining hard copy scans via Stanford Lane Medical Library’s interlibrary loan and document delivery service. The detailed steps of the literature review are shown in Published studies were considered eligible for inclusion based on the following criteria: 1. an original study investigating ADAMTS7 SNP associated with CAD, 2. a human study, 3. published in English, 4. Coronary stenosis defined as > 50% narrowing in coronary angiographic exam, 5. data regarding CAD outcomes. Selected studies were divided according to whether the data was related to CAD development, or survival rate in patients with CAD. The exclusion criteria for our study were: 1. duplicated studies, 2. review articles without original data on ADAMTS7 SNP associated with CAD, 3, letters and case reports, 4. studies without gene polymorphism, 5. Unavailable data and abstracts from unpublished studies. Additional studies identified by reviewing the reference lists of the retrieved literature were likewise manually checked using the same inclusion and exclusion criteria.Two authors (S.A. and H.S.) independently assessed the eligibility of studies, with any discrepancies settled by consensus with a third author (D.K.H). We excluded duplicate studies using Zetero software prior to screening. Initial screening was done with the article abstract and title to generate a list of potentially relevant studies. Full-text review was undertaken to determine eligibility by our inclusion criteria.The following data was extracted from the included studies by two authors (S.A. and H.S.): 1. basic information: first author, publication year, sample size of case (patients with CAD) and control groups (patients without CAD), 2. demographic data: mean age, male/female ratio, country and ethnicity of cases and controls, 3. method of coronary artery evaluation, genotyping, genotype distributions, and relevant SNP polymorphism. Newcastle-Ottawa scale (NOS) was used to assess the quality of each included study. Studies with a score greater than 7 were considered as high-quality studies. Disagreements were resolved by consensus with a third author (D.K.H).Q statistic, 2I statistic and Tau-squared were calculated to assess heterogeneity. Given that the various heterogeneities among individual ORs and HRs, the random effects model was utilized to generate summary statistics. P-value < 0.05 was considered to be statistically significant unless otherwise specified.All analyses were conducted using CMA  Software (Version 3) . From ea


This systematic review and meta-analysis was aimed to assess the overall effects of meteorological factors on the incidence of HFMD to help clarify these inconsistencies and serve as a piece of evidence for policy makers to determine relevant risk factors. (2) Methods: Articles published as of 24 October 2020, were searched in the four databases, namely, PubMed, Web of Science, Embase, and MEDLINE. We applied a meta-analysis to assess the impact of ambient temperature, relative humidity, rainfall, wind speed, and sunshine duration on the incidence of HFMD. We conducted subgroup analyses by exposure metrics, exposure time resolution, regional climate, national income level, gender, and age as a way to seek the source of heterogeneity. (3) Results: Screening by the given inclusion and exclusion criteria, a total of 28 studies were included in the analysis. We observed that the incidence of HFMD based on the single-day lag model is significantly associated with ambient temperature, relative humidity, rainfall, and wind speed. In the cumulative lag model, ambient temperature and relative humidity significantly increased the incidence of HFMD as well. Subgroup analysis showed that extremely high temperature and relative humidity significantly increased the risk of HFMD. Temperate regions, high-income countries, and children under five years old are major risk factors for HFMD. (4) Conclusions: Our results suggest that various meteorological factors can increase the incidence of HFMD. Therefore, the general public, especially susceptible populations, should pay close attention to weather changes and take protective measures in advance. Hand, foot, and mouth disease (HFMD) is an airborne disease that causes a huge global disease burden . HFMD waOver the past decade, the relationship between meteorological factors and HFMD has drawn widespread attention. However, the results are inconsistent, especially in terms of rainfall, wind speed, and sunshine duration. For example, Nguyen et al. 2017)  found th  found tDue to inconsistent epidemiological studies mentioned above, we believe that a systematic review and meta-analysis may clarify these inconsistencies and help us see the big picture. Prior to this work, we were fully aware that a meta-analysis published in 2018 has done similar work . HoweverWith these concerns in mind, we conducted this study to systematically assess the impact of meteorological factors on the risk of HFMD, hoping to help policy makers identify high-risk factors and protect susceptible populations.To find the related articles, we searched databases including PubMed, Web of Science, Embase, and MEDLINE using the following keywords:  AND . Studies published up to the date of the search (24 October 2020) were considered. The inclusion criteria of our literature were as follows: (1) studies were written in English, or in other languages if an English translation was available; (2) studies provided effect estimates of relative risk (RR), incidence rate ratio (IRR), or the excess risk (ER); (3) studies reported cases of HFMD rather than death; (4) the associations were reported as effect estimates calculated based on one unit increase in meteorological factors  the full text of the article could not be found; (2) the format of the paper is not a research article; (3) articles do not contain data for meta-analysis; and (4) articles do not estimate the effect of confounding from any source.The titles and abstracts derived from the databases have been downloaded to the reference manager Endnote  prior to the analysis. All records were independently evaluated by two investigators, and disputes are arbitrated by the third investigator. Upon removing the irrelevant articles and duplicate studies, the articles that met the selection criteria were included in our analysis. We extracted the following information from eligible articles: (1) study characteristics, (2) participants’ demographic factors, (3) the relative risks and 95% CLs of HFMD associated with meteorological factors, (4) outcomes of studies.The quality of the selected articles was assessed by a Newcastle Ottawa Scale (NOS). The NOS included eight items in three dimensions . Two invIn selected studies, reporting associations on different lag days is a common practice. Among them, most studies were interested in single-day lag effects ,23,24,25As for the exposure metrics, we selected results according to the following criteria. If only one exposure metric was presented , then the effect of these metrics was included in the analysis. If associations of HFMD with the maximum and minimum exposure were reported rather than the mean exposure, then both were included. Additionally, if a study included results from more than one location, then results from all locations were included.2) statistics [Forest plots were used to assess the heterogeneity of the associations of HFMD with temperature, relative humidity, wind speed, rainfall, and sunshine duration. Both the Cochran Q  and the atistics  were useatistics . To repoatistics .Stata  was used for data cleaning and merging. The “forest” package in R software  was used to perform the meta-analysis. Publication bias was assessed by the Begg rank correlation test and Egger weighted regression test ,36. To assess the stability of the aggregated estimates, two sensitivity analyses were performed. The first sensitivity analysis was conducted to compare whether there is a difference in associations between meteorological factors and HFMD with extreme exposure values included or not, while the second sensitivity analysis was to compare the differences in effects, which has been previously reported by Cheng et al. (2018)  and effeA total of 10,668 records were searched through the first round of screening. After removing articles that did not meet the inclusion criteria, 28 studies were kept in this study. The screening process is presented in 2 is 99.6% for ambient temperature in The overall effects of ambient temperature and relative humidity at single-day lags are shown in Our subgroup analysis focuses on the following variables to explore the sources of heterogeneity: exposure measures, exposure time resolution, regional climate, national income level, gender, and age. n = 16), the incidence of HFMD increased by 5.7% . Meanwhile, a 1 °C increase in maximum temperature (n = 4) was significantly associated with the incidence of HFMD . There was no significant association between the minimum temperature (n = 3) and the incidence of HFMD. For relative humidity, a 1% increase in average (n = 13) and maximum (n = 5) relative humidity can both increase the incidence of HFMD  and , respectively. The minimum relative humidity (n = 4) had no significant association with the incidence of HFMD. As for rainfall and wind speed, the included articles mainly used average values, and they were all positively associated with the risk of HFMD. In terms of ambient temperature, we found that for every 1 °C increase in average temperature, (n = 19) and weekly (n = 6) exposure values. Only one article used monthly exposure values to report results. Overall, for almost all meteorological factors, the RRs based on the daily and weekly exposure values are both significant (p < 0.05). Further, we found that the RRs generated by using the weekly exposure values are greater than the RRs produced by using the daily exposure values.We observed that most of the included articles reported the RR values based on daily  to verify whether the overall effect was affected by the extreme values. The results showed that the effects with extremes removed are comparable to those with extremes retained in the analysis, except for the ambient temperature, which had a higher effect on the risk of HFMD with extremes included than without them included . Since aThis systematic review and meta-analysis explored the relationship between meteorological factors and the incidence of HFMD. We found that ambient temperature, relative humidity, rainfall, and wind speed were all significantly associated with the risk of HFMD. Further subgroup analyses also revealed that temperate regions, high-income countries, and children under five years of age are at high risk of developing HFMD. This article is the first study to include rainfall, wind speed, and sunshine duration into a meta-analysis of meteorological factors and HFMD, and it is also the first article to take the cumulative effect into the analysis.We observed that both the maximum and mean ambient temperatures were significantly associated with the incidence of HFMD, and the effect of the maximum temperature was stronger than that of the mean temperature, which is consistent with the results of the previous meta-analysis . Our senConsistent with the result of , we founConventionally, HFMD is regarded as a tropical disease, though we found a higher meteorologically associated risk in temperate areas than in the tropics. This may be due to the various weather conditions in different climatic zones . In tempOur study found that in high-income countries, ambient temperature, relative humidity, and rainfall all had a significant effect on the incidence of HFMD, while the previous meta-analysis did not find such statistical significance . The posFor the subgroup analysis on gender and age, we found that the risk of HFMD did not differ between genders. Children under five are at higher risk than those older than five. This may be due to their imperfect immune system development ,60. It hWe conducted two sensitivity analyses. The first sensitivity analysis showed that the overall effect of including extreme temperatures is higher than that of excluding extreme temperatures , which sp value of its results, which ignores other factors that may affect publication. Meta-regression requires a large number of samples for the calculation to make sense [Our paper has the following limitations. First, we observed significant publication bias, especially on ambient temperature and relative humidity. The main reason for publication bias is that researchers tend to report statistically significant results and ignore those that are not significant. Some approaches to solve the problem of publication bias include: (1) trim and fill, (2) selection models, and (3) meta-regression. However, all of them have their own flaws. For example, the trim and fill method requires the elimination of articles that affect the symmetry of the funnel plot. The second method uses a selection model to screen the included articles, assuming that the probability of publication is associated with the ke sense . TherefoThis systematic review and meta-analysis found that ambient temperature, relative humidity, rainfall, and wind speed were statistically significantly associated with HFMD. Extremely high temperature and relative humidity significantly increased the risk of HFMD. The overall impact of ambient temperature on the risk of HFMD has increased over time. Policy makers need to take preventive measures to deal with the impact of climate factors on the incidence of HFMD. Future research should focus on the non-Asia-Pacific region and relatively less studied meteorological factors, such as rainfall, wind speed, and sunshine duration.


Whether “periodontal disease” can be considered as an independent risk factor for head and neck cancer (HNC) remains controversial. The aim of the current meta-analysis was to quantitatively assess this relationship in order to determine whether this represents a true risk factor, with implications for cancer prevention and management. PubMed, Scopus, and Embase databases were systematically searched. Selective studies were reviewed, and meta-analysis was performed to estimate the pooled odds ratio (OR) with 95% confidence intervals (CIs) on eligible studies using a random effects model. In total, 21 eligible observational studies (4 cohorts and 17 case-controls) were identified for qualitative synthesis after a review of 1051 articles. Significant heterogeneity could be identified in measures utilized for reporting of periodontal disease. Meta-analysis performed on nine studies that employed objective measures for reporting periodontal disease demonstrated a significant association between periodontal disease and HNC . A diseased periodontium represents an independent risk marker, and a putative risk factor, for HNC. Prospective studies with standardized measures of periodontal disease severity and extent, integrated with microbiological and host susceptibility facets, are needed to elucidate the mechanisms of this positive association and whether treatment of the former influences the incidence and outcomes for HNC. Periodontal health is defined by the absence of clinically detectable inflammation of the gingivae or periodontal membrane, without periodontal pockets or ongoing loss of attachment of the teeth to the alveolar bone . “PeriodFusobacterium nucleatum and Porphyromonas gingivalis are often isolated from malignant neoplasms of the oral cavity [Periodontal diseases have been strongly linked with numerous systemic conditions, including diabetes mellitus, cardiovascular diseases, poor pregnancy outcomes, and pulmonary, renal, and immunologic disorders . Whilst l cavity ,8 as well cavity , intensil cavity .The term head and neck cancer includes all malignancies of the upper aerodigestive tract (UADT), the majority of which are of mucosal origin, arising from the paranasal sinuses; nasal cavity; oral cavity; naso-, oro-, and hypo-pharynx; and larynx . SeveralTo critically analyze the evidence of any links between “periodontal disease” and head and neck cancer, we reviewed the available literature on periodontal disease and HNC risk. Meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to obtain an accurate assessment on the association between this important ‘oral health indicator’ and HNC.Nine articles were retrieved from two meta-analysis ,18 and oThe main characteristics of the selected studies are illustrated in Positive associations between periodontal disease and head and neck cancer risk were reported in four cohort studies . Three sIn total, 12 out of 21 articles used self-reported signs of gingival/periodontal disease, including self-reported gum bleeding ,34,35,37All the included studies had adjusted for various confounding factors except the study by Rezende et al., which did not report any adjustments . MoreoveA summary of the quality assessment of the studies according to the New-Castle Ottawa Scale is presented in 2 = 93.3%). Twenty-one studies evaluating the relationship between periodontitis and head and neck cancer were included in our qualitative analysis. However, meta-analysis was performed by pooling the OR/RRs from nine articles that measured periodontal diseases with valid instruments. The combined effect estimate (pooled OR) using the random-effects model is presented in 2 = 67.6%) (2 = 42%), with a decline in heterogeneity  . Of the ogeneity . Tezal eThe effect estimate  was derived from the primary meta-analysis, which consisted of nine studies. However, the funnel plot looked asymmetric with evident bias in publications  and EggeInteractions between periodontal diseases and systemic health are well established. However, the recent upsurge of publications relating inflammation and cancer, and the visible local inflammation in periodontal diseases has encouraged scientists to explore the relationship between periodontal disease and cancer risk. The overall findings from our qualitative and quantitative analyses assert an association between periodontal disease and HNC. However, the cross-sectional design utilized by most of the included studies limits affirmation of the course of this association, nevertheless revealing periodontal disease as a risk indicator for HNC. Furthermore, four large trials that evaluated the risk prospectively showed that people with periodontal disease had an increased risk of developing head and neck cancer. The most recent and comprehensive prospective study reported an elevated risk of HNC development, with HR of 2.25 (1.30–3.90) for periodontal disease alone and 6.29 (2.13–18.6) for periodontal disease with tooth loss (presumptively indicating a more advanced periodontitis) among males .To date, two meta-analyses have been published investigating the relationship between periodontal disease and risk of HNC, the most recent in 2013 ,18. AlthOne of the major challenges in assessing the relationship between periodontal disease and other diseases is the variability in measurement tools used to define disease. In the included studies, periodontal disease has been measured by self-reported outcomes of periodontitis or clinical measurements, such as attachment levels, pocket depths, and alveolar bone loss from panoramic radiographs . ClinicaPeriodontitis and HNC share many factors in addition to heavy use of tobacco and alcohol, both environmental and inherited ,59,60,61Many studies have considered tooth loss as a marker for periodontal disease ,63. As dPorphyromonas gingivalis, a member of the red complex consortium of Gram-negative anaerobes, and Fusobacterium nucleatum [F. nucleatum has been shown to result in upregulation of several kinases involved in cell proliferation and DNA repair [P. gingivalis has been shown to induce epithelial mesenchymal transition in vitro, which is a major event in carcinogenesis [F. Nucleatum and P. gingivalis has been shown to facilitate the progression of oral cancer in an in vivo model [P. gingivalis and F. nucleatum have been linked recently to pancreatic and colorectal cancers, respectively [Fusobacterium has been labeled an “oncobacterium” in numerous cancers [Links between chronic inflammation and cancer are increasingly understood ,69. Periucleatum ,73,74,75A repair , whereasogenesis . Moreovevo model . Both P.ectively ,80. Inde cancers , and oth cancers . Apart fThough our review covers several geographic regions and ethnic groups, most studies were performed in developed countries: The drivers in low and low-and middle-income countries might be different . SmokingThe methodology of this review was documented as a protocol and registered in PROSPERO (CRD42018074223).P—Any population.E—Exposed to periodontal diseases.C—Not exposed to periodontal disease,O—Head and neck cancer,The search strategy was defined based on the following PECO framework : The strategies for the screening and inclusion were decided by authors in advance. A thorough electronic search of literature for observational studies published to identify articles without date limitations, using specific search terms. The search was conducted on three major databases, PubMed, Scopus, and Embase, utilizing comprehensive literature search strategies with keywords that included “Head and Neck Neoplasms”, “Mouth Neoplasms”, “Tongue Neoplasms”, “Mandibular Neoplasms”, “Carcinoma, Squamous Cell”, “Oropharyngeal Neoplasms”, “Facial Neoplasms”, “Pharyngeal Neoplasms”, “Laryngeal Neoplasms”, “Periodontal Diseases”, “Periodontitis”, “Periodontal Attachment Loss”, “Periodontal Pocket” “Alveolar Bone Loss”, “Tooth mobility”, and “loose teeth”. Boolean operators, such as "and" and "or", were used to stratify the search. Moreover, manual searches of reference lists of relevant reviews were also conducted in order to exclude the possibility of omitting any important study. The search strategy was confined to English language comprising human studies. Two authors independently evaluated the eligibility of all the retrieved studies. The level of agreement between the authors was calculated utilizing Cohen’s kappa coefficient at every level of selection. To improve the sensitivity, papers were excluded only if both authors eliminated them based on the title and abstract and disagreements were resolved by discussion with a third author. The selection was done according the following criteria:Observational studies (both case control and cohort) that assessed the association between any measure of periodontal status with HNC were included if they met the following criteria: (1) Controls and cases were clearly defined and (2) hazard ratios (HRs), odds ratios (ORs), or risk ratios (unadjusted/adjusted) and related 95% confidence intervals (CIs) were reported, or else the figures that can help to determine any of these ratios were present in the article.Head and neck cancer (HNC) in our study was defined as any malignant neoplasm of the lip and oral cavity, any part of the pharynx, larynx, sinuses, and salivary glands reported collectively or individually. ‘Periodontal disease’ was defined as the presence of gingivitis and/or periodontitis by employing objective methods  and subjective methods (self-reported based on questionnaires or face-to-face interviews). Similar definitions were described in other reviews on the association of periodontal diseases and systemic conditions ,88 MeasuScreening of the titles and abstracts was performed by two authors (DG and RKM) and relevant information from the full texts selected were extracted and tabulated. Two authors independently extracted data regarding the characteristics of each study using a standardized data collection form. When involving more than a single study involving the same sample group, the report with the most recent and comprehensive data on the study population was used.Quality assessment of each of the included studies was performed using the Newcastle–Ottawa scale (NOS) for case-control and cohort studies . The stuTwo authors independently graded the quality of each article and no discrepancies were identified.0) + (Pa × OR), where P0 refers to the risk of outcome of interest in the non-exposed group [2 statistics. Sensitivity analyses were performed to test the robustness of the results by excluding studies that reported unadjusted OR. Subgroup analyses were conducted based on alveolar bone loss as a measure of periodontal disease. Publication bias was assessed with a funnel plot and Egger regression asymmetry test [p < 0.05 was considered to be statistically significant). This method, a rank-based data-imputation technique, considers the possibility of hypothetical “missing” studies that might be present, inputs their potential effects, and recalculates the effect size. For statistical analysis and graph generation, we used Stata version 15.0 .A meta-analysis using the random-effects model was performed to estimate the pooled odds ratio (OR) with a 95% confidence interval (CI) of studies that used objective measures to describe periodontal diseases. In the studies in which the hazard ratio (HR) or risk ratio (RR) were reported, we calculated OR through the following method. We directly considered HR as RR, and then transformed RR into OR by using the Zhang equation: RR = OR/(1 − Ped group . Heterogtry test  (p < 0.0This comprehensive systematic review and meta-analysis strongly supports that periodontal disease is an independent risk factor for head and neck cancer. Periodontally compromised individuals with co-existing lifestyle risk factors should be encouraged to monitor and maintain periodontal health to minimize cancer risk. Dental/medical care providers should provide regular oral health and cancer screenings to detect cancer at an early stage, thus improving survival and quality of life. Standardized definitions and measurements of periodontal disease are necessary for future epidemiologic studies, which should include longitudinal studies of the oral and periodontal microbiome. Ultimately, this will allow discrimination of patients at high risk of cancer, in this era of personalized medicine.


Besides environment and living habits, such as a sedentary lifestyle, smoking and drinking, genetic variation also plays an important role in the development of colorectal cancer (CRC). This study was aimed to investigate the role of miR‑27a rs895819 polymorphism on CRC risk in Chinese population.In a case‐control study including 208 CRC and 312 age‐ and gender‐matched healthy control subjects, the rs895819 polymorphism was genotyped using the TaqMan allelic discrimination assay. Furthermore, a pooled analysis based on eligible studies was performed by using the STATA software.Pz < .01; (AG + GG) vs AA: OR = 1.14, 95% CI = 1.01‐1.30, Pz = .04; GG vs (AG + AA): OR = 1.54, 95% CI = 1.27‐1.88, Pz < .01; G vs A: OR = 1.20, 95% CI = 1.09‐1.33, Pz < .01).Logistic regression analysis showed that the rs895819 polymorphism was not associated with CRC risk. However, a pooled analysis based on five studies from Chinese population showed a statistically significant association between the rs895819 polymorphism and CRC risk (GG vs AA: OR = 1.56, 95% CI = 1.27‐1.92, Our study suggests that miR‑27a rs895819 polymorphism plays an important role in CRC risk in Chinese population and may serve as a valuable biomarker for predicting an individual's susceptibility to CRC. Rs895819 polymorphism located in miR‐27a was associated with colorectal cancer risk in Chinese population. Growing evidence suggests that miRNAs play a major role in the development of cancer.Besides environment and living habits, such as a sedentary lifestyle, smoking, and drinking, genetic variation also plays an important role in the development of CRC.22.1P = .69). The ratio of male and female was 156:52 and 230:82 in CRC patients and healthy individuals, respectively (P = .74). CRC patients were diagnosed by histological examination. Written informed consent was obtained from all participants. The research protocol was approved by the ethics committee of Xuhui District Central Hospital of Shanghai.A total of 208 CRC patients and 312 healthy check‐up individuals matched with age and gender were recruited from Xuhui District Central Hospital of Shanghai between October 2017 and December 2019. All enrolled individuals were Chinese Han population. The mean age (mean ± SD) of CRC patients and healthy individuals was 60.1 ± 8.6 and 59.8 ± 8.1 years, respectively  according to the manufacturer's instruction. The miR‐27a rs895819 polymorphism was detected using the TaqMan allelic discrimination assay. The primer and probe sequences and reaction conditions were used according to a description of previous literature.2.2P value for Hardy‐Weinberg equilibrium (PHWE) in the control group > .05. The relevant data, including the first author's name, publication year, country, cancer type, genotyping method, and genotype frequency distribution of the rs895819 polymorphism in cases and controls, were extracted independently by two investigators .In the case‐control study, chi‐square test and Student's I2 index. If a significant Q‐statistic (Phet < .05) or I2 > 50% indicating the existence of between‐study heterogeneity, the random effect model was used. Otherwise, the fixed effect model was used. In addition, sensitivity analysis was performed by omitting each study in turn to assess the consistency of the results. Begg's and Egger's tests were used to evaluate potential publication bias. P < .05 was set as the criterion of statistical significance. These analyses were conducted using the Stata software, version 12.0 . Furthermore, false‐positive report probability (FPRP) was calculated with threshold value = .2, prior probability = .01 and OR value = 1.50 to evaluate the significant findings.In the pooled analysis, the pooled ORs with 95% CIs were calculated based on the random or fixed effect model under the additive (G vs A), dominant [(GG + GA) vs AA], recessive [GG vs (GA + AA)], and codominant model . Between‐study heterogeneity was evaluated through the chi‐square‐based Q test and 3PHWE = .75). Logistic regression analysis showed that rs895819 polymorphism was not significantly associated with CRC risk in a Chinese population (Table Pz < .01). Under the dominant , recessive , and additive  models, significant associations between rs895819 polymorphism and CRC risk were also observed (Table In the current case‐control study, there were no significant differences in the distribution of age or gender between cases and controls. Genotype distributions had no deviation from HWE in control groups (on Table . Howeveron Table . Under t4In recent years, the role of miR‑27a rs895819 polymorphism on CRC risk has been investigated in Chinese population.Although the pooled analysis revealed the role of miR‑27a rs895819 polymorphism on CRC risk in Chinese population, some limitations should be addressed. Firstly, the pooled result was not adjusted for potential confounding factors, while a more precise assessment should be performed if individual information, such as smoking, drinking, and red meat intake, was available. Furthermore, sensitivity analysis showed that the pooled OR was unstable under the dominant model, suggesting that the result needed to be further confirmed by more case‐control studies.5Our study observed a significant association between miR‑27a rs895819 polymorphism and CRC risk in Chinese population. The rs895819 polymorphism might serve as a valuable biomarker for predicting an individual's susceptibility to CRC.Shulong Zhang, Qi Han, Kaihua Zhu, and Quan Wang conceived of the study and participated in its design. Shulong Zhang, Qi Han, and Kaihua Zhu conducted the systematic literature review. Shulong Zhang and Quan Wang performed the experiment and data analyses. Shulong Zhang drafted the study.


CTLA-4) polymorphisms and digestive system malignancies were controversial. The authors designed this meta-analysis to more precisely estimate relationships between CTLA-4 polymorphisms and digestive system malignancies by pooling the results of related studies.The results of genetic association studies regarding cytotoxic T lymphocyte-associated antigen 4 (The authors searched PubMed, Embase, Web of Science, and CNKI for eligible studies. Thirty-one eligible studies were pooled analyzed in this meta-analysis.The pooled meta-analysis results showed that genetic distributions of rs231775, rs4553808, and rs733618 polymorphisms among patients with digestive system malignancies and controls differed significantly. Moreover, genotypic distribution differences were also observed for rs231775 polymorphism among patients with colorectal cancer/pancreatic cancer and controls, for rs4553808 and rs5742909 polymorphisms among patients with gastric cancer and controls, for rs3087243 polymorphism among patients with liver cancer and controls, and for rs733618 polymorphism among patients with colorectal cancer and controls in pooled meta-analyses.This meta-analysis suggested that rs231775 polymorphism was associated with predisposition to colorectal cancer and pancreatic cancer, rs4553808 and rs5742909 polymorphisms were associated with predisposition to gastric cancer, rs3087243 polymorphism was associated with predisposition to liver cancer, and rs733618 polymorphism was associated with predisposition to colorectal cancer. Digestive system malignancies such as liver cancer, gastric cancer, and colorectal cancer are leading types of cancer among both males and females , 2. AlthCytotoxic T lymphocyte-associated antigen 4 (CTLA-4) serves as a negative regulator of immune responses and is essential for modulating anti-tumor immune responses , 10. So,CTLA-4 polymorphisms and digestive system malignancies, yet the relationships between CTLA-4 polymorphisms and digestive system malignancies are still controversial and ambiguous. Thus, the authors designed this meta-analysis to get a more statistically reliable conclusion regarding the relationships between CTLA-4 polymorphisms and digestive system malignancies by pooling the results of related studies.In the last two decades, investigators across the world have extensively explored the relationship between The PRISMA guideline was followed by the authors when conducting this meta-analysis .Literature searching of PubMed, Web of Science, Embase, and CNKI was performed by the authors using the following terms: (Cytotoxic T lymphocyte antigen-4 or CTLA-4) and  and  and . The authors also checked the references of retrieved articles for additional related studies.CTLA-4 polymorphisms and digestive system malignancies, (II) provide genotypic distributions of CTLA-4 polymorphisms in patients with digestive system malignancies and controls, and (III) the full manuscript is available in English or Chinese. Articles were excluded if at least one of the following three conditions was fulfilled: (I) studies not concerning CTLA-4 polymorphisms and digestive system malignancies, (II) reviews or expert comments, and (III) case series that only involved patients with digestive system malignancies. When duplicate reports were observed during literature searching, only the most complete one was included for pooled analyses.Eligible studies must meet all of the three inclusion criteria: (I) formally published case-control studies evaluating relationships between CTLA-4 polymorphisms in patients and control subjects. We also calculated the p values of Hardy-Weinberg equilibrium (HWE) based on genotypic distributions of CTLA-4 polymorphisms.We extracted the following items from eligible studies: (I) surname of the first author, (II) year of online publication, (III) country and ethnicity of involved subjects, (IV) number of patients and controls in each study, and (V) genotypic distributions of The authors used the Newcastle-Ottawa scale (NOS) to assess the quality of included studies . The scoData extraction and quality assessment of eligible studies were performed by two authors separately. We would write to the corresponding authors of eligible studies for additional data if we fail to extract necessary information from included studies.Z test to evaluate the relationships between CTLA-4 polymorphisms and predisposition to digestive system malignancies. The authors set the statistical significant threshold at 0.05. We compared genetic distributions of CTLA-4 polymorphisms among cases and controls in dominant, recessive, over-dominant, and allele models; the dominant genetic model is defined as M/M vs. M/m + m/m, recessive genetic model is defined as m/m vs. M/M + M/m, over-dominant genetic model is defined as M/m vs. M/M + m/m, and the allele genetic model is defined as M vs. m. The authors used I2 statistics to estimate heterogeneity. The authors used the DerSimonian-Laird method to pool the results if I2 is larger than 50%. Otherwise, the authors used the Mantel-Haenszel method to pool the results. The authors also conducted subgroup analyses by type of diseases. The authors examined the stabilities of pooled meta-analysis results by omitting one study each time and pooling the results of the other studies. The authors examined publication biases by using funnel plots.The authors used Review Manager to pool the results of eligible studies. The authors used One hundred and thirty-two articles were retrieved by the authors through our literature searching strategy. The authors assessed 54 articles for eligibility after omitting unrelated and repeated reports. Twenty reviews were further excluded by the authors, and another three articles were also excluded by the authors due to the lack of crucial data. Totally, 31 studies were finally pooled in our meta-analyses , rs4553808 , and rs733618  polymorphisms were found to be significantly associated with digestive system malignancies in overall pooled meta-analyses. We also obtained positive findings for rs231775 polymorphism in colorectal cancer (recessive and over-dominant comparisons) and pancreatic cancer  subgroups, for rs4553808 polymorphism in gastric cancer (recessive and over-dominant comparisons) subgroup, for rs5742909 polymorphism in gastric cancer  subgroup, for rs3087243 polymorphism in liver cancer  subgroup, and for rs733618 polymorphism in colorectal cancer  subgroup. Nevertheless, no any positive results were observed for rs16840252 polymorphism in pooled meta-analyses (see Table Twenty-eight studies were eligible for estimation of relationship between rs231775 polymorphism and digestive system malignancies, three studies were eligible for estimation of relationship between rs4553808 polymorphism and digestive system malignancies, six studies were eligible for estimation of relationship between rs5742909 polymorphism and digestive system malignancies, eight studies were eligible for estimation of relationship between rs3087243 polymorphism and digestive system malignancies, eight studies were eligible for estimation of relationship between rs733618 polymorphism and digestive system malignancies, and four studies were eligible for estimation of relationship between rs16840252 polymorphism and digestive system malignancies. Stabilities of pooled meta-analysis results were examined by omitting one study each time and pooling the results of the other studies. The trends of associations remained unchanged in sensitivity analyses, indicating that our pooled meta-analysis results were statistically stable.Publication biases were examined by funnel plots. Funnel plots were overall symmetrical, suggesting that our pooled meta-analysis results were not likely to be severely influenced by publication biases.CTLA-4 gene has been documented in many types of cancers, and it might contribute to cancer initiation and progression [CTLA-4 gene polymorphisms have also been extensively explored with regard to their relationships with different types of malignant disorders. In this meta-analysis, we summarized potential relationships between CTLA-4 gene polymorphisms and digestive system malignancies by pooling the results of 31 related studies. Our pooled meta-analysis results demonstrated that rs231775 polymorphism was associated with predisposition to colorectal cancer and pancreatic cancer, rs4553808 and rs5742909 polymorphisms were associated with predisposition to gastric cancer, rs3087243 polymorphism was associated with predisposition to liver cancer, and rs733618 polymorphism was associated with predisposition to colorectal cancer. The trends of associations remained unchanged in sensitivity analyses, suggesting that our pooled meta-analysis results were quite statistically stable.CTLA-4 is expressed on activated T cells, and it negatively regulates T cell activation and proliferation. Previous studies have demonstrated that CTLA-4 modulates the duration and strength of T cell-mediated immune responses by competitive binding with co-stimulating B7 molecules and activating of FAS-dependent apoptosis of T cells , 10. Recgression –15. ConsCTLA-4, give rise to immune dysfunction, jeopardize anti-tumor immune responses, and influence predisposition to malignancies, and this is the reason why we investigated these polymorphisms in this meta-analysis. Second, although we pooled the results of related studies, the sample size of many comparisons were still relatively small, so future genetic association studies with larger sample sizes are still needed to estimate the relationship between CTLA-4 polymorphisms and different types of digestive system malignancies so as to get more statistically robust findings. Third, the etiologies and pathogenesis mechanisms of digestive system malignancies are extremely sophisticated, so further association studies also need to investigate the potential influence of gene-gene or gene-environmental interactions on predisposition to digestive system malignancies [CTLA-4 polymorphisms at the beginning. However, we did not find sufficient eligible articles to support pooled meta-analyses of other CTLA-4 polymorphisms, so we only examined six polymorphisms in this meta-analysis.A few points should be considered when interpreting our findings. First, previous experimental studies demonstrated that all investigated polymorphisms might result in altered gene expression or protein structure of CTLA-4 , 17. Thugnancies . Fourth,CTLA-4 polymorphisms and digestive system malignancies. However, most investigators only focused on genetic associations in their works, so gene-environmental interactions were not explored in this meta-analysis [Like all meta-analyses, a few limitations of our pooled meta-analyses should also be acknowledged. Firstly, our pooled meta-analysis results were derived from pooling unadjusted findings because we did not have access to raw data of eligible studies . Secondlanalysis . Thirdlyanalysis .CTLA-4 polymorphisms might have the potential to serve as genetic biomarkers of digestive system malignancies. Nevertheless, detailed functional analyses are still required to reveal the precise molecular mechanisms of the observed significant associations between CTLA-4 polymorphisms and digestive system malignancies. Moreover, future studies should also test whether these CTLA-4 polymorphisms can be used to detect digestive system malignancies in clinical practice.So to conclude, this meta-analysis demonstrated that rs231775 polymorphism was associated with predisposition to colorectal cancer and pancreatic cancer, rs4553808 and rs5742909 polymorphisms were associated with predisposition to gastric cancer, rs3087243 polymorphism was associated with predisposition to liver cancer, and rs733618 polymorphism was associated with predisposition to colorectal cancer. These results indicated that these


The increasing number of hip arthroplasties (HA), due to the growing elderly population, is associated with the risk of femoral periprosthetic fractures (FPFs). The purpose of this study was to identify potential risk factors for the development of FPFs after HA.A systematic review was conducted in five data bases  according to the Preferred Reporting Items for Systematic reviews and Meta-analysis (PRISMA) guidelines up to May 2019, using the key words “risk factor,” “periprosthetic fracture,” and “hip replacement or arthroplasty.” Meta-analysis of the clinical outcomes of HA and subgroup analysis based on the factors that were implicated in FPFs was performed.Sixteen studies were included . Risk factors statistically associated with increased incidence of FPFs were female gender (+ 40%), previous revision arthroplasty surgery (× 3 times), and the presence of rheumatoid arthritis (× 2.1 times), while osteoarthritis (− 57%), cement application (− 59%), and insertion of Biomet (− 68%) or Thompson’s prosthesis (− 75%) were correlated with low prevalence of FPFs. Obesity, cardiac diseases, advanced age, bad general health (ASA grade ≥ 3), and use of Exeter or Lubinus prosthesis were not linked to the appearance of FPFs.This meta-analysis suggested that female gender, rheumatoid arthritis, and revision arthroplasty are major risk factors for the development of FPFs after a HA. In those patients, frequent follow-ups should be planned. Further prospective studies are necessary to clarify all the risk factors contributing to the appearance of FPFs after HA.The online version contains supplementary material available at 10.1186/s13018-020-02152-0. Femoral periprosthetic fractures (FPFs) after total hip arthroplasty (THA) were first described by Horwitz and Lenobel in 1954 –4. The iAlthough FPFs were not correlated with a specific implantation procedure, it was reported that they occurred more frequently after the application of cementless HA . FactorsTherefore, it is crucial to determine the potential risk factors that are associated with FPFs after total HA and hemiarthroplasty. Identification of risk factors for FPFs not only bridges the gap between clinical and basic or translational science but also improves the surgical practice in operating room as surgeons may incorporate novel concepts in their surgical techniques , 11. FurDespite the fact that multiple identified risk factors for FPF have been described in the international literature including older age, female sex, bone fragility disorders, and systematic diseases , 6, therThis study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines . PRISMA A systematic computer-based literature review search with predefined criteria was attained on 08 May 2019 in the following databases: PubMed (1947 to present), Cochrane Database of Systematic Reviews (1992 to present), Embase (1974 to present), Cinahl, and WHO International Clinical Trials Registry platform (ICTRP). Research methodology was based on the combination of the following terms: “factors [All Fields],” “risk [All Fields],” “periprosthetic fractures [All Fields],” and “hip replacement, hemiarthroplasty or arthroplasty [All Fields].” The entire electronic literature search was conducted independently by two authors (CB and ODS) and an experienced clinical librarian. Moreover, the two senior authors (CB and ODS) screened the titles and abstracts independently in order to identify studies examining the clinical outcomes after the application of HA. If there was a disagreement between them, the final decision was made by the senior author.Studies that examined the risk factors, the outcome, and the incidence of post-operative FPFs after performing HA were identified. HA was defined as the replacement of all or part of the hip joint by a prosthetic implant . FPFs weStudies that examined primary or metastatic hip cancers treated with HA, or surveys without comparative results, or being written in a language other than English were excluded. Case reports, reviews, letters to the editor, expert opinions articles, studies concerning PFs of acetabulum, research with insufficient details about the type of intervention, the clinical outcome, and surveys without obtainable data, were excluded.All data of each study was assembled in a Microsoft Excel spreadsheet, classified per intervention and type of periprosthetic fracture. Characteristics extracted from clinical studies included authorship, publication year, study design , single or multicenter status, enrolled sample number, population gender and age, and risk factors in both control and treatment groups, HA procedure, outcomes regarding the frequency of periprosthetic fracture development, and the type of HA. Data from each study are summarized in Table Two reviewers (CB and ODS) examined all the identified surveys and extracting data by using a predetermined form. The presence of duplicate studies was examined using Endnote software .The methodology of each study was assessed independently by the two senior authors (CB and ODS) using the Newcastle–Ottawa quality assessment scale . IncludeQ and the inconsistency (I2) test. The degree of heterogeneity was graded as low (I2 < 25%), moderate (I2 from 25 to 75%), and high (I2 > 75%). A random effect model was used to calculate pooled ORs in the case of significant heterogeneity, while the fixed effect model was used in the studies with low heterogeneity. This was undertaken because in sensitivity analysis the presentation of both models provides comprehensive evaluation of how differences in datasets affected the observed outcomes [p < 0.05.This meta-analysis was conducted in line with the recommendations from Cochrane and PRISMA statement . Statistoutcomes . Egger’sIn the initial search, a total of 126 relevant trials were detected. After the initial evaluation of the studies based on the abstract and title, 103 publications were included. The further analysis of the remaining papers resulted in the exclusion of 104 surveys. Twenty-eight studies were excluded due to inadequate methodology, while 49 studies were declined being statistically unsatisfactory. Moreover, 13 studies examined acetabular PFs, 3 were written in other language than English and 11 surveys were not original studies and were analyzed in the flowchart of Fig. Finally, sixteen studies published between 2003 and 2018 met our inclusion criteria for the analysis of potential risk factors for the development of FPFs after THA –34. The In Tables Furthermore, funnel plots were created to evaluate publication bias. After this evaluation, all studies were found to lie within a 95% CI as represented by the inverted funnel, suggesting absence of publication bias.In total, 599.677 HA were included in the meta-analysis. Fourteen studies were used to reveal the prevalence of FPFs , 22–34, Q = 27.4, I2 = 56.2%, P = 0.007) revealed that female gender was as much as 40% more likely to sustain FPFs   revealed that age (older than 80 and 70 years) was not a significant risk factor for the development of FPFs .Five studies , 27–29 aQ = 0.17, I2 = 0.0%, p = 0.982) demonstrated that obesity was not an important risk factor associated with increased frequency of FPFs .Obesity was examined as a risk factor for FPF appearance in four surveys , 32, 33.Q = 11.3, I2 = 81.9%, p = 0.001) did not identify the ASA score ≥ 3 as statistically significant risk factor for FPF appearance .In three studies , 27, 28,Q = 4.56, I2 = 56.1%, p = 0.102) of three studies [p = 0.289).Similarly, meta-analysis  of four surveys [p = 0.009)  Fig. .Fig. 4aQ = 2.06, I2 = 2.09%, p = 0.357) of three studies [p = 0.010)  of these studies identified that the risk of FPFs after revision HA is 3 times higher than primary HA   Fig. .Fig. 6aQ = 286.4, I2 = 97.9%, p = 0.001) confirmed that the use of cemented femoral prosthesis was a significant protective factor, decreasing the possibility of FPFs  , Thompson  , Lubinus  , and Biomet   prosthesis, respectively, indicated that Thompson    and Lubinus  implants did not favor the development of FPFs.The impact of the implant type that was inserted during THA was also evaluated. Meta-analysis of four –21, 23, Femoral periprosthetic fractures after HA constitute a major complication and are usually associated with increased mortality rate and inadequate functional recovery . HoweverOur analysis indicated that the prevalence of FPFs after HA was 0.71%. Interestingly, during the last 4 years the frequency of FPFs was limited to 0.27%. The reported incidences range from 0.3 to 27.8% after primary HA and from 0.3 to 17.6% after revision HAs , 40. DesThe frequency of FPFs was higher after the insertion of uncemented HA ranging from 3 to 18% , 40, 41.Based on our results, revision HA was strongly associated with FPFs, a consistent result in many surveys , 44, 45.Little is known about the association between femoral implant design characteristics and the frequency of FPFs. Our results did not confirm the previously reported correlation of Exeter prosthesis to increased rate of FPFs . ConversOur results showed that OA was a protective factor in FPF appearance, while RA was a significant risk factor being in line with previous studies , 44, 45.Based on our findings, female gender was an important epidemiological factor that increased the risk of FPFs by 40%. Although female gender has been suggested to be an independent risk factor, it is obviously confounded by osteoporosis . ContrarStrength of our analysis was that it included all the current international literature comprising a large number of prospective studies and a large population sample  , 15. HowThis meta-analysis suggested that female gender, RA, and revision arthroplasty are major risk factors for the development of FPFs whereas OA, cement application, and insertion of Biomet or Thompson’s prosthesis were correlated with low prevalence of FPFs. Obesity, cardiac diseases, advanced age, poor general health (ASA grade ≥ 3), and use of Exeter or Lubinus prosthesis did not conduce to the appearance of FPFs. Based on the meta-analysis data, it could be recommended that (a) insertion of a femoral implant designed with anatomic characteristics can reduce the risk of re-operation in patients of similar age, sex, and bone quality; (b) intra-operative application of cortical grafts may prevent possible bone defects or stress risers in patients with known risk factors like RA or revision surgery ; (c) cemFuture basic science and clinical prospective studies are warranted to establish stronger evidence regarding the mechanisms that alter bone strength and quality in female patients and in those suffering of rheumatic diseases resulting in FPFs, to strengthen the efficacy of insertion of Biomet or Thompson’s prostheses though cemented procedure in the prevention of FPFs and to produce more robust results for the clarification of the potential risk factors contributing to the development of FPFs after HAs.Additional file 1: Supplemental Table 1. PRISMA checklist


ObjectiveThe objective of the article is to summarize the current evidence regarding the association between angiotensin-converting enzyme insertion/deletion (ACE I/D) gene polymorphism and vitiligo disease.Methodsclicktime.com, Inc., San Francisco, US) was utilized in the meta-analysis. A computerized search was performed through four electronic databases  with the relevant keywords. Included studies comprised of papers examining the association of ACE gene polymorphisms with vitiligo. Data were pooled as an odds ratio (OR) in random- and fixed-effect models using the Mantel-Haenszel (M-H) method. Review Manager 5.3 software  matching the inclusion criteria were included in the systematic review and meta-analysis. Results showed no significant difference between individuals carrying deletion/deletion (D/D) genotype and individuals with deletion/insertion (D/I) + insertion/insertion (I/I) genotypes in terms of vitiligo risk . However, vitiligo risk was higher in the individuals carrying the I/D genotype when compared with individuals with D/D + I/I genotypes . Moreover, the increased risk was observed in individuals carrying D/D when compared with I/I . D allele was associated with significant risk when compared with the I allele .ConclusionThe current evidence suggests that there is a significant association between ACE I/D gene polymorphism and vitiligo. These findings support the use of ACE polymorphism in the prediction of vitiligo as a biomarker. Vitiligo is a common, acquired, idiopathic, and progressive skin disorder characterized by loss of functional melanocytes and melanin from hair follicles and skin, which leads to one or more white patches of depigmented skin , 2. AccoSymmetrical and generalized distributions of depigmented skin are the most common presentation of the disease; however, segmental, non-segmental, focal, and mixed distributions are sporadically seen . DespiteMany researchers identified several vitiligo susceptibility genes that regulate the immune system, such as cytotoxic T-lymphocyte antigen-4 (CTLA4), human leukocyte antigens (HLA), and NACHT leucine-repeat protein 1 -8. One oHowever, the results of the previous studies showed partial disagreement due to multiple factors such as small sample size, racial/ethnic differences, and minor polymorphism effect on vitiligo risk. Therefore, in this systematic review and meta-analysis, the aim was to summarize and investigate the current evidence regarding the association between vitiligo and ACE gene I/D polymorphism.This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) checklist .Search strategyComputerized searches in four databases  were done. Research records were exported into EndNote Windows version X8 . Articles were identified using the relevant search keywords “Vitiligo”, “gene polymorphism”, “Angiotensin-converting enzyme”, “ACE”, and “I/D.”Selection of studiesRetrieved records were screened in two steps: 1) title and abstract screening, and 2) full-text articles screening for eligibility to meta-analysis. Multiple publications/reports from the same study were excluded, and the latest publication with complete data was considered for meta-analysis.Inclusion and exclusion criteriaIncluded studies examined the association of ACE gene polymorphisms with vitiligo. Eligible studies determined the distribution of alleles and⁄or genotypes for the ACE gene I⁄D polymorphism in unrelated cases with vitiligo and in unrelated controls without vitiligo. Studies of other ACE polymorphisms in relation to vitiligo were excluded. Utilized data was from published papers and not from conference abstracts, case reports, or review articles. Moreover, studies were excluded in the following conditions: studies with a population encompassing healthy volunteers, studies with non-reliable data for extraction and analysis, thesis and conference papers, and animal models.Data extractionTwo independent reviewers extracted the data using an offline data extraction form . The extracted data include the following: characters of populations and study design .Data synthesis and heterogeneityHeterogeneity was assessed and interpreted according to the Cochrane Handbook for Systematic Reviews and Meta-analysis recommendations, by visual inspection of the forest plots and measured by I-square and Chi-square tests . An alphclicktime.com, Inc., San Francisco, US).The Mantel-Haenszel method was chosen above the Peto method due to the relatively few obtained studies with different sample sizes and were not investigating a rare outcome. Studies included subjects from different ethnicities; therefore, a random-effects model was provided in addition to the fixed effects model to examine the change in variability in case of failure to assume that the true effect size was equal across all studies. The odds ratio was pooled in the random effect model meta-analysis (Der-Simonian Liard method). Statistical analyses were performed using Review Manager 5.3  ethnicity of the included population ; 2) vitiligo type ; and 3) association with other autoimmune diseases.Search resultsFour databases were searched  and records were exported into EndNote. After removing duplicates, 450 unique records are retrieved and ready for screening against the inclusion and exclusion criteria. Title and abstract screening led to exclusion of 412 studies and the finding of 38 potential full-text articles that can be included. After the full-text screening, ten studies  matched the inclusion and exclusion eligibility criteria for this systematic review and meta-analysis , 14-22. Demographic characteristics of included studies and individualsThe majority of the included studies are from India (four studies) and Egypt (three studies). The other three studies are from Korea, Turkey, and the UK. The age of the included participants is ranging between two to 85 years. The number of patients with vitiligo was 1,181 and the control group was 1,559. The summary of the included studies is presented in Table D/D versus I/I + I/D (recessive model)2=73, p=0.0003). A sensitivity analysis was applied by removing Badran et al. [2=57, p=0.02), see Table 2=45, p=0.12). No significant association was observed in both Egyptians and Europeans . In patients with no associated autoimmune disease, a significant association between the recessive model and vitiligo was observed  with homogenous data . There was no significant difference among all types of vitiligo in terms of association with the recessive model.The pooled analysis showed that there was no significant association between the deletion/deletion (D/D) versus insertion/insertion (I/I) + insertion/deletion (I/D) (recessive model) and vitiligo in random or fixed effect models , see Table Observing D/I versus I/I + D/D, pooled analysis showed a significant association with vitiligo whether by random or fixed effect models 2=53, p=0.03). Heterogeneity was unraveled by performing a sensitivity analysis removing Dwivedi et al., [2=23, p=0.23), see Table 2=68, p=0.02). No significant association was observed in both Egyptians and Europeans . There was no significant association between the dominant model and vitiligo in both populations with/without autoimmune disease. Moreover, there was no significant difference among all subtypes of vitiligo in terms of association with the dominant model; however, the overall effect size showed a significant association with vitiligo in general .Regarding the dominant model, the pooled analysis demonstrated a significant association with vitiligo whether by random or fixed effect models 2=69, p=0.001), which was not solved by sensitivity analysis, see Table The random model of the pooled analysis showed no significant association between homozygous genotypes and vitiligo , which was reduced by sensitivity analysis, see Table The random-effects model of the pooled analysis showed no significant association between D versus I alleles and vitiligo , Figure The development of vitiligo can be processed by the action of ACE, which participates in degrading the substance P and peptide mediators -25. The To the best of our knowledge, this is the largest and most updated systematic review and meta-analysis that evaluated the association between vitiligo and ACE gene polymorphism. Our findings showed that there was no significant difference between the individuals carrying the D/D genotype and the individuals with D/I + I/I genotypes in the term of risk of vitiligo. On the other hand, the risk of vitiligo was higher in the individuals carrying the I/D when compared with individuals carrying D/D + I/I genotypes. Moreover, this risk was also observed in individuals carrying D/D when compared with I/I. D allele was associated with significant risk when compared with the I allele. Remarkably, the I/I genotype has a protective effect against the risk of vitiligo when compared with D/D + D/I genotypes. Asian populations carrying the D/D genotype and D allele have a higher risk of vitiligo when compared with other populations. Egyptians carrying the D/I genotype have a higher risk of vitiligo when compared with other populations. Furthermore, individuals carrying D/D genotype and D allele have a higher risk of non-segmental vitiligo when compared with other types of vitiligo. The observed significant heterogeneity can be explained by the variation between the studies in terms of vitiligo clinical classification, ethnicity, and associated diseases. These findings were supported by published data reporting D allele, and D/D and D/I genotypes associated with a higher risk of vitiligo, especially in Indian populations . In addiData from a previous meta-analysis reported a significant association between the recessive model and vitiligo (p<0.0001) . MoreoveOne of the published case-control studies evaluated the distribution of ACE I/D gene polymorphism in the Egyptian population. They reported that the D allele was more distributed in vitiligo patients when compared with control (p<0.001) . In contDespite this study’s significant findings, there are some limitations. This study mainly relied on genetic factors for vitiligo without accounting for environmental factors. In addition, none of the included studies had detailed information about the patients with a family history of vitiligo, which is considered as a major contributor to the occurrence of vitiligo. Moreover, this study showed a significant heterogeneity; however, sensitivity and subgroup analyses were performed to mediate this heterogeneity. In conclusion, the current evidence suggests that there is a significant association between ACE I/D gene polymorphism and vitiligo. This risk may be higher in some populations such as Egyptians and Indias when compared with Europeans. These findings support the use of ACE polymorphism in the prediction of vitiligo as a biomarker.


Statin may confer anticancer effect. However, the association between statin and risk of hepatocellular carcinoma (HCC) in patients with hepatitis B virus (HBV) or hepatitis C (HCV) virus infection remains inconsistent according to results of previous studies. A meta-analysis was performed to summarize current evidence.Related follow-up studies were obtained by systematic search of PubMed, Cochrane’s Library, and Embase databases. A random-effect model was used to for the meta-analysis. Stratified analyses were performed to evaluate the influences of study characteristics on the outcome.p < 0.001; I2 = 86%). Stratified analyses showed that the association between statin use and reduced HCC risk was consistent in patients with HBV or HCV infection, in elder (≥ 50 years) or younger (< 50 years) patients, in males or females, in diabetic or non-diabetic, and in those with or without cirrhosis . Moreover, lipophilic statins was associated with a reduced HCC risk , but not for hydrophilic statins . The association was more remarkable in patients with highest statin accumulative dose compared to those with lowest accumulative dose (p = 0.002).Thirteen studies with 519,707 patients were included. Statin use was associated with reduced risk of HCC in these patients (risk ratio [RR]: 0.54, 95% CI: 0.44 to 0.66, Satin use was independently associated with a reduced risk of HCC in patients with HBV or HCV infection. Hepatocellular carcinoma (HCC) is one of the most prevalent cancers in digestive system, and approximately 500,000 cases of HCC are newly diagnosed annually worldwide . PatientStatins, also known as 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitors, are a category of cholesterol-lowering medications which have become the mainstays for the primary and secondary prevention of cardiovascular diseases . MoreoveThe MOOSE   and CochSystematic search of electronic databases of PubMed, Cochrane’s Library, and Embase were performed to identify potentially relevant studies, via the following terms: (1) “statin” OR “3-hydroxy-3-methyl-glutaryl CoA reductase inhibitor” OR “CS-514” OR “statin” OR “simvastatin” OR “atorvastatin” OR “fluvastatin” OR “lovastatin” OR “rosuvastatin” OR “pravastatin” OR “pitavastatin”; and (2) “chronic hepatitis B” OR “chronic hepatitis C” OR “hepatitis B virus” OR “hepatitis C virus” OR “HBV” OR “HCV”. We used this extensive search strategy to avoid missing of potentially relevant studies. The search was limited to human studies, and no language restriction was applied. Besides, we also studied the reference lists of related original studies and review articles using a manual approach. The final literature search was conducted on September 15, 2019.The inclusion criteria were: (1) full-length articles reporting longitudinal follow-up studies, including randomized controlled trials (RCTs), cohort studies, and nested case-control studies; (2) enrolled at least 1000 adult patients with HBV or HCV infection and without HCC at baseline; (3) investigated the association between statin use and HCC risk during follow-up, with a minimal follow-up duration of 1 year; and (4) reported the relative risk for this association after adjustment of potential confounding factors. Review articles, preclinical studies, and studies irrelevant to the purpose of current meta-analysis were excluded.Two authors indepdently performed database search, data extraction, and study quality assessment according to predefined criteria. If discrepancies occurred, they were solved by consensus between the two authors or discussion with the corresponding author. Data extracted included: (1) study information: name of first author, publication year, and study country; (2) study design characteristics; (3) patient characteristics: disease status, sample size, age, sex, prevalence of diabetes, and proportions of patients with cirrhosis at baseline; (4) definition of statin use; (5) follow-up durations; (6) strategy for HCC validation and number of HCC cases during follow-up; and (7) confounding factors adjusted. The Newcastle-Ottawa Scale was used as an instrument for study quality evaluation . This scp values, and a logarithmical transformation was performed to stabilize variance and normalized the distribution [2 statistic was also estimated [2 > 50% indicates significant heterogeneity. We used a random-effect model for the meta-analysis of RR data because this model incorporates the potential heterogeneity among the included studies to calculate a more generalized result [A risk ratio (RR) with corresponding 95% confidence interval (CI) was used as the main measure for the association between statin use and HCC risk in patients with HBV or HCV infection. Data of RRs and their corresponding stand errors (SEs) were calculated from 95% CIs or ribution . The Cocstimated . An I2 >d result , By omitd result . We alsod result . RevMan Figure The characteristics of the studies were presented in Table p < 0.001; Fig. 2 = 86%). Sensitivity analyses by omitting one datasets at a time did not significantly change the results .Pooled results of all included studies using a random-effect model showed that statin use was associated with a reduced risk of HCC in patients with HBV or HCV infection  or HCV infection  or ≥ 50 years  or females  or non-diabetic patients  or without cirrhosis , but not for hydrophilic statins  compared to those with lowest cDDD category .The funnel plots for the meta-analysis of the association between statin use and HCC risk in patients with HBV or HCV infection were shown in Fig. By summarizing the current evidence from epidemiological studies, our meta-analysis showed that statin use was indepdently associated with reduced risk of HCC in patients with HBV or HCV infection. Subsequently stratified analyses showed that the association between statin use and reduced risk of HCC in these patients were consistent in patients with HBV and HCV infection, in elder (≥ 50 years) and younger (< 50 years) patients, in males and females, in diabetic and non-diabetic, and in those with and without cirrhosis. Moreover, exploring stratified analyses showed that use of lipophilic statins was associated with reduced risk of HCC in patients with HBV or HCV infection, but not for hydrophilic statins. Besides, the association between statin use and reduced risk of HCC in these patients was more remarkable in patients with highest accumulative dose of statin prescription compared to those with lowest accumulative dose category. Taken together, these results demonstrated that statin use was indepdently associated with a reduced risk of HCC in patients with HBV or HCV infection, which may be primarily driven by studies with lipophilic statins and probably via a dose-dependent manner. Although large-scale prospective cohort studies and RCTs are needed to validate these findings, results of this meta-analysis highlight the potential role of statins as chemoprevention agents for HCC in patients with HBV or HCV infection.To the best of our knowledge, our study is the first meta-analysis focusing on the association between statin use and HCC risk in patients with HBV or HCV infection. The strengths of our study included follows. Firstly, this meta-analysis included only longitudinal follow-up studies, which could therefore establish a sequential association between statin use and reduced risk of HCC in patients with HBV or HCV infection. Secondly, we only studies with adequate adjustment of confounding factors, which therefore may suggest an independently association between statin use and reduced risk of HCC in these patients. Thirdly, we used sensitivity analysis to confirm the robustness of the finding, which was not primarily driven by either of the included study. Finally, multiple stratified analyses were performed to evaluate the stability of the results, which showed that association between statin use and reduced risk of HCC in these patients were consistent and not affected by hepatitis virus type, patient age, sex, diabetic status, and with and without cirrhosis. These results supported the hypothesis that statins may be applied as a chemoprevention agent against the development of HCC in high-risk patients with HBV or HCV infection. Since no RCTs have been published in this field, our results highlighted the need of large-scale RCTs to validate the potential chemoprevention role of statins for HCC.Results of our stratified analyses showed that use of lipophilic statins was associated with reduced risk of HCC in patients with HBV or HCV infection, but not for hydrophilic statins. However, only three datasets were available for each stratum of the stratified analyses, and the results were mainly driven by one study . TherefoThe potential molecular mechanisms underlying the chemoprevention effects of statins for HCC may be multiple. An early experimental study showed that combinatorial treatment with statin and protein kinase C-beta inhibitor displayed enhanced anti-tumor efficacy in cultured HCC cells and in a mouse model of HCC . SubsequOur study has limitations Firstly, significant heterogeneity was found for the meta-analysis. Although stratified analyses were performed to evaluate the patient and statin prescription characteristics on the outcome, we could not exclude some other study characteristics that may also contribute to the heterogeneity, such as concurrent medications including antiviral agents  and metfIn conclusion, results of meta-analysis demonstrated that statin use was indepdently associated with a reduced risk of HCC in patients with HBV or HCV infection, which may be primarily driven by studies with lipophilic statins and probably via a dose-dependent manner. Satins may be potential chemoprevention agents for HCC in patients with HBV or HCV infection.