MTHFR A1298C gene polymorphism on stroke risk. But the results of published studies remained inconclusive and controversial. So we conducted a meta-analysis to accurately estimate the potential association between MTHFR A1298C gene polymorphism and stroke susceptibility.Previous studies have shown the effect of p value. Funnel plots and Begger’s regression test were applied for testing the publication bias. Statistical analysis of all data was performed by Stata 12.0.A systematic literature search on Embase, Pubmed, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI) and WanFang electronic database identified 40 articles including 5725 cases and 8655 controls. Strength of association was evaluated by pooled odds ratio (OR), 95% confidence interval (CI) and MTHFR gene A1298C polymorphisms and stoke risk under the C allelic genetic model , dominant genetic model  and recessive genetic model . In subgroup analysis, we discovered obvious correlation in three genetic model of Asian, stroke type, adult by ethnicity, population, stroke type, source of control and case size. Additionally, in studies of control from hospital and case size equal 100, obvious correlation was also found in the three genetic model.The meta-analysis results indicated a significant relationship between THFR A1298C polymorphism and stroke susceptibility, especially in adults and ischemic stroke.Our meta-analysis results indicated that there was evidence to support the correlation between M MTHFR. Their missense mutations resulted in the replacement of 677 base C with T and the substitution of A with C in 1298, which changed the amino acid structure of MTHFR and caused the decrease of MTHFR enzyme activity , we screened all retrieved documents and constructed an information flow chart using the final qualified data.ALL selected studies complied with the inclusion criteria: (1) Full text can be searched in electronic databases; (2) Case-control studies on Two researchers screened the retrieved studies by inclusion and exclusion standard. We selected following information from the included researches: first author, publication years, study country / region, type of stroke, study population, control group source, sample size (case and control) and genotype type. we evaluated each included study by Newcastle-Ottawa Scale (NOS) . And we MTHFR A1298C polymorphism and stroke susceptibility by different genetic comparison models: the C allele model (C and A), recessive model (CC and AA + CA) and dominant model (CC + CA and AA). Heterogeneities of different genetic comparison models was evaluated by the χ2 based Q-statistic and I2 [p < 0.10) or I2 > 50% indicates that there was heterogeneity between studies. The pooled OR was estimated by fixed effect model (Mantel–Haenszel) when no heterogeneity existed. Otherwise, the pooled OR was estimated by random effect model. To determine the possible causes of heterogeneity, ethnicity , study population (children and adults), type of stroke (ischemic and hemorrhagic), control source  and case group sample sizes  were analyzed in subgroups. In addition, sensitivity analysis was performed on different genetic comparison models to evaluate the effect of a single research on pooled OR. We used Egger test and funnel plots to evaluate the potential publication bias [Odds ratio (OR) and 95% confidence interval (CI) were calculated to estimate the relationship among c and I2 , 24. Sigion bias . Stata 1p < 0.05). In the 40 case-control studies, 22 were conducted among Asian populations, 16 were Caucasian, and 2 were African population. Thirty-one studies were based on adults. Other 9 studies were based on children. Ten studies were based on IS. Four studies based on HS and other studies based on both (MIXED). Four studies based on population (PB), 21 studies based on hospital (HB). other studies based on no report (NR) in this article. The sample group of 21 studies was less than 100, and the sample group of the other 19 studies was greater than or equal to 100. The main features of the study and the genotype distribution results of the HWE test were shown in Table Flowcharts of the detailed selection process were shown in Fig. MTHFR A1298C gene had significant association with stoke risk under the C allelic genetic model , dominant genetic model  and recessive genetic model .The meta-analysis included 14,380 participants (5725 cases and 8655 controls) in 40 case-control studies . No significant correlation among MTHFR A1298C Polymorphism and stroke risk was found in the three genetic models of Caucasian and African. Among the three genetic models grouped by study population, only adult MTHFR A1298C polymorphisms were found to be obviously correlated with stroke susceptibility . There was no obvious association among MTHFR A1298C polymorphism and children stroke risk. Stratified analysis by stroke type found that MTHFR A1298C polymorphism was obviously correlated with increased stroke risk in the three genetic models of ischemic stroke . In the control source stratification, three control genetic models from hospitals found an obvious correlation among the MTHFR A1298C polymorphism and increased stroke risk . Finally, we stratified the case group according to whether the sample size was greater than or equal to 100. The study discovered that MTHFR A1298C polymorphism was obviously correlated with increased stroke risk under the three genetic models with a sample size of 100 or more   , recessive model (CC vs CA + AA) and allele model (C vs A). In stratified analysis based on race, study population, stroke type, source of controls population and sample size of cases, a significant association was discovered among MTHFR A1298C polymorphism and stroke in three genetic models of Asians. In Caussian and African, MTHFR A1298C polymorphism was not significantly correlated with stroke. In stratified analysis according to study population, it was discovered that MTHFR A1298C polymorphism was obviously correlated with stroke in adults. But the correlation between MTHFR A1298C polymorphism and stroke in children lacked corresponding evidence. In stratified analysis of stroke types, the association among MTHFR A1298C polymorphism and stroke was found only in ischemic stroke. The stratified analysis of source of the control group showed that there was obvious correlation among MTHFR A1298C polymorphism and stroke in hospital study. The stratified analysis of the sample size showed that the correlation among MTHFR A1298C polymorphism and stroke was found only when the number of samples in the case group was greater than or equal to 100. The above analysis showed that the source of control group and the sample size of case group may be the influencing factors of the correlation study among MTHFR A1298C polymorphism and stroke. This was undiscovered in early meta-analysis. Although Kumar et al. [MTHFR gene can encode MTHFR enzyme, which plays a key role in regulating cellular homocysteine (Hcy) and folate metabolism by catalyzing the conversion of 5,10-methylpentylenetetrahydrofolate to 5- methyltetrahydrofolate, and elevated homocysteine level in blood circulation is considered as an independent risk factor for cerebral, coronary and peripheral atherosclerosis [This meta-analysis resolved the correlation among r et al.  conducter et al.  indicateclerosis .This meta-analysis has several limitations. Our results show the genetic differences in ethnic differences and stroke risk, but the study only includes Asian, Caucasian and African populations, and there are few studies in African populations, and there are no corresponding studies for other ethnic populations. The occurrence of stroke is often caused by the interaction of genetic factors and environmental factors. This study is only conducted from the perspective of genetics without the influence of environmental exposure. In previous studies, especially in meta-analysis, the data was still insufficient. We have checked as many articles as possible, but many studies have omitted data, such as control sources and genetic testing methods.MTHFR A1298C and stroke risk in Asians, adults and ischemic strokes. However, for the Caucasian, African, children and hemorrhagic stroke, the risk of MTHFR A1298C could not be confirmed because of the relatively limited sample size. In addition, sample size of case group and source of control group would also have an impact on the results in the stratified analysis of this study. Therefore, in future research, we can explore more about the correlation among MTHFR A1298C and stroke in other races (except for Asian population), children, and hemorrhagic stroke.In conclusion, we found obvious correlation among


Novel evidence showed that the Geriatric Nutritional Risk Index (GNRI) may lead to poor prognosis of human cancers. Therefore, we conducted a meta-analysis to explore the impact of GNRI in lung cancer and its prognostic value.We searched the databases of PubMed, Web of Science, Embase, Scopus, and Cochrane Library up to July 2021 for relevant research and merged the hazard ratios (HRs) and 95% confidence intervals (CIs) to evaluate the association between GNRI and overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS) in patients with lung cancer. Eight studies involving 2,399 patients were included in our primary meta-analysis. The results indicated that lower level of GNRI was associated with poorer OS, RFS, and CSS of lung cancer patients . The association was robust after subgroup analysis and sensitivity analysis.GNRI may be a prognostic factor of lung cancer, which can lead to poorer survival. However, more prospective studies are necessary to confirm the results.International Prospective Register of Systematic Reviews (PROSPERO), identifier CRD42021269574. The novel cancer statistics revealed that 2.2 million new cases and 1.8 million new deaths of lung cancer occurred, which demonstrated that lung cancer is still the leading cause of cancer death . TherefoThe current meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement  and was The systematic search for the eligible literature was performed in the following databases including PubMed, Web of Science, Scopus, Embase, and the Cochrane Library up to July 2021. The following key words were used to retrieve potential research: “pulmonary neoplasms,” “lung cancer,” “geriatric nutritional risk index,” “GNRI,” “survival,” and “prognosis.” Additional articles were manually retrieved from the reference lists of relevant research, and the included articles were restricted to English. The detailed search strategy for PubMed was presented in Studies were included if they met the following criteria: 1) All patients were pathologically diagnosed with non-small cell lung cancer; 2) Studies investigated the prognostic value of GNRI that was calculated by pretreatment albumin level, pretreatment weight, and ideal weight; 3) The outcomes included the OS with hazard ratios (HRs) and corresponding 95% confidence intervals (95% CIs); 4) retrospective or prospective studies with the full-text paper published before July 2021.Studies were excluded if they met the following criteria: 1) reviews, conference abstracts, case reports, letters, or comments; 2) laboratory research of clinical samples, cell lines, or animals; 3) insufficient data of GNRI or lack of control; 4) Full-text paper written in English was not available.Two researchers extracted the following data from the eligible studies independently: family name of the first author, year of publication, study design, region, median follow-up (in months), sample size, GNRI cutoff value, tumor stage, therapy, and outcomes with HRs and their corresponding 95% CIs. Any disagreement was resolved by discussion and consensus.The risk of bias assessment was conducted by the Newcastle–Ottawa quality assessment Scale (NOS), and studies labeled with 6 points or higher were regarded as high-quality studies.2 statistics. Significant heterogeneity was defined as p-value <0.05 and I2 > 50%, and the random-effects model was used under this condition. Otherwise, we chose the fixed-effects model. Subgroup analyses were performed to investigate potential confounding factors of this meta-analysis. Sensitivity analysis was conducted by excluding each study independently from our meta-analysis to find out the overrepresentation of every single study. Publication bias was evaluated by Begg’s test  and R Studio (version 1.3.1). HRs from the multivariate analysis were used wherever available, and HRs from univariate analysis were substituting only if the results of univariate analysis were provided. Besides, HRs of multiple groups were merged using a fixed-effects model for the main analysis if HRs of different GNRI levels were provided independently. In addition, HRs were estimated by applying the method of Tierney in case they were not provided directly. Pooled HRs and 95% CIs were combined with the random effects or fixed-effects model according to heterogeneity. Heterogeneity was assessed by forest plots, Q tests, and Ig’s test , Egger’sg’s test , and fung’s test . p-valueAccording to our search strategy, a total of 274 potential publications were obtained, and 220 separate articles were further screened after removing duplicates. According to titles and abstracts, 35 studies were selected for the screening of full-text version, and finally, 8 studies were included in our present meta-analysis. The NOS scores of these studies ranged from 6 to 9, which represented a low risk of bias. The PRISMA flow diagram and checklist of this meta-analysis were presented in The main characteristics of the included studies were displayed in 2 = 25%, p = 0.23)   .To detect the potential origin of the heterogeneity among the included studies, we subsequently performed subgroup analyses stratified by region, tumor stage, therapy, sample size, GNRI cutoff value, median follow-up (months), and publishing time. As shown in 2 = 0%, p = 0.51), which suggested that this publication might be the main source of heterogeneity.We then performed a sensitivity analysis to further explore the source of heterogeneity by removing each study from the meta-analysis independently. As shown in Funnel plots, Begg’s test, and Egger’s test were applied to assess the publication bias. The funnel plot for OS was basically symmetrical Figure 4In the present study, we aimed to evaluate the prognostic value of GNRI in lung cancer patients, and the pooled results revealed that the lower GNRI was significantly associated with OS, CSS, and RFS in lung cancer patients. Moreover, these results remained stable even after subgroup analysis and sensitivity analyses for detecting underlying confounders, which suggested that a lower pretreatment GNRI was an independent indicator for worse prognosis in lung cancer patients. To the best of our knowledge, this is the first meta-analysis that comprehensively explored the impact of GNRI on non-small cell lung cancer.Malnutrition is important to the immune system and related to inflammation and cachexia, which can even lead to the mortality of many diseases including tumors –26. HencTaken together, we found that a lower GNRI was an independent indicator of poorer prognosis in lung cancer patients. However, these findings must be applied seriously in clinical practice, and more prospective cohort studies are needed to confirm our results.The original contributions presented in the study are included in the article/WL and DL contributed to conceptualization and supervision. HW formulated the study question and objectives and planned the search strategy. HW and RY carried out the primary search and data extraction. HW performed the statistical analysis and data interpretation and wrote the primary article. CL, JJ, DL, and WL reviewed the article. All authors read and approved the final article. All authors contributed to the article and approved the submitted version.This work was supported by the National Natural Science Foundation of China (grant numbers 91859203 and 81871890) and Major Science and Technology Innovation Project of Chengdu City (grant number 2020-YF08-00080-GX).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


We screened four databases  for the observational studies about the OSA and T2DM. Studies were collected from database establishment to October 2020. We performed a traditional subgroup meta-analysis. What is more, linear and spline dose-response models were applied to assess the association between apnea-hypopnea index (AHI), an indicator to evaluate the severity of OSA, and the risk of T2DM. Review Manager, version 5.3, software and Stata 16.0 were used for the analysis. P < 0.05). Moderate-dose AHI increased the risk of T2DM with a higher odds ratio . Moderate-to-severe-dose AHI increased the risk of T2DM with a higher odds ratio . Severe-dose AHI increased the risk of T2DM with a higher odds ratio . Furthermore, the spline and linear dose-response meta-analysis results revealed that the risk of T2DM increased with increasing AHI values.  Seven observational studies were included in the research. We excluded a study in the conventional meta-analysis. In the subgroup analysis, mild-dose AHI increased the risk of T2DM (odds ratio = 1.23, 95% confidence interval = 1.06–1.41,  Through the dose-response meta-analysis, we found a potential dose-response relationship existed between the severity of OSA and the risk of T2DM. This relationship in our passage should be considered in the prevention of T2DM in the future. Obstructive sleep apnea (OSA) is one of the sleep disorders due to the refractory hypoxemia episodes and sleep fragments, leading to daytime sleepiness, impaired performance, and reduced quality of life.b=rSy/Sx to estimate the corresponding AHI [There are 90% elderly males and 78% elderly females suffering from OSA approximately worldwide . The apnding AHI . Intermiding AHI , suggestType 2 diabetes mellitus (T2DM) is a systemic disease and a massive health threat, causing considerable damage to each organ. The incidence of T2DM is still rising, which has become severe and expanding worldwide wellbeing burden. The global figures read that 381.8 million adults are affected, and these data will come to 591.9 million in 2035. In developed countries, most T2DM patients are older than 50, while in developing countries, 41% of T2DM are elderly [According to previous research works, OSA was closely associated with the high death rate from all causes. OSA damages all the systems in human bodies and organs with significant vascular structure, including the brain, heart, and kidneys. Besides, Xu et al.  reportedOSA has been defined as a risk factor for T2DM by many studies . MoreoveIn our present research, there were seven observational studies included. We planned to explore the association between OSA and different T2DM severity from these six OSA-related studies. To ensure our results' preciseness, we not only did a traditional meta-analysis but a dose-response meta-analysis was also accomplished. This study would offer strong evidence and new thought for the prevention of T2DM for OSA patients.We registered this systematic review and dose-response meta-analysis with the INPLASY register (INPLASY2020110027). In addition, we followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines for meta-analyses.In the present study, we included cross-sectional studies, cohort studies, and case-control studies that had clear outcomes and reported hazard ratio (HR), odds ratio (OR), or relative risk (RR) and 95% confidence interval (CI) for the association between OSA and T2DM. HR and OR were considered approximately RRs . The resFurthermore, the participants' ages were older than 18 years. We excluded patients with type 1 DM, and researchers used other indexes as indicators. As for the research type, case reports and reviews were also excluded. The criteria for inclusion and exclusion are shown in We screened the PubMed, Embase, Cochrane Library, and CNKI (Chinese) databases. The retrieval time was from incipiency to September 2020. To fit different demands in different databases, we modified the search terms and strategy. In addition, we screened all references of the included articles to ensure we collected the related studies as many as possible. Moreover, we communicated with senior specialists when conceivable to complete the search methodology. The search strategy in PubMed is shown in Supplementary Materials Two independent investigators (YZX and JXC) extracted data from the included articles. Discrepancies were handled by consultation and guide from JQH. In addition, data about baseline information of participants, study design, and relevant statistics were extracted. No qualification was made to measure the seriousness stratification of T2DM.We evaluated the included studies according to the Newcastle-Ottawa scale (NOS) . A quantTwo investigators (YZX and YF) finished the conventional meta-analyses with Cochrane Review Manager, version 5.3, software to assess a specific outcome's risk.Q and I2. We adopt a standard for P-value that P value < 0.1 means the results possessed statistical heterogeneity. I2 describes the extent of variation due to heterogeneity rather than chance. The lower the I2 is, the less the variation is. I2 < 25% was considered little heterogeneity; 25% < I2 < 50%, a little heterogeneity. I2 > 50% showed there existed enough heterogeneity to select a random-effects model. While I2 < 50%, a fixed-effect model was employed [The evaluation of heterogeneity among studies was carried out with the use of employed .P < 0.05 means the existence of a significant difference.Funnel plots were selected to assess whether the report existed publication bias. Egger's and Begg's texts were designed to recognize the plots' asymmetry, suggestive of bias. In this plot, α = 0.05 was taken as a cut-off for the regression parameters [b = r×sy/sx [For further research, we performed a dose-response meta-analysis using Stata, version 16.0, software. We performed the dose-response meta-analysis based on a two-step method , 16. Firrameters . For a s r×sy/sx . Accordi r×sy/sx , the difThis study complied with the Declaration of Helsinki. Given the study was a meta-analysis, no prior ethical approval was required.After a primary search, we identified 537 articles. There were 49 duplicated publications. In the left passages, from the title, we knew that there were 160 reviews. After abstracts screening, we excluded 290 studies, for they were not related to the topic. Then, we screened the whole text. We found 15 passages that did not mention the indicators we were interested in, and ten articles did not declare accurate RR/OR or 95% CI. Five research works did not perform OSA subgrouping. Natalia et al.  was a leAll the research studies included in this meta-analysis were cohort studies, including 15252 participants. The study sizes were different from each other (303 to 8678). There existed a sex difference between the included research studies (women count 0 to 54.2%). As for the outcomes of the research works, 2381 new cases of T2DM were diagnosed . The preP = 0.002) (P < 0.001) for moderate (P < 0.001) for moderate-to-severe (P < 0.001) for severe (All the included studies researched the correlation between mild-dose AHI (5–15) and the risk of occurrence of T2DM. Three observational studies paid attention to the effect of moderate-to-severe-dose AHI (>15). Only two studies reported the association between moderate-dose AHI (15–29) and T2DM. Moreover, some research did not select 0 < AHI < 4.9 as a reference, which led to difficulty in merging these data. Besides, Appleton et al.  only per= 0.002)  for mildmoderate , OR = 2.o-severe , and OR r severe .P < 0.05 means that there existed bias in the selection of the studies. The P value of Begg's or Egger's texts for all subgroups was more than 0.05. The results of the heterogeneity in the different subgroups were as follows: 0 (P = 0.47) for mild, 59% (P = 0.12) for moderate, 0 (P = 0.8) for moderate-to-severe, and 79% (P = 0.008) for severe. For further heterogeneity research, the funnel plot , which means the existence of a linear model. We performed linear (P < 0.05). The spline analysis showed that the risk of occurrence of T2DM increased with increasing OSA severity.There were statistically significant differences in the risk of T2DM between the mild-dose, moderate-to-severe-dose, and zero-dose groups of OSA. What is more, the linear model test result was not significant . This suggested the result of the conventional meta-analysis was receivable, but accepting should be cautious. We speculated heterogeneity might be for the following reasons. First, there were different proportions of age and gender participants in the included studies. Male OSA has higher AHI compared to age-matched females [For the meta-analysis of two subgroups, the mild-dose subgroup and moderate-to-server-dose AHI analysis showed heterogeneity when merging the related research works. The mild-dose, moderate-dose, and moderate-to-severe-dose subgroups' heterogeneity showed no significant differences; the severe-dose subgroups were gross ( females . Older a females . The pre females . Second, females . Reichmu females  selectedOur study provided strong evidence that OSA was related to the risk of T2DM occurrence and performed a prediction for the RR to different AHI doses with the linear and spline models. The results were consistent with previous meta-analyses –30. In QOSA is characterized by intractable hypoxemia, which leads to various pathologic conditions, including neural activation, systemic inflammation, oxidative stress loading, and hormone disorder. The changes in hormonal systems will add an influence on energy metabolism. Xu et al.  and ZhanThere are a few impediments to our research. First, some studies' sample size was limited. Marshall et al.  only resOur research has proved that OSA is a risk factor for DM. Besides, for different severity, OSA shows a different OR. As a quantitative indicator of OSA, the AHI was positively related to the risk of DM, which indicates that doctors should pay more attention to the patients' breath events during sleep after ablation treatment. In this research, we set up a dose-response model for AHI and DM. With the help of the model we built, physicians will have more evidence to decide the intervention time for OSA patients to prevent DM.In a word, our study concluded that the AHI is positively correlated to the risk of DM occurrence. OSA is associated with the occurrence of T2DM. Further studies are needed to assess whether OSA treatment would decrease T2DM risk and benefit the management of T2DM.


Previous literature on the association between infections and the risk of developing ankylosing spondylitis (AS) presented controversial results. This meta-analysis aimed to quantitatively investigate the effect of infections on the risk of AS.We searched the PubMed, Embase, and Web of Science databases until March 26, 2021 for analytical epidemiological studies on the association between infections and the risk of AS. Fixed or random effect models were used to calculate total risk estimates based on study heterogeneity. Subgroup analysis, and sensitivity analysis were also performed. Publication bias was estimated using funnel plots and Begg’s test.Six case-control articles  and seven cohort articles  were incorporated into our meta-analysis. The pooled odds ratio (OR) from these case-control studies showed that infections were associated with an increased risk of AS , and the pooled relative risk (RR) from the cohort studies showed the same findings . Subgroup analysis showed that infections in participants with unadjusted comorbidities , other types of infection , and infection of the immune system  were associated with the risk of AS in case-control studies. In cohort studies, infections with adjusted comorbidities , viral infection , other types of infection , and other sites of infection  were associated with an increased risk of AS.via the avoidance of infections. The findings of this meta-analysis confirm that infections significantly increase the risks of AS. This is helpful in providing an essential basis for the prevention of AS  Ankylosing spondylitis (AS), a complex autoimmune inflammatory rheumatic disease, has long been considered the archetype of spondyloarthritis (SpA). Common symptoms of AS include arthritic symptoms , potential extra-articular symptoms , and the involvement of the heart, bone, lung, kidneys, and skin , 2. The The pathogenesis of AS is complex and multifactorial. Early studies have confirmed that AS is strongly associated with the inheritance of HLA allele B27, which might misfold in the endoplasmic reticulum (ER), leading to the upregulation of interleukin (IL)-23 in dendritic cells . It may via IL-17 or C reactive protein levels that can induce inflammatory response   and PrefWe systematically searched the PubMed, Embase, and Web of Science electronic databases to identify such literature published up until March 26, 2021, using terms related to infection and AS. The search strategy was developed and implemented under the guidance of experts on library services from Shandong First Medical University. The main search strategy involved the following:  AND  AND . The complete search strategy of the three databases is listed in Studies were included according to the following criteria: (1) the study design was a cohort or case-control study; (2) the studies defined infections using self-reporting, clinical diagnosis, or basic medical experiment, and focused on infections that developed before AS did; (3) the outcome of interest was AS; and (4) the studies provided the effect size  or raw data that could be used to calculate RR, HR, or OR. The exclusion criteria were as follows: (1) non-human-based studies; (2) studies that were poster presentations, reviews, conference summaries, or dissertations; and (3) the scores of quality evaluation according to the Newcastle-Ottawa Scale (NOS) were <4 . In the According to the study design, the included studies were divided into two extraction forms of case-control studies and cohort studies. The following data were extracted from the eligible case-control studies using a customized form: the first name of the first author, year of publication, study location, types of infection, definition of infection, definition of AS, age, sex, sample size, adjustment for potential confounding factors, and estimates of association. The follow-up duration in cohort studies was also included. The Cochrane Non-randomized Studies Methods Working Group recommended the use of the NOS to assess the quality of observational studies (range: 0–9 stars) . AccordiP values <0.05 were considered statistically significant, though P values >0.1 illustrated no heterogeneity among studies in the heterogeneity test , the Dersimonian and Laird random effects model (REM) was adopted as the pooling method; otherwise, the Mantel-Haensze fixed effects model (FEM) was applied as the pooling method.The statistical analyses were performed using Stata 15.1 software . All of the tests were bilateral, and ity test . ORs, RRo chance . In the Subgroup analyses were performed based on adjusting for comorbidities, infection type, and infection site. In addition, considering that publication year, study location, sample size, definition of infection, and duration of follow-up (only in cohort studies) may affect between-study heterogeneity, subgroup analysis was also conducted based on these possible factors. Sensitivity analyses were performed to validate the stability of pooled ORs of case-control literature and pooled RRs of cohort literature by removing each individual study. In addition, we used the funnel plot and Begg’s test to assess publication bias.via hand-searching found 1 relevant article. An additional 12 articles were excluded because they did not meet the inclusion criteria. Therefore, 13 articles that met the inclusion criteria were ultimately included , and the seven cohort studies (QP<0.001. I2 = 70.5%). Therefore, REM was used to pool the OR for case-control studies and RR for cohort studies. Our meta-analysis showed that, compared to the control group, the infection group was significantly associated with an increased risk of AS. The pooled OR calculated by REM was 1.46  for the case-control studies, and the pooled RR was 1.35  for the cohort studies.vs. unadjusted), infection type , and infection site (immune system vs. other).P=0.139). Similar results were reported with the infection type  and the infection site .In the case-control studies, our analysis showed no significant difference between adjusted comorbidities  and unadjusted comorbidities  (P=0.157). No differences were also found in the infection type  and infection site .In the cohort studies, our analysis showed no statistically significant difference between adjusted comorbidities  and unadjusted comorbidities  and basic medical experiment . Definition of infection might be one of the sources of heterogeneity in the cohort studies.We also conducted subgroup analysis based on publication year, study location, sample size, definition of infection, and duration of follow-up. As shown in I2 = 58.6%) by omitting this study.As shown in P=0.721) and cohort studies (P=0.368).The funnel plots for estimating publication bias were roughly symmetrical for the case-control  infection may reduce the risk for developing AS. Another study found that H. pylori infection was eradicated in more than 80% of cases in the same cohort as that of Bartels et al. . The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


MTHFR polymorphisms result in reduced enzyme activity and altered levels of DNA methylation and synthesis. MTHFR polymorphisms have been linked to increased risks of several pathologies, including cancer. Breast cancer, gliomas and gastric cancer are highly heterogeneous and aggressive diseases associated with high mortality rates. The impact of MTHFR polymorphisms on these tumors remains controversial in the literature. This review discusses the relationship between the MTHFR C677T and A1298C polymorphisms and the increased risk of breast cancer, gliomas, and gastric cancer. Additionally, we highlight the relevance of ethnic and dietary aspects of population-based studies and histological stratification of highly heterogeneous tumors. Finally, this review discusses these aspects as potential factors responsible for the controversial literature concerning MTHFR polymorphisms.Folate (vitamin B9) is found in some water-soluble foods or as a synthetic form of folic acid and is involved in many essential biochemical processes. Dietary folate is converted into tetrahydrofolate, a vital methyl donor for most methylation reactions, including DNA methylation. 5,10-methylene tetrahydrofolate reductase (MTHFR) is a critical enzyme in the folate metabolism pathway that converts 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate, which produces a methyl donor for the remethylation of homocysteine to methionine.  Folate is a water-soluble vitamin (vitamin B9) found in some foods  or in a synthetic form (folic acid) used in fortification and dietary supplementation programs ,2. This Folates in nature are present in a reduced form. The in vivo biological activation of folic acid requires a reduction in the intermediate forms of dihydrofolate and tetrahydrofolate by adding hydrogen atoms in the pyrazine ring and pteridine at positions 7, 8 and 5, 6, 7 and 8, respectively. Folate can also bind to the carbon units of methyl groups (CH3), methylene (CH2), formyl (–CHO–) or formimino (–CHNH–) at positions N5, N10, or both positions of the structure. This process imparts function to folate coenzyme in various enzymatic systems as a carbon carrier unit at different degrees of oxidation. Carbon donor unit function is essential for methylation reactions, nucleotide synthesis, DNA synthesis and repair ,5,6 and MTHFR , MTR (methionine synthase) and MTRR (methionine synthase reductase) are key enzymes in the metabolism of folate. MTHFR occupies a central position while maintaining homeostasis between DNA synthesis and methylation , promotiDNA methylation causes the covalent modification of genomic DNA that alters gene expression and the transmission of epigenetic information that is perpetuated through DNA replication and cell division. Changes in the patterns of DNA methylation are critical features in the process of carcinogenesis, and global DNA hypomethylation and hypermethylation of specific promoters may occur. Global DNA hypomethylation is associated with low folate intake in animals and experimental studies with human models ,19. AberMTHFR gene with the process of breast, glioma and gastric carcinogenesis.Breast tumors are characterized by a high incidence among women and are one of the main causes of mortality. Gliomas are heterogeneous tumors and have high rates of recurrence and mortality. Gastric cancer is the fifth most common type of tumor with the third highest mortality rate. Literature reports have demonstrated the impact of folate metabolism on DNA synthesis and methylation, resulting in an increased risk of several cancer types when this pathway is dysregulated. In this context, this review discusses the relationship of changes in the folate pathway resulting from the C677T and A1298C polymorphisms of the MTHFR is a key enzyme in the folate metabolism pathway that converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the primary circulatory form of folate, producing a methyl donor for the remethylation of homocysteine to methionine in a conversion catalyzed by MTR using vitamin B12  as a cofMTHFR gene is located at the end of the short arm of chromosome 1 (1p36.3), and the DNA sequence for this gene is approximately 2.2 kilobases (kb) and includes 11 exons [MTHFR polymorphisms have been extensively investigated to assess their association in various medical conditions, primarily cardiovascular disease, thrombosis, pregnancy complications, neural tube defects, cancer risk, and psychiatric disease [MTHFR gene already well described as associated with numerous pathologies: C677T and A1298C [The 11 exons ,25. MTHF disease ,26. Therd A1298C ,27,28.MTHFR gene whose exchange of nucleotide cysteine for thymine culminates in the replacement of alanine by valine in the MTHFR enzyme. This mutation is associated with reduced enzyme activity and increased thermolability of the enzyme already reported in vitro, leading to a decrease in 5-methyltetrahydrofolate and an increase in the accumulation of the substrate 5,10-methylenetetrahydrofolate. The reduction in enzyme activity leads to an increase in plasma homocysteine levels in mutant homozygous subjects and high plasma homocysteine levels; in heterozygotes, homocysteine levels are high compared with normal individuals but lower than homozygotes [The C677T polymorphism is an exchange at position 677 of the ozygotes ,29,30,31MTHFR A1298C polymorphism occurs in exon 7 and results in glutamate transformation into alanine at codon 429. This polymorphism is located in the regulatory domain S-adenosyl methionine (SAM) of the enzyme and causes conformational changes in the MTHFR enzyme that also reflect a reduction in enzyme activity but do not result in a thermolabile protein [MTHFR polymorphism and pathologies. As already reported in the literature, it has been associated with vascular diseases, diabetes, neurological diseases, recurrent pregnancy loss and infertility, and psoriasis [The  protein ,27. Unli protein ,33,34. Msoriasis ,42,43,44MTHFR polymorphisms may directly affect the incidence of cancer, likely by causing an imbalance in maintaining the epigenome. However, data regarding the association between the MTHFR polymorphism status and cancer risk have also been conflicting [MTHFR. The MTHFR gene polymorphisms show a relationship with leukemias and lymphomas with a more marked presence of the C677T polymorphism than A1298G in studies with significant results obtained [Studies have shown that folate deficiencies and the presence of polymorphisms in genes related to the folate pathway increase the incidence of cancer. MTHFR is directly involved in folate metabolism. Therefore, flicting ,45. Seveobtained ,48,49,50MTHFR C677T polymorphism was significantly associated with an increased risk of tumors, and stratified analyses showed an increased risk of stomach and esophageal cancer in addition to an increased risk in Asian ethnicities [MTHFR C677T CT and TT genotypes with low folate intake, and these effects could be largely modified using tobacco. Individuals with the MTHFR 1298 CC polymorphism have no significantly increased risk of esophageal cancer [In a meta-analysis of 134 case-control studies, the nicities . Other ml cancer ,53. The l cancer , and thiMTHFR variant is associated with a reduced risk of developing carcinoma in the presence of high doses of folic acid and vitamins B6, B12 and/or B2 in subjects with a low intake of alcohol. However, the risk increases in deficient vitamin nutrition [MTHFR 677TT genotype is associated with global DNA hypomethylation, which can be enhanced in situations of folate depletion. The overall hypomethylation is associated with hypermethylation of tumor suppressor genes, particularly in subjects with MTHFR 677TT [MTHFR 677TT cancer can be due to the separation of carbon from methylation cycle group-1 and synthesis of thymidine [MTHFR seem to be somewhat related to several cancer types.In adenomatous polyposis, a precursor stage of colorectal adenocarcinoma, the 677TT utrition . This reutrition ,20. The FR 677TT ,57. The hymidine . TherefoBreast cancer (BC) is the most common cancer type among women worldwide and has a high mortality rate. It is characterized by the expression of aberrant genes that confer heterogeneous morphology and aggressiveness to the tumor in addition to varied clinical manifestations ,60. GenoMTHFR genotype reduce the catalytic activity of MTHFR, and this activity is essential for DNA synthesis, methylation and repair [MTHFR have been shown to influence the risk of BC, although this finding remains controversial, and the data from the evaluated studies are shown in Several environmental and genetic elements are involved in different BC types, and various mutations in tumor suppressor genes and oncogenes are involved in the process of carcinogenesis . Thus, pd repair . FunctioMTHFR gene and the risk of BC compared with the wild homozygous genotype CC (p = 0.007). Additionally, the CC genotype reduced the risk of the breast carcinogenesis process (p = 0.004) in addition to reducing the risk of death compared with the TT genotype [MTHFR polymorphism between cases and controls in the risk of BC [In a case-control study conducted in China with 560 patients diagnosed with BC and 560 healthy individuals, a significant association was observed between the homozygous TT genotype for the C677T polymorphism of the genotype . Anotherp < 0.0001). Furthermore, the polymorphic genotype correlated strongly with the risk of BC (p < 0.0001) and correlated with women in the menopausal period (p = 0.036), although with no relationship to age, weight, body mass or height. These results corroborate previous data from Gao et al., who showed an association between polymorphic homozygotes and the risk of BC [Analyses of the C677T polymorphism from peripheral blood samples obtained from 100 Iranian women with BC and 142 healthy women showed that the T allele and TT genotype had a higher prevalence in patients  and heterozygous (CT) genotypes for the MTHFR C677T polymorphism. This risk was increased in women of Asian and Caucasian ethnicities, suggesting that polymorphism may be a risk factor for tumorigenesis [MTHFR gene, although the risk of BC in the presence of the polymorphism was higher among Caucasian and Asian populations of the evaluated groups [A meta-analysis publication performed by He igenesis . Howeverd groups . Analysed groups .p = 0.02, p = 0.04, and p = 0.01, respectively). However, no association was observed between the A1298C polymorphism and the risk of developing BC in Latino American populations [p = 0.03). These data corroborated previous case-control studies of Chinese women who also showed a risk of developing BC in women with the 677TT genotype [Considering the possible relationship between the polymorphism and Caucasian and Asian ethnicities, another group evaluated the influence of the C677T and A1298C polymorphisms in Latin American populations and found a high risk for the development of BC in homozygous, recessive and allelic genetic models for the C677T polymorphism  and with the expression of ER (p = 0.02). Interestingly, analyses of the A1298C polymorphism performed by the same group showed an association of the wild-type homozygous (AA) genotype with higher degrees of severity of sporadic breast cancer given the lower prevalence of patients with this genotype in stage 0 of the disease. The authors suggested that the C677T and A1298C polymorphisms were not associated with the risk of BC, but might modulate the severity of the disease [Another group that evaluated 253 Brazilian women with BC and 257 healthy women aged older than 50 years found an association of the C677T polymorphism with distant metastases  and the mutant allele variants of the C677T and A1298C polymorphisms. The association of the biophenotype and polymorphisms highlighted the risk of presenting a more aggressive biophenotype two or three times higher in patients with the C677T and A1298C polymorphisms, respectively, suggesting an association of the polymorphisms with tumor progression. Additionally, the group also showed an association of the A1298C polymorphism with the risk of lymph node metastasis and an increased risk of developing BC in patients with polymorphic homozygous (CC) genotypes and overweight individuals . HoweverCentral nervous system (CNS) tumors represent approximately 1.4% of the global tumor burden, with an increasing incidence worldwide ,89. The MTHFR C677T and MTHFR A1298C polymorphisms confer lower functioning MTHFR enzymes and are associated with increased cancer risk [MTHFR polymorphisms in CNS tumors. The studies evaluated in this review and their results are shown in WHO classification influences treatment choices and is a predictor of tumor biological behavior. Molecular classification provides insights to understand disease initiation, progression, and the development of targeted therapies. In this context, understanding the controversial impact of genetic polymorphisms involving folate metabolism in brain tumors is relevant. As previously detailed, cer risk . The procer risk . Severalcer risk ,98. ThusMTHFR A1298C polymorphism was associated with a 3.9-fold increased risk of embryonic tumors such as medulloblastoma, pineoblastoma and primitive neuroectodermal tumor (PNET). This polymorphism was not associated with an increased risk of glial and germ cell tumors [MTHFR C677T; however, this increase was not statistically significant. Conversely, Salnikova and colleagues (2013) found no association of the MTHFR polymorphism and pediatric brain tumor risk [MTHFR polymorphisms, reducing tumor risk.In pediatric tumors, a case-control study of 73 Thai children with different types of brain tumors demonstrated that the CC allele of the l tumors . They almor risk . Severalmor risk ,102. Bunmor risk . Some Asmor risk ,105. TheMTHFR C677T polymorphism frequency. Populations with a folate-rich diet have a higher frequency of the MTHFR 677TT genotype. This genotype has been associated with fetal survival, although it has also been associated with increased cancer risk. The MTHFR 677TT genotype has been associated with a protective role in adequate folate concentrations; nonetheless, it can enhance cancer risk when the folate supply is inadequate [MTHFR polymorphism studies in cancer risk assessment. One literature report observed no significant difference in the serum folic acid and vitamin B12 levels concerning MTHFR polymorphisms [MTHFR C677T polymorphism in the Indian population. This literature report supports that the MTHFR C677T polymorphism does not increase the risk of cancer development when there is adequate folate intake.The geographical distribution of folate-rich nutrients may be associated with the adequate . Therefoorphisms . AdditioMTHFR upregulation and hypomethylation compared with monolayers [Folate supplementation in animal models has a chemopreventive effect on the initial development of lesions in the colon. However, after establishing preneoplastic lesions, folate favors increased tumor growth, likely due to folate-dependent DNA synthesis in tumor cells ,108,109.nolayers . Folate MTHFR polymorphisms is associated with glioma risk. The genotypic frequency of MTHFR polymorphisms differs among ethnicities and can be a bias source in risk assessment [MTHFR 677TT genotype with glioma, even when stratified by histological type or WHO grade [MTHFR 677TT polymorphism in astrocytic tumors, suggesting a protective role for this genotype [MTHFR 677CC and 677CT genotypes. The lack of significance could be associated with the small sample size in each stratification group. Conversely, a case-control study in Turkey with 74 patients and 94 controls demonstrated a higher frequency of the MTHFR 677TT genotype in high-grade gliomas than in the meningioma and control groups [MTHFR 677TT polymorphism frequencies , while the Indian population has a lower frequency (3.8–5%) [Several studies have found no association between polymorphisms and glioma development ,107,111 sessment . TherefoHO grade . Additiogenotype . The autl groups . Brazili(3.8–5%) ,114,115.MTHFR C667T polymorphism [MTHFR TC present an increased risk of meningioma [MTHFR C677T presented a statistically non-significant higher risk of brain tumors, likely due to the small sample size. However, Caucasians showed no difference [Systematic reviews and meta-analyses can be useful tools to address the impact of publications with small sample sizes in the field. Two meta-analyses demonstrated no enhanced risk of glioma development based on the morphism ,117. Onefference ,117.MTHFR A1298C polymorphism on meningioma and glioma risk [MTHFR A1298C genotype. Furthermore, an increased risk was observed in the Caucasian population but not in the Asian population. However, an Indian population-based study demonstrated that the CC genotype had a 38% reduced chance of meningioma compared with the AA genotype of the MTHFR A1298C polymorphism [MTHFR C677T and polymorphisms in MTRR and MTR.A meta-analysis was conducted to evaluate the impact of the oma risk . The anamorphism . AdditioMTHFR 677TT and the T allele [MTHFR A1298C polymorphism. Additionally, no significant differences were found after WHO grade stratification [MTHFR 677CT genotype was associated with an increased risk of meningioma [MTHFR A1298C polymorphism was associated with an increased meningioma risk only in the Caucasian population [In the Chinese population, two studies presented opposing results on meningioma risk. One study observed that meningiomas have a lower frequency of T allele , while tT allele . Both refication ,120. A mningioma . Stratifpulation .MTHFR polymorphisms. A large case-control study with 1005 glioma cases, 631 meningioma cases and 1098 controls demonstrated that the heterozygosity for MTHFR A1298C and MTHFR C677T was associated with an increased risk of meningioma [MTHFR A1298C heterozygosity. Additionally, the authors stratified samples into GBM, oligodendrocytes, other astrocytomas and other glioma subtypes. They demonstrated that the MTHFR A1298C polymorphism was mostly associated with GBM and oligodendrocytes increased the risk. Regarding GBM, another study found no association between the MTHFR C677T polymorphism and disease risk [MTHFR C677T polymorphism is associated with poorer overall survival in GBM, likely mediated by reduced enzymatic activity [MTHFR c.677TT genotype is an independent poor prognostic factor in the younger patient group (<60 years). Reduced enzymatic activity has also been associated with the MGMT promoter and DNA hypomethylation [MTHFR 677TT genotype was associated with reduced DNA methylation and suggested that patients harboring the MTHFR 677TT could benefit from treatment with a new approach based on perillyl alcohol inhalation.Meningiomas and gliomas are the most studied CNS tumors regarding ase risk . Linnebaactivity . The MTHhylation . Additiohylation . The autMTHFR C677T polymorphism with DNA hypomethylation in GBM cell lines and patient samples [MTHFR is located at Chr1p, a region commonly deleted in GBM. Hence, four GBM samples presented allelic loss of MTHFR. The loss of the MTHFR allelic region and presence of low-functioning-allelic (CT and TT) genotypes were associated with a lower DNA methylation profile. Thus, only tumors with a CC genotype (Ala/Ala) presented no genomic hypomethylation. Collectively, these studies point to a central role of the MTHFR genotype in DNA hypomethylation in GBM. However, the impact of this phenomenon on glioma risk requires further confirmation.Cadieux and colleagues (2006) evaluated the association of the  samples . All theMTHFR polymorphisms on glioma risk. Herein, we discussed the following factors that might contribute to the controversial literature: a) ethnicity; b) histological subtypes; and c) dietary intake of vitamins B6 and B12 and folate. Despite the effort of several studies to address the ethnic impact in the risk assessment of MTHFR polymorphisms, small patient samples have limited the results. Additionally, histological stratification has limited statistical power due to the small sample size. A comprehensive evaluation in a larger cohort is essential to elucidate the influence of these factors on the relationship between MTHFR polymorphisms and glioma risk.In the present review, we detailed studies with controversial results regarding the impact of Gastric cancer (GC) is the fifth most common cancer and third leading cause of cancer-related death, responsible for almost 800,000 deaths each year . GeneralHelicobacter pylori (classified as group 1 carcinogenic and associated with 80% of cases), Epstein–Barr virus (associated with 10% of tumors) and multiple genetic and epigenetic alterations [GC is a multifactorial disease comprising lifestyle, aging, socioeconomic factors, infectious agents such as erations ,130. Accerations ,131,132.Recently, new molecular classifications of GC have become available. The Cancer Genome Atlas (TCGA), using high-throughput technologies, has molecularly characterized gastric adenocarcinoma into four subtypes: Epstein–Barr virus (EBV)-infected tumors, microsatellite instability tumors (MSI), genomically stable tumors (GS), and chromosomally unstable tumors (CIN) . SimilarMTHFR polymorphism and clinical outcomes of GC patients has been determined in many populations; however, the results remain controversial to some degree, demonstrating that the association between the methylenetetrahydrofolate reductase polymorphism and risk of GC is a complex issue. The relationship between the presence of C677T and A1298C polymorphisms and risk of GC among different populations is shown in The relationship between the MTHFR A1298C and C677T polymorphisms in gastrointestinal tumor development and included 70 GC patients. Individuals carrying genotype AC of the A1298C polymorphism compared with those with AA had a 4.13 times higher risk (p = 0.001) of developing GC, and individuals with the CC genotype compared with the AA genotype had a 2.91 times higher risk (p = 0.027). However, the risk of developing GC in individuals carrying the TT genotype of the C677T polymorphism compared with those with CC was not higher; regarding the genotypes, no difference was found in the life spans of the patients [n = 307) control (n = 560) study in a Chinese Han population, patients carrying the TT genotype of C677T polymorphism were associated with a decreased risk of GC in older individuals and patients who never drank alcohol [MTHFR C677T polymorphism and the combined use of alcohol and smoking have a coordinate effect influencing GC risk [MTHFR C677T polymorphisms  [MTHFR C677T polymorphism but not in Caucasian populations [n = 2727), where MTHFR C677T was associated with GC  [A prospective study performed with an eastern Turkish population assessed the relationship between the patients . Recentl alcohol  Moreover GC risk . However12–1.42) . Furtherulations . Similarulations . Additioulations . Similar × 10−8) .MTHFR C677T polymorphism significantly increased the susceptibility to GC, but no significant correlation was found with the A1298C polymorphism. Furthermore, the authors found that MTHFR C677T but not MTHFR A1298C was associated with an increased risk of GC in Asian and Caucasian populations [MTHFR C677T and GC susceptibility in a population (n = 167) from the Ardabil Province in Iran found that CT heterozygous individuals had a lower susceptibility to GC. Additionally, CT was correlated with a reduced risk in female and older participants [In a meta-analysis involving 6572 cases and 9584 controls comprising Caucasian, Asian and mixed ethnicity samples, the ulations . Anotherulations , who evaulations . Furthericipants . Similaricipants  and Mexiicipants .MTHFR polymorphisms also play important roles in the response of GC patients to treatments. In a meta-analysis involving seven case-control studies and six cohort studies (n = 1718), Tang and colleagues evaluated the impact of the C677T polymorphism in GC patients treated with 5-fluorouracil (5-FU)-based chemotherapy [MTHFR polymorphisms. In the Netherlands, a multicenter phase 2 study investigated the use of bevacizumab combined with docetaxel, oxaliplatin, and capecitabine as a first-line treatment for advanced HER2-negative GC patients and found that the MTHFR C677T polymorphism was related to outcomes in which patients carrying the TT genotype had inferior progression-free survival  and OS  control (n = 780) study of an Iranian population in patients carrying the MTHFR C677T polymorphism who were also positive for Helicobacter pylori infection [ lesions . Saberi nfection . The TT nfection .MTHFR polymorphisms in GC is not homogeneous among the populations. This complex variation may be caused by the interaction of genetic and environmental factors, such as variant alleles, dietary habits, smoking, folate intake, alcohol consumption, Helicobacter pylori infection, and the molecular background specific to each population. Thus, it is difficult to draw conclusions about MTHFR polymorphisms and the risk of GC.As discussed above, the effect of the MTHFR polymorphisms on breast cancer, glioma and gastric cancer risk. In addition to the controversial literature, we observed a more relevant influence of the MTHFR C677T polymorphism, particularly in the Caucasian and Asian populations, on the risk of developing BC. However, the MTHFR A1298C polymorphism also showed relevance in some cases concerning the risk of breast cancer and relation to more aggressive phenotypes or lymphonodal metastases. MTHFR C677T polymorphisms are more associated with an increased meningioma risk, primarily in Caucasian populations. Regarding MTHFR A1298C polymorphisms, it appears to be more associated with glioma risk, mainly the heterozygous genotype. The effect of the MTHFR polymorphisms in GC is heterogeneous and may be associated with epigenetic and environmental factors.In the present review, we detailed studies with controversial results regarding the impact of MTHFR C677T polymorphism and a Mediterranean diet rich in fruits and vegetables and the modulation of the serum levels of the 5-MTHFR enzyme [MTHFR polymorphism and the prevention and/or induction of colorectal cancer [MTHFR polymorphisms and the mechanisms of DNA repair and metabolomic studies can better clarify the relationship of the influence of these polymorphisms on the risk of BC, glioma and CG. Additionally, comprehensive evaluation in a larger cohort stratified by ethnicity, histological subtype and considering vitamins B6 and B12 and folate levels is crucial to further understand the association of MTHFR polymorphisms and BC and glioma and CG risk.In a metabolomic study performed using serum samples from Greek women who were BC controls, a significant interaction was observed between the R enzyme . Anotherl cancer . Further


Erectile dysfunction (ED) and osteoporosis are both common health problems and have similar risk factors. Recent studies have found that people with ED have a higher risk of osteoporosis.We aimed to systematically assess osteoporosis risk in patients with ED.A systematically research was carried out in Medline via PubMed, Cochrane Library, EMBASE, and Web of Science up to June 4, 2020, to identify articles related to ED and osteoporosis. The 2 researchers independently reviewed the literature, extracted the data, and evaluated the quality of the literature. All analyses were done using RevMan5.3 and Stata14.P = .002, I2 = 68%]. Interestingly, compared with older participants, the increased risk of osteoporosis in ED patients seemed to be more pronounced in younger participants. Despite the lack of data for meta-analysis, more than half of the literature mentioned this tendency. We found the source of heterogeneity through sensitivity analysis, and there was no significant effect on the results before and after the removal of this literature, indicating that our results were robust. No obvious publication bias was found through Egger method (P = .672).A total of 4 studies involving 22,312 participants were included. The meta-analysis results showed that the risk of osteoporosis in the ED group was significantly higher than that in the non-ED group [odds ratio (OR) = 2.66, 95% confidence interval (95% CI) 1.42 to 4.98, People with ED have a higher risk of osteoporosis, especially among younger males. Because the assessment of osteoporosis is economical and noninvasive, ED patients should be evaluated by bone mineral density or men with osteoporosis should be further assessed for erectile function. ED is a very common male health problem, defined as the inability to achieve and maintain sufficient erections to achieve satisfactory sexual intercourse, affecting nearly a third of men over the age of 50. ED can have harmful effects on mental health, interpersonal relationships, and a wide range of psychosocial domains. A variety of ED-related risk factors have been identified, such as cigarette smoking, diabetes mellitus, cardiovascular events, chronic kidney disease, metabolic syndrome, and depression.–11 Interestingly, osteoporosis also has similar risk factors, and several studies have suggested a correlation between ED and osteoporosis.,13Penile erection is the result of a complex neurovascular process involving the synchronic effects of vascular endothelium, smooth muscle, psychological, and neuroendocrine systems. Osteoporosis has previously been associated with postmenopausal women, and male osteoporosis patients have rarely been the focus of previous research.,16 In fact, osteoporosis is also very common in men and is closely related to ED. Osteoporosis and ED significantly affect the quality of life in men.Osteoporosis is a systemic metabolic bone disease characterized by impaired bone strength due to attenuated bone mineral density (BMD) and compromised bone quality, making patients prone to brittle fractures. proposed that there seemed to be a potential link between ED and osteoporosis. They found that the incidence of ED and osteoporosis increased with age, but the 2 appeared to be independent, with no increased risk associated with each other. Contrary to the results of Keles et al, another study on the relationship between ED and osteoporosis in 95 men with ED and 82 men with normal sexual function found that patients with ED had lower bone mineral density and a higher risk of osteoporosis than non-ED participants. A subsequent nationwide population-based retrospective cohort study also observed an increased risk of osteoporosis in ED patients, particularly among younger males (40–59 years). Although several articles have been published, whether ED increases the risk of osteoporosis, whether it can be an early predictor of osteoporosis, and the mechanisms underlying these relationships are still controversial. In this study, meta-analysis was used to further integrate and clarify the relationship between ED and osteoporosis, and the potential mechanism was integrated and systematically elaborated in order to provide ideas for future studies and guide clinical practice.As early as 2005, Keles et al22.1 In addition, this study is a meta-analysis and does not involve ethical issues.Two researchers independently conducted systematic retrieval of PubMed, EMBASE, Cochrane, and Web of Science, and the retrieval time was up to June4, 2020. The search terms used include  and . We also browsed references of key articles and manually searched the gray literature to make sure no relevant articles were omitted. This system review and meta-analysis is reported in accordance with the preferred reporting items of the system review and meta-analysis (PRISMA).2.2Inclusion criteria were as follows: The subjects were men with ED or osteoporosis. The study type was observational study. The outcome was the incidence of osteoporosis. There are clear, widely accepted diagnostic criteria for both ED and osteoporosis. The literature provided sufficient data to satisfy the completion of the meta-analysis.).Exclusion criteria were as follows: Outcomes were unclear and data were missing. Diagnostic criteria for osteoporosis and ED were unclear. Republished literature. Poor quality , prevalence of diabetes, cases, ED-measurement, BMD-measurement, and quality score.2.4For included observational studies, including case--control studies, cohort studies, and cross-sectional studies, we used an 11-item checklist, which was recommended by Agency for Healthcare Research and Quality (AHRQ). If an item is answered “no” or “unclear,” it will be rated “0”; If the answer is “yes,” the score is “1.” Methodological quality of the literature can be assessed according to the total score: low quality = 0 to 3; moderate quality = 4 to 7; high quality = 8 to 11.2.5P < .05. We estimated the effect size of continuous variables by the mean difference (MD) and its 95% confidence interval (CI) and estimated the effect size of binary variables by the odds ratio (OR) of the calculated results and its 95% CI. Heterogeneity was evaluated using inconsistencies (I2) statistics. If I2 is greater than 50%, the heterogeneity is very significant and the random effect model should be adopted. If I2 is less than 50%, it indicates that the heterogeneity is within an acceptable range, and a fixed-effect model should be adopted.All statistical analyses and meta-analyses were performed using Cochrane Review Manager 5.3 (China) and Stata14 software, and the significance level was set at 2.6I2 through Revman5.3 and obtained the forest plot of sensitivity analysis through Stata14. After the source of heterogeneity is found, the target literature is analyzed in detail in order to find out the reason why it is the source of heterogeneity in this study.In order to find the source of heterogeneity, sensitivity analysis was conducted by eliminating each literature article one by one, recalculating and recording the heterogeneity and pooled effect values after removing a single study. After successively removing each study, we calculated the change of P value obtained by egger method is greater than .05, it means there is no significant publication bias. If P < .05, it indicated the existence of publication bias. In this case, the rim and fill method will be used to evaluate the impact of publication bias on our meta-analysis results. If publication bias is found to have a significant effect on results, we will discuss it in detail in our discussion.Publication bias was assessed quantitatively by the Egger method. When the 33.1,13,17,18 including 22,672 participants were finally included in our meta-analysis. Among the 4 studies, 3 are cross-sectional,17,18 and 1 is cohort. The baseline data of the studies included in the meta-analysis are summarized in Table We searched a large number of literatures, carefully studied and screened them, and the specific process is shown in Fig. 3.2We conducted a methodological quality assessment of the included studies using 11-item checklist recommended by Agency for Healthcare Research and Quality (AHRQ) and found that 2 articles were of high quality and the remaining 2 were of medium to high quality. Specific 11-item checklist and scoring values of various items can be found in Table 3.3,13,17,18 reported age data and two,18 reported BMI data. Meta-analysis results showed that there was no significant difference in age    . The meta-analysis results of the random-effect model showed that the incidence of osteoporosis in ED patients was significantly higher than that in the non-ED group   in the body and slow down the apoptosis of osteoblasts and mesenchymal cells by combating oxidative stress, thus playing an important role in male bone formation.,23 Multiple studies have shown a significant decrease in bone density and an increased risk of brittle fractures in patients with low testosterone levels.,25 In addition, patients with prostate cancer who undergo androgen deprivation therapy or orchiectomy also experience decreased bone density and increased risk of fracture.,27 There is also a link between the testosterone and vitamin D pathway. Testosterone deficiency is associated with decreased renal 1α-hydroxylase activity, which indirectly affects the parathyroid hormone-vitamin D axis, resulting in decreased 1,25-hydroxy vitamin D concentration. Vitamin D plays an important role in influencing bone metabolism and maintaining bone health, and several studies have shown that vitamin D deficiency leads to decreased bone density and an increased risk of osteoporosis and bone fractures.,31 Thus, low testosterone levels and vitamin D deficiency in ED patients may be important mechanisms that increase the risk of osteoporosis.The underlying mechanism of the relationship between ED and osteoporosis may be very complex, and several possible mechanisms have been proposed. First of all, ED patients are often accompanied by hypogonadism, and their natural free testosterone is often lower than that of non-ED men. Studies have also shown that 5-item International Index of Erectile Function (IIEF-5) scores are negatively correlated with levels of several inflammatory markers. Inflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-1), and tumor necrosis factor-alpha can damage the endothelial cells in the peripheral vascular bed of the penis, leading to vascular endothelial dysfunction and thereby promoting ED. These inflammatory cytokines may also be involved in regulating the function of osteoblasts and osteoclasts, thereby inhibiting bone growth and leading to osteoporosis.,34 Nitric oxide (NO) bioactivity is essential for penile erection and is the main pathogenic mechanism of ED. Meanwhile, the decrease of NO may also lead to bone loss. Studies have found that NO has a biphasic effect on bone resorption. Low concentration of NO has been shown to enhance IL-1-induced bone resorption, while high level of NO has an inhibitory effect on bone resorption. Therefore, inflammatory bone loss in ED patients and the promotion of IL-1-induced bone resorption by low NO level may be the underlying mechanism of the relationship between ED and osteoporosis.ED is closely related to inflammation, and chronic low-level inflammation is an important component of ED, which may be a mediator of endothelial dysfunction. Several studies have shown that depressed people have a higher risk of ED, and that people with ED are also more likely to have anxiety and even depression.,40 Depression was also found to be a risk factor for osteoporosis. In depressed patients, hypothalamic–pituitary–adrenal axis is activated, and excessive secretion of corticotropin-releasing hormone leads to elevated cortisol levels. Cortisol can reduce the proliferation and differentiation of osteoblasts, promote the apoptosis of osteoblasts and osteoblasts, increase the excretion of calcium in urine, and reduce the absorption of calcium in the small intestine, all of which will lead to a decrease in bone density and thereby increase the risk of osteoporosis. Different from cortisol, growth hormone can act on osteoblasts and osteoclasts respectively to promote bone formation and absorption to play a role in bone remodeling and finally achieve the effect of bone accumulation. However, in depressed patients, the secretion of growth hormone is often reduced, and the somatotrophic axis is interrupted, thus affecting bone accumulation. It can be seen that ED patients are often accompanied by depression, which is also involved in the occurrence of osteoporosis.Depression may also be a key factor in explaining the relationship between ED and osteoporosis. There is a close interaction between depression and ED. Interestingly, our study also found that the increased risk of osteoporosis in ED patients seemed to be more pronounced in younger participants (40–59 years old) than in older participants (60 years or more). Although the exact mechanism still needs to be studied, the consistency also suggests that depression plays an important role in the relationship between ED and osteoporosis.A study based on the Japanese population pointed out that compared with older ED patients (55 years or more), younger ED patients (45–54 years old) had lower relationship satisfaction, lower job satisfaction, more negative reactions from sexual partners, more difficulties in adjusting to life with ED, and thus tended to have higher incidence of depression and more severe depressive symptoms. was the source of heterogeneity in this study. We compared Wu2016 with other studies and found that its data came from the National Health Insurance Research Database (NHIRD), and the diagnosis of ED and osteoporosis was based on ICD-9-CM codes. When diagnosis is based on ICD-9-cm codes, the accuracy is often dependent on the performance of clinicians at the time. In addition, data such as body mass index, exercise ability, and dietary habits are often lacking in the database, which may have an impact on the study results. The above may be the reason why Wu2016 became the source of heterogeneity in this study.Our sensitivity analysis found that Wu2016It is undeniable that our study has several limitations. First of all, only 4 studies were included, all of which were observational studies. Second, due to limited data, we were unable to conduct subgroup analysis of organic ED and psychogenic ED. Third, although we found that the increased risk of osteoporosis in ED patients seemed to be more pronounced in younger participants, we were unable to conduct a subgroup analysis by age due to data limitations. Fourth, although we have provided a comprehensive description of the possible underlying mechanisms, more clinical trials are needed to confirm the underlying mechanisms of this relationship.5People with ED have a higher risk of osteoporosis, especially among younger males. Doctors should be aware of this relationship in order to make appropriate recommendations to patients. Because the assessment of osteoporosis is economical and noninvasive, ED patients should be evaluated by bone mineral density or men with osteoporosis should be further assessed for erectile function. In order to further validate the relationship between ED and osteoporosis and to further explore its underlying mechanism, more prospective studies with large samples are needed for further study.Acquisition, analysis, or interpretation of data: All authors.Concept and design: Jianglei Zhang, Jiangnan Xu, Chao WangConceptualization: Jiangnan Xu, Chao Wang, Jianglei Zhang.Critical revision of the manuscript: Jun Ouyang, Jianglei Zhang.Data curation: Jiangnan Xu, Chao Wang, Yuhui Zhang, Zekun Xu, Jun Ouyang.Drafting of the manuscript: Jiangnan Xu, Chao Wang.Formal analysis: Jiangnan Xu.Software: Jiangnan Xu.Statistical analysis: Jiangnan Xu, Chao Wang, Yuhui Zhang.Writing – original draft: Jiangnan Xu.Writing – review & editing: Chao Wang, Yuhui Zhang, Zekun Xu, Jun Ouyang, Jianglei Zhang.


We search the PubMed, Embase, Google Scholar, and Wanfang (China) databases  to identify all eligible publications. The pooled odds ratio (OR) correspondence with 95% confidence interval (CI) was calculated to evaluate the associations. SEPP1 and susceptibility to colorectal, breast, and prostate cancer in all comparison models. Subsequently, subgroup analysis based on tumor type, no significant association was identified for prostate, breast, and colorectal cancer. In addition, when the stratification analyses were conducted by the source of control, HWE status, and ethnicity, yet no significant association was found.  Finally, nine eligible studies with 7,157 cases and 6,440 controls and five studies with 2,278 cases and 2,821 controls were enrolled in rs3877899 and rs7579 polymorphisms, individually. However, a null significant association was detected between the two polymorphisms in  The current meta-analysis shows that SEPP1 rs3877899 and rs7579 polymorphisms may not be associated with susceptibility to colon cancer, breast cancer, and prostate cancer, and further well-designed studies with a larger sample size are warranted to validate our findings. There has been a progressive increase in the global incidence of malignancies, causing a serious threat to human health, presently, among the main causes of death . Increas2O2), can cause DNA damage due to the continuous production of various cellular metabolic processes in the body, which may lead to malignant transformation of cells [2O2 [Oxidative stress, which causes mitochondrial damage and DNA breakage by reactive oxygen species (ROS), is closely related to tumor progression , 4. ROS,of cells . Selenopof cells . The insof cells . In Calvof cells . Gonzalells [2O2 .SEPP1) were associated with susceptibility of tumors, including breast cancer (BC) [SEPP1 and cancer susceptibility.Nowadays, more and more studies have demonstrated that several polymorphisms of the selenoprotein P gene (cer (BC) , coloreccer (BC) , and PCacer (BC) . HoweverSEPP1 polymorphisms and cancer susceptibility was performed on PubMed, Embase, and Google Scholar databases  by using the following searching terms: “SEPP1 OR Selenoprotein P” AND “polymorphism OR variation OR SNP OR genotype OR allele OR mutation” AND “cancer OR malignancy OR tumor OR neoplasm OR carcinoma”. We also conducted manual searches on the references of these selected original studies to identify other eligible studies.We conducted this meta-analysis on the basis of the PRISMA meta-analysis guidelines . A comprIncluded literature should be in line with the following criteria: (1) studies that evaluated the relationship between SEPP1 polymorphisms (rs3877899 and rs7579) and cancer susceptibility; (2) sufficient genotype data from the text or the supporting information; (3) case-control studies. Moreover, these studies should also be excluded when they were as follows: (1) insufficient data; (2) not a case-control study, such as Comments, Case Reports, and Reviews; (3) the total scores of Newcastle-Ottawa Scale (NOS) is less than 5 , which is presented in Two reviewers (Hanjiang Xu and Fan Mo) have devoted themselves to the data extraction process referring to the predetermined criteria. All the discrepancies were settled through discussion till all consensus was settled. Furthermore, the following details should also be extracted: name of the first author, publication year, source of controls, ethnicity of a case-control study, genotype frequencies of cases and controls, and so on.SEPP1 polymorphisms (rs3877899 and rs7579) and cancer susceptibility in the following genetic models: allele contrast (A vs. G), recessive (AA vs. AG+GG), dominant (AA+AG vs. GG), heterozygous (AG vs. GG), and homozygous (AA vs. GG) models . We assessed the statistical heterogeneity hypothesis through I2 statistics to quantify the inconsistency, which represents the proportion of variability between studies that potentially arose from heterogeneity instead of contingency. I2 values greater than 50% are considered to have significant heterogeneity [P ≤ 0.05 was considered statistically significant.We calculated the odds ratio (OR) with 95% CI confidence interval (CI) to appraise the intensity of relationships between ogeneity , indicatogeneity . We use SEPP1 polymorphisms (rs3877899 and rs7579) and cancer susceptibility were available for our meta-analysis [Overall, 10 publications with 14 independent studies on analysis , 16–23, analysis , 20, 23,SEPP1 polymorphisms with cancer susceptibility in all of the genetic models is presented in A result of the detailed associations of P = 0.243; AA vs. GG: OR = 1.129, 95% CI: 0.794-1.605, P = 0.498; AG vs. GG: OR = 1.035, 95% CI: 0.909-1.179, P = 0.603; AA+AG vs. GG: OR = 1.079, 95% CI: 0.919-1.267, P = 0.356; AA vs. AG+GG: OR = 1.017, 95% CI: 0.871-1.189, P = 0.555, P = 0.309; AA vs. GG: OR = 1.267, 95% CI: 0.861-1.866, P = 0.230; AG vs. GG: OR = 1.022, 95% CI: 0.908-1.151, P = 0.715; AA+AG vs. GG: OR = 1.075, 95% CI: 0.897-1.287, P = 0.434; AA vs. AG+GG: OR = 1.209, 95% CI: 0.878-1.666, P = 0.245, For rs3877899 polymorphism, no significant association was found when pooling all the eligible studies .As to a stratification analysis conducted by cancer type, no association was identified for PCa, BC, and CRC of rs3877899 polymorphism in all five genetic models . In addiQ-statistic test. When P > 0.10, the fixed-effects model (the Mantel-Haenszel model) was used; else, the random-effects model (the DerSimonian-Laird model) was adopted.We explored the impact of each study on the pooled OR by excluding one study from the pooled analysis, thereby performing a sensitivity analysis. It turns out there is no material influence on the stability of the results. So as to assess the publication bias of the existing literature, we performed Begg's funnel plot as well as Egger's test. In all comparison models, the pattern of the funnel chart was roughly symmetrical Figures . In addiSEPP1 plays an important role in both supplying selenium to tissues and exerting antioxidant defenses. The delivery of selenium is accomplished by the C-terminal domain of SEPP1, which includes nine selenocysteine residues, while antioxidation is accomplished by selenocysteine that has been shown to have peroxidase activity . The antSEPP1 will produce some nonfunctional or low-functional protein subtypes, reducing the antioxidant activity of SEPP1. At the same time, the accumulation of peroxide is conducive to the production and development of cancer. Therefore, mutations in SEPP1 theoretically increase the susceptibility of tumors.The human SEPP gene (SEPP1) contains two functional polymorphisms, rs3877899 (Ala234Thr) and rs7579 (Gram A base mutation in SEPP1 mRNA 3′UTR), which affect the selenoprotein activity of plasma and lymphocytes and the relative proportion of plasma SEPP isotypes in vivo experiments , 27. TheSEPP1 have been reported to be related to the risk of PCa [SEPP1 rs3877899 mutation and the risk of BC was also found. However, in a study by Jablonska et al. [SEPP1 polymorphism, we conducted this meta-analysis. After pooling all data from 7,157 cases and 6,440 controls for the rs3877899 polymorphism and 2,278 cases and 2,821 controls for the rs7579 polymorphism, a null significant association was identified between SEPP1 polymorphism and cancers  in all comparative models. We subsequently did subgroup analyses based on cancer type control source HWE status and race for both polymorphisms and found no significant association.Both polymorphisms of k of PCa  and CRC k of PCa . Furtherk of PCa , a connea et al.  in PolisSEPP1 polymorphism affects tumor susceptibility through the antioxidant activity of SEPP1 protein. However, there may be more than one factor that can change the antioxidant activity of SEPP1 protein. The study by Sutherland et al. [SEPP1 (rs3877899 and rs7579) are not associated with the risk of CRC, which may be due to the inconsistent dietary selenium intake of the subjects. It is possible that when the plasma selenium level is low, the difference in the plasma level of SEPP1 caused by genetic polymorphism can be reflected, and this difference will disappear after selenium supplementation [This result contradicts our previous theoretical speculation. In fact, d et al.  showed tentation . Furtherentation , cancer SEPP1 polymorphism and cancer susceptibility.In conclusion, despite providing a sufficient statistical sample size to enhance the reliability of our findings, there are some shortcomings of the study. Firstly, the relatively small number of included studies would be a limitation and may constrain our conclusions. Secondly, we only searched papers published in a limited number of databases and some studies may have been overlooked. Finally, the results may be false negative, because some included studies show a significant relation between SEPP1 rs3877899 and rs7579 polymorphisms and susceptibility to CRC, BC, and PCa. Taking into account the complex interactions between genes and the environment, it is necessary to conduct unbiased studies with more sample sizes and more cancer types in different ethnic groups.In this meta-analysis, our results find no association between